U.S. patent application number 11/346770 was filed with the patent office on 2010-05-27 for contact drug delivery system.
Invention is credited to Mark E. Byrne, Siddarth Venkatesh.
Application Number | 20100129424 11/346770 |
Document ID | / |
Family ID | 36778036 |
Filed Date | 2010-05-27 |
United States Patent
Application |
20100129424 |
Kind Code |
A9 |
Byrne; Mark E. ; et
al. |
May 27, 2010 |
Contact drug delivery system
Abstract
A drug delivery system is disclosed. The drug delivery system
includes a recognitive polymeric hydrogel through which a drug is
delivered by contacting biological tissue. The recognitive
polymeric hydrogel is formed using a bio-template, which is a drug
or is structurally similar to the drug, functionalized monomers,
preferably having coamplexing sites, and cross-linking monomers,
which are copolymerized using a suitable initiator. The complexing
sites of the recognitive polymeric hydrogel that is formed
preferably mimics receptor sites of a target biological tissue,
biological recognition, or biological mechanism of action. The
system in accordance with an embodiment of the intention is a
contact lens for delivering a drug through contact with an eye.
Inventors: |
Byrne; Mark E.; (Auburn,
AL) ; Venkatesh; Siddarth; (Auburn, AL) |
Correspondence
Address: |
HAVERSTOCK & OWENS LLP
162 N WOLFE ROAD
SUNNYVALE
CA
94086
US
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Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20060177483 A1 |
August 10, 2006 |
|
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Family ID: |
36778036 |
Appl. No.: |
11/346770 |
Filed: |
February 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60692049 |
Jun 17, 2005 |
|
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60736140 |
Nov 10, 2005 |
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60650450 |
Feb 4, 2005 |
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Current U.S.
Class: |
424/427 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61L 27/52 20130101; A61L 2300/426 20130101; A61P 27/06 20180101;
A61P 27/14 20180101; A61L 2300/41 20130101; A61L 27/54 20130101;
A61L 2300/602 20130101; B29K 2105/0035 20130101; A61L 2300/452
20130101; A61K 9/0051 20130101; A61L 2300/402 20130101; G02B 1/043
20130101; B29L 2011/0041 20130101; A61L 2300/406 20130101; A61P
27/02 20180101; A61P 3/04 20180101 |
Class at
Publication: |
424/427 |
International
Class: |
A61F 2/00 20060101
A61F002/00 |
Claims
1. A method for making a drug delivery system, the method
comprising: a) forming a recognitive polymeric hydrogel; and b)
forming a recognitive polymeric hydrogel into contact lenses.
2. The method of claim 1, wherein forming a recognitive polymeric
hydrogel comprises forming a solution comprising amounts of a
bio-template, a functionalized monomer cross-linking monomer and
initiating copolymerization of the functionalized monomer and
cross-linking monomer.
4. The method of claim 2, further comprising washing a portion of
the bio-template from the recognitive polymeric hydrogel and
loading the recognitive polymeric hydrogel with a drug.
5. The method of claim 4, wherein the drug is selected from the
group consisting of an antibiotic, an anti-inflammatory, an
antihistamine, an antiviral agent, a cancer drug, an anesthetic, a
cycloplegic, a mydriatics, a lubricant agent, a hydrophilic agent,
a decongestant, a vasoconstrictor, vasodilater, an
Immuno-suppressant, an immuno-modulating agent and an anti-glaucoma
agent.
6. The method of claim 2, further comprising washing a portion of
the bio-template from the contact lenses and loading the contact
lenses with a drug by soaking the contact lenses in an aqueous drug
solution.
7. The method of claim 6, wherein the drug a drug selected from the
group consisting of an antibiotic, an anti-inflammatory, an
antihistamine, an antiviral agent, a cancer drug, an anesthetic, a
cycloplegic, a mydriatics, a lubricant agent, a hydrophilic agent,
a decongestant, a vasoconstrictor, vasodilater, an
Immuno-suppressant, an immuno-modulating agent and an anti-glaucoma
agent.
8. The method of claim 2, wherein the bio-template is a drug.
9. The method of claim 8, wherein the drug is selected from the
group consisting of an antibiotic, an anti-inflammatory, an
antihistamine, an antiviral agent, a cancer drug, an anesthetic, a
cycloplegic, a mydriatics, a lubricant agent, a hydrophilic agent,
a decongestant, a vasoconstrictor, vasodilater, an
Immuno-suppressant, an immuno-modulating agent and an anti-glaucoma
agent.
10. The method of claim 2, further comprising identifying molecules
associated with a target biological tissue and synthesizing the
functionalized monomer with functional groups that are structurally
similar the molecules.
11. A method of dispensing a drug comprising: a) forming a
recognitive polymeric hydrogel matrix impregnated with a drug; and
b) placing the recognitive polymeric hydrogel is contact with a
biological tissue to dispense the drug.
12. The method of claim 11, wherein the drug is selected from the
group consisting of an antibiotic, an anti-inflammatory, an
antihistamine, an antiviral agent, a cancer drug, an anesthetic, a
cycloplegic, a mydriatics, a lubricant agent, a hydrophilic agent,
a decongestant, a vasoconstrictor, vasodilater, an
Immuno-suppressant, an immuno-modulating agent and an anti-glaucoma
agent.
13. The method of claim 11, wherein forming the recognitive
polymeric hydrogel matrix comprises generating a solution
comprising amounts of a bio-template, a functionalized monomer
cross-linking monomer and initiating co-polymerization of the
functionalized monomer and cross-linking monomer.
14. The method of claim 13, wherein forming the recognitive
polymeric hydrogel matrix is a contact lens.
15. The method of claim 13, wherein the bio-template is a drug.
16. The method of claim 15, wherein the drug is selected from the
group consisting of an antibiotic, an anti-inflammatory, an
antihistamine, an antiviral agent, a cancer drug, an anesthetic, a
cycloplegic, a mydriatics, vasodilater, a lubricant agent, a
hydrophilic agent, a decongestant, a vasoconstrictor, an
immuno-suppressant, an immuno-modulating agent and an anti-glaucoma
agent.
17. The method of claim 11, further comprising reloading the
recognitive polymeric hydrogel matrix with the drug by soaking the
recognitive polymeric hydrogel matrix in an aqueous solution of the
drug.
18. A drug delivery system comprising a contact lens, the contact
lens comprising a hydrogel matrix with complexing sites that
complex a drug and release the drug from the hydrogel matrix over
time while in contact with a surface of an eye.
19. The drug delivery system of claim 18, wherein the hydrogel
matrix comprises silicon-base polymer chains.
20. The drug delivery system of claim 18, wherein the complexing
sites comprise amino acid functional groups.
21. The drug delivery system of claim 18, wherein the group
consisting of an antibiotic, an anti-inflammatory, an
antihistamine, an antiviral agent, a cancer drug, an anesthetic, a
cycloplegic, a mydriatics, a lubricant agent, a hydrophilic agent,
a decongestant, a vasoconstrictor, vasodilater, an
Immuno-suppressant, an immuno-modulating agent and an anti-glaucoma
agent.
