U.S. patent application number 10/234922 was filed with the patent office on 2003-07-31 for medical uses of in situ formed gels.
Invention is credited to Henry, Raymond L., Reeve, Lorraine E., Viegas, Tacey X..
Application Number | 20030143274 10/234922 |
Document ID | / |
Family ID | 25135059 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030143274 |
Kind Code |
A1 |
Viegas, Tacey X. ; et
al. |
July 31, 2003 |
Medical uses of in situ formed gels
Abstract
Balanced pH, hyperosmotic, hypoosmotic, or isoosmotic gels are
ideal vehicles for drug delivery. They are especially suited for
topical body cavity or injection application of drugs or diagnostic
agents; for drug or diagnostic agent delivery to the eye of a
mammal; as protective corneal shields; or as ablatable corneal
masks useful in laser reprofiling of the cornea. The compositions
without the addition of a drug or diagnostic agent are useful as
medical devices, for instance, in separating surgically or
otherwise injured tissue as a means of preventing adhesions.
Inventors: |
Viegas, Tacey X.;
(Birmingham, AL) ; Reeve, Lorraine E.; (Dexter,
MI) ; Henry, Raymond L.; (St. Clair Shores,
MI) |
Correspondence
Address: |
Pillsbury Winthrop, LLP
Suite 200
11682 El Camino Real
San Diego
CA
92130
US
|
Family ID: |
25135059 |
Appl. No.: |
10/234922 |
Filed: |
September 4, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10234922 |
Sep 4, 2002 |
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09628227 |
Jul 28, 2000 |
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09628227 |
Jul 28, 2000 |
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09330618 |
Jun 11, 1999 |
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6136334 |
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09330618 |
Jun 11, 1999 |
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08773755 |
Dec 23, 1996 |
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5958443 |
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08773755 |
Dec 23, 1996 |
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08174101 |
Dec 28, 1993 |
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5587175 |
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08174101 |
Dec 28, 1993 |
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07785305 |
Oct 30, 1991 |
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5318780 |
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Current U.S.
Class: |
424/486 ;
424/487; 424/488 |
Current CPC
Class: |
A61L 2430/16 20130101;
Y10S 514/913 20130101; A61F 2009/00872 20130101; Y10S 514/967
20130101; A61L 2300/00 20130101; Y10S 623/905 20130101; A61L 27/26
20130101; A61L 31/041 20130101; Y10S 514/914 20130101; Y10S 514/912
20130101; A61L 24/0031 20130101; A61L 24/043 20130101; A61L 31/041
20130101; A61L 31/16 20130101; Y10S 514/944 20130101; A61L 15/44
20130101; A61L 31/041 20130101; A61L 15/225 20130101; A61K 9/0048
20130101; A61F 9/00819 20130101; A61L 27/54 20130101; Y10S 514/966
20130101; A61L 27/52 20130101; A61L 24/043 20130101; A61L 24/0015
20130101; C08L 1/26 20130101; C08L 5/04 20130101; C08L 5/04
20130101 |
Class at
Publication: |
424/486 ;
424/487; 424/488 |
International
Class: |
A61K 009/14 |
Claims
The embodiments of the invention in which an exclusive property or
privilege is claimed are defined as:
1. A drug delivery composition capable of gelling in situ
containing approximately 0.01% to about 60% by weight of medicament
or pharmaceutical, approximately 1-50% of water soluble film
forming polymer and an ionic polysaccharide capable of
cross-linking.
2. The drug delivery composition of claim 2 wherein the drug
delivery composition is an aqueous composition.
3. The drug delivery composition of claim 2 wherein the drug
delivery composition is a gel selected from the group consisting of
hyperosmotic gel, hypoosmotic gel and an isoosmotic gel.
4. The drug delivery composition of claim 2 wherein the film
forming polymer is water soluble.
5. The drug delivery composition of claim 2 wherein the film
forming polymer is selected from the group consisting of methyl
cellulose, ethyl cellulose, hydroxypropylmethyl cellulose,
hydroxyethyl cellulose, hyalauronic acid and salts thereof, sodium
hyaluronate, chondroitin sulfate, polyacrylic acid, polyacrylamide,
polycyanolacrylades, alkyl methacrylatepolymers, hydroxyalkyl
methacrylate polymers, cyclodextrin, polydextrose, dextran,
gelatin, polygalacturonic acid, poly vinyl alcohol, polyvinyl
pyrollidone, polyalkylene glycols and polyethylene alcohol.
6. The drug delivery composition of claim 2 wherein the film
forming polymer is selected from the group consisting of
cyclodextrin, polydextrose, carrageenan and maltodextrins.
7. The drug delivery composition of claim 2 wherein the ionic
poysaccharide is selected from the group consisting of natural gums
such as gellan gum, alginate gums, ammonium and alkali metal salts
of alginic acid, chitin and chitosan.
8. The drug delivery composition of claim 8 wherein the alginate
gums are alkali metal alginates and the metal is selected from the
group consisting of sodium, potassium, lithium, rubidium and cesium
salts.
9. The drug delivery composition of claim 2 wherein the medicament
is selected from the group consisting of antibacterials,
antihistamines, decongestants, antiinflammatories, antiparisitics,
miotics, anticholinergies, antivirals, local anesthetics,
antifungals, immunosuppressants, amoebicidals, trichomonocidals,
analgesics, mydriatics, antiglaucoma drugs, carbonic anyhydrase
inhibitors, opthalmic diagnostic agents, opthalimic agents used as
adjuvents in surgery, chelating agents, antineoplastics,
antihypertensives, muscle relaxants and diagnostics.
10. The drug delivery composition of claim 2 wherein the medicament
is an antibacterial substance selected from the group consisting of
beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin,
carbenicillin, colistin, penicillin G, polymyxin B, vancomycin,
cefazolin, cephaloridine, chibrorifamycin, gramicidin, bacitracin
and sulfonamides, gentamycin, kanamycin, amikacin, sisomicin,
tobramycin.
11. A drug delivery composition capable of gelling in situ upon
release of a counter ion containing approximately 0.01% to about
60% by weight of medicament or pharmaceutical, approximately 1-50%
of water soluble film forming polymer and an ionic polysaccharide
capable of cross-linking.
12. The drug delivery composition of claim 12 wherein the counter
ion is provided in latent form by microencapsulation of the counter
ion in a heat sensitive medium which releases the counter ion at
body temperature and causes the drug delivery composition to
gel.
13. The drug delivery composition of claim 12 wherein the drug
delivery composition further contains ion exchange resins which
release the counter ion to gel the drug delivery composition in
situ.
14. The drug delivery composition of claim 12 wherein the drug
delivery composition contains anticancer agents.
15. The drug delivery composition of claim 12 wherein the ionic
poysaccharide is selected from the group consisting of natural gums
such as gellan gum, alginate polysaccharides, ammonium and alkali
metal salts of alginic acid and chitin.
16. The drug delivery composition of claim 12 wherein the ionic
polysaccharide is selected from the group consisting of gellan gum
and alganite polysaccharides and the counter ions for gelling the
ionic polysaccharide are selected from the group consisting of
calcium, strontium, sodium, potassium, lithium, rubidium, cesium
salts, strontium chloride and calcium chloride.
