U.S. patent application number 17/507593 was filed with the patent office on 2022-02-10 for preservative removal from eye drops.
The applicant listed for this patent is TearClear Corp.. Invention is credited to Deniz HAY, Michael S. WILLIAMS.
Application Number | 20220040037 17/507593 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-10 |
United States Patent
Application |
20220040037 |
Kind Code |
A1 |
WILLIAMS; Michael S. ; et
al. |
February 10, 2022 |
PRESERVATIVE REMOVAL FROM EYE DROPS
Abstract
A particulate plug for removing a preservative from a solution,
suspension, or emulsion comprising a drug is presented. The plug
comprises microparticles of a hydrophobic polymer/fatty acid blend.
The microparticles of hydrophobic polymer/fatty acid blend
selectively absorb preservative allowing the drug to remain in
solution for delivery.
Inventors: |
WILLIAMS; Michael S.;
(Keystone Heights, FL) ; HAY; Deniz; (Gainesville,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TearClear Corp. |
Copley |
OH |
US |
|
|
Appl. No.: |
17/507593 |
Filed: |
October 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17200595 |
Mar 12, 2021 |
11179294 |
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17507593 |
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PCT/US2020/066216 |
Dec 18, 2020 |
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17200595 |
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62950866 |
Dec 19, 2019 |
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International
Class: |
A61J 1/14 20060101
A61J001/14; A61K 9/00 20060101 A61K009/00; A61K 9/08 20060101
A61K009/08; A61K 47/18 20060101 A61K047/18; B01D 67/00 20060101
B01D067/00; B01D 71/26 20060101 B01D071/26; B01J 20/26 20060101
B01J020/26; B01J 20/28 20060101 B01J020/28; B01D 69/14 20060101
B01D069/14 |
Claims
1. A particulate plug for removing a preservative from a solution,
suspension, or emulsion comprising a drug, the particulate plug
comprising microparticles of a hydrophobic polymer/fatty acid
blend, wherein the microparticles form a particulate plug capable
of being fitted to an outlet of a container for the solution,
emulsion, or suspension, wherein the particulate plug selectively
removes a preservative from the solution, emulsion, or
suspension.
2. The particulate plug of claim 1, wherein the microparticles have
a dimension of 5 .mu.m to about 10,000 .mu.m.
3. The particulate plug of claim 1, wherein the preservative
comprises benzalkonium chloride (BAK).
4. The particulate plug of claim 1, wherein the hydrophobic
polymer/fatty acid blend comprises a hydrophobic polymer selected
from isotactic polypropylene, low density polyethylene, or high
density polyethylene.
5. The particulate plug of claim 4, wherein the isotactic
polypropylene has an average MW of about 250,000.
6. The particulate plug of claim 4, wherein the isotactic
polypropylene has an average MW of about 100,000 to about
300,000.
7. The particulate plug of claim 4, wherein the isotactic
polypropylene has an average MW of greater than 300,000.
8. The particulate plug of claim 1, wherein the hydrophobic
polymer/fatty acid blend comprises a hydrophobic polymer selected
from homopolymers of ethylene, propylene, 1-butene,
4-methyl-l-pentene, 3-methyl-1-butene, 4,4-dimethyl-1-pentene,
3-methyl-1-pentene, 4-methyl-1-hexene, 5-ethyl-1-hexene,
6-methyl-1-heptene, 1-hexene, 1-heptene, 1-octene, 1-nonene, or
1-decene.
9. The particulate plug of claim 1, wherein the hydrophobic
polymer/fatty acid blend comprises a hydrophobic polymer selected
from copolymers comprising monomers selected from the group
consisting of ethylene, propylene, 1-butene, 4-methyl-1-pentene,
3-methyl-1-butene, 4,4-dimethyl-l-pentene, 3-methyl-1-pentene,
4-methyl-1-hexene, 5-ethyl-1-hexene, 6-methyl-1-heptene, 1-hexene,
1-heptene, 1-octene, 1-nonene, or 1-decene.
10. The particulate plug of claim 1, wherein the hydrophobic
polymer/fatty acid blend comprises a hydrophobic polymer or
copolymer selected from polyethylene, polystyrene,
polyvinylchloride, polytetrafluorethylene, polydimethylsiloxane,
polyesters, polyurethanes, acrylic, or epoxy.
11. The particulate plug of claim 1, wherein the hydrophobic
polymer has an average MW of about 10,000, about 20,000, about
50,000, about 100,000, about 200,000, about 210,000, about 220,000,
about 230,000, about 240,000, about 250,000, about 260,000, about
270,000, about 280,000, about 290,000, about 300,000, about
300,000, or greater than 300,000.
12. The particulate plug of claim 1, wherein the hydrophobic
polymer/fatty acid blend comprises a fatty acid selected from a
fatty acid having the structure: CH.sub.3(CH.sub.2)nCO.sub.2H,
wherein n is 2 to 24.
13. The particulate plug of claim 12, wherein n is 14 to 20.
14. The particulate plug of claim 13, wherein n is 16.
15. The particulate plug of claim 1, wherein the fatty acid is
selected from caprylic acid, capric acid, lauric acid, myristic
acid, palmitic acid, stearic acid, arachidic acid, behenic acid,
lignoceric acid, or cerotic acid.
16. The particulate plug of claim 1, wherein the fatty acid is
selected from Myristoleic acid, Palmitoleic acid, Sapienic acid,
Oleic acid, Elaidic acid, Vaccenic acid, Linoleic acid, Linoelaidic
acid, a-Linolenic acid, Arachidonic acid, Eicosapentaenoic acid,
Erucic acid, or Docosahexaenoic acid.
17. The particulate plug of claim 1, wherein the fatty acid is
selected from a fatty acid having a melting point greater than
70.degree. C.
18. The particulate plug of claim 1, wherein the weight-to-weight
percentage of fatty acid is at least 5% to at least 95%.
19. The particulate plug of claim 1, wherein the microparticles
have a dimension of 5 .mu.m to about 10,000 .mu.m.
20. The particulate plug of claim 1, wherein the fatty acid is
stearic acid.
Description
CROSS-REFERENCE
[0001] This application is a continuation application of U.S.
application Ser. No. 17/200,595 filed Mar. 12, 2021, which is a
continuation application of International Application Serial No.
PCT/US2020/066216, filed Dec. 18, 2020, which claims the benefit of
U.S. Provisional Application Ser. No. 62/950,866, filed Dec. 19,
2019, each of which is incorporated herein by reference for all
purposes.
BACKGROUND
[0002] Ophthalmic diseases are commonly treated with prescribed
multi-dose medications packaged in eye drop bottles due to ease of
use, availability, affordability, and patient compliance. The
frequency of topical eye drop application varies from one or two
times a day for diseases like glaucoma to as many as ten times a
day for severe infections. Although eye drops formulations are
packed under sterile conditions, the potential risk of
contamination after prolonged use or improper handling can be a key
factor contributing to ocular infections. In some cases, as a
frugal measure, multiple patients tend to use the same multi-dose
containers to administer medications, overlooking the possibility
of ocular infections due to cross-contamination, particularly if
the protocol for disinfecting the nozzle is not followed. Most
ophthalmic formulations now contain an added preservative to
maintain the shelf life of the sterile medication and eliminate
microbial growth. The United States Food and Drug Administration
has imposed regulations on multi-dose ophthalmic formulations,
mandating the addition of preservatives to providing microbe-free
medication. A variety of preservatives are used to serve this
purpose. Preservatives are needed for maintaining sterility, but
the benefit is often offset by adverse side effects of the
preservatives, even among healthy subjects.
[0003] Benzalkonium chloride (BAK), a quaternary ammonium compound
with high efficacy, is used prominently. BAK is an active detergent
disinfecting agent, which interrupts the lipid membranes of cells,
thereby inhibiting the growth of microorganisms. Despite an
acceptable tolerance and safety profile of BAK, many studies have
shown commercial topical medications with added BAK content to
induce severe toxic side effects. Well-documented adverse effects
of BAK include tear film instability, trabecular and corneal cells
growth retardation and corneal and conjunctival inflammation.
Cytotoxicity studies show that BAK disrupts ocular surface cells
and tissues, whose impact in glaucoma and dry eye patients
requiring long-term and frequent dosing is deleterious. Corneal
endothelial damage occurs upon prolonged use of topical medication
with added benzalkonium chloride. High tear film instability and
disruption of the corneal barrier is observed using the preserved
glaucoma drug Timolol to a greater extent than when using
preservative-free Timolol in healthy subjects. The detergent action
of BAK solution disrupts superficial lipid layers of the tear film
into oil droplets solubilized by a single drop of 0.01% BAK
solution.
SUMMARY
[0004] Embodiments of the disclosure are directed to particulate
plugs comprising hydrophobic polymer/fatty acid blend comprising a
hydrophobic polymer and a fatty acid in a ratio from about 1:1 to
about 1:20 for selectively removing a large fraction of the
preservative without significantly removing the drug and
specifically directed to achieving this for each eluting drop. The
material of the plug may be designed to minimize drug binding. The
material of the plug may depend on the properties of the drug whose
binding is to be minimized. The binding may depend on the structure
of the drug and/or the detailed structure of the matrix materials
of the particles of the tip. Broadly, ophthalmic drugs can be
divided into hydrophobic and hydrophilic categories depending of
the affinity of the drug for water. Hydrophilic drugs are more
soluble in water while hydrophobic drugs are less soluble.
[0005] Embodiments of the disclosure are directed to particulate
plugs for removing a preservative from a drug solution where
microparticles comprising the plug are hydrophobic polymer/fatty
acid blend comprising a hydrophobic polymer and a fatty acid in a
ratio from about 1:1 to about 1:20.
[0006] The drug can be a hydrophilic drug selected from Tables 1-4
such as, for example, Timolol Maleate, Levofloxacin, Dorzolamide,
Brimonidine Tartrate, and/or hydrophobic drugs, for example,
latanoprost or bimatoprost, and/or a combination of drugs, for
example, Combigan. The preservative may be Benzalkonium chloride
(BAK).
[0007] One embodiment provides a particulate plug for removing a
preservative from a solution, suspension, or emulsion comprising a
drug, the particulate plug comprising microparticles of a
hydrophobic polymer/fatty acid blend, wherein the microparticles
form a particulate plug capable of being fitted to an outlet of a
container for the solution, emulsion, or suspension, wherein the
particulate plug rapidly and selectively removes a preservative
from the solution, emulsion, or suspension.
[0008] Another embodiment provides the particulate plug wherein the
microparticles have a dimension of 5 .mu.M to about 10,000
.mu.M.
[0009] Another embodiment provides the particulate plug wherein the
preservative comprises benzalkonium chloride (BAK).
[0010] Another embodiment provides the particulate plug wherein the
drug is selected from Table 1, Table 2, Table 3, or Table 4.
[0011] Another embodiment provides the particulate plug wherein the
hydrophobic polymer/fatty acid blend comprises a hydrophobic
polymer selected from isotactic polypropylene, low density
polyethylene, or high density polyethylene. Another embodiment
provides the particulate plug wherein the isotactic polypropylene
has an average MW of about 250,000. Another embodiment provides the
particulate plug wherein the hydrophobic polymer/fatty acid blend
comprises a hydrophobic polymer that is a thermoplastic. Another
embodiment provides the particulate plug wherein the hydrophobic
polymer/fatty acid blend comprises a hydrophobic polymer that is a
thermoset. Another embodiment provides the particulate plug wherein
the hydrophobic polymer/fatty acid blend comprises a product of a
melt blend. Another embodiment provides the particulate plug
wherein the hydrophobic polymer/fatty acid blend comprises a
product of a solution blend. Another embodiment provides the
particulate plug wherein the hydrophobic polymer/fatty acid blend
comprises a product of a spray-dry blend.
[0012] Another embodiment provides the particulate plug wherein the
hydrophobic polymer/fatty acid blend comprises a fatty acid
selected from a fatty acid having the structure of
CH.sub.3(CH.sub.2).sub.nCO.sub.2H, wherein n is 2 to 24. Another
embodiment provides the particulate plug wherein n is 6 to 24.
Another embodiment provides the particulate plug wherein n is 8 to
24. Another embodiment provides the particulate plug wherein n is 8
to 20. Another embodiment provides the particulate plug wherein n
is 10 to 20. Another embodiment provides the particulate plug
wherein n is 12 to 20. Another embodiment provides the particulate
plug wherein n is 14 to 20. Another embodiment provides the
particulate plug wherein n is 14 to 18. Another embodiment provides
the particulate plug wherein n is 14 or 16. Another embodiment
provides the particulate plug wherein n is 16. Another embodiment
provides the particulate plug wherein the fatty acid is selected
from caprylic acid, capric acid, lauric acid, myristic acid,
palmitic acid, stearic acid, arachidic acid, behenic acid,
lignoceric acid, or cerotic acid. Another embodiment provides the
particulate plug wherein the fatty acid is selected from
Myristoleic acid, Palmitoleic acid, Sapienic acid, Oleic acid,
Elaidic acid, Vaccenic acid, Linoleic acid, Linoelaidic acid,
a-Linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Erucic
acid, or Docosahexaenoic acid. Another embodiment provides the
particulate plug wherein the fatty acid is selected from a fatty
acid having a melting point greater than 70.degree. C.
[0013] Another embodiment provides the particulate plug wherein the
weight-to-weight ratio of the hydrophobic polymer-to-fatty acid is
from about 1:1 to about 1:20. Another embodiment provides the
particulate plug wherein the weight-to-weight ratio of the
hydrophobic polymer-to-fatty acid is about 1:1. Another embodiment
provides the particulate plug wherein the weight-to-weight ratio of
the hydrophobic polymer-to-fatty acid is about 1:2. Another
embodiment provides the particulate plug wherein the
weight-to-weight ratio of the hydrophobic polymer-to-fatty acid is
about 1:3. Another embodiment provides the particulate plug wherein
the weight-to-weight ratio of the hydrophobic polymer-to-fatty acid
is about 1:4. Another embodiment provides the particulate plug
wherein the weight-to-weight ratio of the hydrophobic
polymer-to-fatty acid is about 1:5. Another embodiment provides the
particulate plug wherein the weight-to-weight ratio of the
hydrophobic polymer-to-fatty acid is about 1:6. Another embodiment
provides the particulate plug wherein the weight-to-weight ratio of
the hydrophobic polymer-to-fatty acid is about 1:7. Another
embodiment provides the particulate plug wherein the
weight-to-weight ratio of the hydrophobic polymer-to-fatty acid is
about 1:8. Another embodiment provides the particulate plug wherein
the weight-to-weight ratio of the hydrophobic polymer-to-fatty acid
is about 1:9. Another embodiment provides the particulate plug
wherein the weight-to-weight ratio of the hydrophobic
polymer-to-fatty acid is about 1:10.