22. The drug delivery system of claim 18, wherein the drug is
Ketotifen.
Description
RELATED APPLICATIONS
[0001] This application claims the priority under 35 U.S.C.
.sctn.119(e) of the co-pending U.S. Provisional Application Ser.
No. 60/692,042, titled Sustained Ophthalmic Drug Delivery Via
Biomimetic Recognitive Contact Lens", filed Jun. 17, 2005, the U.S.
Provisional Application Ser. No. 60/736,140, titled "Sustained
Ophthalmic Drug Delivery Via Biomimetic Recognitive Contact Lens",
filed Nov. 10, 2005, and the U.S. Provisional Application Ser. No.
60/650,450, titled "Enhanced Loading and Extended Release Contact
Lens for Histamine Antagonist Drug Ketotifen", filed Feb. 4, 2005,
all of which are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to drug delivery systems. More
specifically, this invention relates to systems for and method of
time released ophthalmic drug delivery using contact lenses.
BACKGROUND OF THE INVENTION
[0003] Delivering medications via contact lenses has been a
prevailing notion since the inception of using hydrophilic,
crosslinked polymer gels on the surface of the eye. In fact, the
first patent in the field from Otto Wichterle in 1965 states that
"bacteriostatic, bacteriocidal or otherwise medicinally active
substances such as antibiotics may be dissolved in the aqueous
constituent of the hydrogels to provide medication over an extended
period, via diffusion." However, there is evidence that this notion
of a dissolved component in an aqueous constituent has been around
for a much longer period of time. Evidence exists that honey soaked
linen was used in ancient Rome as an ophthalmic dressing in the
treatment of disease.
[0004] The biggest obstacle to using the fluid entrained in the
aqueous portion of the polymer gel is maintaining a significant
concentration of drug within the fluid to have a therapeutically
relevant effect, which is ultimately limited by the solubility of
the drug. This has been the primary reason why drug release from
contact lenses has not become a clinical or commercial success. To
an equivalent extent, the control over the drug delivery profile
and an extended release profile is also important to therapeutic
success and has not been demonstrated using these methods. Drug
uptake and release by conventional (i.e., currently available) soft
contact lenses can lead to a moderate intraocular concentration of
drug for a very short period of time, but does not work very well
due to a lack of sufficient drug loading and poor control of
release. The use of soft, biomimetic contact lens carriers (i.e.,
recognitive polymeric hydrogels) described herein has the potential
to greatly enhance ocular drug delivery by providing a significant
designed and tailorable increase in drug loading within the carrier
as well as prolonged and sustained release with increased
bioavailability, less irritation to ocular tissue, as well as
reduced ocular and systemic side effects.
[0005] The ocular bioavailability of drugs applied to the eye is
very poor (i.e., typically less than 1-7% of the applied drug
results in absorption with the rest entering the systemic
circulation). Factors such as ocular protective mechanisms,
nasolacrimal drainage, spillage from the eye, lacrimation and tear
turnover, metabolic degradation, and non-productive
adsorption/absorption, etc., lead to poor drug absorption in the
eye. Currently, more efficient ocular delivery rests on enhancing
drug bioavailability by extending delivery and/or by increasing
drug transport through ocular barriers (e.g., the cornea--a
transparent, dome-shaped window covering the front of the eye; the
sclera--the tough, opaque, white of the eye; and the conjunctiva--a
mucous membrane of the eye with a highly vascularized stroma that
covers the visible part of the sclera). A topically applied drug to
the eye is dispersed in the tear film and can be removed by several
mechanisms such as: [0006] (i) irritation caused by the topical
application, delivery vehicle, or drug which induces lacrimation
leading to dilution of drug, drainage, and drug loss via the
nasolacrimal system into the nasopharynx and systemic circulation
(e.g., the rate drainage increases with volume); [0007] (ii) normal
lacrimation and lacrimal tear turnover (16% of tear volume per
minute in humans under normal conditions); [0008] (iii) metabolic
degradation of the drug in the tear film; [0009] (iv) corneal
absorption of the drug and transport; [0010] (v) conjunctival
absorption of the drug and scleral transport; [0011] (vi)
conjunctival `non-productive` absorption via the highly
vascularized stroma leading to the systemic circulation; and [0012]
(vii) eyelid vessel absorption leading to systemic circulation.
Therefore, due to these mechanisms, a relatively low proportion of
the drug reaches anterior chamber ocular tissue via productive
routes such as mechanisms (iv) and (v).
[0013] For posterior eye tissue and back of the eye diseases (e.g.,
age-related macular degeneration, retinal degeneration, diabetic
retinopathy, glaucoma, retinitis pigmentosa, etc.), the amount of
drug delivered can be much less compared to front of the eye
disease. To treat back of the eye disease, four approaches have
typically been used, topical, oral (systemic delivery),
intraocular, and periocular delivery.
[0014] Topically applied drugs diffuse through the tear film,
cornea/sclera, iris, ciliary body, and vitreous before reaching
posterior tissues, but due to the added transport resistances do
not typically lead to therapeutically relevant drug concentrations.
However, researchers have shown that topically applied drugs do
permeate through the sclera by blocking corneal absorption and
transport. Intravitreal injections (injections into the eye)
require repeated injections and have potential side effects
(hemorrhage, retinal detachment, cataract, etc.) along with low
patient compliance. Extended release devices have been used but
require intraocular surgery and often have the same incidence of
side effects. Periocular drug delivery is less invasive and also
requires injections or implant placement for predominantly
transscleral delivery.
[0015] To overcome most of these protective mechanisms, topical
formulations have remained effective by the administration of very
high concentrations of drug multiple times on a daily basis. For a
number of drugs high concentrations can lead to negative effects
such as burning, itching sensations, gritty feelings, etc., upon
exposure of the medication to the surface of the eye as well as
increased toxicity and increased ocular and systemic side effects.
However, traditional ophthalmic dosage forms such as solutions,
suspensions, and ointments account for 90% of commercially
available formulations on the market today. Solutions and
suspensions (for less water soluble drugs) are most commonly used
due to the ease of production and the ability to filter and easily
sterilize. Ointments are used to much lesser extent due to vision
blurring, difficulty in applying to the ocular surface, and
greasiness. The term "eye drops" herein is meant to refer to all
topological medications administered to a surface of the eye
including but not limited to solutions, suspensions, ointments and
combination thereof. In addition to the aforementioned problems,
drug delivery through the use of eye drops does not provide for
controlled time release of the drug. Eye drops medications
typically have a low residence time of the drug on the surface of
the eye.
[0016] The efficacy of topical solutions has been improved by
viscosity enhancers that increase the residence time of drugs on
the surface of the eye, which ultimately lead to increased
bioavailability as well as more comfortable formulations. Also,
inclusion complexes have been used for poorly soluble drugs, which
increase solubility without affecting permeation.
[0017] Other recent delivery methods have included in situ
gel-forming systems, corneal penetration or permeation enhancers,
conjunctival muco-adhesive polymers, liposomes, and ocular
inserts.