17. A drug delivery composition which gels in situ which may be
delivered topically to body cavities or by injection comprising
approximately 0.01% to about 60% by weight of medicament or
pharmaceutical, approximately 1-50% of water soluble film forming
polymer, and an ionic polysaccharide which cross-links only after
the drug delivery composition is administered in situ.
18. The drug delivery composition of claim 18 wherein the
medicament of pharmaceutical is selected from the group consisting
of antibacterials, antihistamines, decongestants,
antiunflammatories, antiparisitics, miotics, anticholinergies,
antivirals, local anesthetics, antifungals, immunosuppressants,
amoebicidals, trichomonocidals, analgesics, mydriatics,
antiglaucoma drugs, carbonic anyhydrase inhibitors, opthalmic
diagnostic agents, opthalimic agents used as adjuvents in surgery,
chelating agents, antineoplastics, antihypertensives, muscle
relaxants and diagnostics.
19. The drug delivery composition of claim 18 wherein the ionic
poysaccharide is selected from the group consisting of natural gums
such as gellan gum, alginate polysaccharides, ammonium and alkali
metal salts of alginic acid and chitin.
20. The drug delivery composition of claim 18 wherein the drug
delivery composition of is water soluble.
Description
[0001] This application is a continuation of U.S. Ser. No.
09/628,227, filed Jul. 28, 2000, which is a continuation of U.S.
Ser. No. 09/330,618, filed Jun. 11, 1999, now U.S. Pat. No.
6,136,334, which is a continuation of U.S. Ser. No.08/773,755,
filed Dec. 23, 1996, now U.S. Pat. No. 5,958,443 which is a
continuation of U.S. Ser. No. 08/174,101 filed Dec. 28, 1993, now
U.S. Pat. No. 5,587,175, which is a divisional of U.S. Ser. No.
07/785,305, filed Oct. 30, 1991, now U.S. Pat. No. 5,318,780.
FIELD OF THE INVENTION
[0002] This invention relates to drug delivery system, the
prevention of post-surgical adhesions, ophthalmic corneal
protective devices, and a surgical device used in the correction,
for instance, of corneal ulcers, irregularities, scarring,
astigmatism, myopia, and hyperopia.
DESCRIPTION OF THE PRIOR ART
[0003] Over the years, methods have been developed to achieve the
efficient delivery of a therapeutic drug to a mammalian body part
requiring pharmaceutical treatment. Use of an aqueous liquid which
can be applied at room temperature as a liquid but which forms a
semisolid gel when warmed to body temperature has been utilized as
a vehicle for drug delivery since such a system combines ease of
application with greater retention at the site requiring treatment
than would be the case if the aqueous composition were not
converted to a gel as it is warmed to mammalian body temperature.
In U.S. Pat. No. 4,188,373, PLURONIC.RTM. polyols are used in
aqueous compositions to provide thermally gelling aqueous systems.
Adjusting the concentration of the polymer provides the desired
sol-gel transition temperature, that is, the lower the
concentration of polymer, the higher the sol-gel transition
temperature, after crossing a critical concentration minimum, below
which a gel will not form.
[0004] In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822, drug
delivery systems are described which utilize thermosetting gels;
the unique feature of these systems is that both the gel transition
temperature and/or the rigidity of the gel can be modified by
adjustment of the pH and/or the ionic strength, as well as by the
concentration of the polymer.
[0005] Other patents disclosing pharmaceutical compositions which
rely upon an aqueous gel composition as a vehicle for the
application of the drug are U.S. Pat. Nos. 4,883,660, 4,767,619,
4,511,563, and 4,861,760. Thermosetting gel systems are also
disclosed for application to injured mammalian tissues of the
thoracic or peritoneal cavities in U.S. Pat. No. 4,911,926.
[0006] Ionic polysaccharides have been used in the application of
drugs by controlled release. Such ionic polysaccharides as chitosan
or sodium alginate are disclosed as useful in providing spherical
agglomerates of water-insoluble drugs in the Journal of
Pharmaceutical Sciences volume 78, number 11, November 1989,
Bodmeier et al. Alginates have also been used as a depot substance
in active immunization, as disclosed in the Journal of Pathology
and Bacteriology volume 77, (1959), C. R. Amies. Calcium alginate
gel formulations have also found use as a matrix material for the
controlled release of herbicides, as disclosed in the Journal of
Controlled Release, 3 (1986) pages 229-233, Pfister et al.
[0007] In U.S. Pat. No. 3,640,741, a molded plastic mass composed
of the reaction product of a hydrophilic colloid and a
cross-linking agent such as a liquid polyol, also containing an
organic liquid medium such as glycerin, is disclosed as useful in
the controlled release of medication or other additives. The
hydrophilic colloid can be carboxymethyl cellulose gum or a natural
alginate gum which is cross-linked with a polyol. The cross-linking
reaction is accelerated in the presence of aluminum and calcium
salts.
[0008] In U.S. Pat. No. 4,895,724, compositions are disclosed for
the controlled release of pharmacological macromolecular compounds
contained in a matrix of chitosan. Chitosan can be cross-linked
utilizing aldehydes, epichlorohydrin, benzoquinone, etc.
[0009] In U.S. Pat. No. 4,795,642, there are disclosed
gelatin-encapsulated, controlled-release compositions for release
of pharmaceutical compositions, wherein the gelatin encloses a
solid matrix formed by the cation-assisted gelation of a liquid
filling composition incorporating a vegetable gum together with a
pharmaceutically-active compound. The vegetable gums are disclosed
as polysaccharide gums such as alginates which can be gelled
utilizing a cationic gelling agent such as an alkaline earth metal
cation.
[0010] While the prior art is silent with respect to aqueous drug
delivery vehicles and isotonicity thereof, osmotic drug delivery
systems are disclosed in U.S. Pat. No. 4,439,196 which utilize a
multi-chamber compartment for holding osmotic agents, adjuvants,
enzymes, drugs, pro-drugs, pesticides, and the like. These
materials are enclosed by semipermeable membranes so as to allow
the fluids within the chambers to diffuse into the environment into
which the osmotic drug delivery system is in contact. The drug
delivery device can be sized for oral ingestion, implantation,
rectal, vaginal, or ocular insertion for delivery of a drug or
other beneficial substance. Since this drug delivery device relies
on the permeability of the semipermeable membranes to control the
rate of delivery of the drug, the drugs or other pharmaceutical
preparations, by definition, are not isotonic with mammalian
blood.
[0011] Corneal protective devices are needed in cases in which
corneal injury occurs and the immobilization of the eye using an
eye patch is not resorted to. Molded collagen shields have been
developed for this use. These are often not satisfactory because
they lack sufficient flexibility to adequately conform to the
individual corneal curvature. Wetting a collagen shield will
increase conformance of the shield to the cornea but fragmentation
can occur upon exceeding the flexibility of the collagen shield.