[0014] Another embodiment provides the particulate plug wherein the
microparticles have a dimension of 5 .mu.M to about 50 .mu.M.
Another embodiment provides the particulate plug wherein the
microparticles have a dimension of 50 .mu.M to about 100 .mu.M.
Another embodiment provides the particulate plug wherein the
microparticles have a dimension of 100 .mu.M to about 500 .mu.M.
Another embodiment provides the particulate plug wherein the
microparticles have a dimension of 500 .mu.M to about 1000 .mu.M.
Another embodiment provides the particulate plug wherein the
microparticles have a dimension of 1,000 .mu.M to about 10,000
.mu.M.
[0015] One embodiment provides a hydrophobic polymer/fatty acid
blend comprising a hydrophobic polymer and a fatty acid in a ratio
from about 1:1 to about 1:20. Another embodiment provides the blend
wherein the hydrophobic polymer and the fatty are combined in a
vessel suitable for chemical reaction; heated to above the melting
point of each component forming a homogenous composition; and
poured into cool water.
[0016] One embodiment provides a particulate plug, for removing a
preservative from a solution, suspension, or emulsion comprising a
drug, the particulate plug comprising microparticles of a
hydrophobic polymer/fatty acid blend, wherein the microparticles
form a particulate plug capable of being fitted to an outlet of a
container for the solution, emulsion, or suspension, wherein the
particulate plug rapidly and selectively removes a preservative
from the solution, emulsion, or suspension, wherein the hydrophobic
polymer/fatty acid blend comprises a hydrophobic polymer and a
fatty acid in a ratio from about 1:1 to about 1:20. Another
embodiment provides the particulate plug wherein the blend is
prepared by the process of the hydrophobic polymer and the fatty
are combined in a vessel suitable for chemical reaction; heated to
above the melting point of each component forming a homogenous
composition; and poured into cool water.
[0017] One embodiment provides a particulate plug for removing a
preservative from a solution, suspension, or emulsion comprising a
drug, the particulate plug comprising microparticles of a fatty
acid, wherein the microparticles form a particulate plug capable of
being fitted an outlet of a container for the solution, emulsion,
or suspension, wherein the particulate plug rapidly and selectively
removes a preservative from the solution, emulsion, or suspension.
Another embodiment provides the particulate plug wherein the fatty
acid is stearic acid.
[0018] One embodiment provides a particulate plug for removing a
preservative from a solution, suspension, or emulsion comprising a
drug, the particulate plug consisting essentially of microparticles
of a fatty acid, wherein the microparticles form a particulate plug
capable of being fitted an outlet of a container for the solution,
emulsion, or suspension, wherein the particulate plug rapidly and
selectively removes a preservative from the solution, emulsion, or
suspension. Another embodiment provides the particulate plug
wherein the fatty acid is stearic acid.
INCORPORATION BY REFERENCE
[0019] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
[0020] To the extent publications and patents or patent
applications incorporated by reference contradict the disclosure
contained in the specification, the specification is intended to
supersede and/or take precedence over any such contradictory
material.
DETAILED DESCRIPTION
[0021] The present disclosure provides a preservative removal
agent. A preservative removal agent may rapidly and selectively
remove preservatives of the present disclosure from a solution,
emulsion, or suspension comprising a therapeutic agent. The
preservative removal agent may rapidly and selectively extract the
preservative, allowing the eye drop formulation to flow through the
plug with minimal pressure drop, yet with sufficient time to remove
the preservative and with sufficient surface area to adsorb the
preservative. The matrix may comprise a material with a high
affinity for the preservative, such as for example benzalkonium
chloride (BAK), and low affinity for a therapeutic agent, such as a
drug or other ophthalmological agent.
[0022] In 2009, the European Medicines Agency's Committee for
Medicinal Products for Human Use concluded that unpreserved
formulations "are needed for patients with lower tolerance to
preservatives," and "for long-term treatment, formulations without
preservatives are valuable alternatives." Considering the adverse
effects of preservatives, the development of safe eye drop
dispensing devices to deliver preservative-free formulations has
been pursued for more than a decade. Preservative-free formulations
are available in single-dose containers to eliminate the need for
preservatives; however, these are not convenient and too expensive
for wide public use.
[0023] It would therefore be useful to have systems and methods for
delivering a preservative free ophthalmic drug to the eye, whereby
a preserved ophthalmic solution is dispensed through a media at the
tip that accomplishes one or more of the following: [0024] i. Would
effectively remove all the preservative (e.g., benzalkonium
chloride); [0025] ii. Would have a high BAK uptake (partition
coefficient); [0026] iii. Would leave the API largely (nearly 100%)
unreduced or unhindered or unabsorbed; [0027] iv. Would consist of
ridged, flowing particles, mostly free of fine particulate matter;
[0028] v. Would have low restriction of liquid flow; [0029] vi.
Would allow for higher viscosity drug formulations to be used; and
[0030] vii. Was largely unaffected by the pH of the drug
formulation in accomplishing the above. Preservative removal
agent
[0031] In some embodiments, the disclosure provides pharmaceutical
formulations comprising a preservative and a therapeutic agent. The
formulation may comprise a solution, emulsion, or suspension of a
therapeutic agent and a preservative. In some embodiments, the
formulation may comprise a preservative removal agent, (e.g., in
embodiments where the preservative removal agent may comprise a
portion of a solution, emulsion, or suspension comprising a
therapeutic agent and a preservative). In other embodiments, the
preservative removal agent may be separate from the solution,
emulsion, or suspension comprising the therapeutic agent and the
preservative (e.g., in embodiments where the preservative removal
agent may be located within the neck of a bottle). Optionally in
any embodiment, the solution, emulsion, or suspension may
additionally comprise one or more pharmaceutically acceptable
excipients.
[0032] A preservative removing device may comprise a matrix. In
some embodiments, a matrix may be a particulate plug. In some
embodiments, a matrix disposed within a nozzle may be a porous
polymeric matrix. Applying a pressure behind the nozzle may cause
fluid to flow through the nozzle via the flow path, along which
path the preservative may be removed by adsorption onto the matrix.
The polymer material, the hydraulic permeability, the partition
coefficient, the adsorption rate, and the pore size in combination
may provide for the absorption of all or most of the preservative
from the solution and thus from the drop administered to the
patient eye. The reduced-preservative solution may subsequently be
delivered directly to the eye. The porous polymeric matrix may
rapidly and selectively extract the preservative, allowing the eye
drop formulation to flow through the plug with minimal pressure
drop, yet with sufficient time to remove the preservative and with
sufficient surface area to adsorb the preservative.
[0033] The matrix (e.g., particulate plug) may comprise a blend of
a hydrophobic polymer and a fatty acid in a ratio from about 1:1 to
about 1:20. Such material may be safe and biocompatible. The matrix
comprises a material with a high affinity for the preservative,
such as for example benzalkonium chloride (BAK), and low affinity
for a drug or other ophthalmological agent. The porous hydrophobic
polymer/fatty acid blend may comprise a high affinity for the
preservative, such that at least 50 percent of the preservative may
be removed and at least 50 percent of the drug may be retained by
the solution. In some embodiments, a matrix disposed within a
nozzle may be a porous polymeric matrix.
[0034] The polymer/fatty acid blend may comprise a weight-to-weight
percentage of fatty acid which is at least 5%, at least 10%, at
least 15%, at least 20%, at least 25%, at least 30%, at least 35%,
at least 40%, at least 45%, at least 50%, at least 55%, at least
60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99%. The
polymer/fatty acid blend may comprise a weight-to-weight percentage
of fatty acid which is no greater than 5%, no greater than 10%, no
greater than 15%, no greater than 20%, no greater than 25%, no
greater than 30%, no greater than 35%, no greater than 40%, no
greater than 45%, no greater than 50%, no greater than 55%, no
greater than 60%, no greater than 65%, no greater than 70%, no
greater than 75%, no greater than 80%, no greater than 85%, no
greater than 90%, no greater than 95%, or no greater than 99%.
Examples of ranges which the weight-to-weight percentage fatty acid
falls within can be created by combining any two of the preceding
percentages. For example, the polymer/fatty acid blend may comprise
a weight-to-weight percentage of fatty acid which is from 5% to
99%, by 10% to 95%, by 20% to 70% or by 35% to 55%.
[0035] The polymer/fatty acid blend may comprise a weight-to-weight
percentage of hydrophobic polymer which is at least 5%, at least
10%, at least 15%, at least 20%, at least 25%, at least 30%, at
least 35%, at least 40%, at least 45%, at least 50%, at least 55%,
at least 60%, at least 65%, at least 70%, at least 75%, at least
80%, at least 85%, at least 90%, at least 95%, or at least 99%. The
polymer/fatty acid blend may comprise a weight-to-weight percentage
of hydrophobic polymer which is no greater than 5%, no greater than
10%, no greater than 15%, no greater than 20%, no greater than 25%,
no greater than 30%, no greater than 35%, no greater than 40%, no
greater than 45%, no greater than 50%, no greater than 55%, no
greater than 60%, no greater than 65%, no greater than 70%, no
greater than 75%, no greater than 80%, no greater than 85%, no
greater than 90%, no greater than 95%, or no greater than 99%.
Examples of ranges which the weight-to-weight percentage
hydrophobic polymer falls within can be created by combining any
two of the preceding percentages. For example, the polymer/fatty
acid blend may comprise a weight-to-weight percentage of
hydrophobic polymer which is from 5% to 99%, by 10% to 95%, by 20%
to 70% or by 35% to 55%.
[0036] The weight-to-weight ratio of a fatty acid to a polymer
(e.g., a hydrophobic polymer) can be about 100 : about 1, about 95
: about 1, about 90 : about 1, about 85 : about 1, about 80 : about
1, about 75 : about 1, about 70 : about 1, about 65 : about 1,
about 60 : about 1, about 55 : about 1, about 50 : about 1, about
45 : about 1, about 40 : about 1, about 35 : about 1 about 30 :
about 1, about 25 : about 1, about 20 : about 1, about 15 : about
1, about 10 : about 1, about 9 : about 1, about 8 : about 1, about
7 : about 1, about 6 : about 1, about 5 : about 1, about 4 : about
1, about 3 : about 1, about 2 : about 1, about 1 : about 1, about 1
: about 2, about 1 : about 3, about 1 : about 4, about 1 : about 5,
about 1 : about 6, about 1 : about 7, about 1 : about 8, about 1 :
about 9, or about 1 : about 10. The weight-to-weight ratio of a
fatty acid to a polymer (e.g., a hydrophobic polymer) can be within
the range of between about 100: about 1 and about 1 to about 10,
between about 10 : about 1 and about 1 : about 1, between about 5 :
about 1 and about 2 : about 1.
[0037] The matrix material (e.g., particulate plug) may comprise a
blend of a fatty acid and a polymer. The matrix may comprise a
blend of a hydrophobic polymer and a fatty acid. The matrix may
comprise a blend of a polypropylene and a fatty acid. The matrix
may comprise a blend of a polypropylene and steric acid. The
polymer/fatty acid blend may comprise a hydrophobic polymer
selected from isotactic polypropylene, low density polyethylene, or
high density polyethylene.
[0038] The matrix materials disclosed herein are not limited to
fatty acids blended with homopolymers and copolymers of
polypropylene. The matrix materials disclosed herein may also
comprise fatty acids blended with other types of homopolymeric or
copolymeric crystallizable or partially crystallizable
poly-alpha-olefins, such as, homopolymers and copolymers of
ethylene, propylene, 1-butene, 4-methyl-1-pentene,
3-methyl-1-butene, 4,4-dimethyl-1-pentene, 3-methyl-1-pentene,
4-methyl-1-hexene, 5-ethyl-1-hexene, 6-methyl-1-heptene, 1-hexene,
1-heptene, 1-octene, 1-nonene, 1-decene, and the like. Also
included are oxidized waxes formed by the Fischer-Tropsch
process.
[0039] The polymer of the polymer/fatty acid blend may be a
hydrophobic polymer. Hydrophobic polymers may be generally water
repellant. Hydrophobic polymers may generally not be soluble in
water. Hydrophobic polymers may comprise homopolymers or copolymers
of materials such as polyethylene, polystyrene, polyvinylchloride,
polytetrafluorethylene, polydimethylsiloxane, some polyesters, some
polyurethanes, acrylics, epoxies, etc. The hydrophobic
polymer/fatty acid blend may comprise a hydrophobic polymer
selected from isotactic polypropylene, low density polyethylene, or
high density polyethylene.
[0040] A polypropylene may comprise a crystallinity. Polypropylene
may be characterized as isotactic, syndiotactic, or atactic. The
term tacticity may describe how the methyl group is oriented in the
polymer chain of polypropylene. Tacticity may be indicated in
percent, using the isotactic index (according to DIN 16774).
Isotactic polypropylene may comprise methyl groups which are
substantially located at the same side. Isotactic polypropylene may
be helical in shape. An isotactic propylene may comprise a
semi-crystalline structure. The higher the isotacticity (e.g., the
isotactic fraction), the greater the crystallinity, which may
result in a higher softening point, rigidity, elastic-modulus, and
hardness. Atactic polypropylene may lack regularity of the
orientation of the methyl groups in the chain. Atactic
polypropylene may be less crystalline and more amorphous.
Syndiotactic polypropylene may comprise methyl groups which are
substantially alternating.
[0041] An isotactic polypropylene may comprise a tacticity between
85% and 95%, between 85% and 99%, between 90% and 100%, etc. An
isotactic polypropylene may comprise a tacticity greater than 85%,
greater than 90%, greater than 95%, greater than 99% or more.
Syndiotactic polypropylene may comprise methyl groups which are
substantially alternating. Syndiotactic polypropylene may comprise
greater than 85% racemo diads, greater than 90% racemo diads,
greater than 95% racemo diads, greater than 99% racemo diads, or
more. Atactic polypropylene may comprise less than 99% meso diads,
less than 98% meso diads, less than 95% meso diads, less than 90%
meso diads, less than 85% meso diads, or less.
[0042] Isotactic polypropylene may exist in several crystal
structures. The crystalline modifications may be categorized as
having .alpha.-, .beta.- and .gamma.-modification as well as
mesomorphic (smectic) forms. The .alpha.-modification may be common
in isotactic polypropylene. Crystals with .alpha.-modifications may
comprise lamellae in the form of folded chains. The lamellae may be
arranged a "cross-hatched" structure. The melting point of
.alpha.-crystalline regions may be 185 to 220.degree. C. The
density may be 0.936 to 0.946 gcm-3. The .beta.-modification may be
somewhat less ordered. The (3-modification may be formed faster.