[0018] Ocular inserts, in some cases, achieve a relatively stable
or constant, extended release of drug. For example, ocular inserts
such as Ocusert.TM. (Alza Corp., FDA approved in 1974) consist of a
small wafer of drug reservoir enclosed by two ethylene-vinyl
acetate copolymer membranes, which is placed in the corner of the
eye and provides extended release of a therapeutic agent for
approximately 7 days (i.e., pilocarpine HCL, for glaucoma treatment
reducing intraocular pressure of the eye by increasing fluid
drainage). Lacrisert (Merck) is a cellulose based polymer insert
used to treat dry eyes. However, inserts have not found widespread
use due to occasional noticed or unnoticed expulsion from the eye,
membrane rupture (with a burst of drug being released), increased
price over conventional treatments, etc.
[0019] Mucoadhesive systems and in-situ forming polymers typically
have problems involving the anchorage of the carrier as well as
ocular irritation resulting in blinking and tear production.
Penentration enhancers may cause transient irritation, alter normal
protection mechanisms of the eye, and some agents can cause
irreversible damage to the cornea.
[0020] The novel soft, biomimetic contact lens carriers proposed in
this work will provide a significant increase in drug loading
within the gel as well as prolonged and sustained release. This
will lead to prolonged drug activity and increased bioavailability,
reduced systemic absorption, reduced ocular and systemic side
effects, and increased patient compliance due to reduced frequency
of medication and reduced irregularity of administration (i.e., eye
drop volume depends on angle, squeeze force, etc., and has been
experimentally verified to be highly variable). They will also be
able to be positioned easily as well as easily removed with or
without use to correct vision impairment. Since they will be
positioned on the cornea, this will lead to enhanced comeal
permeability as well.
SUMMARY OF THE INVENTION
[0021] The present invention is directed to a drug delivery methods
and systems. The drug delivery system includes a recognitive
polymeric hydrogel through which a drug is delivered by contacting
biological tissue. The recognitive polymeric hydrogel is formed
using a bio-template, which is a drug or is structurally similar to
the drug, functionalized monomers, preferably having complexing
sites, and cross-linking monomers, which are copolymerized using a
suitable initiator, such as described in detail below. The
complexing sites of the recognitive polymeric hydrogel that is
formed preferably mimics receptor sites of a target biological
tissue, biological recognition, or biological mechanism of action.
The system unitizes what is referred to herein as a biomimetic
recognitive polymeric hydrogel.
[0022] The system in accordance with an embodiment, the system is
an ophthalmic drug system. The ophthalmic drug system includes soft
contact lenses formed from the biomimetic recognitive polymeric
hydrogel and that are impregnated with a drug that can be release
over a duration of time while in contact with eyes. The invention
is directed to both corrective or refractive contact lenses and
non-corrective or non-refractive contact lenses. While the
invention as described herein refers primarily to ophthalmic drug
systems, it is understood that the present invention has
applications in a number of different contact drug delivery
systems. For example, the biomimetic recognitive polymeric hydrogel
can be used in bandages, dressings, and patch-type drug delivery
systems to name a few.
[0023] In accordance with the embodiments of the invention a
hydrogel matrix that is formed from silicon-based cross-linking
monomers, carbon based or organic-based monomers, macromers or a
combination thereof. Suitable cross-linking monomers include but
are not limited to Polyethylene glycol (200) dimethacrylate
(PEG200DMA), ethylene glycol dimethacrylate (EGDMA),
tetraethyleneglycol dimethacrylate (TEGDMA),
N,N'-Methylene-bis-acrylamide and polyethylene glycol (600)
dimethacrylate (PEG600DMA). Suitable silicon-based cross-linking
monomers can include tris(trimethylsiloxy)silyl propyl methacrylate
(TRIS) and hydrophilic TRIS derivatives such as
tris(trimethylsiloxy)silyl propyl vinyl carbamate (TPVC),
tris(trimethylsiloxy)silyl propyl glycerol methacrylate (SIGMA),
tris(trimethylsiloxy)silyl propyl methacryloxyethylcarbamate
(TSMC); polydimethylsiloxane (PDMS) and PDMS derivatives, such as
methacrylate end-capped fluoro-grafted PDMS crosslinker, a
methacrylate end-capped urethane-siloxane copolymer crosslinker, a
styrene-capped siloxane polymer containing polyethylene oxide and
polypropylene oxide blocks; and siloxanes containing hydrophilic
grafts or amino acid residue grafts, and siloxanes containing
hydrophilic blocks or containing amino acid residue grafts. The
molecular structure of these monomers can be altered chemically to
contain moieties that match amino acid residues or other biological
molecules. In cases where the above monomers, when polymerized with
hydrophilic monomers, a solubilizing cosolvent may be used such as
dimethylsulfoxide (DMSO), isopropanol, etc. or a
protecting/deprotecting group strategy.
[0024] Crosslinking monomer amounts can be from (0.1 to 40%, moles
crosslinking monomer/moles all monomers); Functional monomers,
99.9% to 60% (moles functional monomer/moles all monomers) with
varying relative portions of multiple functional monomers;
initiator concentration ranging from 0.1 to 30 wt %; solvent
concentration ranging from 0% to 50 wt % (but no solvent is
preferred); monomer to bio-template ratio (M/T) ranging from 0.1 to
5,000, preferably 200 to 1,000, with 950 preferred for the
ketotifen polymers presented herein, under an nitrogen or air
environment (in air, the wt % of initiator should be increased
above 10 wt %.
[0025] The ophthalmic drug delivery system also includes a
bio-template, that is drug molecules, prodrugs, protein, amino
acid, proteinic drug, oligopeptide, polypeptide, oligonucleotide,
ribonucleic acid, deoxyribonucleic acid, antibody, vitamin, or
other biologically active compound. This also includes a drug with
an attached bio-template. The bio-template is preferably bound to
the hydrogel matrix through one or more of electrostatic
interactions, hydrogen bonding, hydrophobic interactions,
coordination complexation, and Van der Waals forces.
[0026] Bio-templates are preferably weakly bound to a hydrogel
matrix through functionalized monomer units, macromer units or
oligomer units that are co-polymerized into the hydrogel matrix to
form receptor locations within the hydrogel matrix that resemble or
mimic the receptor sites or molecules associated with the
biological target tissue to be treated with the drug or the
biological mechanism of action
[0027] In accordance with the embodiments of the invention, a
portion of the bio-template can be washed out from the recognitive
hydrogel polymer, loaded with a drug. The polymerization reaction
forms a contact lens. For example, the gel is polymerized in a mold
or compression casting. After contact lenses are formed they can be
used to administer the drug through contact with eyes.
Alternatively, the recognitive hydrogel polymer can be formed into
contact lenses, washed to remove a portion of the bio-template and
then loaded with the drug. Where the bio-template is the drug, the
washing step can be illuminated or truncated. In formulations where
the bio-template is a drug, the free base form of the drug or
hydrochloride salt of the drug can be used.