The clinical uses of collagen shields are disclosed by Poland et
al. in Journal of Cataract Refractive Survey, Volume 14, September
1988, pages 489-491. The author describes the use of collagen
shields immersed in tobramycin solution in order to rehydrate the
collagen prior to use. These are described as useful following
cataract extraction or in patients having nonsurgical epithelial
healing problems. More rapid healing of epithelial defects after
surgery resulted from the use of the collagen shield. Collagen
shields have also been utilized as agents for the delivery of drugs
to the cornea as disclosed in Reidy et al. Cornea, in press, 1989
the Raven Press, Ltd., New York and Shofner et al., Ophthalmology
Clinics of North America, Vol. 2, No. 1, March 1989, pages
15-23.
[0012] Refractive surgery has been promoted in the United States
and Russia over the past few years but its acceptance has been
limited because of the poor predictability of the final optical
results which include resulting glare from incisions that encroach
upon the optical zone. Techniques that rely upon the surgical
production of corneal incisions have yielded inconsistent results
because these surgical incisions in the cornea have been found to
vary considerably in depth and length.
[0013] Laser keratectomy has been shown to be capable of yielding a
more accurately controlled depth of corneal excision since each
individual laser pulse excises a specific amount (0.2 to 10.0 um)
of corneal tissue. Accordingly, the depth of excised tissue is in
theory uniform and predictable, provided that the energy
distribution is homogeneous across the laser beam. Since the
primary locus of astigmatism is in the cornea, surgical
intervention for astigmatism is more important than for the
correction of other refractive errors, especially since spectacle
or contact lens correction is of limited value in compensating for
large astigmatic errors.
[0014] The excimer laser was introduced to ophthalmology in 1983
(Trokel, S., et al., "Excimer surgery of the cornea," Am. J.
Ophthalmol. 96: 710-715 1983). The depth of incision with short
intense pulses permitted great precision to be achieved in tests on
freshly enucleated cow eyes. The photochemical laser-tissue
interaction is not thermal, permitting direct breaks of organic
molecular bonds without involving optical breakdown in adjacent
tissue. Early experimental results in rabbits revealed problems of
1) corneal stromal swelling, probably in response to disturbed
water relationships due to compromise of the epithelial barrier and
severing of the lamellae and 2) rearrangement of endothelial cells
resulting from loss of contact inhibition (Marshall, J. et al., "An
ultrastructural study of corneal incisions induced by an excimer
laser at 193 nm", Ophthalmology 92: 749-758, 1985). Experiments
with freshly enucleated human eyes indicated that flattening
obtained by excimer laser ablation correlated with results of
clinical scalpel radial keratotomy, but evaluation of the effects
on wound healing and possible damage to adjacent structures was not
addressed (Cotliar, A. M., et al., "Excimer laser radial
keratotomy," Ophthalmology 92: 206-208, 1985). It was, however,
suggested that this laser may become very useful in applications
including penetrating and lamellar keratoplasty, keratomileusis,
and epikeratophakia. Control of the area and depth of pulses using
photolithographed masks resulted in ability to produce narrow cuts
(20 um) and at depths depending on pulse number (Puliafito, C. A.,
et al., "Excimer laser ablation of the cornea and lens", 5
Ophthalmology 92: 741-748, 1985). These controlled ablations had
only very narrow bands of destruction at the adjacent edges. These
studies led to the quantitation of laser ablation (Kruegar, R. R.
and S. L. Trokell "Quantitation of corneal ablation by ultraviolet
laser light", Arch. Ophthalmol. 103: 1741-1742, 1985). Excimer far
UV radiation can be controlled to produce minimal adjacent tissue
damage providing the angle and depth can be precisely controlled.
The remaining problem of effects on healing could then be
addressed.
[0015] Wound healing was assessed in rabbits following excimer
laser surface ablation (Hanna, K. D., et al., "Corneal stromal
wound healing in rabbits after 193 run excimer laser surface
ablation", Arch. Ophthalmol. 107: 895-901, 1989). Healing appeared
to be excellent except when over 85% to 90% of the corneal
thickness had been cut. Endothelial cell disruption, junction
separation and individual cell dropout occurred with corneal haze
development with deeper cuts. A delivery system designed to deliver
predictable depths of cut is, therefore, essential. Similar
findings were reported in studies on human blind eyes (Taylor, D.
M. et al., "Human excimer laser lamellar Keratectomy",
Ophthalmology 96: 654-664, 1989). Attention was directed to the
challenges of improved procedures and equipment, the problems of
individual variation, and the control of biologic responses to
trauma before excimer laser lamellar keratectomy could become a
clinically useful means of correcting refractive errors. In living
monkey eyes, it was concluded that mild, typical wound healing
occurred after excimer laser lamellar keratomileusis (Fantes, F.
E., et al., "Wound healing after excimer laser keratomileusis
(photorefractive keratectomy) in monkeys", Arch. Ophthalmol. 108:
665-675, 5 1990). All corneas were epithelialized by 7 days. By 6
weeks, mild to moderate haze was apparent with clearing by 6 to 9
months. The epithelium was thickened at 21 days after ablation, but
returned to normal by 3 months. Subepithelial fibroblasts were
three times the density of normal keratocytes, but returned to
nearly normal numbers by 9 months. One conclusion reached was that
control of the contour and uniformity of the ablated surface is
important for the structural and biological responses of the
cornea.
[0016] Review of the literature clearly reveals that far UV
vaporization (ablation with an excimer laser at 193 nm, for
example) is a feasible means to sculpture or reprofile the cornea
to correct nearsightedness, farsightedness, astigmatism, corneal
scars, corneal densities, etc. The healing appears to parallel or
to be equal to healing after scalpel intervention, providing the
proper guidelines for pulsing and duration are followed. There
remains a need to control the contour and uniformity of the ablated
surface. Such control will reduce the adverse structural and
biological response of the cornea and insure that a desired
corrective change results.
[0017] The use of a mask, of nearly identical optical density to
the cornea, which can be preformed on the corneal surface so as to
provide a smooth surface of exact contour and accurate dimensions
would correct many of the problems that have prevented the precise
control of the laser beam during keratotomy. This mask would be
required to withstand exposure to moist gases direct tangentally to
the corneal surface throughout the duration of exposure to the
laser to remove ablated debris. The modulation of the beam energy
distribution of the laser in a controlled fashion should also be
provided by such a corneal mask. The use of a smooth ablatable mask
having a known contour and having the density of the cornea would
aid in insuring accurate direction and depth of a tangental cut
utilizing a laser beam. The ablatable mask of the invention
provides such advantages.
[0018] Ionic polysaccharides have been used in the application of
drugs by controlled release. Such ionic polysaccharides as chitosan
or sodium alginate are disclosed as useful in providing spherical
agglomerates of water-insoluble drugs in the Journal of
Pharmaceutical Sciences, volume 78, number 11, November 1989,
Bodmeier et al. Alginates have also been used as a depot substance
in active immunization, as disclosed in the Journal of Pathology
and Bacteriology, volume 77, (1959), C. R. Amies. Calcium alginate
gel formulations have also found use as a matrix material for the
controlled release of herbicides, as disclosed in the Journal of
Controlled Release, 3 (1986) pages 229-233, Pfister et al.
Alginates have also been used to form hydrogel foam wound
dressings, as disclosed in U.S. Pat. No. 4,948,575.