The .beta.-modification may have a lower melting point of 170 to
200.degree. C. The formation of the .beta.-modification may be
promoted by nucleating agents, suitable temperatures, and shear
stress. The mesomorphic form may result from quick cooling of the
polypropylene. The degree of order of the mesomorphic phase may
range between the crystalline and the amorphous phase. The density
of the mesomorphic phase may comprise a density of about 0.916
gcm-3.
[0043] The length of a polypropylene (e.g., isotactic
polypropylene) may be characterized by a molecular weight. The
molecular weight may be about 250,000 g/mol. The molecular weight
may be greater than about 10,000, about 20,000, about 50,000, about
100,000, about 200,000, about 210,000, about 220,000, about
230,000, about 240,000, about 250,000, about 260,000, about
270,000, about 280,000, about 290,000, about 300,000, about
300,000, or more.
[0044] Polypropylene may be characterized by a melting point. The
melting point of polypropylene may occur in a range, so the melting
point may be determined by finding the highest temperature of a
differential scanning calorimetry chart. High tacticity, isotactic
polypropylene may have a melting point of about 171.degree. C.
(340.degree. F.). Lower tacticity isotactic polypropylene may have
a melting point that ranges from 160 to 166.degree. C. (320 to
331.degree. F.), depending on atactic material and crystallinity.
Syndiotactic polypropylene with a crystallinity of 30% may have a
melting point of 130.degree. C. (266.degree. F.).
[0045] In some cases, the polymer of the polymer/fatty acid blend
(e.g., hydrophobic polymer/fatty acid blend) may be characterized
by a melting point. The melting point of a polymer of the
polymer/fatty acid blend may be greater than 70.degree. C. The
melting point of a polymer of a polymer/fatty acid blend may be
greater than 40.degree. C., 50.degree. C., 60.degree. C.,
70.degree. C., 80.degree. C., 90 .degree. C., 100.degree. C.,
110.degree. C., 120.degree. C., 130.degree. C., 140.degree. C.,
150.degree. C., 160.degree. C., 170.degree. C., 180.degree. C.,
190.degree. C., 200.degree. C., 300 .degree. C., 400.degree. C.,
500.degree. C., 600.degree. C., 700.degree. C., 800.degree. C.,
900.degree. C., 1000.degree. C., or more. The melting point of a
polymer of a polymer/fatty acid blend may be less than 1000.degree.
C., 900.degree. C., 800.degree. C., 700.degree. C., 600.degree. C.,
500.degree. C., 400.degree. C., 300.degree. C., 200.degree. C.,
100.degree. C., or less. The melting point of a polymer of a
polymer/fatty acid blend may be within a range defined by any two
of the preceding values.
[0046] The matrix material (e.g., particulate plug) may comprise a
blend of a fatty acid and a polymer. The matrix may comprise a
blend of a polymer and a saturated fatty acid. The matrix may
comprise a blend of a polymer and steric acid. The matrix may
comprise a blend of a polypropylene and steric acid.
[0047] In some embodiments, a fatty acid may comprise a saturated,
monounsaturated, or polyunsaturated fatty acid. A saturated fatty
acid may not comprise C.dbd.C double bonds. An unsaturated fatty
acid may comprise one or more C.dbd.C double bonds. A fatty acid
may comprise any of the saturated, monounsaturated, or
polyunsaturated fatty acid disclosed herein.
[0048] A saturated fatty acid may be characterized by a number of
carbon atoms, e.g., C3 where three is the number of carbon atoms.
In some embodiments, a saturated fatty acid is a C2-C28 fatty acid.
In some embodiments, a saturated fatty acid is a C10-C25 fatty
acid. In some embodiments, a saturated fatty acid is a C16-C20
fatty acid. In some embodiments, a saturated fatty acid is a
greater than C10 fatty acid. In some embodiments, a saturated fatty
acid is a greater than C14 fatty acid.
[0049] A saturated fatty acid may comprise one or more of:
Propanoic acid, Butanoic acid, Pentanoic acid, Hexanoic acid,
Heptanoic acid, Octanoic acid, Nonanoic acid, Decanoic acid,
Undecanoic acid, Dodecanoic acid, Tridecanoic acid, Tetradecanoic
acid, Pentadecanoic acid, Hexadecanoic acid, Heptadecanoic acid,
Octadecanoic acid, Nonadecanoic acid, Eicosanoic acid,
Heneicosanoic acid, Docosanoic acid, Tricosanoic acid,
Tetracosanoic acid, Pentacosanoic acid, Hexacosanoic acid,
Heptacosanoic acid, Octacosanoic acid, Nonacosanoic acid,
Triacontanoic acid, Hentriacontanoic acid, Dotriacontanoic acid,
Tritriacontanoic acid, Tetratriacontanoic acid, Pentatriacontanoic
acid, Hexatriacontanoic acid, Heptatriacontanoic acid,
Octatriacontanoic acid, Nonatriacontanoic acid, or Tetracontanoic
acid.
[0050] An unsaturated fatty acid may generally be referred to by
the following conventions. The carbon next to the carboxylate is
known as .alpha., the next carbon .beta., and so forth. Since
biological fatty acids can be of different lengths, the last
position is labelled as a "w", the last letter in the Greek
alphabet. The physiological properties of unsaturated fatty acids
may correlate with the position of the first unsaturation relative
to the end position (.omega.). For example, the term .omega.-3
signifies that the first double bond exists as the third
carbon-carbon bond from the terminal end (.omega.) of the carbon
chain. The number of carbons and the number of double bonds may
also be listed in short descriptions of unsaturated fatty acids.
For instance, .omega.-3 C18:4, or C18:4 .omega.-3, or C18:4 n-3
indicates stearidonic acid, an 18-carbon chain with 4 double bonds,
and with the first double bond in the third position from the CH3
end.
[0051] A blend may comprise a monounsaturated fatty acid. A
monounsaturated fatty acid may comprise one or more of Crotonic
acid, Myristoleic, Palmitoleic acid, Sapienic acid, Oleic acid,
Elaidic acid, Vaccenic acid, Gadoleic acid, Eicosenoic acid, Erucic
acid, or Nervonic acid.
[0052] A monounsaturated fatty acid may be characterized by a
number of carbon atoms, e.g., C3:1 where three is the number of
carbon atoms and 1 is the number of double bonds. In some
embodiments, a monounsaturated fatty acid is a C2:1-C28:1 fatty
acid. In some embodiments, a monounsaturated fatty acid is a
C10:1-C25:1 fatty acid. In some embodiments, a monounsaturated
fatty acid is a C16:1-C20:1 fatty acid. In some embodiments, a
monounsaturated fatty acid is a greater than C10:1 fatty acid. In
some embodiments, a monounsaturated fatty acid is a greater than
C14:1 fatty acid.
[0053] A blend may comprise a polyunsaturated fatty acid. A
polyunsaturated fatty acid may comprise one or more of: Linoleic
acid, Eicosadienoic acid, Docosadienoic acid, Linolenic acid,
Pinolenic acid, Eleostearic acid, Mead acid,
Dihomo-.gamma.-linolenic acid, Eicosatrienoic acid, Stearidonic
acid, Arachidonic acid, Eicosatetraenoic acid, Adrenic acid,
Bosseopentaenoic acid, Eicosapentaenoic acid, Ozubondo acid,
Sardine acid, Tetracosanolpentaenoic acid, Cervonic acid, and
Herring acid.
[0054] A polyunsaturated fatty acid may be characterized by a
number of carbon atoms, e.g., C3:1 where three is the number of
carbon atoms and 1 is the number of double bonds. In some
embodiments, a di-unsaturated fatty acid is a C2:2-C28:2 fatty
acid. In some embodiments, a di-unsaturated fatty acid is a
C10:2-C25:2 fatty acid. In some embodiments, a di-unsaturated fatty
acid is a C16:2-C20:2 fatty acid. In some embodiments, a
di-unsaturated fatty acid is a greater than C10:2 fatty acid. In
some embodiments, a di-unsaturated fatty acid is a greater than
C14:2 fatty acid.
[0055] In some embodiments, a polyunsaturated fatty acid is a CM:N
.omega.-L fatty acid, where N and L are numbers of less than M. In
some embodiments, a poly-unsaturated fatty acid is a C10:N-C25:N
.omega.-L fatty acid. In some embodiments, a poly-unsaturated fatty
acid is a C16:N-C20:N w-L fatty acid. In some embodiments, a
poly-unsaturated fatty acid is a greater than C10:N w-L fatty acid.
In some embodiments, a poly-unsaturated fatty acid is a greater
than C14:N w-L fatty acid.
[0056] In some embodiments a fatty acid may include caprylic acid,
capric acid, lauric acid, myristic acid, palmitic acid, stearic
acid, arachidic acid, behenic acid, lignoceric acid, or cerotic
acid Myristoleic acid, Palmitoleic acid, Sapienic acid, Oleic acid,
Elaidic acid, Vaccenic acid, Linoleic acid, Linoelaidic acid,
a-Linolenic acid, Arachidonic acid, Eicosapentaenoic acid, Erucic
acid, Docosahexaenoic acid, or the like.
[0057] In some cases, the fatty acid of the polymer/fatty acid
blend (e.g., hydrophobic polymer/fatty acid blend) may be
characterized by a melting point. The melting point of a fatty acid
of a polymer/fatty acid blend may be greater than 70.degree. C. The
melting point of a fatty acid of a polymer/fatty acid blend may be
greater than 40.degree. C., 50.degree. C., 60.degree. C.,
70.degree. C., 80.degree. C., 90.degree. C., 100.degree. C.,
110.degree. C., 120.degree. C., 130.degree. C., 140.degree. C.,
150.degree. C., 160.degree. C., 170.degree. C., 180.degree. C.,
190.degree. C., 200.degree. C., 300.degree. C., 400.degree. C.,
500.degree. C., 600.degree. C., 700.degree. C., 800.degree. C.,
900.degree. C., 1000.degree. C., or more. The melting point of a
fatty acid of a polymer/fatty acid blend may be less than
1000.degree. C., 900.degree. C., 800.degree. C., 700.degree. C.,
600.degree. C., 500.degree. C., 400 .degree. C., 300.degree. C.,
200.degree. C., 100.degree. C., or less. The melting point of a
fatty acid of a polymer/fatty acid blend may be within a range
defined by any two of the preceding values.
[0058] The present disclosure provides methods of manufacturing a
particulate plug comprising a polymer/fatty acid blend. A
polymer/fatty acid blend may be formed by combining powders of the
polymer and the fatty acid to be blended. Heating the mixture to a
melt and, optionally, stirring. The resultant material may be added
to water. The wet cooled material may be dried, e.g., vacuum dried.
The dried blended material may be added to a grinder and ground
until a particle size is reached. The resultant particles may be
packed to form a particulate plug. The plug may be disposed
proximate an outlet of a container, such as a compressible bottle
(e.g., an eyedrop bottle).
[0059] Methods of manufacturing a particulate plug comprising a
polymer/fatty acid blend may also include solution blending or
spray dry blending. For example, each of the polymer and the fatty
acid may be dissolved, the resultant solutions may be mixed, and
the solvent may be removed, for example, by decanting of off a
precipitate, evaporation, etc.
[0060] In certain embodiments, particles (e.g., microparticles)
described herein have an average largest dimension from about 1 nm
to about 10 .mu.m, about 1 nm to about 5 .mu.m, about 1 nm to about
2 .mu.m, about 1 nm to about 1 .mu.m, about 1 nm to about 900 nm,
about 1 nm to about 800 nm, about 1 nm to about 700, about 1 nm to
about 600 nm, about 1 nm to about 500 nm, about 1 nm to about 400
nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, or even
from about 1 nm to about 100 nm. In certain embodiments, the
average largest dimension is the average largest diameter or the
average equivalent diameter.
[0061] In certain embodiments, greater than 80%, greater than 90%
or greater than 95% of the particles (e.g., microparticles) have an
average largest particle diameter of from about 1 nm to about 10
.mu.m, about 1 nm to about 5 .mu.m, about 1 nm to about 2 .mu.m,
about 1 nm to about 1 .mu.m, about 1 nm to about 900 nm, about 1 nm
to about 800 nm, about 1 nm to about 700 nm, about 1 nm to about
600 nm, about 1 nm to about 500 nm, about 1 nm to about 400 nm,
about 1 nm to about 300 nm, about 1 nm to about 200 nm, or even
from about 1 nm to about 100 nm. In certain embodiments, the
average diameter is the average largest diameter or the average
equivalent diameter.
[0062] In certain embodiments, particles (e.g., microparticles)
described herein have an average diameter from about 100 nm to
about 10 .mu.m, about 100 nm to about 5.mu.m, about 100 nm to about
2.mu.m, about 100 nm to about 1 .mu.m, about 100 nm to about 900
nm, about 100 nm to about 800 nm, about 100 nm to about 700 nm,
about 100 nm to about 600 nm, about 200 nm to about 500 nm, about
250 nm to about 600 nm, about 300 nm to about 600 nm, about 350 nm
to about 700 nm, about 450 nm to about 550 nm, about 475 nm to
about 525 nm, or from about 400 nm to about 700 nm. In certain
embodiments, the average diameter is the average largest diameter
or the average equivalent diameter.
[0063] In certain embodiments, greater than 80%, greater than 90%
or greater than 95% of the particles (e.g., microparticles) have an
average diameter from about 100 nm to about 10 .mu.m, about 100 nm
to about 5.mu.m, about 100 nm to about 2 .mu.m, about 100 nm to
about 1.mu.m, about 100 nm to about 900 nm, about 100 nm to about
800 nm, about 100 nm to about 700 nm, about 100 nm to about 600 nm,
about 200 nm to about 500 nm, about 250 nm to about 600 nm, about
300 nm to about 600 nm, about 350 nm to about 700 nm, about 450 nm
to about 550 nm, about 475 nm to about 525 nm, or from about 400 nm
to about 700 nm. In certain embodiments, the average diameter is
the average largest diameter or the average equivalent
diameter.
[0064] In some cases, the drug's (e.g., ophthalmic agent's)
partition coefficient into the matrix may be lower by at least an
order of magnitude than the matrix's affinity for the preservative.
For example, the particulate plug may bind BAK with a partition
coefficient of about 100-500 depending on the BAK concentration and
the structure of the particulate plug. In some embodiments, the
particulate plug may comprise a partition coefficient for the
preservative from the solution, emulsion, or suspension of, for
example, at least 10, at least 100, at least 1000, at least 10,000,
or within a range defined by any two of the preceding values.