[0028] In accordance with the method of the present invention, a
biomimetic recognitive polymeric hydrogel is formed by making a
mixture or solution that includes amounts of a bio-template or
drug, functionalized monomer or monomers, cross-linking monomer or
monomers and polymerization initiator in a suitable solvent or
without solvent. Suitable initiators include water and non-water
soluble initiators, but are not limited to azobisisobutyronitrile
(AIBN), 2,2-dimethoxy-2-phenyl acetophenone (DMPA),
1-hydroxycyclohexyl phenyl ketone (Irgacure.RTM. 184),
2,2-dimethoxy-1,2-diphenylethan-1-one (Irgacure 651), ammonium
persulfate, iniferter such as tetraethylthiuram disulfide, or
combinations thereof. The polymerization can be photo-initiated,
thermally-initiated, redox-initiated or a combinations thereof.
[0029] The functionalized monomer or monomers complex with the
bio-template and copolymerize with cross-linking monomer or
monomers to form a biomimetic recognitive polymeric hydrogel, such
as described above. Functional or reactive monomers useful herein
are those which possess chemical or thermodynamic compatibility
with a desired bio-template. As used herein, the term functional
monomer includes moieties or chemical compounds in which there is
at least one double bond group that can be incorporated into a
growing polymer chain by chemical reaction and one end that has
functionality that will interact with the bio-template through one
or more of electrostatic interactions, hydrogen bonding,
hydrophobic interactions, coordination complexation, and Van der
Waals forces. Functional monomers includes macromers, oligomers,
and polymer chains with pendent functionality and which have the
capability of being crosslinked to create the recognitive hydrogel.
Crosslinking monomer includes chemicals with multiple double bond
functionality that can be polymerized into a polymer network.
Examples of functionalized monomers include, but are not limited
to, 2-hydroxyethylmethacrylate (HEMA), Acrylic Acid (AA),
Acrylamide (AM), N-vinyl 2-pyrrolidone (NVP), 1-vinyl-2-pyrrolidone
(VP), methyl methacrylate (MMA), methacrylic acid (MAA), acetone
acrylamide, 2-ethyl-2-(hydroxymethyl)-1,3-propanediol
trimethacrylate, N-(1,1-dimethyl-3-oxobutyl)acrylamide,
2-ethyl-2-(hydroxymethyl)-1,3-propanediol trimethacrylate,
2,3-dihydroxypropyl methacrylate, allyl methacrylate,
3-[3,3,5,5,5-pentamethyl-1,1-bis[pentamethyldisiloxanyl)oxy]trisiloxanyl]-
propyl methacrylate,
3-[3,3,3-trimethyl-1,1-bis(trimethylsiloxy)disiloxanyl]propyl
methacrylate (TRIS), N-(1,1-dimethyl-3-oxybutyl)acrylamide,
dimethyl itaconate, 2,2,2,-trifluoro-1-(trifluoromethyl)ethyl
methacrylate, 2,2,2-trifluroethyl methacrylate,
methacryloxypropylbis(trimethylsiloxy)methylsilane,
methacryloxypropylpentamethyldisiloxane,
(3-methacryloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilane-
, 4-t-butyl-2-hydroxycyclohexyl methacrylate, dimethylacrylamide
and glycerol methacrylate. Once formed the biomimetic recognitive
polymeric hydrogel can be formed into contact lenses or as
described above the polymerization reaction forms the contact
lenses.
[0030] In accordance with further embodiments of the invention,
functionalized monomers are synthesized or selected by identifying
receptor sites or molecules associated with the target biological
tissue to be treated by the drug or that are associated with
metabolizing the drug. Then functionalized portions of the
functionalized monomers are synthesized to chemically and/or
structurally resemble or mimic the receptor sites or molecules that
are associated with the biological mechanism of action of the drug.
These functionalized monomers are then copolymerized with the
cross-linking monomer or monomers used to form the hydrogel matrix,
such as described above.
[0031] After the drug has been depleted from the contact lenses
through the eyes, the contact lenses can be re-loaded with the drug
by soaking the contact lenses in the reconstituting drug solution.
While the contact lense have been described in detail as being used
to deliver antihistamines and other allergy drugs, ophthalmic drug
delivery systems and methods of the present invention can be used
to deliver any number of drugs through contact on the eye and/or
systemically.
[0032] Drugs that can be delivered by the system and method of the
present invention include, but are not limited to, Anti-bacterials
Anti-infectives and Anti-microbial Agents (genteelly referred to as
antibiotics) such as Penicillins (including Aminopenicillins and/or
penicillinas in conjunction with penicillinase inhibitor),
Cephalosporins (and the closely related cephamycins and
carbapenems), Fluoroquinolones, Tetracyclines, Macrolides,
Aminoglycosides. Specific examples include, but are not limited to,
erythromycin, bacitracin zinc, polymyxin, polymyxin B sulfates,
neomycin, gentamycin, tobramycin, gramicidin, ciprofloxacin,
trimethoprim, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin,
norfloxacin, sodium sulfacetamide, chloramphenicol, tetracycline,
azithromycin, clarithyromycin, trimethoprim sulfate and
bacitracin.
[0033] The ophthalmic drug delivery system and method of the
present invention can also be used to deliver Non-steroidal
(NSAIDs) and Steroidal Anti-inflammatory Agents (genteelly referred
to as anti-inflammatory agents) including both COX-1 and COX-2
inhibitors. Examples include, but are not limited to,
corticosteroids, medrysone, prednisolone, prednisolone acetate,
prednisolone sodium phosphate, fluormetholone, dexamethasone,
dexamethasone sodium phosphate, betamethasone, fluoromethasone,
antazoline, fluorometholone acetate, rimexolone, loteprednol
etabonate, diclofenac(diclofenac sodium), ketorolac, ketorolac
tromethamine, hydrocortisone, bromfenac, flurbiprofen, antazoline
and xylometazoline.
[0034] The ophthalmic drug delivery system and method of the
present invention can also be used to deliver Anti-histamines, Mast
cell stabilizers, and Anti-allergy Agents (generally referred to as
anti-histamines). Examples include, but are not limited, cromolyn
sodium, lodoxamide tromethamine, olopatadine HCl, nedocromil
sodium, ketotifen fumurate, levocabastine HCL, azelastine HCL,
pemirolast (pemirolast potassium), epinastine HCL, naphazoline HCL,
emedastine, antazoline, pheniramine, sodium cromoglycate,
N-acetyl-aspartyl glutamic acid and amlexanox.