SUMMARY OF THE INVENTION
[0019] Compositions and a process for drug or diagnostic agent
delivery by topical, injection, or body cavity delivery are
disclosed. The pharmaceutical compositions in one embodiment of the
invention contain pharmacologically active medicaments which are
useful in providing treatments to ophthalmic areas of the mammalian
body requiring the controlled release application of a medicament
or requiring the administration of a diagnostic agent. In addition,
the compositions of the invention are useful, with or without the
inclusion of a medicament, as injectable compositions for depot
drug delivery, as a protective corneal shield, as a second skin for
application to wounds, as an ablatable corneal mask in a laser
keratectomy process, or as medical devices, for instance, in the
separation of organs, injured in surgical procedures or otherwise,
in order to prevent the formation of undesirable adhesions as part
of the healing process.
[0020] The compositions of the invention provide a physiologically
acceptable vehicle having a buffered pH and hypoosmotic,
hyperosmotic, or isoosmotic characteristics. The pH and osmotic
pressure is, preferably, made similar to bodily fluids, such as
lacrimal tears. The pH and osmotic pressure of lacrimal tears is
about pH 7.4 and 290 m0sm/kg. In addition, the pharmaceutical
compositions are, optionally, sterilized so as to insure that the
pharmaceutical compositions of the invention do not provide a
source of infection.
[0021] Polyphase systems are also useful and may contain
non-aqueous solutes, non-aqueous solvents, and other non-aqueous
additives. Homogeneous, polyphase systems can contain such
additives as water insoluble high molecular weight fatty acids and
alcohols, fixed oils, volatile oils and waxes, mono-, di-, and
triglycerides, and synthetic, water insoluble polymers without
altering the functionality of the system.
[0022] The compositions of the invention in a preferred embodiment
comprise aqueous mixtures of a film forming, water soluble polymer
and an ionic polysaccharide, optionally containing a latent
counter-ion to gel the polysaccharide upon release of the
counter-ion. Alternatively, the compositions of the invention can
comprise a two part aqueous system, one of which contains the ionic
polysaccharide and film forming polymer and the other part
containing an aqueous solution of a counter-ion.
[0023] The counter-ion can be provided in latent form by
microencapsulation in a heat sensitive medium, for instance, the
walls of the microcapsule can be made of mono-, di-, or
tri-glycerides or other natural or synthetic heat sensitive polymer
medium. Alternatively, ion exchange resins can be incorporated in
the compositions of the invention so as to release the desired
counter-ion upon contact with an environment opposite in pH to the
pH of the ion exchange resin. The aqueous mixture can be delivered
to the ophthalmic area of the mammalian body requiring treatment as
a low viscosity liquid at ambient temperatures. Activation of the
latent form of the counter-ion gels the aqueous mixture in situ.
The two part system can be separately applied to gel the mixture in
situ. Because the compositions of the invention are low viscosity
liquids at ambient temperatures, they easily pass to various
ophthalmic areas insuring maximum contact between exposed tissue
and the composition of the invention. The gel compositions of the
invention can be either peeled away or allowed to be absorbed over
time. The gels are gradually weakened upon exposure to mammalian
body pH conditions.
[0024] The useful film forming polymers are, preferably, water
soluble polymers such as those which have been used in ophthalmic
applications. The hydroxyalkyl cellulosics and methyl celluloses,
sodium hyaluronate, and polyvinyl alcohol are representative
polymers which have been found useful in ophthalmic
applications.
[0025] The useful ionic polysaccharides are natural polymers such
as chitosan, gellan gum or alginates. Aqueous solutions of alginate
ionic polysaccharides form gels upon contact with aqueous solutions
of counter-ions such as calcium, strontium, aluminum, etc. Aqueous
solutions of chitosan form gels upon contact with a metal
tripolyphosphate counter-ion. The discovery forming the basis of
this application is that when ionic polysaccharides are present in
aqueous solutions in admixture with film forming polymers and a
counter-ion, that such mixtures form useful gels. The osmolality of
which can be calculated by assuming that the film forming polymer,
if water soluble, does not contribute to the osmolality in the gel
state.
DETAILED DESCRIPTION OF THE INVENTION
[0026] It has been found that aqueous pharmaceutical vehicles
containing a film forming polymer and an ionic polysaccharide can
be gelled and rendered resistant to shear thinning by contacting
the mixture with a counter-ion. The gel compositions can be made
isotonic or iso-osmotic and adjusted to the pH of mammalian body
fluids, such as lacrimal tears. The pH and osmotic pressure of such
bodily fluids are 7.4 and 29U mOsm/kg, respectively. It is
advantageous to deliver a pharmacologically active medicament to an
area of the mammalian body requiring pharmacological treatment
under pH and osmotic pressure conditions which, for instance, match
those of bodily fluids. Optionally, the, pharmaceutical
compositions of the invention can be provided in a sterile
condition.
[0027] A complete listing of useful water soluble, film forming
polymers is not possible. Representative useful polymers are the
water soluble alkyl celluloses, i.e., methyl and ethyl cellulose;
the hydroxyalkyl celluloses, i.e., hydroxypropylemethyl cellulose
and hydroxyethyl cellulose; hyaluronic acid and water soluble salts
thereof, i.e., sodium hyaluronate; chondroitin sulfate and water
soluble salts thereof i.e., sodium chondroitin sulfate; polymers of
acrylamide, acrylic acid, and polycyanoacrylates; polymers of
methyl methacrylate and 2-hydroxyethyl methacrylate; polydextrose,
cyclodextrin; polydextrin; maltodextrin, dextran; polydextrose;
gelatin, collagen, natural gums, i.e. xanthan, locust bean, acacia,
tragacanth, carrageenan, and agar; derivatives of polygalacturonic
acid such as pectin; polyvinyl alcohol; polyvinyl pyrrolidone;
polyethylene glycol; and polyethylene oxide. A preferred film
forming agent is carboxymethyl ullulose and its sodium salt.
[0028] More complete descriptions of some of the preferred water
soluble, film forming polymers are as follows. Cyclodextrin also
known as cycloamylose is a cyclic oligosaccharide. Cyclodextrins
are produced by the enzyme conversion of prehydrolized starch to a
mixture of alpha, beta, and gamma cyclodextrins and some linear
dextrins. The cyclodextrins are composed of glucose units linked
together by alpha (1-4) glycosidic bonds.
[0029] Sodium hyaluronate also known as hyaluronic acid is composed
of repeating units of sodium glucuronate and N-acetylglucosamine.
Sodium hyaluronate was originally extracted from the comb of the
rooster. Hyaluronic acid is a common biological agent present in a
number of sources including the human umbilical cord. Sodium
hyaluronate can also be manufactured by fermentation of a strain of
streptococcus zooepidemicus.
[0030] Polydextrose is a randomly bonded condensation polymer of
dextrose which is only partially metabolized by mammals. The
polymer can contain a minor amount of bound sorbitol, citric acid,
and glucose.