Additionally, or alternatively, the adsorption rate constant may be
sufficiently high so that the time for adsorption of a drug
molecule to the polymer may be less than the time to form a drop.
The time to form a drop may comprise a time within a range from 0.1
to 10 seconds. The time to form a drop may be about 2 seconds,
between about 1 second and 5 seconds, about 3 seconds, less than 5
seconds, etc.
[0065] The uptake of the drug or therapeutic agent by the
particulate plug may be characterized by a percent uptake. The
percent uptake may be expressed as percentage of the original drug
concentration which is delivered after passing through the
particulate plug. In some cases, the percent uptake may be less
than 20%, less than 10%, less than 5%, less than 2%, less than 1%,
or less. In some cases, the percent uptake may be about 2%. In some
cases, the percent uptake may be about 1%.
[0066] The uptake of the preservative by the particulate plug may
be characterized by a percent uptake. The percent uptake may be
expressed as percentage of the original preservative concentration
which is delivered after passing through the particulate plug. In
some cases, the percent uptake may be greater than 80%, greater
than 90%, greater than 95%, greater than 98%, greater than 99%, or
more. In some cases, the percent uptake may be about 98%. In some
cases, the percent uptake may be about 99%. In some cases, the
preservative may be undetectable after passing though the
particulate plug. In some cases, the preservative may be below a
detectable threshold based on comparison of the area counts of the
HPLC peaks of the starting solution to the area counts of the drop,
etc. In some cases, the preservative may be below a detectable
threshold based on UV absorption.
[0067] The matrix (e.g., the particulate plug) may display a high
hydraulic permeability such that relatively little pressure may be
required to dispense a fluid. The hydraulic permeability may depend
on the matrix material, its dimensions, and how it is packed.
Larger pores or channels around packed particles or within the
particles themselves may allow for higher flow for a given pressure
drop. In some embodiments, hydraulic permeability may be larger
than about 0.01 Darcy. A nozzle may comprise a permeability of
about 0.1 Darcy. A hydraulic permeability of 1 to 10 Darcy may
allow fluid to be retained in the filter during instances when the
pressure may be lowered subsequent to formation of a drop. A larger
hydraulic permeability may allow the same plug to work for a wide
range of formulations including, for example, high viscosity
formulations, such as rewetting eye drops. In some embodiments, the
porous polymeric matrix comprises a hydraulic permeability of, for
example, 0.01 Da, 0.1 Da, 1 Da, 10 Da, 100 Da, 1000 Da or a
hydraulic permeability within a range defined by any two of the
preceding values.
[0068] In some embodiments, the matrix may be highly porous
containing large channels through which liquid can flow. The pore
or channel size in the matrix may be small enough so that the
molecules, which may initially be far from the surface of the
polymer in the matrix, may diffuse towards the polymer and adsorb.
A matrix may comprise large interconnected pores or channels which
may allow flow of solution and adsorption of the preservative into
the pores or channels. The matrix may be formed as a porous gel, as
a packed bed, and/or a structure formed by 3D printing soft
lithography, electrospinning, or any other appropriate method. In
some embodiments, the matrix may comprise a microporous gel. In
some embodiments, the matrix comprises a packed bed of hydrophobic
polymer/fatty acid blend particles. The particles may be
macroporous.
[0069] In some embodiments, the particles may need to be stably
held in the nozzle from which the formulation elutes from a
container and thereby prevented from eluting from the nozzle. In
some cases, the matrix may be sintered to fuse the particulate plug
into porous monolith. In some cases, the device may have a
cartridge or other assembly to retain the matrix in the nozzle. The
device may have a solution permeable bag to retain the matrix. The
device may comprise solid walls with a solution permeable bottom.
The device may comprise entrance and exit faces with a matrix
material therebetween. The entrance and exit faces may comprise
solution permeable membranes. The entry and exit faces may comprise
a filter. The entrance and exit faces may comprise a screen. The
particles may be attached to the container walls through long
polymeric chains and/or by placing a filter at the exit from the
device. The device may comprise a packaging for delivery to a
patient. The packaging may secure the device such that the device
may not be compressed until the device is delivered to the patient.
The packaging may secure the exit face from allowing the
formulation to exit the bottle. The packaging may comprise a
removable cap, a break-off cap, a resealable cap, etc.
[0070] The matrix may comprise a tortuosity such that the flow path
of a solution, emulsion, or suspension through the nozzle may be
significantly increased. In an embodiment where the matrix is a
packed bed of macroporous particles, the packed beds of macroporous
particles may have three levels of porosity: the space between the
particles, the macropores in the particles, and the inherent
porosity of the polymer. In some embodiments, all three levels of
porosity may contribute to the tortuosity of the matrix.
Therapeutic Agent
[0071] Embodiments of the present disclosure may provide a
therapeutic agent for delivery to an eye selected from a
therapeutic agent listed in Tables 1-4. A therapeutic agent may be
integrated into a fluid, which may flow from a container to an eye
through a nozzle comprising a matrix comprising a polymer/fatty
acid blend. In some embodiments, the fluid may comprise a solution,
emulsion, or suspension comprising a therapeutic agent. The
solution, emulsion, or suspension may comprise a therapeutic
agent.
[0072] Example therapeutic agents which may be used in conjunction
with a nozzle include but are not limited to: timolol, dorzolamide,
dexamethasone phosphate, dexamethasone, Betimol.RTM., olopatadine,
brimonidine, tetrahydrozoline, latanoprostene bunod, latanoprost,
and combinations of any two or more thereof. Therapeutic agents may
comprise brand name drugs and formulations including, but not
limited to, Timoptic, Xalatan, Combigan, Lumigan, Pataday, Pazeo,
Trusopt, Cosopt, Alphagan, Visine, Vyzulta, Veseneo, and other
agents described herein such as in the following tables. The
therapeutic agents may be dissolved in aqueous solution. The
solution may be sterilized and buffered to appropriate pH. In some
embodiments, the solution may comprise inactive ingredients such as
sodium chloride, sodium citrate, hydroxyethyl cellulose, sodium
phosphate, citric acid, sodium dihydrogen phosphate, polyoxyl 40
hydrogenated castor oil, tromethamine, boric acid, mannitol,
edetate disodium, sodium hydroxide, and/or hydrochloric acid.
[0073] In some embodiments, the fluid comprises a preservative in
addition to a therapeutic agent. Example preservatives include but
are not limited to: benzalkonium chloride (BAK), alcohols,
parabens, methyl paraben, propylparaben, EDTA, chlorhexidine,
quaternary ammonium compounds, Purite.RTM., stabilized oxychloro
complexes, Sofzia.RTM., sorbic acid, Sodium perborate,
polyquaternium-1, chlorobutanol, cetrimonium chloride, edatate
disodium, etc. In some embodiments, the preservative is
benzalkonium chloride (BAK). In some embodiments, the preservative
is one or more quaternary ammonium compounds. In some embodiments,
the preservative is polyquaternium-1. In some embodiments, the
preservative is cetrimonium chloride.
[0074] Therapeutic agents for the treatment of for example, dry
eye, bacterial infection, glaucoma, hypertension, inflammation,
allergic conjunctivitis, hypotrichosis of the eyelashes, fungal
infection, etc. and therapeutic agents used for local anesthetic,
pupil dilation, etc. may be administered to a patient as a
solution, emulsion, or suspension delivered to an eye topically via
a dropper bottle or similar delivery mechanism. The solution,
emulsion, or suspension may be subject to contamination such as
microbial, fungal, or particulate contamination, which may be
averse to patient health. In order to prevent such contamination a
preservative may be added to the solution, emulsion, or suspension;
however, patient exposure to preservatives may have adverse effects
to eye health.
[0075] The present disclosure provides one or more therapeutic
agents formulated with a preservative capable of being removed by a
preservative removing device of the present disclosure. Therapeutic
agents may comprise compounds and salts, for use in the treatment
of ophthalmic diseases. The disclosed compounds and salts can be
used, for example, for the treatment or prevention of vision
disorders and/or for use during ophthalmological procedures for the
prevention and/or treatment of ophthalmic disorders. The following
list of examples are not intended to be limiting.
[0076] In some embodiments, the therapeutic agent to be dispensed
comprises an active ingredient selected from cyclosporine and
lifitegrast. In some embodiments, the therapeutic agent may be an
active ingredient in the treatment of dry eye.
[0077] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from
sulfacetamide sodium, ofloxacin, gatifloxacin, ciprofloxacin,
moxifloxacin, tobramycin, levofloxacin, prednisolone acetate,
polymyxin B sulfate, and trimethoprim. In some embodiments, the
therapeutic formulation to be dispensed comprises the active
ingredients sulfacetamide sodium and prednisolone acetate. In some
embodiments, the therapeutic formulation to be dispensed comprises
the active ingredients polymyxin B sulfate and trimethoprim. In
some embodiments, the therapeutic agent may be an active ingredient
in the treatment of a bacterial infection.
[0078] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from
brimonidine tartrate, bimatoprost, levobunolol hydrochloride,
brinzolamide, betaxolol hydrochloride, pilocarpine hydrochloride,
apraclonidine, travoprost, timolol maleate, latanoprost,
dorzolamide hydrochloride, and tafluprost. In some embodiments, the
therapeutic formulation to be dispensed comprises the active
ingredients brimonidine tartrate and timolol maleate. In some
embodiments, the therapeutic formulation to be dispensed comprises
the active ingredients brinzolamide and brimonidine tartrate. In
some embodiments, the therapeutic agent may be an active ingredient
in the treatment of glaucoma or hypertension.
[0079] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from ketorolac
tromethamine, fluorometholone, prednisolone acetate, difluprednate,
fluorometholone acetate, nepafenac, dexamethasone, diclofenac
sodium, bromfenac, gentamicin, tobramycin, neomycin, and polymyxin
B sulfate. In some embodiments, the therapeutic formulation to be
dispensed comprises the active ingredients gentamicin and
prednisolone acetate. In some embodiments, the therapeutic
formulation to be dispensed comprises the active ingredients
tobramycin and dexamethasone. In some embodiments, the therapeutic
formulation to be dispensed comprises the active ingredients
neomycin, polymyxin B sulfate and dexamethasone. In some
embodiments, the therapeutic agent may be an active ingredient in
the treatment of inflammation.
[0080] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from
nedocromil sodium, epinastine HCl, alcaftadine, lodoxamide
tromethamine, emedastine difumarate, and olopatadine hydrochloride.
In some embodiments, the therapeutic agent may be an active
ingredient in the treatment of allergic conjunctivitis.
[0081] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from
proparacaine hydrochloride and tetracaine hydrochloride. In some
embodiments, the therapeutic agent may be a local anesthetic.
[0082] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from
cyclopentolate hydrochloride, atropine sulfate, and tropicamide. In
some embodiments, the therapeutic formulation to be dispensed
comprises the active ingredients cyclopentolate hydrochloride and
phenylephrine hydrochloride. In some embodiments, the therapeutic
agent may dilate pupils.
[0083] In some embodiments, the at least one therapeutic agent to
be dispensed comprises the active ingredient natamycin. In some
embodiments, the therapeutic agent may be an active ingredient in
the treatment of fungal infection.
[0084] In some embodiments, the at least one therapeutic agent to
be dispensed comprises an active ingredient selected from lipoic
acid choline ester chloride, rebamipide, pilocarpine, aceclidine,
tropicamide, sodium hyaluronate, diclofenac sodium, pilocarpine
HCl, and ketorolac. In some embodiments, the therapeutic
formulation to be dispensed comprises the active ingredients
aceclidine and tropicamide. In some embodiments, the therapeutic
formulation to be dispensed comprises the active ingredients sodium
hyaluronate and diclofenac sodium and pilocarpine HCl. In some
embodiments, the therapeutic formulation to be dispensed comprises
the active ingredients pilocarpine and ketorolac. In some
embodiments, the therapeutic agent may be an active ingredient in
the treatment of presbyopia.
[0085] In some cases, the therapeutic agent is a weak acid. Weak
acids may undergo partial or incomplete dissociation in aqueous
solution or water. Weak acids may generally be less attractive to
the surface of the particulate plug, which is acidified by the
fatty acid. The carboxylic acid functional groups of the fatty acid
may increase hydrophilicity of the particulate plug while
maintaining low affinity for the drug. The therapeutic agent may
comprise a pKa of about 1 to about 14. The therapeutic agent may
comprise a pKa of at least about 1. The therapeutic agent may
comprise a pKa of at most about 14. The therapeutic agent may
comprise a pKa of about 1 to about 3, about 1 to about 5, about 1
to about 7, about 1 to about 9, about 1 to about 11, about 1 to
about 13, about 1 to about 14, about 3 to about 5, about 3 to about
7, about 3 to about 9, about 3 to about 11, about 3 to about 13,
about 3 to about 14, about 5 to about 7, about 5 to about 9, about
5 to about 11, about 5 to about 13, about 5 to about 14, about 7 to
about 9, about 7 to about 11, about 7 to about 13, about 7 to about
14, about 9 to about 11, about 9 to about 13, about 9 to about 14,
about 11 to about 13, about 11 to about 14, or about 13 to about
14. The therapeutic agent may comprise a pKa of at least about 1,
about 2, about 3, about 4, about 5, about 6, about 7, about 8,
about 9, about 10, about 11, about 12, about 13, about 14, or about
14.
[0086] Illustrative solutions, emulsions, or suspensions which can
be used in aspects of the pharmaceutical formulation disclosed
herein are shown in Tables 1 to 4. Example solutions, emulsions, or
suspensions in the table below may be integrated into preservative
removing devices and methods of removing a preservative of the
present disclosure. One or more embodiments, variations, and
examples of the preservative removing devices, matrices, and
methods described herein may be incorporated into an eye drop
dispensing system, which system may comprise a squeezable bottle. A
squeezable bottle may comprise a reservoir in which a fluid may be
stored. A fluid stored in the reservoir may comprise an embodiment,
variation, or example of solutions, emulsions, or suspensions
described herein, including those examples provided in Tables 1 to
4.