[0035] In yet further embodiments of the invention the ophthalmic
drug delivery system and method are used to deliver Anti-viral
Agents including, but not limited to, trifluridine and vidarabine;
Anti-Cancer Therapeutics including, but not limited to,
dexamethasone and 5-fluorouracil (5FU); Local Anesthetics
including, but are not limited to, tetracaine, proparacaine HCL and
benoxinate HCL; Cycloplegics and Mydriatics including, but not
limited to, Atropine sulfate, phenylephrine HCL, Cyclopentolate
HCL, scopolamine HBr, homatropine HBr, tropicamide and
hydroxyamphetamine Hbr; Comfort Molecules or Molecules (generally
referred as lubricating agents) to treat Keratoconjunctivitis Sicca
(Dry Eye) including, but not limited to, Hyaluronic acid or
hyaluronan (of varying Molecular Weight, MW), hydroxypropyl
cellulose (of varying MW), gefarnate, hydroxyeicosatetranenoic acid
(15-(S)-HETE), phospholipid-HETE derivatives, phoshoroylcholine or
other polar lipids, carboxymethyl cellulose (of varying MW),
polyethylene glycol (of varying MW), polyvinyl alcohol (of varying
MW), rebamipide, pimecrolimus, ecabet sodium and hydrophilic
polymers; Immuno-suppressive and Immuno-modulating Agents
including, but not limited to, Cyclosporine, tacrolimus, anti-IgE
and cytokine antagonists; and Anti-Glaucoma Agents including beta
blockers, pilocarpine, direct-acting miotics, prostagladins, alpha
adrenergic agonists, carbonic anhydrase inhibitors including, but
not limited to betaxolol HCL, levobunolol HCL, metipranolol HCL,
timolol maleate or hemihydrate, carteolol HCL, carbachol,
pilocarpine HCL, latanoprost, bimatoprost, travoprost, brimonidine
tartrate, apraclonidine HCL, brinzolamide and dorzolamide HCL;
decongestants, vasodilaters vasoconstrictors including, but not
limited to epinephrine and pseudoephedrine
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is a block diagram showing the steps for making
contact lenses, in accordance with the embodiments of the
invention.
[0037] FIG. 2 illustrates the formation of a recognitive polymeric
hydrogel, in accordance with the embodiments of the invention.
[0038] FIG. 3 illustrates a block diagram outlining steps for
making funtionalized monomer used in the synthesis of recognitive
polymeric hydrogels, in accordance with the embodiments of the
invention.
[0039] FIGS. 4A-C illustrate examples of sets of molecules that
match, resemble or mimic each other.
[0040] FIGS. 5A-B are graphs that compare Ketotifen equilibrium
isotherms in water for a recognitive polymeric hydrogel and a
control hydrogel.
[0041] FIGS. 5C graphs drug loading for recognitive polymeric
hydrogels of the present invention against control hydrogels to
show the enhanced drug loading for recognitive polymeric hydrogels
of the present invention.
[0042] FIG. 6 shows a graph of drug release profiles for
therapeutic contact lenses, in accordance with the embodiments of
the invention.
[0043] FIG. 7A-B show graphs of drug release profiles for
recognitive polymeric hydrogels, in accordance with the embodiments
of the invention
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0044] Hydrogels are insoluble, cross-linked polymer network
structures composed of hydrophilic homo- or hetero-co-polymers,
which have the ability to absorb significant amounts of water.
Consequently, this is an essential property to achieve an
immunotolerant surface and matrix (i.e., with respect to protein
adsorption or cell adhesion). Due to their significant water
content, hydrogels also possess a degree of flexibility very
similar to natural tissue, which minimizes potential irritation to
surrounding membranes and tissues.
[0045] The hydrophilic and hydrophobic balance of a gel carrier can
be altered to provide tunable contributions that present different
solvent diffusion characteristics, which in turn influence the
diffusive release of a drug contained within the gel matrix. In
general, one may polymerize a hydrophilic monomer with other less
hydrophilic or more hydrophobic monomers to achieve desired
swelling properties.
[0046] These techniques have led to a wide range of swellable
hydrogels. Knowledge of the swelling characteristics is of major
importance in biomedical and pharmaceutical applications since the
equilibrium degree of swelling influences the diffusion coefficient
through the hydrogel, surface properties and surface mobility,
mechanical properties, and optical properties. Drug release depends
on two simultaneous rate processes: water migration into the
network and drug diffusion outward through the swollen gel.
[0047] Soft contact lenses are made of hydrogels. The typical
material properties for contact lenses involve a number of
considerations such as optical quality (good transmission of
visible light), high chemical and mechanical stability,
manufacturability at reasonable cost, high oxygen transmissibility,
tear film wettability for comfort, and resistance to accumulation
of protein and lipid deposits, as well as a suitable cleaning and
disinfecting scheme.
[0048] Soft contact lenses typically consist of poly(2-hydroxyethyl
methacrylate) (PHEMA). Other lens materials include HEMA
copolymerized with other monomers such as methacrylic acid, acetone
acrylamide, and vinyl pyrrolidone. Also, commonly used are
copolymers of vinyl pyrrolidone and methyl methacrylate as well as
copolymers of glycerol methacrylate and methyl methacrylate. Minor
ingredients have included a variety of other monomers as well as
cross-linking agents.
[0049] The immersion and soaking of soft contact lenses in drug
solutions has shown promise in the increase of drug bioavailability
with a minimization of side effects. However, the materials and
constituent chemistry of the macromolecular chains and subsequent
interaction with drugs is random and typically leads to poor drug
loading.
[0050] In order to address the above referenced shortcomings, the
present invention is directed to the use of biomimetic imprinting
of hydrogels to make hydrogels matrices that can selectively bind a
drug through complexing sites leading to improved loading of a drug
and controlled time release of the drug. These hydrogels are
referred to as recognitive polymeric hydrogels. The polymerization
reaction forms the contact lenses, which can be used to administer
drugs through contact with the eyes, thereby replacing traditional
eye drop therapies. Alternatively, the recognitive polymeric
hydrogels can be formed or fashioned into contact lenses which can
be used to administer drugs through contact with the eyes, thereby
replacing traditional eye drop therapies or other mechanisms of
delivery.
[0051] For example, ketotifen fumurate is a potent fast acting and
highly selective histamine H1 antagonists with a sustained duration
of action. Levocabastine and ketotifen fumurate inhibits itching,
redness, eyelid swelling, tearing, and chemosis induced by
conjunctival provocation with allergens and histamine. With topical
application in the form of eye drops, absorption is incomplete and
bioavailability is low. Thus, the dose is usually administered
multiple times daily. Also, due to a high concentration of drug and
other constituents of the ophthalmic suspension preparation,
patients are advised not to wear soft contact lenses. Accordingly,
a soft contact lens that could be used to administer ketotifen
fumurate would not only enhance the efficacy of the treatment, but
also allow allergy sufferers to wear contact lenses.
[0052] Referring to FIG. 1 which is a block diagram 100 outlining
steps for making contact lenses, in accordance with the embodiments
of the invention and FIG. 2 which is a graphical representation of
forming a recognitive polymeric hydrogel 221. In the step 101, the
recognitive hydrogel matrix 221 is formed. The recognitive hydrogel
221 is formed by generating a solution 200 comprising one or more
bio-template 201, one or more functionalized monomers 203 and 203',
one or more cross-linking monomers 205 with or without a solvent.