[0031] Chondroitin sulfate also known as sodium chondroitin sulfate
is a mucopolysaccharide found in every part of human tissue,
specifically cartilage, bones, tendons, ligaments, and vascular
walls. This polysaccharide has been extracted and purified from the
cartilage of sharks.
[0032] Carrageenan is a linear polysaccharide having repeating
galactose units and 3,6 anhydrogalactose units, both of which can
be sulfated or nonsulfated, joined by alternating 1-3 and beta 1-4
glycosidic linkages. Carrageenan is a hydrocolloid which is heat
extracted from several species of red seaweed and irish moss.
[0033] Maltodextrins are water soluble glucose polymers which are
formed by the reaction of starch with an acid and/or enzymes in the
presence of water.
[0034] Further details of the composition and derivation of other
useful water soluble, film forming polymers can be found in the
HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, published by the American
Pharmaceutical Association Washington, D.C. copyright 1986,
incorporated herein by reference.
[0035] The gel forming ionic polysaccharides found useful in the
represent invention are hydrophilic colloidal materials and include
the natural gums such as gellan gum, alginate gums, i.e., the
ammonium and alkali metal of salts of alginic acid and mixtures
thereof. In addition, chitosan, which is the common name for
deacetylated chitin is useful. Chitin is a natural product
comprising poly-(N-acetyl-D-glucosamine). Gellan gum is produced
from the fermentation of pseudomonas elodea to yield an
extracellular heteropolysaccharide. The alginates and chitosan are
available as dry powders from Protan, Inc., Commack, N.Y. Gellan
gum is available from the Kelco Division of Merck & co., Inc.
San Diego, Calif.
[0036] Generally, the alginates can be any of the water-soluble
alginates including the alkali metal alginates, such as sodium,
potassium, lithium, rubidium and cesium salts of alginic acid, as
well as the ammonium salt, and the soluble alginates of an organic
base such as mono-, di-, or tri-ethanolamine alginates, aniline
alginates, and the like. Generally, about 0.2% to about 1% by
weight and, preferably, about 0.5% to about 3.0% by weight of
gellan, alginate or chitosan ionic polysaccharides, based upon the
total weight of the composition, are used to obtain the gel
compositions of the invention.
[0037] In general, the drug delivery composition of the invention
will contain about 0.01% to about 60% by weight of medicament or
pharmaceutical, about 1% to about 50% by weight of the water
soluble, film forming polymer, together with the above amounts of
ionic polysaccharide and the balance of water. In special
situations, these amounts of gel forming ionic polysaccharide and
water soluble, film forming polymer may be varied to increase or
decrease the gel properties.
[0038] Many polysaccharides may be used with the present invention
to enhance the physical properties of the gel. For example,
carboxymethylcellulose may reduce the rate of erosion of the
polymer when compared to the polymer without the
carboxymethylcellulose. In this regard, the carboxymethylcellulose
competes with the polymer for the association of the water
molecule, therefore, enhancing the stability of the gel to remain
intact when in an aqueous environment.
[0039] When polysaccharides are utilized to enhance the physical
properties of the gel, cross-linking of the polysaccharide is not
necessary.
[0040] Polysaccharides that have not been crosslinked, and can be
used to enhance the physical properties of the gel, include
hydroxyalkyl cellulose and methylcellulose. More specifically, the
useful polysaccharides are natural cellulose, hyaluronic acid and
water soluble salts thereof, i.e. sodium hyaluronate, chondroitin
sulfate and water soluble salts thereof, i.e. sodium chondroitin
sulfate; polydextrose, cyclodextrin, polydextrin, maltodextrin,
dextran; polydextrose; gelatin, collagen, natural gums, i.e.
xanthan, locust bean, acacia, tragacanth, carrageenan, and agar,
and derivatives of polygalacturonic acid such as pectin. A
preferred polysaccharide is carboxymethylcellulose.
[0041] The drug delivery composition of the invention will contain
about a 0.1% to about 25% by weight of the non-crosslinked
polysaccharide to enhance the physical properties of the gel.
[0042] If an irreversible gel is required or an elastic gel, that
is, one that retains its shape, cross-linking is required.
Cross-linking is the physical, co-valent or ionic bonding of two or
more molecules of the same polymer.
[0043] Any cross linking agent having more than one functional
group wherein the function group is either chemical or ionic may be
utilized to cross link the polysaccharides described above.
[0044] As known in the art, cross linking can occur between
molecules of similar polymers by physical reaction as long as
appropriate functional groups are present on the polymers.
[0045] Useful counter-ions for gelling the gellan gum or alginate
ionic polysaccharides in combination with the film forming, water
soluble polymer compositions of the invention are cationic gelling
agents, preferably, comprising a divalent or trivalent cation.
Useful divalent cations include the alkaline earth metals,
preferably, selected from the group consisting of calcium and
strontium. Useful trivalent cations include aluminum. The most
preferred counter-ions for gelling gellan gum or alginate ionic
polysaccharides are contained in ionic compounds selected from
pharmaceutically-acceptable gluconates, flourides, citrates,
phosphates, tartrates, sulfates, acetates, borates, chlorides, and
the like having alkaline earth metal cations such as calcium and
strontium. Especially preferred counter-ion containing inorganic
salts for use as ionic polysaccharide gelling agents include such
inorganic salts as the chloride salts, such as strontium chloride,
calcium chloride, and mixtures thereof. Generally, a molar ratio of
counter-ion to gellan, 5 chitosan or alginate of about 1:1 to about
10:1, preferably, about 2:1 to about 5:1, and, most preferably,
about 3:1 to about 5:1 is used.
[0046] While the counter-ion, such as calcium or other counter-ions
may be obtained by contact of the compositions of the invention
with bodily fluids, it is preferred that a counter-ion in latent
form be used in combination with the gellan gum or alginate ionic
polysaccharide and film forming, water soluble polymer compositions
of the invention. Alternatively, a counter-ion can be combined with
the ionic polysaccharide and water soluble, film forming polymer
compositions of the invention utilizing a two part system in which
the counter-ion is topically or otherwise applied to the
compositions of the invention subsequent to their topical or other
application.
[0047] Incorporation of the counter-ion in a latent form together
with the ionic polysaccharide and film forming, water soluble
polymer compositions of the invention may be accomplished by either
encapsulating an aqueous solution of one of the counter-ion gelling
agents, previously described above or by the incorporation of the
counter-ion gelling agent into a matrix which provides for the
controlled, slow-release of gelatin-encapsulated controlled release
compositions disclosed in U.S. Pat. No. 4,795,642, incorporated
herein by reference, disclose the preparation of a gelatin shell
encapsulating a controlled release formulation in which the gelatin
composition includes calcium chloride as the gelling agent.
Alternatively, the counter-ion can be incorporated as an aqueous
solution of a cationic gelling agent encapsulated in a vesical
composed, for instance, of alphatocopherol, as disclosed in U.S.
Pat. No. 4,861,580, incorporated herein by reference.
[0048] Generally, aqueous compositions comprising chitosan can be
gelled with multivalent anion gelling agents, preferably,
comprising a metal polyphosphate, such as an alkali metal or
ammonium polyphosphates, pyrophosphates, or metaphosphates.