TABLE-US-00001 TABLE 1 Pharmaceuticals Sorted by Indication %
Active Formulation Market Name Drug Ingredient Type Indication
Preservative Dry Eye Restasis Cyclosporine 0.05% emulsion
keratoconjunctivitis none sicca Xiidra Lifitegrast 5% solution
keratoconjunctivitis none sicca Visine Tetrahydrozoline
keratoconjunctivitis sicca Bacterial Infection Bleph 10
sulfacetamide 10% solution conjunctivitis and benzalkonium sodium
other ocular chloride infections 0.005% Blephamide sulfacetamide
10%/0.2% suspension bacterial ocular benzalkonium sodium- infection
chloride prednisolone 0.004% acetate Ocuflox Ofloxacin 0.3%
solution bacterial ocular benzalkonium infection; corneal chloride
ulcers (0.005%) Polytrim polymyxin B polymyxin B solution ocular
bacterial benzalkonium sulfate and sulfate 10,000 infections;
chloride 0.04 trimethoprim units/mL; conjunctivitis; mg/mL
trimethoprim blepharo- sulfate conjunctivitis equivalent to 1 mg/mL
Zymaxid Gatifloxacin 0.3% and solution bacterial benzalkonium 0.5%
conjunctivitis chloride 0.005% Zymar Gatifloxacin 0.3% solution
bacterial benzalkonium conjunctivitis chloride 0.005%; Ciloxan
Ciprofloxacin 0.3% solution bacterial None conjunctivitis Moxeza
Moxifloxacin 0.5% solution bacterial none conjunctivitis Tobrex
Tobramycin 0.3% solution infections of the benzalkonium eye and its
adnexa chloride caused by 0.01% susceptible bacteria Vigamox
Moxifloxacin 0.5% solution bacterial none conjunctivitis Iquix
Levofloxacin 1.5% solution bacterial benzalkonium conjunctivitis
chloride 0.005% Quixin Levofloxacin 0.5% solution bacterial
benzalkonium conjunctivitis chloride 0.005% Glaucoma or
Hypertension Alphagan brimonidine 0.01% solution open-angle Purite
.RTM. tartrate glaucoma or ocular 0.005% (0.05 hypertension mg/mL)
Lumigan Bimatoprost 0.01% solution open angle benzalkonium glaucoma
or ocular chloride 0.2 hypertension mg/mL Betagan levobunolol 0.5%
solution chronic open-angle benzalkonium hydrochloride glaucoma or
ocular chloride hypertension 0.004% Combigan brimonidine 0.2%/0.5%
solution glaucoma or ocular benzalkonium tartrate/timolol
hypertension who chloride maleate require adjunctive 0.005% or
replacement therapy due to inadequately controlled IOP Azopt
Brinzolamide 1% suspension ocular hypertension benzalkonium or
open-angle chloride 0.1 glaucoma mg Betoptic S betaxolol 0.25% and
suspension ocular hypertension benzalkonium hydrochloride 0.5% or
chronic open chloride 0.1 angle glaucoma mg in 1 mL Isopto Carpine
pilocarpine 1%, 2% and solution IOP reduction; benzalkonium
hydrochloride 4% open-angle chloride glaucoma or ocular 0.01%
hypertension; acute angle-closure glaucoma; induction of miosis
Iopidine Apraclonidine 0.5% and solution Short term benzalkonium
1.0% adjunctive therapy chloride in patients on 0.01% maximally
tolerated medical therapy who require additional IOP reduction
Simbrinza brinzolamide/ 1%/0.2% suspension reduction of
benzalkonium brimonidine elevated IOP in chloride 0.03 tartrate
patients with open- mg angle glaucoma or ocular hypertension
Travatan Z Travoprost 0.004% solution open-angle ionic buffered
glaucoma or ocular system, sofZia hypertension who are intolerant
of other intraocular pressure lowering medications Isralol Timolol
maleate 0.5% solution ocular hypertension benzalkonium or
open-angle chloride 0.05 glaucoma mg/mL Xalatan Latanoprost
approximately solution open-angle benzalkonium 1.5 .mu.g per
glaucoma or ocular chloride, drop hypertension 0.02% Trusopt
dorzolamide 2% solution ocular hypertension benzalkonium
hydrochloride or open-angle chloride glaucoma 0.0075% Timoptic
timolol maleate 0.25% and solution ocular hypertension benzalkonium
0.5% or open-angle chloride glaucoma Ziotan Tafluprost 0.0015%
solution open-angle none glaucoma or ocular hypertension Vesneo
Latanoprostene glaucoma Bunod Vyzulta Latanoprostene glaucoma Bunod
Cosopt Dorzolamide + Glaucoma Timolol Inflammation Acular LS
ketorolac 0.4% solution ocular pain and benzalkonium tromethamine
burning/stinging chloride following corneal 0.006% refractive
surgery Acular ketorolac 0.5% solution inflammation benzalkonium
tromethamine following cataract chloride surgery; relief of 0.01%
ocular itching due to seasonal allergic conjunctivitis Acuvail
ketorolac 0.45% solution treatment of pain none tromethamine and
inflammation following cataract surgery FML Forte Fluorometholone
0.25% ointment corticosteroid- benzalkonium responsive chloride
inflammation of the 0.005% palpebral and bulbar conjunctiva, cornea
and anterior segment of the globe FML Fluorometholone 0.1%
suspension corticosteroid- benzalkonium responsive chloride
inflammation of the 0.004% palpebral and bulbar conjunctiva, cornea
and anterior segment of the globe Pred Forte prednisolone 1%
suspension steroid-responsive benzalkonium acetate inflammation of
the chloride palpebral and bulbar conjunctiva, cornea, and anterior
segment of the globe Pred Mild prednisolone 0.12% suspension mild
to moderate benzalkonium acetate noninfectious chloride allergic
and inflammatory disorders of the lid, conjunctiva, cornea, and
sclera, including chemical and thermal burns Pred-G gentamicin and
0.3%/1% suspension steroid-responsive Benzalkonium prednisolone
inflammatory; chloride acetate bacterial infection; 0.005% thermal
burns or penetration of foreign bodies Durezol Difluprednate 0.05%
emulsion inflammation and sorbic acid pain associated 0.1% with
ocular surgery Flarex fluorometholone 0.1% suspension
steroid-responsive benzalkonium acetate inflammatory chloride
conditions of the 0.01% palpebral and bulbar conjunctiva, cornea
and anterior segment of the eye Ilevro Nepafenac 0.3% suspension
pain and benzalkonium inflammation chloride associated with 0.005%
cataract surgery Maxidex Dexamethasone 0.1% suspension Steroid
responsive benzalkonium inflammatory chloride conditions; corneal
0.01% injury from chemical, radiation, or thermal bums, or
penetration of foreign bodies Maxitrol neomycin and neomycin
solution steroid-responsive methylparaben polymyxin B sulfate
inflammatory 0.05%, sulfates and equivalent to ocular conditions
propylparaben dexamethasone neomycin 3.5 for which a 0.01% mg,
corticosteroid is polymyxin B indicated and where sulfate 10,000
bacterial infection units, or a risk of bacterial dexamethasone
ocular infection 0.1% exists Nevanac Nepafenac 0.1% suspension pain
and benzalkonium inflammation chloride associated with 0.005%
cataract surgery Omnipred prednisolone 1.0% suspension steroid
responsive benzalkonium acetate inflammatory chloride conditions;
corneal 0.01% injury from chemical, radiation, or thermal bums, or
penetration of foreign bodies Tobradex ST tobramycin/ 0.3%/0.05%
suspension steroid-responsive benzalkonium dexamethasone
inflammatory chloride 0.1 ocular conditions mg for which a
corticosteroid is indicated and where superficial bacterial ocular
infection exists Voltaren diclofenac 0.1% solution inflammation
from None Ophthalmic sodium cataract extraction; temporary relief
of pain and photophobia following corneal refractive surgery
Bromday Bromfenac 0.09% solution postoperative benzalkonium
inflammation in chloride 0.05 patients who have mg/mL undergone
cataract extraction Xibrom Bromfenac 0.09% solution postoperative
benzalkonium inflammation in chloride (0.05 patients who have
mg/mL) undergone cataract extraction Xibrom Bromfenac 0.09%
solution postoperative benzalkonium inflammation in chloride 0.05
patients who have mg/mL undergone cataract extraction Allergic
Conjunctivitis Alocril nedocromil 2% solution itching associated
benzalkonium sodium with allergic chloride conjunctivitis 0.01%
Elestat epinastine HCl 0.05% suspension itching associated
Benzalkonium with allergic chloride conjunctivitis 0.01%; Lastacaft
Alcaftadine 0.25% solution itching associated benzalkonium with
allergic chloride conjunctivitis 0.005% Alomide lodoxamide 0.1%
solution vernal benzalkonium tromethamine keratoconjunctivitis;
chloride giant papillary 0.007% w/v conjunctivitis; allergic/atopic
conjunctivitis Emadine emedastine 0.5% solution allergic
benzalkonium difumarate conjunctivitis chloride, 0.01% Pataday
olopatadine 0.2% solution ocular itching benzalkonium hydrochloride
associated with chloride allergic 0.01% conjunctivitis Pazeo
olopatadine 0.7% solution ocular itching benzalkonium hydrochloride
associated with chloride allergic 0.015% conjunctivitis Hair Growth
Latisse Bimatoprost 0.03% solution hypotrichosis of the
benzalkonium eyelashes chloride 0.05 mg/mL Local Anesthetic Alcaine
proparacaine 0.5% solution topical anesthesia - benzalkonium
hydrochloride removal of foreign chloride bodies; 0.01% measurement
of intraocular pressure; conjunctive scraping Tetracaine Tetracaine
0.5% solution procedures None hydrochloride requiring a rapid and
short acting topical ophthalmic anesthetic Pupil Dilation Cyclogyl
cyclopentolate 0.5%, 1.0% or solution pre- and post- Benzalkonium
hydrochloride 2.0% operative states chloride 0.1 when mydriasis is
mg in 1.0 mL required and when a shorter acting mydriatic and
cycloplegic is needed in the therapy of iridocyclitis Cyclomydril
cyclopentolate 0.2%/1.0% solution For the production Benzalkonium
hydrochloride of mydriasis (pupil chloride and dilation) 0.01%
phenylephrine hydrochloride Isopto atropine sulfate 1% solution
mydriasis; benzalkonium Atropine cycloplegia; chloride penalization
of the 0.01% healthy eye in the treatment of amblyopia Mydriacyl
Tropicamide 0.5% or 1.0% solution mydriasis and benzalkonium
cycloplegia chloride 0.01% Fungal infection Natacyn Natamycin 5%
suspension anti-fungal; fungal benzalkonium blepharitis, chloride
conjunctivitis, and 0.02% keratitis
TABLE-US-00002 TABLE 2 Experimental Presbyopia Formulations. %
Active Formulation Drug Code Drug Ingredient Type Indication
Preservative Presbyopia EV06/ lipoic acid 3.0% solution presbyopia
benzalkonium UNR844 choline ester chloride, 0.01% chloride PRX-100
aceclidine/ 0.25-2.0%/ Solution or presbyopia benzalkonium
tropicamide 0.025-0.1% suspension chloride, 0.02% CSF-1 sodium
0.1-0.9%/ Solution or presbyopia Any, hyaluronate/ 0.006-0.012%/
suspension benzalkonium diclofenac 0.2-0.4% chloride, 0.01% sodium/
pilocarpine HCl AAGN- Pilocarpine 0.1%-1% Solution or presbyopia
Any, 199201 and/or suspension benzalkonium oxymetazoline chloride,
0.01% AAGN- ketorolac 0.1%-1% Solution or presbyopia Any, 190584
suspension benzalkonium chloride, 0.01%
TABLE-US-00003 TABLE 3 Additional Pharmaceuticals % Active
Formulation Market Name Drug Ingredient Type Indication
Preservative Restasis cyclosporine 0.05% emulsion
keratoconjunctivitis none sicca Latisse bimatoprost 0.03% solution
hypotrichosis of the benzalkonium eyelashes chloride 0.05 Alphagan
brimonidine 0.01% solution open-angle glaucoma mg/mL Tartrate or
ocular Purite .RTM. hypertension 0.005% (0.05 mg/mL) Lumigan
bimatoprost 0.01% solution open angle glaucoma benzalkonium or
ocular chloride 0.2 hypertension mg/mL Acular LS ketorolac 0.4%
solution ocular pain and benzalkonium tromethamine burning/stinging
chloride following corneal 0.006% refractive surgery Acular
ketorolac 0.5% solution inflammation benzalkonium tromethamine
following cataract chloride surgery; relief of 0.01% ocular itching
due to seasonal allergic conjunctivitis Acuvail ketorolac 0.45%
solution treatment of pain and none tromethamine inflammation
following cataract surgery Alocril nedocromil 2% solution itching
associated benzalkonium sodium with allergic chloride
conjunctivitis 0.01% Betagan levobunolol 0.5% solution chronic
open-angle benzalkonium hydrochloride glaucoma or ocular chloride
hypertension 0.004% Bleph 10 sulfacetamide 10% solution
conjunctivitis and benzalkonium sodium other ocular chloride
infections 0.005% Blephamide sulfacetamide 10%/0.2% suspension
bacterial ocular benzalkonium sodium - infection chloride
prednisolone 0.004% acetate Combigan brimonidine 0.2%/0.5% solution
glaucoma or ocular benzalkonium tartrate/timolol hypertension who
chloride maleate require adjunctive or 0.005% replacement therapy
due to inadequately controlled iop Elestat epinastine HCl 0.05%
suspension itching associated benzalkonium with allergic chloride
conjunctivitis 0.01%; FML Forte fluorometholone 0.25% ointment
corticosteroid- benzalkonium responsive chloride inflammation of
the 0.005% palpebral and bulbar conjunctiva, cornea and anterior
segment of the globe FML fluorometholone 0.1% suspension
corticosteroid- benzalkonium responsive chloride inflammation of
the 0.004% palpebral and bulbar conjunctiva, cornea and anterior
segment of the globe Lastacaft alcaftadine 0.25% solution itching
associated benzalkonium with allergic chloride conjunctivitis
0.005% Ocuflox ofloxacin 0.3% solution bacterial ocular
benzalkonium infection; corneal chloride ulcers (0.005%) Polytrim
polymyxin B polymyxin B solution ocular bacterial benzalkonium
sulfate and sulfate infections; chloride 0.04 trimethoprim 10,000
conjunctivitis; mg/mL units/mL; blepharo- trimethoprim
conjunctivitis sulfate equivalent to 1 mg/mL Pred Forte
prednisolone 1% suspension steroid-responsive benzalkonium acetate
inflammation of the chloride palpebral and bulbar conjunctiva,
cornea, and anterior segment of the globe Pred Mild prednisolone
0.12% suspension mild to moderate benzalkonium acetate
noninfectious allergic chloride and inflammatory disorders of the
lid, conjunctiva, cornea, and sclera, including chemical and
thermal burns Pred-G gentamicin and 0.3%/1% suspension
steroid-responsive benzalkonium prednisolone inflammatory; chloride
acetate bacterial infection; 0.005% thermal burns or penetration of
foreign bodies Zymaxid gatifloxacin 0.3% and solution bacterial
benzalkonium 0.5% conjunctivitis chloride 0.005% Zymar gatifloxacin
0.3% solution bacterial benzalkonium conjunctivitis chloride
0.005%; Alcaine proparacaine 0.5% solution topical anesthesia -
benzalkonium hydrochloride removal of foreign chloride bodies;
measurement 0.01% of intraocular pressure; conjunctive scraping
Alomide lodoxamide 0.1% solution vernal benzalkonium tromethamine
keratoconjunctivitis; chloride giant papillary 0.007% w/v