In the solution 200' the functionalized monomers 203 and 203'
complexes with the bio-templates 201. A suitable initiator or
mixture initiators 207 is used to co-polymerize the functionalized
monomers 203 and 203' with a cross-linking monomer 205 to form the
loaded hydrogel 220 comprising a hydrogel matrix 221 with
bio-templates 201 complexing at site 209 through the hydrogel
matrix 221.
[0053] Preferably, the bio-templates are complexed with the
hydrogel matrix 221 through weak or non-covalent interactions, as
explained above, whereby the bio-templates can be washed or rinsed
from the complexed hydrogel 220 to form an un-complexed recognitive
polymeric hydrogel 221, which has vacant complexing sites 209 that
can be used to complex drug molecules that are structurally and/or
chemically similar to the bio-templates 201. It will be clear from
the discussions above and below that the bio-templates can be a
drug and, therefore, washing the bio-templates from the hydrogel
matrix 221 may not be necessary for all drug delivery systems that
are synthesized.
[0054] Still referring to both FIG. 1 and FIG. 2, after the
recognitive hydrogel 221 is formed, in the step 101, in the step
103 the recognitive hydrogel 221 can be formed into contact lenses
using any technique known in the art. Its is understood that the
step the step 103 is not necessary, when the polymerization
reaction forms the contact lenses, such as described previously.
Where the bio-template is a drug, the contact lenses can be placed
in contact with eyes in the step 107 to administer or deliver the
drug to or through the eyes. Where, the bio-template 201 has been
washed from the recognitive hydrogel matrix prior to or after the
step 103 of forming the contact lenses from the recognitive
hydrogel matrix, then in the step 109 or the step 105,
respectively, the recognitive hydrogel matrix or the contact lenses
are loaded with a drug. The recognitive hydrogel matrix or the
contact lenses can be loaded with the drug by soaking the
recognitive hydrogel matrix or the contact lenses in an aqueous
drug solution.
[0055] Now referring to FIG. 2 and FIG. 3. In accordance with
further embodiments of the invention prior to the step of making an
ophthalmic drug delivery system, such as described with reference
to FIG. 1, in the step 301 the target tissue to be treated with the
drug or biological mechanism of action is studied to determine the
types of molecules or functional groups that are associated with
the action of the drug at the target tissue to effect the target
tissue. Based on this information, in the step 303, funtionalized
monomers are synthesized with functional groups that mimic or
resemble molecules or functional groups that are associated with
the action of the drug at the target tissue. The functionalized
monomers with the functional groups that mimic or resemble
molecules or functional groups that are associated with
metabolizing the drug at the target tissue are then used to
synthesize a drug delivery system, such as described above with
reference to FIG. 1. The biomimetic approach is the processes of
mimicking biological recognition or exploiting biological
mechanisms. Specifically, it is the process of coordinating
biological molecular recognition, interactions, or actions to
design materials that can be structurally similar to and/or
function in similar ways as biological structures.
[0056] FIGS. 4A-C illustrate examples of sets of molecules that
match, resemble or mimic each other. With reference to the
bio-mimetic approach for synthesizing recognitive hydrogel polymers
described above, acrylic acid can be used to mimic aspartic acid
(FIG. 4A), acrylaminde can be used to mimic asparagine (FIG. 4B)
and N-vinyl pyrrolidinone can be used to mimic tyrosine (FIG. 4C).
Aspartic acid, asparagine, and tyrosine are known to be of the
group of amino acids providing the non-covalent interactions in the
ligand binding pocket for histamine. For example, structural
analysis of ligand binding pockets and amino acids involved in
multiple non-covalent binding points provide one of many rational
frameworks to synthesize recognitive networks from functional
monomers. Antihistamine has been shown to bind more tightly and
have a higher affinity than histamine for the histamine binding
pocket.
EXAMPLE
[0057] Materials and Methods: Acrylic Acid (AA), Acrylamide (AM),
N-Vinyl-2-Pyrrolidone (NVP) and 2-hydroxyethylmethacrylate (HEMA),
Azobisisobutyronitrile (AIBN), and Ketotifen Fumarate were
purchased from Sigma-Aldrich. Polyethylene glycol (200)
dimethacrylate (PEG200MA) was purchased from Polysciences, Inc. All
chemicals were used as received. Polymer and copolymer networks
were made using various mixtures of above monomers (e.g.
Poly(AA-co-AM-HEMA-PEG200DMA), Poly(AA-co-HEMA-co-PEG200DMA), Poly
(AM-co-HEMA-co-PEG200DMA),
Poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA)). Current work is directed
to producing networks that can also be used in the formation of
contact lens for anti-histamines with monomers and copolymers of
molecules such as N-vinyl 2-pyrrolidone (NVP),
1-vinyl-2-pyrrolidone (VP), methyl methacrylate (MMA), methacrylic
acid (MAA), acetone acrylamide, ethylene glycol dimethacrylate
(EGDMA), 2-ethyl-2-(hydroxymethyl)-1,3-propanediol trimethacrylate,
N-(1,1-dimethyl-3-oxobutyl)acrylamide,
2-ethyl-2-(hydroxymethyl)-1,3-propanediol trimethacrylate,
2,3-dihydroxypropyl methacrylate, allyl methacrylate any other
suitable monomers, such as those referenced previously.
[0058] Accurate quantities of monomers, template molecules and
crosslinkers were added in that order, and the mixture was
sonicated to obtain a homogenous solution. In particular, a typical
formulation consisted of 5 mole % cross-linking monomer (PEG200DMA)
in a solution of Acrylamide (M), HEMA (M), Ketotifen (T), with an
M/T ratio of approximately 950 (92% HEMA, 1% of remaining monomers,
and approximately 1 mole % drug depending on the M/T ratio).
Controls were also prepared without the template. Next, initiator
AIBN was added in low light conditions, and the solutions were
allowed to equilibrate for 12 hours in darkness. This step allowed
the monomers and template to orient them selves and reach their
free energy minima, thus beginning the configurational imprinting
at the molecular level. However, this step occurs very quickly such
as on the order of minutes.
[0059] The solutions were then transferred to an MBRAUN Labmaster
130 1500/1000 Glovebox, which provides an inert nitrogenous and
temperature-controlled atmosphere for free-radical
photopolymerization. With an increase in photoinitiator wt. %, this
step can proceed in air. The solutions were uncapped and left open
to the nitrogen until the oxygen levels reached negligible levels
(<0.1 ppm). The solutions were inserted into glass molds (6 in.
by 6 in.) separated by a Teflon frame 0.8 mm wide, as measured by a
Vernier caliper. The glass plates were coated with
chlorotrimethylsilane in order to prevent the polymer matrix from
sticking to the glass, as it demonstrates a strong adherent
tendency due to hydrogen bonding. Polymerization was carried out
for ten minutes at 325 V using a Dymax UV light source. The
intensity of radiation was 40 mW/cm.sup.2, as measured with a
radiometer, and the temperature was 36.degree. C., as measured by a
thermocouple.