Representative metaphosphate, pyrophosphate, and polyphosphate
gelling agents include sodium and potassium, polyphosphates, sodium
and potassium pyrophosphates, sodium and potassium metaphosphates,
and sodium and ammonium (mono-, di-, tri-) phosphates.
[0049] With specific reference to the use of the compositions of
the invention as ophthalmic drug delivery compositions, laser
ablatable shields, or corneal protective compositions, it is noted
that, generally, for the avoidance of adverse physiological effects
to the eye, it is desirable that the pH and osmolality of the
pharmaceutical vehicle be matched to the pH and osmolality of the
eye. In addition, it is noted that a large percentage of drugs
administered to the eye are lost as a result of lacrimal drainage.
This applies especially in situations in which a liquid composition
containing a pharmacologically active medicament is applied to the
cornea of the eye. Accordingly, in such cases, only a small
fraction of the pharmaceutical composition administered to the eye
remains in contact with the cornea for a few minutes and an even
smaller fraction penetrates into the cornea. To overcome these
disadvantages, it is known to use viscous solutions, gels,
ointments, or solid eye implants containing pharmacologically
active medicaments. While progress has been made in the delivery of
drugs by the use of solid implants, many patients find it difficult
to tolerate the introduction of the implants into the conjunctival
areas.
[0050] To solve this problem, drug delivery vehicles which are
liquid at room temperature and assume a semi-solid form at human
body temperature have been proposed, such as those described in
U.S. Pat. No. 4,188,373, which disclose the use of PLURONIC.RTM.
polyols. In U.S. Pat. No. 4,861,760 and U.S. Pat. No. 4,474,751,
ophthalmic drug delivery systems are disclosed which show
liquid-gel phase transitions. In the '751 Patent, polymers are
disclosed which are tetra substituted derivatives of
ethylenediamine, propylenediamine, butylenediamine,
pentylenediamine, or hexylenediamine. These are described as block
copolymers of poly(oxypropylene) and poly(oxyethylene) of various
chain lengths. These polymers were utilized as aqueous drug
delivery vehicles contain from 10% to 50% by weight of polymer
based on the weight of the total drug delivery vehicle. In the '760
Patent, the liquid-gel phase transition compositions for
ophthalmological use contain polymers which form gels at
concentrations 10-100 fold lower than those used in systems such as
the '751 Patent, involving thermogelation. Accordingly, the drug
delivery vehicles for the '760 Patent are said to be very well
tolerated by the eye. The polymers utilized in the drug delivery
vehicles of the '760 patent are described as polysaccharides
obtained by fermentation of a microorganism.
[0051] The drug delivery vehicles and corneal protective shield
compositions of the invention are an improvement over those
compositions used in prior art methods of ophthalmological drug
delivery in that the compositions can be not only optimized for
physiological tolerance in the eye by formulating the vehicles
useful as drug delivery compositions so as to have isoosmotic,
hyperosmotic, and hypoosmotic characteristics in the gel state but
are made more useful because of increased resistance to shear
thinning, as the result of higher gel strength. These advantages
are obtained by the incorporation of an ionic polysaccharide in
admixture with a film forming, water soluble polymer. By matching
the osmolality of the drug delivery compositions of the invention,
for instance, to those of the lacrimal fluid of the eye, it is
possible to eliminate burning or other discomfort upon application
of the drug delivery vehicles of the invention to the eye. The gel
compositions formed upon contact with a counter ion for the ionic
polysaccharide allow retention of the gel at the desired locus for
longer intervals thus increasing the efficiency of action of the
delivered drug. Drugs or diagnostic agents which can be
administered by means of the drug delivery vehicles according to
the invention are, for example:
[0052] Antibacterial substances such as beta-lactam antibiotics,
such as cefoxitin, n-formamidoylthienamycin and other thienamycin
derivatives, tetracyclines, chloramphenicol, neomycin,
carbenicillin, colistin, penicillin G, polymyxin B, vancomycin,
cefazolin, cephaloridine, chibrorifamycin, gramicidin, bacitracin
and sulfonamides;
[0053] aminoglycoside antibiotics such as gentamycin, kanamycin,
amikacin, sisomicin and tobramycin;
[0054] nalidixic acid and its analogs such as norfloxacin and the
antimicrobial combination fluoroalanine/pentizidone, nitrofurazones
and analogs thereof;
[0055] antihistaminics and decongestants such as pyrilamine,
chlorpheniramine, tetrahydrazoline, antazoline and analogs thereof;
mast-cell inhibitors of histamine release, such as cromolyn;
[0056] anti-inflammatories such as cortisone, hydrocortisone,
hydrocortisone acetate, betamethasone, dexamethasone, dexamethasone
sodium phosphate, prednisone, methylprednisolone, medrysone,
fluorometholone, prednisolone, prednisolone sodium phosphate,
triamcinolone, indainethacin, sulindac, its salts and its
corresponding sulfides, and analogs thereof;
[0057] miotics and anticholinergics such as echothiophate,
pilocarpine, physostigmine salicylate, diisopropylfluorophosphate,
epinephrine, dipivaloylepinephrine, neostigmine echothiopate
iodine, demecarim bromide, carbamoyl choline chloride,
methacholine, bethanechol, and analogs thereof;
[0058] mydriatics such as atrophine, homatropine, scopolamine,
hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine,
cyclopentolate, oxyphenonium, eucatropine, and analogs thereof;
[0059] Other drugs can be used in the treatment of conditions and
lesions of the eyes such as:
[0060] antiglaucama drugs, for example, timalol, and especially its
maleic salt and R-timolol and a combination of timolol or R-timolol
with pilocarpine, as well as many other adrenergic agonists and/or
antagonists: epinephrine and an epinephrine complex, or prodrugs
such as bitartrate, borate, hydrochloride and dipivefrine
derivatives; carbonic anhydrase inhibitors such as acetazolamide,
dichlorphenamide, 2-(p-hydroxyphenyl)-thiothiophenesulfonamide,
6-hydroxy-2-benzothiazolesu- lfonamide; and
6-pivaloyloxy-2-benzothiazolesulfonamide;
[0061] anitparasitic compounds and/or anti-protozoal compounds such
as ivermectin, pyrimethamine, trisulfapidimidine, clindamycin and
corticosteroid preparations;
[0062] compounds having antiviral activity such as acyclovir,
5-iodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A),
trifluorothymidine, interferon, and interferon-inducing agents such
as poly I:C;
[0063] antifungal agents such as amphotericin B, nystatin,
flucytosine, natamycin and miconazole;
[0064] anesthetic agents such as etidocaine cocaine, benoxinate,
dibucaine hydrochloride, dyclonine hydrochloride, naepaine,
phenacaine hydrochloride, piperocaine, proparacaine hydrochloride,
tetracaine hydrochloride, hexylcaine, bupivacaine, lidocaine,
mepivacaine and prilocaine;
[0065] ophthalmic diagnostic agents, such as:
[0066] (a) those used to examine the retina such as sodium
fluorescein;
[0067] (b) those used examine the conjunctiva, cornea and lacrimal
apparatus, such as fluorescein and rose bengal; and
[0068] (c) those used to examine abnormal pupillary responses such
as methacholine, cocaine, adrenaline, atropine, hydroxyamphetamine
and pilocarpine;
[0069] opthalmic agents used as adjuncts in surgery, such as
alpha-chymotrypsin and hyaluronidase;
[0070] chelating agents such as ethylenediaminetetraacetic acid
(EDTA) and deferoxamine;
[0071] immunosuppressants and anti-metabolites such as
methotrexate, cyclophosphamide, 6-mercaptopurine and azathioprine
and combinations of the compounds mentioned above, such as
antibiotics/antiinflammatories combinations such as the combination
of neomycin sulfate and dexamethasone sodium phosphate and
combinations concomitantly used for treating glaucoma, for example,
a combination of timolol maleate and aceclidine.