conjunctivitis; allergic/atopic conjunctivitis Azopt brinzolamide
1% suspension ocular hypertension benzalkonium or open-angle
chloride 0.1 glaucoma mg Betoptic S betaxolol 0.25% and suspension
ocular hypertension benzalkonium hydrochloride 0.5% or chronic open
angle chloride 0.1 glaucoma mg in 1 mL Ciloxan ciprofloxacin 0.3%
solution bacterial None conjunctivitis Cyclogyl cyclopentolate
0.5%, 1.0% solution pre- and post- benzalkonium hydrochloride or
2.0% operative states when chloride 0.1 mydriasis is required mg in
1.0 mL and when a shorter acting mydriatic and cycloplegic is
needed in the therapy of iridocyclitis Cyclomydril cyclopentolate
0.2%/1.0% solution for the production of benzalkonium hydrochloride
and mydriasis (pupil chloride phenylephrine dilation) 0.01%
hydrochloride Durezol difluprednate 0.05% emulsion inflammation and
sorbic acid pain associated with 0.1% ocular surgery Emadine
emedastine 0.5% solution allergic conjunctivitis benzalkonium
difumarate chloride, 0.01% Flarex fluorometholone 0.1% suspension
steroid-responsive benzalkonium acetate inflammatory chloride
conditions of the 0.01% palpebral and bulbar conjunctiva, cornea
and anterior segment of the eye Ilevro nepafenac 0.3% suspension
pain and benzalkonium inflammation chloride associated with 0.005%
cataract surgery Iopidine apraclonidine 0.5% and solution short
term adjunctive benzalkonium 1.0% therapy in patients on chloride
maximally tolerated 0.01% medical therapy who require additional
iop reduction Isopto atropine sulfate 1% solution mydriasis;
benzalkonium Atropine cycloplegia; chloride penalization of the
0.01% healthy eye in the treatment of amblyopia Isopto Carpine
pilocarpine 1%, 2% and solution iop reduction; open- benzalkonium
hydrochloride 4% angle glaucoma or chloride ocular hypertension;
0.01% acute angle-closure glaucoma; induction of miosis Maxidex
dexamethasone 0.1% suspension steroid responsive benzalkonium
inflammatory chloride 0.01 conditions; corneal % injury from
chemical, radiation, or thermal bums, or penetration of foreign
bodies Maxitrol neomycin and neomycin solution steroid-responsive
methylparaben polymyxin B sulfate inflammatory ocular 0.05%,
sulfates and equivalent to conditions for which propylparaben
dexamethasone neomycin 3.5 a corticosteroid is 0.01% mg, indicated
and where polymyxin B bacterial infection or sulfate a risk of
bacterial 10,000 units, ocular infection exists dexamethasone 0.1%
Moxeza moxifloxacin 0.5% solution bacterial None conjunctivitis
Mydriacyl tropicamide 0.5% or 1.0% solution mydriasis and
benzalkonium cycloplegia chloride 0.01% Natacyn natamycin 5%
suspension anti-fungal; fungal benzalkonium blepharitis, chloride
conjunctivitis, and 0.02% keratitis Nevanac nepafenac 0.1%
suspension pain and benzalkonium inflammation chloride associated
with 0.005% cataract surgery Omnipred prednisolone 1.0% suspension
steroid responsive benzalkonium acetate inflammatory chloride
conditions; corneal 0.01% injury from chemical, radiation, or
thermal bums, or penetration of foreign bodies Pataday olopatadine
0.2% solution ocular itching benzalkonium hydrochloride associated
with chloride allergic conjunctivitis 0.01% Pazeo olopatadine 0.7%
solution ocular itching benzalkonium hydrochloride associated with
chloride allergic conjunctivitis 0.015% Simbrinza brinzolamide/
1%/0.2% suspension reduction of elevated benzalkonium brimonidine
iop in patients with chloride 0.03 tartrate open-angle glaucoma mg
or ocular hypertension Tetracaine hydrochloride 0.5% solution
procedures requiring None a rapid and shortacting topical
ophthalmic anesthetic Tobradex ST tobramycin/ 0.3%/0.05% suspension
steroid-responsive benzalkonium dexamethasone inflammatory ocular
chloride 0.1 conditions for which mg a corticosteroid is indicated
and where superficial bacterial ocular infection exists Tobrex
tobramycin 0.3% solution infections of the eye benzalkonium and its
adnexa caused chloride by susceptible 0.01% bacteria Travatan Z
travoprost 0.004% solution open-angle glaucoma ionic buffered or
ocular system, sofZia hypertension who are intolerant of other
intraocular pressure lowering medications
Vigamox moxifloxacin 0.5% solution bacterial None conjunctivitis
Voltaren diclofenac sodium 0.1% solution inflammation from
Ophthalmic cataract extraction; temporary relief of None pain and
photophobia following corneal refractive surgery Trusopt
dorzolamide 2% solution ocular hypertension benzalkonium
hydrochloride or open-angle chloride glaucoma 0.0075% Timoptic
timolol maleate 0.25% and solution ocular hypertension benzalkonium
0.5% or open-angle chloride glaucoma Ziotan tafluprost 0.0015%
solution open-angle glaucoma none or ocular hypertension Xalatan
latanoprost approximately solution open-angle glaucoma benzalkonium
1.5 .mu.g per or ocular chloride, drop hypertension 0.02% Bromday
bromfenac 0.09% solution postoperative benzalkonium inflammation in
chloride 0.05 patients who have mg/mL undergone cataract extraction
Isralol timolol maleate 0.5% solution ocular hypertension
benzalkonium or open-angle chloride 0.05 glaucoma mg/mL Xibrom
bromfenac 0.09% solution postoperative benzalkonium inflammation in
chloride (0.05 patients who have mg/mL) undergone cataract
extraction Iquix levofloxacin 1.5% solution bacterial benzalkonium
conjunctivitis chloride 0.005% Quixin levofloxacin 0.5% solution
bacterial benzalkonium conjunctivitis chloride 0.005% Xibrom
bromfenac 0.09% solution postoperative benzalkonium inflammation in
chloride 0.05 patients who have mg/mL undergone cataract extraction
Xiidra lifitegrast 5% solution Dry Eye None
TABLE-US-00004 TABLE 4 Other Pharmaceuticals Code of Drug in %
Active Formulation Clinical Trial Drug Ingredient Type Indication
Preservative EV06/ lipoic acid 3.0% solution presbyopia
benzalkonium UNR844 choline ester chloride, 0.01% chloride PRX-100
aceclidine/ 0.25-2.0%/ Solution or presbyopia benzalkonium
tropicamide 0.025-0.1% suspension chloride, 0.02% SF-1 sodium
0.1-0.9%/ Solution or presbyopia Any, hyaluronate/ 0.006-0.012%/
suspension benzalkonium diclofenac 0.2-0.4% chloride, 0.01% sodium/
pilocarpine HCl ECF843 0.1%-1% Solution or Dry eye Any, suspension
benzalkonium chloride, 0.01% None rebamipide 1%, 2% solution Dry
eye Any, (keratocon- benzalkonium junctivitis sicca) chloride,
0.01% AAGN- Pilocarpine 0.1%-1% Solution or presbyopia Any, 199201
and/or suspension benzalkonium oxymetazoline chloride, 0.01% AAGN-
ketorolac 0.1%-1% Solution or presbyopia Any, 190584 suspension
benzalkonium chloride, 0.01% pilocarpine 0.3% Solution or
presbyopia Any, suspension benzalkonium chloride, 0.01% pilocarpine
varies with Solution or presbyopia Any, severity of suspension
benzalkonium presbyopia, chloride, 0.01% 0.3%-2.2%
Preservative
[0087] The present disclosure provides one or more preservatives
for solutions, emulsions, or suspensions of therapeutic agents of
the present disclosure. Preservatives may comprise compounds and
salts, for use as preservatives for solutions, emulsions, or
suspensions of therapeutic agents. The one or more preservatives
may for example prevent microbial and/or fungal growth. The one or
more preservatives may for example prevent physical or chemical
deterioration of a therapeutic agent.
[0088] Non-limiting examples of preservative agents include
benzalkonium chloride or bromide, ethylenediaminetetraacetic acid
(EDTA), sodium salt of EDTA, chlorobutanol, phenylmercuric acetate,
phenylmercuric nitrate, chlorhexidine acetate, thimerosal,
benzethonium chloride, sorbic acid, alcohols, parabens (e.g.,
methylparaben, polyparaben), chlorhexidine, quaternary ammonium
compounds, polyquaternium-1 (Polyquad.RTM.) Purite.RTM., stabilized
oxychloro complexes, Sofzia.RTM., sodium perborate (GenAqua.RTM.),
cetrimonium chloride, cetrimide, edetate disodium, etc. In some
embodiments, a formulation of the disclosure does not include a
preservative. In some embodiments, the preservative is benzalkonium
chloride. In some embodiments, the preservative is a quaternary
ammonium compound. In some embodiments, the preservative is
polyquaternium-1. In some embodiments, the preservative is
cetrimonium chloride.
[0089] In some embodiments, the particulate plug may further
include a preservative removing compound or a preservative
deactivating compound. Preservative removing or deactivating
compounds can decrease toxicity of a formulation to be delivered
through typical separation methods including, but not limited to,
adsorption, ion exchange, chemical precipitation, or solvent
extraction. Preservative removing or deactivating compounds can
include, but are not limited to, activated charcoal, antioxidants,
ethylenediaminetetraacetic acid (EDTA), anionic hydrogels, cationic
compounds, neutralizing agents, or combinations thereof.
[0090] The Purite.RTM. preservative system includes Stabilized
Oxychloro Complex (SOC), a combination of chlorine dioxide,
chlorite, and chlorate. When exposed to light, SOC dissociates into
water, oxygen, sodium and chlorine free radicals which cause
oxidation of intracellular lipids and glutathione, interrupting
vital enzymes for cell function and maintenance. For preservatives
such as Purite.RTM. which produce chlorine free radicals, the
particulate plug of the disclosure can include a material that has
a high affinity for free radicals such as activated charcoal or
antioxidants such as vitamin E.
[0091] The SofZia.RTM. preservative system in Travatan Z (Alcon
Laboratories, Fort Worth, Tex.) contains borate, sorbitol,
propylene glycol, and zinc. Without intending to be bound by
theory, it is believed that the preservative effect is from a
combination of borate and zinc. For preservatives including borate
and zinc, such as SofZia .RTM., the particulate plug of the
disclosure can include a metal chelating agent such as EDTA,
anionic hydrogels that can extract cationic zinc through
electrostatic interactions, cationic hydrogels or resins that can
extract anionic borate ions through electrostatic interactions, or
a neutralizing agent that can neutralize boric acid.
[0092] The materials that can sequester the preservative can be
incorporated into the particulate plug as microparticles, such as
particles of activated charcoal. The microparticles can be packed
into the particulate plug such that the liquid has sufficient space
in between the particles to flow out, while also providing
sufficient contact area for binding. Alternatively, the
sequestering materials could be incorporated into particles of
other suitable materials such as the polymer particles of the
disclosure to facilitate the contact between the eluding
formulation and the sequestering material. In some cases, the
sequestration material, can be integrated into the polymer
covalently. For example, negative ions that can complex with zinc
could be incorporated into polymers. The sequestering material can
be a nanoparticle or can be incorporated into a nanoparticle, which
could in turn be dispersed into the polymer particles that form a
packed bed in the tip. The nanoparticle could also be deposited
just on the surface of the larger particles. The sequestering
material could also form tubes that can be arranged in parallel to
provide the path for liquid to flow out and sequestration to occur
on the surface.
[0093] The materials present in the particulate plug to neutralize
the free radicals in the formulation, for example, vitamins, can be
incorporated into the polymer particles that form the particulate
plug. Bases can be incorporated to bring the pH to a level that is
comfortable in the eyes. The polymer particles can be loaded with
vitamin E for example by soaking the particles in a solution of
vitamin E dissolved in an organic liquid, leading to uptake of
vitamin E into the particles. Subsequently, the organic liquid such
as ethanol can be evaporated or extracted into water to form
particles loaded with vitamin E. The material of the particles that
is loaded with vitamin E could be chosen to achieve other
beneficial purposes such as extraction of some other component of
the preservative. Bases could be directly integrated into the
hydrogel preparations.
[0094] The preservative effect of the formulations can be improved
by incorporation of another preservative such as Benzalkonium
Chloride so that the formulation can pass EPA criterion as well.
The added BAK or the other preservative can be removed by the
particulate plug to achieve improved preservative performance
without increasing toxicity.
[0095] The particulate plug including a preservative removing
compound or preservative deactivating compound can be formed in
various shapes such as spheres, cylinders, tubes, highly irregular,
flat sheets etc, where the surface could be rough or smooth. The
particles or other shapes integrated into the tip can contain some
preservative to ensure that the tip itself remains sterile. The
preservative pre-loaded into the tip could be loaded via adsorption
or be chemically attached to the material through a bond. For
example, Polyquaternium can be integrated into the polymer forming
the particles. The covalent attachment will prevent diffusion of
the pre-loaded preservative into the tear film. Alternatively, the
pre-loaded preservative could be sufficiently large in molecular
weight or have very low partitioning into the eluding
formulation.
[0096] In cases wherein the particulate plug including a
preservative removing compound or a preservative deactivating
compound is intended to add a component to the eluding formulation,
the amount of that material in the particulate plug will be
sufficiently large to ensure that there is sufficient amount
remaining for the entire bottle, or at least 90% of the bottle. In
cases wherein the particulate plug including a preservative
removing compound or a preservative deactivating compound is
intended to sequester a component from the eluding formulation, the
volume and area in the particulate plug will be sufficiently large
to sequester the desired component from at least 90% of the
formulation in the bottle.