[0060] The polymer was peeled off the glass plates with flowing
deionized water (Millipore, 18.2 mO.cm, pH 6), and then was allowed
to soften for approximately 10 minutes. Circular discs were cut
using a Size 10 cork borer (13.5 mm), and were typically washed for
5 days in a continuous flow system using deionized water. All
washes proceeded until the absence of detectable drug was verified
by spectroscopic monitoring. To obtain dry weights, some discs were
allowed to dry under laboratory conditions (20.degree. C.) for 36
hours. The discs were then transferred to a vacuum oven (27 in. Hg,
33-34.degree. C.) for 48 hours until they were dry (less than 0.1
wt % difference).
[0061] Polymer penetrant uptake and swelling data were obtained in
deionized water with samples taken every 5 min. for the first hour,
and then every hour for 10 hours until equilibrium was reached. As
the gel was removed from the water, excess surface water was dabbed
with a dry Kim wipe. The equilibrium weight swelling ratio at time
t, q, for a given gel was calculated using the weights of the gels
at a time and the dry polymer weights, respectively, using
equations based on Archimedes principle of buoyancy. Dynamic and
Equilibrium Template Binding: Dynamic template drug molecule
binding was performed until equilibrium had been established for
each system. Stock solutions of drug with a concentration 2 mg/ml
were prepared and diluted with deionized water to produce 0.1, 0.2,
0.3, 0.4 and 0.5 mg/ml solutions. Each solution was vortexed for 30
seconds to provide homogeneity, and initial UV absorbances were
noted. Gels were then inserted into the vials and were placed on a
Stovall Belly Button Orbital Shaker over the entire duration of the
binding cycle to provide adequate mixing. A 200 .mu.l aliquot of
each sample was placed in a Corning Costar UV-transparent
microplate, and absorbance readings were taken using a Biotek
Spectrophotometer at 268 nm. After measurement, the reading sample
was returned to the original samples, to avoid fluctuations in
concentrations due to sampling methods.
[0062] Dynamic Release Studies: In obtaining the preliminary
results, dynamic release studies were conducted in DI water,
artificial lacrimal fluid (6.78 g/L NaCl, 2.18 g/L NaHCO.sub.3,
1.38 g/L KCl, 0.084 g/L CaCl.sub.22H.sub.2O, pH 8), and lysozyme (1
mg/ml) in artificial lacrimal fluid. Gels which had been drug
loaded were placed in 30 ml of DI water, and the solutions were
continuously agitated with a Servodyne mixer (Cole Palmer
Instrument Co.) at 120 rpm. Release of drug was monitored at 268 nm
by drawing 200 .mu.L of solution into a 96-well Corning Costar
UV-transparent microplate, and measurements were taken in a Synergy
UV-Vis Spectrophotometer (Biotek). Absorbances were recorded for
three samples, averaged, and corrected by subtracting the relevant
controls. Solutions were replaced after each reading. Separate
studies were conducted to determine if infinite sink conditions
existed and those conditions were matched throughout all
experiments.
[0063] Polymerization Kinetics and Network Formation: Solutions
were prepared with 0, 0.1, 0.5, and 1 mole percent of Ketotifen in
the initial monomer solutions. Kinetic studies were conducted with
a differential scanning photocalorimeter (DPC, Model No. DSC Q100,
TA Instruments with Mercury light source). Samples of 10 .mu.l,
were placed in an aluminum hermetic pan and purged with nitrogen
(flow rate 40 ml/min) in order to prevent oxidative inhibition.
They were allowed to equilibrate at 35.degree..degree. C. for 15
minutes, before shining UV light at 40 mW/cm2 for 12 minutes.
[0064] The heat that evolved was measured as a function of time,
and the theoretical enthalpy of the monomer solution was used to
calculate the rate of polymerization, Rp, in units of fractional
double bond conversion per second. Integration of the rate of
polymerization curve versus time yielded the conversion as a
function of time or reaction rate. The presence of template and a
solvent, if used, was accounted for in the calculations, as it did
not participate in the polymerization reaction. Experimental
results were reproducible and the greatest source of error involved
the assumed theoretical enthalpies in the calculations of the rate
of polymerization and conversion. For all studies, the enthalpies
were assumed to have errors of +5%. The assumptions in the
copolymerization of two monomers (i.e., functional and
cross-linking monomers) were that each monomer had equal reactivity
and the theoretical enthalpy derived for a co-monomer mixture was
an average of the enthalpies of individual monomers. The
theoretical enthalpy of methacrylate double bonds was equal to 13.1
kcal mole-1 and the theoretical enthalpy of acrylate double bonds
was equal to 20.6 kcal mole-1.
RESULTS
[0065] FIG. 5A shows a graph 500 of the equilibrium binding
isotherm for Ketotifen in water for
Poly(acrylamide-co-HEMA-co-poly(ethylene glycol)200
dimethacrylate)hydrogel networks with a cross-linking percentage of
5%. N=3 and T=25.degree. C. The recognitive hydrogel network is
represented by the line 501 and the control hydrogel network is
represented by the line 503. Percentage denotes percent mole
crosslinker per mole total monomers in feed.
[0066] FIG. 5B shows a graph 510 of the equilibrium binding
isotherm for Ketotifen in water for Poly(acrylic
acid-co-HEMA-co-poly(ethylene glycol)200 dimethacrylate) hydrogel
networks with a cross-linking percentage of 5%. N=3 and
T=25.degree. C. The recognitive hydrogel networks is represented by
line 511 and the control hydrogel network is represented by line
513. Percentage denotes percent mole crosslinker per mole total
monomers in feed.
[0067] FIG. 5C shows a graph 540 of enhanced Loading of Ketotifen
for Multiple Monomer Gels for Poly(n-co-HEMA-co-poly(ethylene
glycol)200 dimethacrylate) Networks. The Functional monomers uses
are acrylic acid, acrylamide, NVP, or an equal mole mixture of
both. The Recognitive networks are shown as hatched bars 543 and
the Control networks are shown as clear bars 541.
[0068] FIG. 6 shows a graph 600 of Tailorable Release Profiles Of
Therapeutic Contact Lenses for Poly(n-co-HEMA-co-poly(ethylene
glycol)200 dimethacrylate) Networks in Artificial Lacrimal Fluid,
where n is AM (represented by circles ), AA (represented by
squares), AA-AM(represented by triangles), and NVP-AA-AM
(represented by diamonds) recognitive networks respectively.
Results demonstrate approximately constant release rate of
ketotifen fumurate for 1 to 5 days.
[0069] FIG. 7A shows a graph 700 of Release Data for
Poly(AM-co-HEMA-co-poly(ethyleneglycol)200 dimethacrylate)
Recognitive Networks. Fraction of Mass Released in Artificial
Lacrimal Solution With/Without Lysozyme.
[0070] FIG. 7B shows a graph 725 of Release Data for
Poly(AM-co-AA-co-HEMA-co-poly(ethyleneglycol)200 dimethacrylate)
Networks Mass of Drug Released in Artificial Lacrimal Solution.