[0072] In general the drug delivery composition of the present
invention will contain from about 0.01% to about 60% by weight of
the medicament or pharmaceutical, from about 1% to about 50% of the
polymer, the above amounts of ionic polysaccharide, and the balance
water. In special situations, however, the amounts may be varied to
increase or decrease the dosage schedule.
[0073] If desired, the ophthalmic drug delivery vehicle, laser
ablatable corneal mask, and corneal protective compositions of the
invention may also contain preservatives, cosolvents, suspending
agents, viscosity enhancing agents, ionic-strength and osmolality
adjustors and other excipients in addition to the medicament and
buffering agents. Suitable water soluble preservatives which may be
employed in the inventive drug delivery vehicle are sodium
bisulfite, sodium thiosulfate, is ascorbate, benzalkonilirn
chloride, chlorabutanol, thimerosal, phenylmercurioborate,
parabens, enzylalcohol phenylethanol and others. These agents may
be present, generally, in amounts of about 0.001% to about 5% by
weight and, preferably, in the amount of about 0.01 to about 2% by
weight.
[0074] Suitable water soluble buffering agents are alkali or alkali
earth carbonates, phosphates, bicarbonates, citrates, borates,
acetates, succinates and the like, such as sodium phosphate,
citrate, borate, acetate, bicarbonate, carbonate and tromethamine
(TRIS). These agents are present in amounts sufficient to maintain
the pH of the system at 7.4.+-.0.2 and preferably, 7.4. As such the
buffering agent can be as much as 5% on a weight basis of the total
composition.
[0075] Representative buffering agents or salts useful in
maintaining the pH at about 7.4.+-.0.2 are alkali or alkali earth
carbonates, chlorides, sulfates, phosphates, bicarbonates,
citrates, borates, acetates and succinates. Representative
preservatives are sodium bisulfite, sodium thiosulfate, ascorbate,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric
borate, parabens, benzylalcohol and phenylethanol.
[0076] The corneal mask compositions of the invention are an
improvement over the prior art thermo-reversible gels containing a
polyoxyalkylene polymer as the sole polymer, in that the
compositions of the invention provide greater gel strength because
they are more resistant to shear thinning and are characterized as
thermally-irreversible. These advantages are obtained by the
incorporation of an ionic polysaccharide in admixture with a water
soluble, film forming polymer. They can be optimized for optimum
physiological tolerance in the eye by formulating the compositions
so as to have a neutral pH and isotonic characteristics. These
former advantages are obtained by the incorporation of an ionic
polysaccharide in a mixture with a water soluble, film forming
polymer. By matching the osmolality and pH of the laser ablatable
corneal mask compositions of the invention to those of the lacrimal
fluid of the eye, it is possible to eliminate burning or other
discomfort upon application of the corneal mask of the invention to
the eye. The higher gel strength compositions upon contact with a
counter-ion allow retention of the gel as an in situ formed corneal
mask for long intervals.
[0077] The preparation of the drug delivery compositions, corneal
protective compositions, and ablative corneal shield compositions
of the invention is described below. The Examples which follow were
prepared, generally, in accordance with the following preparation
procedure. A mixture of a water soluble, film forming polymer and
ionic polysaccharide is stirred or shaken in admixture with the
aqueous buffer solution to bring about a more rapid solution of the
polymer. The pharmacologically active medicaments and various
additives such as salts and preservatives can subsequently be added
and dissolved. In some instances the pharmacologically active
substance must be suspended since it is insoluble in water. The pH
of 7.4.+-.0.2 is obtained by of appropriate buffering agents.
[0078] The following Examples illustrate the various aspects of the
invention but are not intended to limit its scope. Where not
otherwise specified throughout this specification and claims,
temperatures are given in degrees centigrade and parts,
percentages, and proportions are by weight.
EXAMPLE 1
[0079] In this Example there is described a composition of the
invention suitable for ophthalmic use as a laser ablatable corneal
mask or protective corneal shield. This composition was
characterized as iso-osmotic and neutral in pH. An aqueous solution
was made by dissolving the hydroxypropyl methyl cellulose in
aqueous buffer solution together with the sodium alginate. The
hydroxypropyl methyl cellulose was characterized as grade F50LV
Premium, obtained from The Dow Chemical Company. The sodium
alginate, characterized as high viscosity grade HF 120 was obtained
from Protan, Inc. The proportions of ingredients in percent by
weight are as follows:
1 Hydroxypropyl methyl cellulose 2.0 Sodium Alginate, high
viscosity 1.0 Glycerin 0.25 Boric acid-sodium borate buffer
96.75
[0080] The boric acid-sodium borate buffer was prepared as follows:
In a two liter volumetric flask, 24.7 grams of boric acid and 3.8
grams of sodium borate decahydrate were dissolved in two liters of
purified water, Usp. The formulation of this Example had a measured
pH of 7.2 and an osmolality of 277 MOSM/Kg. A small amount of the
formulation was placed on a glass slide and evenly spread so as to
create a thin film. The film was subsequently sprayed with an
aqueous solution of calcium chloride having a concentration of 21
to about 5% by weight. The film was characterized as strong,
transparent, and resembled a thin, soft hydrophilic corneal contact
lens which would be useful as a protective corneal mask or as an
ablatable mask useful in laser keratectomy.
[0081] The product was further characterized by measuring the
average penetration in millimeters determined using a Precision
Penetrometer with a 1/4 size (9.38 grams, ASTM D-1043) cone and
plunger. The penetration of the aqueous solution of polymers
prepared above was greater than 20 mm. Subsequent to treatment of
this solution with a few drops of a 2%-5% by weight aqueous
solution of calcium chloride, a gel was formed in which the
penetration was reduced to 5 mm.
EXAMPLES 2 AND 3
[0082] In these Examples there are described compositions of the
invention for ophthalmic use as a corneal protective mask or as a
laser ablatable corneal mask. Utilizing the same procedure as
described in Example 1, an aqueous composition containing sodium
hyaluronate and sodium alginate was prepared in two separate
compositions. Sodium hyaluronate is commercially available from
Meiji Seika Inc. Example 2 was hypoosmotic having an osmotic
pressure of 249 mOSM/Kg and Example 3 was hyperosmotic having an
osmotic pressure of 319 mosm/Kg. Both compositions were
characterized as neutral in pH. The formulations have the following
proportions by weight:
2 Example 2 Example 3 Sodium hyaluronate 1.0 1.0 Sodium Alginate,
high viscosity 1.0 1.0 Glycerin 96.0 0.5 Boric acid-sodium borate
buffer 98.0 97.5
[0083] These compositions were evaluated as described in Example 1
by spreading a small amount of the formulation a glass slide and
subsequently spraying the coated slide with a 5% by weight aqueous
solution of calcium chloride. Similar strong, transparent, soft
films were obtained which would be useful as a protective corneal
shield or as a laser ablatable corneal mask.