[0097] The present disclosure provides salts of any one or both of
a therapeutic agent and a preservative. Pharmaceutically-acceptable
salts include, for example, acid-addition salts and base-addition
salts. The acid that is added to the compound to form an
acid-addition salt can be an organic acid or an inorganic acid. A
base that is added to the compound to form a base-addition salt can
be an organic base or an inorganic base. In some embodiments, a
pharmaceutically-acceptable salt is a metal salt.
[0098] Metal salts can arise from the addition of an inorganic base
to a compound of the present disclosure. The inorganic base
consists of a metal cation paired with a basic counterion, such as,
for example, hydroxide, carbonate, bicarbonate, or phosphate. The
metal can be an alkali metal, alkaline earth metal, transition
metal, or main group metal. In some embodiments, the metal is
lithium, sodium, potassium, cesium, cerium, magnesium, manganese,
iron, calcium, strontium, cobalt, titanium, aluminum, copper,
cadmium, or zinc.
[0099] In some embodiments, a metal salt is a lithium salt, a
sodium salt, a potassium salt, a cesium salt, a cerium salt, a
magnesium salt, a manganese salt, an iron salt, a calcium salt, a
strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a
copper salt, a cadmium salt, or a zinc salt.
[0100] Acid addition salts can arise from the addition of an acid
to a compound of the present disclosure. In some embodiments, the
acid is organic. In some embodiments, the acid is inorganic. In
some embodiments, the acid is hydrochloric acid, hydrobromic acid,
hydroiodic acid, nitric acid, nitrous acid, sulfuric acid,
sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid,
salicylic acid, tartaric acid, ascorbic acid, gentisinic acid,
gluconic acid, glucuronic acid, saccharic acid, formic acid,
benzoic acid, glutamic acid, pantothenic acid, acetic acid,
propionic acid, butyric acid, fumaric acid, succinic acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, citric acid, oxalic acid, or maleic
acid.
[0101] In some embodiments, the salt is a hydrochloride salt, a
hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite
salt, a sulfate salt, a sulfite salt, a phosphate salt,
isonicotinate salt, a lactate salt, a salicylate salt, a tartrate
salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a
glucuronate salt, a saccharate salt, a formate salt, a benzoate
salt, a glutamate salt, a pantothenate salt, an acetate salt, a
propionate salt, a butyrate salt, a fumarate salt, a succinate
salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt,
a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt,
an oxalate salt , or a maleate salt.
Solution, Emulsion, or Suspension
[0102] Provided herein are solutions, emulsions, or suspensions of
a therapeutic agent and a preservative. In some embodiments,
provided herein are compositions comprising a therapeutically
effective amount of any compound or salt of any one of the
preservatives and/or therapeutic agents of the present disclosure.
in some embodiments, a therapeutic solution, emulsion, or
suspension may be used in any of the methods described herein. The
solution, emulsion, or suspension may additionally comprise one or
more pharmaceutically acceptable excipients.
[0103] In some embodiments, a compound of preservative and/or
therapeutic agent may be used for the treatment of a therapeutic
disorder such as, dry eye, bacterial infection, glaucoma,
hypertension, inflammation, allergic conjunctivitis, hypotrichosis
of the eyelashes, fungal infection, etc. Additionally, or
alternatively, a compound of a preservative and/or therapeutic
agent may be used during a preventative, diagnostic, or therapeutic
ophthalmological procedure, for example, local anesthetic, pupil
dilation, etc. A formulation administered to the eye may be
administered topically, for example, with an eye drop.
[0104] A compound of the therapeutic agent described herein can be
present in a solution, emulsion, or suspension of the present
disclosure at a concentration of, for example, about 500 nanomolar
(nM), about 600 nM, about 700 nM, about 800 nM, about 900 nM, about
1 micromolar (.mu.M), about 2 .mu.M, about 3 .mu.M, about 4 .mu.M,
about 5 .mu.M, about 6 .mu.M, about 7 .mu.M, about 8 .mu.M, about 9
.mu.M, about 10 .mu.M, about 20 .mu.M, about 30 .mu.M, about 40
.mu.M, about 50 .mu.M, about 60 .mu.M, about 70 .mu.M, about 80
.mu.M, about 90 .mu.M, about 100 .mu.M, about 150 .mu.M, about 200
.mu.M, about 250 .mu.M, about 300 .mu.M, about 350 .mu.M, about 400
.mu.M, about 450 .mu.M, about 500 .mu.M, about 550 .mu.M, about 600
.mu.M, about 650 .mu.M, about 700 .mu.M, about 750 .mu.M, about 800
.mu.M, about 850 .mu.M, about 900 .mu.M, about 1 mM, about 5 mM,
about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM,
about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM,
about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM,
about 85 mM, about 90 mM, about 95 mM, or about 100 millimolar
(mM). The compound of a therapeutic agent described herein may be
present in a solution, emulsion, or suspension within a range of
concentrations, the range being defined by an upper and lower value
selected from any of the preceding concentrations. For example, the
compound or salt of a therapeutic agent of the disclosure may be
present in the solution, emulsion, or suspension at a concentration
of from about 1 nM to about 100 mM, about 10 nM to about 10 mM,
about 100 nM to about 1 mM, about 500 nM to about 1 mM, about 1 mM
to about 50 mM, about 10 mM to about 40 mM, about 20 mM to about 35
mM, or about 20 mM to about 30 mM.
[0105] In some embodiments, a solution, emulsion, or suspension
such as an aqueous solution of the disclosure, comprises from about
0.001 weight percent (wt %) to about 0.3 wt % of the compound of
any one of the preservatives disclosed herein. In some embodiments,
a solution, emulsion, or suspension such as an aqueous solution of
the disclosure, comprises about 0.001 wt %, about 0.002 wt %, about
0.003 wt %, about 0.004 wt %, about 0.005 wt %, about 0.006 wt %,
about 0.007 wt %, about 0.008 wt %, about 0.009 wt %, about 0.01 wt
%, about 0.02 wt %, about 0.03 wt %, about 0.04 wt %, about 0.05 wt
%, about 0.06 wt %, about 0.07 wt %, about 0.08 wt %, about 0.09 wt
%, about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %,
about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %,
about 0.9 wt %, about 1 wt %, about 1.1 wt %, about 1.2 wt %, about
1.3 wt %, about 1.4 wt %, about 1.5 wt %, about 1.6 wt %, about 1.7
wt %, about 1.8 wt %, about 1.9 wt %, about 2 wt %, about 3 wt %,
about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt
%, about 9 wt %, or about 10 wt % of a compound of the preservative
described herein.
[0106] The preservative described herein can be present in a
solution, emulsion, or suspension of the present disclosure at a
concentration of, for example, about 500 nM, about 600 nM, about
700 nM, about 800 nM, about 900 nM, about 1 .mu.M, about 2 .mu.M,
about 3 .mu.M, about 4 .mu.M, about 5 .mu.M, about 6 .mu.M, about 7
.mu.M, about 8 .mu.M, about 9 .mu.M, about 10 .mu.M, about 20
.mu.M, about 30 .mu.M, about 40 .mu.M, about 50 .mu.M, about 60
.mu.M, about 70 .mu.M, about 80 .mu.M, about 90 .mu.M, about 100
.mu.M, about 150 .mu.M, about 200 .mu.M, about 250 .mu.M, about 300
.mu.M, about 350 .mu.M, about 400 .mu.M, about 450 .mu.M, about 500
.mu.M, about 550 .mu.M, about 600 .mu.M, about 650 .mu.M, about 700
.mu.M, about 750 .mu.M, about 800 .mu.M, about 850 .mu.M, about 900
.mu.M, about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20
mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45
mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70
mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95
mM, or about 100 mM. The compound of a preservative described
herein may be present in a composition within a range of
concentrations, the range being defined by an upper and lower value
selected from any of the preceding concentrations. For example, the
compound of a preservative of the disclosure may be present in the
solution, emulsion, or suspension at a concentration of from about
1 nM to about 100 mM, about 10 nM to about 10 mM, about 100 nM to
about 1 mM, about 500 nM to about 1 mM, about 1 mM to about 50 mM,
about 10 mM to about 40 mM, about 20 mM to about 35 mM, or about 20
mM to about 30 mM.
[0107] Solutions, emulsions, or suspensions of the disclosure can
be formulated at any suitable pH. In some embodiments, the pH of
the solution emulsion or suspension is about 4, about 4.05, about
4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35,
about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about
4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9,
about 4.95, about 5, about 5.1, about 5.2, about 5.3, about 5.4,
about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6,
about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6,
about 6.7, about 6.8, about 6.9, about 7, about 7.1, about 7.2,
about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8,
about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4,
about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9
pH units. In some embodiments, the pH of the solution, emulsion, or
suspension is from about 4 to about 10, about 5 to about 9, about 6
to about 8, about 6.5 to about 8, about 6 to about 7, about 6.2 to
about 7.4, about 6.2 to about 7.8, about 6.3 to about 7.5, or about
6.75 to about 7.1. In some embodiments the pH of the solution,
emulsion, or suspension is about 6.9.
[0108] In some embodiments, solutions, emulsions, or suspensions of
the present disclosure further comprise one or more physiologically
acceptable carriers including excipients and auxiliaries which
facilitate processing of the pharmaceutical agent into preparations
which are used pharmaceutically. Proper formulation is dependent
upon the route of administration chosen.
[0109] In some embodiments, the addition of an excipient to a
pharmaceutical formulation of the present disclosure can increase
or decrease the viscosity of the composition by at least 5%, at
least 10%, at least 15%, at least 20%, at least 25%, at least 30%,
at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80%, at least 85%, at least 90%, at least 95%, or at least
99%. In some embodiments, the addition of an excipient to a
pharmaceutical formulation of the present disclosure can increase
or decrease the viscosity of the composition by no greater than 5%,
no greater than 10%, no greater than 15%, no greater than 20%, no
greater than 25%, no greater than 30%, no greater than 35%, no
greater than 40%, no greater than 45%, no greater than 50%, no
greater than 55%, no greater than 60%, no greater than 65%, no
greater than 70%, no greater than 75%, no greater than 80%, no
greater than 85%, no greater than 90%, no greater than 95%, or no
greater than 99%. Examples of ranges which the viscosity change
falls within can be created by combining any two of the preceding
percentages. For example, the addition of an excipient can increase
or decrease the viscosity of the composition by 5% to 99%, by 10%
to 95%, by 20% to 70% or by 35% to 55%.
[0110] In some embodiments, solutions, emulsions, or suspensions of
the present disclosure further comprise an agent for adjusting the
osmolarity of the solution, emulsion, or suspension, e.g.,
mannitol, sodium chloride, sodium sulfate, dextrose, potassium
chloride, glycerin, propylene glycol, calcium chloride, and
magnesium chloride. In some embodiments, the solution, emulsion, or
suspension comprises from about 0.1 wt % to about 10 wt %, about
0.5 wt % to about 8 wt %, about 1 wt % to about 5 wt %, about 1 wt
% to about 4 wt %, or about 1 wt % to about 3 wt % of an agent for
adjusting the osmolarity of the solution, emulsion, or suspension.
In some embodiments, the solution, emulsion, or suspension of the
disclosure has an osmolarity from about 10 milliosmoles (mOsm) to
about 1000 mOsm, about 100 mOsm to about 700 mOsm, about 200 mOsm
to about 400 mOsm, about 200 mOsm to about 300 mOsm or even about
250 mOsm to about 310 mOsm. In some embodiments, the osmolality is
about 270 mOsm.
[0111] The amount of the excipient in a solution, emulsion, or
suspension of the present disclosure can be about 0.01%, about
0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about
0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about
0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%,
about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%,
about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%,
about 8%, about 9%, about 10%, about 15%, about 20%, about 25%,
about 30%, about 35%, about 40%, about 45%, about 50%, about 55%
about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,
about 90%, about 95%, about 99%, or about 100% by mass or by volume
of the unit dosage form. The amount of the excipient in a solution,
emulsion, or suspension can be between 0.01% and 1000%, between
0.02% and 500%, between 0.1% and 100%, between 1% and 50%, between
0.01% and 1%, between 1% and 10%, between 10% and 100%, between 50%
and 150%, between 100% and 500%, or between 500% and 1000% by mass
or by volume of the unit dosage form.
[0112] The ratio of a compound of a therapeutic agent of the
present disclosure to an excipient in a pharmaceutical formulation
of the present disclosure can be about 100 : about 1, about 95 :
about 1, about 90 : about 1, about 85 : about 1, about 80 : about
1, about 75 : about 1, about 70 : about 1, about 65 : about 1,
about 60 : about 1, about 55 : about 1, about 50 : about 1, about
45 : about 1, about 40 : about 1, about 35 : about 1 about 30 :
about 1, about 25 : about 1, about 20 : about 1, about 15 : about
1, about 10 : about 1, about 9 : about 1, about 8 : about 1, about
7 : about 1, about 6 : about 1, about 5 : about 1, about 4 : about
1, about 3 : about 1, about 2 : about 1, about 1 : about 1, about 1
: about 2, about 1 : about 3, about 1 : about 4, about 1 : about 5,
about 1 : about 6, about 1 : about 7, about 1 : about 8, about 1 :
about 9, or about 1 : about 10. The ratio of a compound of a
therapeutic agent to an excipient in a solution, emulsion, or
suspension of the present disclosure can be within the range of
between about 100: about 1 and about 1 to about 10, between about
10: about 1 and about 1: about 1, between about 5: about 1 and
about 2: about 1.
[0113] Pharmaceutically acceptable carriers are well known in the
art and include, for example, aqueous solutions such as water or
physiologically buffered saline or other solvents or vehicles such
as glycols, glycerol, oils such as olive oil, or organic esters.
The excipients can be chosen, for example, to effect delayed
release of an agent or to selectively target one or more cells,
tissues or organs. The composition can also be present in a
solution suitable for topical administration, such as an eye
drop.
[0114] Pharmaceutically acceptable stabilizers present in the
solution, emulsion, or suspension may comprise one or more of the
following: sodium thiosulfate pentahydrate (or any other salt or
hydrate of thiosulfate), sodium iodide (or any other salt or
hydrate of iodide), sodium sulfate (or any other salt or hydrate of
sulfate), or xanthan gum.
[0115] In some embodiments, the solution emulsion or suspension
provided herein comprises an alcohol as an excipient. Non-limiting
examples of alcohols include ethanol, propylene glycol, glycerol,
polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol,
maltitol, erythritol, threitol, arabitol, ribitol, mannitol,
galactilol, fucitol, lactitol, and combinations thereof.
[0116] Methods for the preparation of compositions comprising the
compounds described herein can include formulating the compounds
with one or more inert, pharmaceutically-acceptable excipients.