[0071] I. Enhanced Loading and Performance of Multiple Monomer
Mixtures In the preliminary work, hydrogels were produced with
enhanced loading for ketotifen fumarate. Polymers were made with
the following monomers: acrylic acid (AA), N-vinyl 2-pyrrolidone
(NVP), acrylamide (AM), 2-hydroxyethylmethacrylate (HEMA), and
polyethylene glycol (200) dimethacrylate (PEG200DMA).
[0072] We hypothesized that gels composed of multiple functional
monomers would outperform those composed of single functional
monomers. For anti-histamine recognitive polymers, this would
better mimic the docking site of histamine at the molecular level
providing all the relevant functionality necessary for non-covalent
interactions. We have proved that loading properties of gels are
improved with multiple monomer mixtures.
[0073] Gels of multiple complexation points with varying
functionalities outperformed the gels formed with less diverse
functional monomer and showed the highest maximum bound of
ketotifen and highest difference over control gels. Equilibrium
binding isotherms for Poly(AM-co-AA-co-HEMA-co-PEG200DMA) networks
demonstrate enhanced loading with a factor of 2 times increase in
the loading of drug compared to conventional networks (i.e., gels
prepared without template and comparable to existing contact
lenses) depending on polymer formulation and polymerization
conditions. Poly(AM-co-HEMA-co-PEG200DMA) networks demonstrated a
factor of 2 or 100% increase in the loading of drug compared to
control networks with lower bound amounts.
Poly(AA-co-HEMA-co-PEG200DMA) networks show a factor of 6 times
increase over control in the loading of ketotifen with the overall
drug bound being the lowest of the polymer formuations studies
(approximately 33% less ketotifen loading than the AM
functionalized network).
[0074] For all systems, an increase in the amount of loaded drug
has been confirmed, but with the most biomimetic formulation
(Poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA)) a significant increase in
loading is demonstrated yielding the greatest loading potential
(the highest loading achieved to date and 6x over control networks
due to multiple binding points with varying functionalities) (FIG.
5C).
[0075] II. Dynamic Drug Release Profiles
[0076] Dynamic release profiles in artificial lacrimal solution and
an artificial lacrimal solution with protein, demonstrated extended
release of a viable therapeutic concentration of ketotifen. Release
studies confirmed that release rates can be tailored via type and
amount of functionality and extended from one to five days. FIG. 6
highlights normalized data of the fraction of drug released versus
time (mass delivered at time t divided by the mass delivered at
infinite time). For poly(n-co-HEMA-co-PEG200DMA) networks (where n
was AA-co-AM, AM, or AA), the release of drug showed a relatively
constant rate of release for approximately 1 day, with little
difference in the release profile. However, the most structurally
biomimetic network, poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA),
exhibited a five fold increase in the extended release profile
(i.e., approximately 5 days).
[0077] It is hypothesized that providing all the relevant
functionality to the mimicked docking site with the proposed
polymer synthesis technique affords a higher affinity of the drug
for the network and thus an even slower release of drug compared to
control networks. Furthermore, a five to seven day release profile
fits quite well into the time usage of one-week extended-wear soft
contacts.
[0078] It has been demonstrated that the loading of drug can be
controlled by the type, number, and diversity of functionality
within the network. The loading (and hence the mass delivered) can
also be controlled by the initial loading concentration of the
drug. We have demonstrated control over the cumulative mass of drug
released by changing the loading concentration. By considering the
relative size of our gels (i.e., gels were slightly bigger than
normal lenses) and mass of drug released in comparison to typical
ophthalmic eye drop dosages (ketotifen 0.25 mg/mL of solution with
one drop every 8 hours), the preliminary results revealed that a
therapeutically relevant dosage could be delivered for extended
periods of time.
[0079] To investigate the effect of protein on dynamic release, we
chose lysozyme as a model protein since it is the largest protein
component in tear fluid. FIGS. 7A-B highlights the
poly(AM-co-HEMA-co-PEG200DMA) network release profile in artificial
lacrimal solution with lysozyme, which leads to a factor of 5
increase in the duration of release. For the most structurally
biomimetic network, poly(AA-co-AM-co-NVP-co-HEMA-PEG200DMA), this
could lead to a sustained release approaching 25 days. These
studies demonstrate that the time of release may be delayed even
further in an in vivo environment, leading to a substantial
increase in applicability of contact lens ocular delivery.
[0080] III. Polymerization Reaction Analysis
[0081] The rate of polymerization for a given conversion decreased
for increasing mole percentage of template molecule in
pre-polymerization monomer solution. Thus, the formation of polymer
chains and the enhanced loading due to the configurational
biomimetic effect may be related to the propagation of polymer
chains. The template molecule poses physical constraints to free
radical and propagating chain motion and hence effectively lowers
the rate of polymerization in the creation of ligand binding
pockets. These results show that CBIP is reflected at the molecular
level. For a given conversion, the rate of polymerization was lower
for the multiple functional monomer pre-polymerization mixtures
than the single monomer mixtures. We hypothesize that CBIP with
multiple monomers results in the formation of better ligand-binding
pockets with enhanced loading properties which leads to slower
rates of polymerization.
[0082] IV Equilibrium Swelling Profiles and Mechanical Property
Analysis:
[0083] Equilibrium swelling studies in DI water and 0.5 mg/ml
concentrated ketotifen solution) indicated that recognitive and
control networks were statistically the same and that 40% of the
swollen gels is water, which indicates that the comfort of wearing
and oxygen permeability of these gels is in agreement with
conventional contact lenses. These studies indicated that CBIP, and
not an increased porosity or surface area of the gel, is
responsible for the enhanced loading properties. It also
demonstrated that the loading process does not affect the rate of
swelling of the polymer matrix.
[0084] Further studies on the mechanical properties of the gels
have shown comparable storage and loss moduli, glass transition
temperatures and damping factors to that of conventional contact
lenses (data not shown). Each gel produced was optically clear and
had sufficient viscoelasticity to be molded in thin films (for
refractive differences)
CONCLUSION
[0085] Polymerization kinetics in the presence of the template
reveal mechanisms of interaction as well as provide criteria with
which other template-monomer systems can be chosen experimentally.
The use of a biomimetic approach for synthesizing recognitive
hydrogel polymers has led to the development of an ophthalmic drug
delivery system using contact lenses formed from the recognitive
hydrogel polymer. The ophthalmic drug delivery system of the
present invention can provide improved bioavailability and efficacy
of drug delivery and exhibit controlled time release of the drug.
The ophthalmic drug delivery system can be tailored to exhibit
properties suitable for the intended drug therapy and has a
potential to replace traditional eye drop therapies and other
methods.
[0086] The present invention has been described in terms of
specific embodiments incorporating details to facilitate the
understanding of the principles of construction and operation of
the invention. Such reference herein to specific embodiments and
details thereof is not intended to limit the scope of the claims
appended hereto. It will be apparent to those skilled in the art
that modifications can be made in the embodiment chosen for
illustration without departing from the spirit and scope of the
invention. Specifically, it will be apparent to one of ordinary
skill in the art that the device of the present invention could be
implemented in several different ways and the apparatus disclosed
above is only illustrative of the preferred embodiment of the
invention and is in no way a limitation.
* * * * *