Liquid compositions include, for example, solutions in which a
compound is dissolved, emulsions comprising a compound, or a
solution containing liposomes, micelles, or nanoparticles
comprising a compound as disclosed herein. These compositions can
also contain minor amounts of nontoxic, auxiliary substances, such
as wetting or emulsifying agents, pH buffering agents, and other
pharmaceutically-acceptable additives.
EXAMPLES
Example 1: 20/80 Polypropylene Stearic acid Blend
[0117] A blend was made with isotactic Polypropylene from Sigma
Aldrich (Lot MKCH9443) avg MW-250,000 and 97% Stearic acid from
Acros Organics (Lot A0404313). A 20/80 weight to weight (w/w) blend
was made by adding 2.0 grams (g) of Polypropylene to 8.0 g of
Stearic acid in a 20 milliliters (mL) scintillation vial. This was
slowly heated while stirring. The viscosity of the mixture allowed
it to be poured into cool, stirred water. Water was decanted and
the material placed under vacuum to dry. The material was then
crushed in a grinder and sieved to <500 micron (.mu.m)
particles. BAK uptake was initially tested by adding 0.2 g of
powder to 5 mL of 1000 parts per million (ppm) United States
Pharmacopeia grade BAK solution. This was stirred for 2 days,
filtered, and analyzed by high performance liquid chromatography
(HPLC) to calculate a BAK partition coefficient of 350 for this
material. Labeled: 2NB78A in the tables herein.
[0118] A Timolol Maleate/Brimonidine tartrate ophthalmic solution
was prepared (e.g., 2NB62, a Combigan analogue, etc) according to
Table 5. The following were added to a 500 mL bottle: 2.151 g of
Sodium Phosphate dibasic heptahydrate (Fisher Chemical L# 187384),
0.432 g of Sodium Phosphate monobasic monohydrate (Fisher Chemical
L#188731), 0.505 g of 0.991% BAK solution (Lot 2NB61), 0.202 g of
Brimonidine Tartrate (BOC Sciences L# BV19V06171), and 0.681 g of
Timolol Maleate (BOC Sciences L# BS19V04062). Ultra-pure water
(100.017 g) of was added and stirred on a rotary shaker overnight
to dissolve. Three mL of the solution, 2NB62, was placed into a 5
mL dropper bottle. Stearic acid/polypropylene powder (0.32 g) was
loaded into a proprietary testing tip. The tip was then placed on
the dropper bottle containing the solution.
TABLE-US-00005 TABLE 5 Timolol Maleate/Brimonidine tartrate
ophthalmic solution TC-Combigan 2NB62 Ingredient Conc % (w/v)
Brimonidine Tartrate 0.2 Timolol Maleate 0.68 BAK (70/30
C12/C14)339.992/368.046 0.005 Sodium Phosphate monobasic
monohydrate 0.43 Sodium Phosphate dibasic heptahydrate 2.15 Sodium
hydroxide Hydrochloric acid mOsm (Total Ionization) pH measured 6.9
mOsm Measured (Vapro 5520) 272
[0119] In a simulated usage, two drops are dispensed and diluted
according to the proper method for HPLC analysis. Additional pairs
of drops are dispensed at intervals no less than 1 hour (hr) apart.
A standard consisting of the starting material is taken and diluted
according to the specific HPLC method. Then each individual drop is
analyzed on the HPLC. The uptake is determined by comparing the
area counts from the HPLC peaks of the starting solution to the
area counts of the drop. Results show (Table 6) that neither the
concentration of Timolol nor Brimonidine are significantly affected
from passing through the powder in the tip.
TABLE-US-00006 TABLE 6 Timolol Maleate/Brimonidine tartrate API
uptake test Timolol Brimonidine Sample Drop Timolol % Brimonidine %
Drops Date and ppm/area counts Description Sample # # Uptake Uptake
mass (g) Time counts ppm/area Combigan 2NB62 158887.0 115132.5
Mimic pH 6.9 20/80 2NB78A 1 2% 2% 0.0821 Oct. 3, 2019 154924.5
113302.5 Polypropylene/ 9:30 Stearic Acid 2 2% 2% 0.0849 Oct. 3,
2019 156203.0 112807.5 Melt 10:30 <500 .mu.m 3 2% 2% 0.0803 Oct.
3, 2019 155159.0 112309.5 particle size 11:30 4 2% 2% 0.0724 Oct.
3, 2019 155777.5 112658.5 12:30 5 1% 2% 0.0814 Oct. 3, 2019
156526.0 112971.5 13:30 6 2% 2% 0.0862 Oct. 3, 2019 156382.5
113301.0 14:30 8 3% 2% 0.0798 Oct. 4, 2019 153459.0 112416.0 10:30
9 2% 2% 0.0805 Oct. 4, 2019 155739.0 113253.0 11:30
[0120] A separate, parallel drop test was performed using the same
materials to test BAK uptake. The separate drop test was performed
since the dilution and UV signal strength are vastly different. In
the data below (Table 7) only the first drop contains about 5% of
the starting BAK. In successive drops, the BAK is not detected
(e.g., is undetectable, is below a detectable threshold based on UV
absorption, etc.).
TABLE-US-00007 TABLE 7 Timolol Maleate/Brimonidine tartrate BAK
uptake test Sample Drop BAK C-12 BAK C-14 Drops ACN Description
Sample # Number remaining remaining mass (g) weight Combigan Mimic.
Right 2NB62 Starting: Starting: phosphate buffers 35 ppm 15 ppm
20/80 Polypropylene/Stearic 2NB78A 1 8% 3% 0.0744 0.0744 Acid Melt
Blend <500 .mu.m 2 0% 0% 0.0725 0.0722 3 0% 0% 0.0827 0.0824 4
0% 0% 0.0569 0.0594 5 0% 0% 0.0838 0.0837 6 0% 0% 0.086 0.086 7 0%
0% 0.085 0.0855
Example 2: Recrystallized Stearic acid
[0121] 15 g of 97% stearic acid (Acros organics Lot# A0404313) was
added to 300 mL of acetone and heated to 40.degree. C. to dissolve.
The solution was allowed to cool to room temperature as stearic
acid crystallized out of solution. The solution was refrigerated
for two hours to complete. The stearic acid formed flakes that were
removed by filtration. The recrystallized stearic acid was dried at
room temperature under vacuum overnight.
[0122] Bimatoprost ophthalmic solution (20 mL) was formulated by
combining 0.0027 g of Citric Acid Anhydrous (Alfa Aesar L#
X16D073), 0.0536 g of Sodium phosphate dibasic, heptahydrate
(Fisher chemical L# 187384) and 0.1619 g of Sodium Chloride (Fisher
chemical L# 177082) to 20 g stock solution (2NB70.1) of 300 ppm
Bimatoprost and 50 ppm BAK.
[0123] Bimatoprost formulation (3 mL), was placed into a 5 mL
dropper bottle. Recrystallized Stearic acid flakes (0.116 g) was
loaded into a proprietary testing tip. The tip was then placed on
the dropper bottle containing the solution.
[0124] In a simulated usage, two drops are dispensed and diluted
according to the proper method for HPLC analysis. Additional pairs
of drops are dispensed at intervals no less than 1 hour apart. A
standard consisting of the starting material is taken and diluted
according to the specific HPLC method. Then each pair of drops was
analyzed on the HPLC. The uptake is determined by comparing the
area counts of the starting solution to the area counts of the
drop. Bimatoprost has a similar linear signal range as BAK in this
formulation so all data is collected from a single drop test.
Results (Table 8) show that Bimatoprost is not significantly
reduced while BAK is eliminated from passing through the
recrystallized stearic acid flakes. In successive drops, the BAK is
not detected (e.g., is undetectable, is below a detectable
threshold based on UV absorption, etc.).
TABLE-US-00008 TABLE 8 Bimatoprost API/BAK uptake test Brimonidine
BAK BAK Date BAK BAK Sample % C-12 C-14 Drops CAN and Bimatopropst
C-12 area C-14 area Description Sample # Drop # Uptake remaining
remaining mass (g) weight Time Area count count count Bimatoprost
2NB76 616041 47926 18306 mimic proper buffer 300 ppm and 50 ppm BAK
(from 2NB70.1) Recrystallized 2NB77 1 -4% 1% 0% 0.0651 0.0651 Sep.
27, 2019 641157 2846 0 Stearic Acid 9:45 Tip mass: 2 3% 0% 0%
0.0700 0.0700 Sep. 27, 2019 398907 0 0 0.116 g 10:45 3 -3% 0% 0%
0.0550 0.0550 Sep. 27, 2019 641620 0 0 11:45 4 -5% 0% 0% 0.0620
0.0620 Sep. 27, 2019 642164 0 0 13:45 5 0% 0% 0% 0.0705 0.0705 Sep.
27, 2019 613921 0 0 14:45 6 -2% 0% 0% 0.0736 0.0736 Sep. 27, 2019
623469 0 0 15:45 7 2% 0% 0% 0.0595 0.0595 Sep. 30, 2019 605200 0 0
14:20 8 0% 0% 0% 0.0733 0.0733 Sep. 30, 2019 608248 0 0 15:20 9 1%
0% 0% 0.0752 0.0752 Sep. 30, 2019 604491 0 0 16:20 10 -1% 0% 0%
0.0725 0.0734 Oct. 1, 2019 613257 0 0 8:00 11 1% 0% 0% 0.0619
0.0619 Oct. 1, 2019 609290 0 0 9:00
Example 3: 50/50 Polypropylene Stearic acid Blend
[0125] In a 20 mL Scintillation vial, 5.0 g of Polypropylene
Isotactic Mw 250000 Aldrich 427888 lot MKCH9443) was combined with
5.0 g of 97% Stearic acid from Acros (Lot A0404313). This mixture
was heated to a melt while stirring. Mixing was difficult due to
the viscosity. The material was spatulated into water. Due to high
viscosity it could not be poured. This material was removed from
the water and briefly dried in a vacuum for 2 hours. This was
placed into a rotary blade grinder and reduced to powder. The
resulting material was sieved to 63-500m.
[0126] A Lifitegrast ophthalmic solution (e.g., Xiidra mimic in the
table) was prepared, consisting of 5.0% Lifitegrast (BOC Sciences
Lot B19V08071), 2.0% Sodium Phosphate Dibasic Anhydrous (J.T. Baker
Lot 0000236665), 0.5% Sodium thiosulfate pentahydrate (Fisher
Chemical Lot 181801), and 0.005% BAK Aldrich 12063 (Lot
#BCBW4741).
[0127] Three mL of the Lifitegrast formulation was placed into a 5
mL dropper bottle. 50/50 polypropylene/steric acid blend (0.328 g)
was loaded into a proprietary testing tip. The tip was then placed
on the dropper bottle containing the solution.
[0128] In a simulated usage, two drops are dispensed and diluted
according to the proper method for HPLC analysis. Due to the
relatively high concentration of Lifitegrast, 2 separate drops
tests were done for the active pharmaceutical ingredient and BAK. A
standard consisting of the starting material is taken and diluted
according to the specific HPLC method. Then each pair of drops was
analyzed on the HPLC. The uptake is determined by comparing the
area counts of the HPLC peaks of the starting solution to the area
counts of the drop.
TABLE-US-00009 TABLE 9 Lifitegrast API uptake test Lifitegrast
Lifitegrast Sample Drop Lifitegrast % (2) Drops Date and Area Area
Description Sample # Number Uptake mass (g) Time Tip Mass counts #1
counts #1 Xiidra Mimic: 2NB84D 1223094 1229995 2% Na.sub.2PO.sub.4
0.05% Na.sub.2S.sub.2O.sub.3 50 ppm BAK mOsm-415 50/50 PP/SA 2TC69
1 0% 0.0672 Nov. 4, 2019 0.328 1211452 1212829 63-500 .mu.m 8:35 2
1% 0.0755 Nov. 4, 2019 1199836 1202356 9:35 3 1% 0.0711 Nov. 4,
2019 1202471 1204737 10:35 4 0% 0.0723 Nov. 4, 2019 1209839 1211933
11:35 5 0% 0.0716 Nov. 4, 2019 1211852 1210927 12:35 6 0% 0.0706
Nov. 4, 2019 1211335 1211229 13:35
TABLE-US-00010 TABLE 10 Lifitegrast BAK uptake test Sample BAK C-12
BAK C-14 (2) Drops ACN Date and BAK C-12 BAK C-14 Description
Sample # Drop # remaining remaining mass (g) weight Time area count
area count Xiidra Mimic: 2NB84D Starting: Starting: 39466 18427 2%
Na.sub.2PO.sub.4 35 ppm 15 ppm 0.05% Na.sub.2S.sub.2O.sub.3 50 ppm
BAK mOsm-415 50/50 PP/SA 63-500 .mu.m 2TC69 1 33% 19% 0.0586 0.0579
Oct. 31, 2019 13234 3610 10:00 2 3% 0% 0.0690 0.0691 Oct. 31, 2019
1102 0 11:00 3 0% 0% 0.0692 0.0692 Oct. 31, 2019 0 0 12:00 4 0% 0%
0.0693 0.0693 Oct. 31, 2019 0 0 13:00 5 0% 0% 0.0634 0.0638 Oct.
31, 2019 0 0 14:00 6 0% 0% 0.0625 0.0645 Oct. 31, 2019 0 0
15:00
[0129] In the HPLC data (Table 9 and 10) it can be seen that the
Lifitegrast was not hindered while only a small amount of BAK came
through on the first drop only and was not detectable in later
drops. After the first drop, the BAK is not detected (e.g., is
undetectable, is below a detectable threshold based on comparison
of the area counts of the HPLC peaks of the starting solution to
the area counts of the drop, etc.).
[0130] All patents, patent applications, provisional applications,
and publications referred to or cited herein are incorporated by
reference in their entirety, including all figures and tables, to
the extent they are not inconsistent with the explicit teachings of
this specification.
[0131] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application.
[0132] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. It is not intended that the invention be limited by
the specific examples provided within the specification. While the
invention has been described with reference to the aforementioned
specification, the descriptions and illustrations of the
embodiments herein are not meant to be construed in a limiting
sense. Numerous variations, changes, and substitutions will now
occur to those skilled in the art without departing from the
invention. Furthermore, it shall be understood that all aspects of
the invention are not limited to the specific depictions,
configurations or relative proportions set forth herein which
depend upon a variety of conditions and variables. It should be
understood that various alternatives to the embodiments of the
disclosure described herein may be employed in practicing the
invention. It is therefore contemplated that the invention shall
also cover any such alternatives, modifications, variations or
equivalents. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
* * * * *