[0084] Example 3 was further characterized by measuring the average
penetration in millimeters determined using a Precision
Penetrometer with a 1/4 size (9-38 grams, ASTM D-1043) cone and
plunger. The penetration of the aqueous solution of polymers
prepared above was greater than 20 mm. Subsequent to treatment of
this solution with a few drops of a 2%-5% by weight aqueous
solution of calcium chloride, a gel was formed in which the
penetration was reduced to 5.9 mm.
EXAMPLE 4
[0085] In this Example there is described a composition of the
invention for ophthalmic use as a protective corneal shield or a
laser ablatable corneal mask. An aqueous mixture comprising
polyvinyl pyrrolidone and sodium alginate, high viscosity was
prepared as follows: The percentages below are by weight.
3 Polyvinyl pyrrolidone 0.8 Sodium Alginate, high viscosity 1.0
Glycerin 0.3 Boric acid-sodium borate buffer 97.9
[0086] The composition was characterized as neutral in pH having a
pH of 7.2. The composition was hypoosmotic having an osmolality of
270 mOsm/Kg.
[0087] The product was further characterized by measuring the
average penetration in millimeters determined using a Precision
Penetrometer with a 1/4 (9.38, ASTM D-1043) cone and plunger. The
penetration of the aqueous solution of polymers prepared above was
greater than 20 mm. Subsequent to treatment of this solution with a
few drops of a 5% by weight aqueous solution of calcium chloride, a
gel was formed in which the penetration was reduced to 4.1 mm.
EXAMPLE 5
[0088] In this Example there is described a composition of the
invention for ophthalmic use as a laser ablatable mask or as a
protective corneal shield. In accordance with the procedure of
Example 1, chondroitin sulfate and sodium alginate were prepared as
an aqueous solution utilizing the percentages by weight indicated
below.
4 Sodium Chondroitin sulfate 2.0 Sodium Alginate, high viscosity
1.0 Glycerin 0.3 Boric acid-sodium borate buffer 96.7
[0089] The aqueous solution was characterized as neutral in pH
having a pH of 7.0. The aqueous solution was hyperosmotic having a
measured osmolality of 354 mOsm/Kg. The penetration utilizing a
Precision Penetrometer with a 1/4 size cone, as described above,
was greater than 20 mm prior to treatment with a few drops of a
2%-5% aqueous solution of calcium chloride. Subsequent to treatment
with the aqueous calcium chloride solution, a gel was formed in
which the penetration was reduced to 5.1 mm.
EXAMPLES 6-10
[0090] Ion exchange resin beads sold under the trade name Duolite
were treated so as to incorporate calcium by first treating a 30
gram sample of the ion exchange resin with a solution of 0.1 molar
hydrochloric acid so as to allow for the exchange of protons for
sodium. After three washings with 0.1 molar hydrochloric acid, the
beads were washed with water and then washed twice with a 2%
aqueous solution of calcium chloride. Each of the washing steps
took place over a period of 16 hours (overnight). The beads were
thereafter filtered and washed with water utilizing coarse filter
paper and a Buchner glass filter assembly. The beads were then left
overnight in a desiccator to dry. The dried beads of ion exchange
resin which were obtained are utilized in the amount of 2 grams to
fill a first compartment (close to the needle of the syringe) of a
glass syringe utilized to apply liquids and dry materials. The
syringe is sold under the trademark Hypak. Into the second
compartment of the syringe, there is placed successively the
solutions of Examples 1-5. Pushing the plunger of the syringe
forward results in mixing the solution of Examples 1-5 with the ion
exchange beads. After 5 to 10 minutes subsequent to mixing, the
mixture is expelled from the syringe. After an additional 15
minutes the expelled material forms (without drying) a strong,
transparent gel on the substrate on which it is expelled.
EXAMPLES 11-15
[0091] These examples describe the successive application of an
aqueous solution of Examples 1 and 3-5 to the cornea of a rabbit
eye and the conversion of the aqueous liquid to a gel by the
application of a 10% calcium chloride solution having a pH of 6.9.
The calcium chloride solution is applied to the concave surface of
a contact lens prior to contacting the surface of the aqueous
liquid coating applied upon the cornea of the rabbit eye. After
applying the compositions of Examples 1 and 3-5 to the cornea of a
rabbit while place under general anesthesia, a liquid coating is
formed upon the cornea. Subsequently, a 10% aqueous solution of
calcium chloride is applied to the concave surface of a hard
contact lens and the contact lens is placed over the coating on the
cornea of the rabbit eye. The time required for the formation of a
gel is less than 5 minutes. Thereafter, the contact lens is removed
to expose a perfectly smooth and optically clear gelled surface of
the composition of Examples 1 and 3-5. Excimer laser keratectomy is
thereafter performed utilizing an argon fluoride excimer laser (193
mm). Further details of the excimer laser keratectomey process can
be found in Archives of Ophthalmology, Vol. 106, Feb., 1988,
entitled "Excimer Laser Keratectomy with a Rotating-slit Delivery
System," Hanna et al, incorporated herein by reference.
EXAMPLES 16-18
[0092] These Examples describe drug compositions of the invention
suitable for ophthalmic use in comparison with Control Examples in
in-vitro tests for drug release.
[0093] EXAMPLE 16 CONTROL--Forming no part of this invention
5 Percentage by weight Timolol maleate 0.50 Poloxamer 407 16.00
Sodium phosphate, monobasic, monohydrate 0.15 Sodium phosphate,
dibasic 0.63 Glycerin 0.75 Sterile water 81.97
[0094] An eye drop or medicated contact lens composition was
prepared using a suitable glass container in which the sodium
phosphate salts and glycerin were dissolved in sterile water. The
polymer was next mixed with the buffer solution at 65.degree. C.
for 1 hour, followed by a further 2-3 hours in cold conditions. To
a fixed weight of the polymer solution was added and dissolved, an
accurate amount to timolol maleate (Huhtamaki OY Pharmaceuticals,
Turku, Finland) to make a 0.5% w/w concentration.
[0095] EXAMPLE 17 CONTROL--Forming no part of this invention
6 Percentage by weight Timolol maleate 0.50 Poloxamer 17.00 Sodium
alginate, high viscosity 1.50 Sodium borate, decahydrate 0.16
Glycerin 1.00 Sterile water 81.27
[0096] A medicated contact lens was prepared using a suitable glass
container in which the sodium borate, boric acid and glycerin were
dissolved in sterile water. Sodium alginate was sprinkled in with
stirring to form a uniform paste. The polymer was next mixed with
this mixture at 65.degree. C. for 1 hour, and for a further 2-3
hours under cold conditions. To a fixed weight of the
polymer-alginate solution, was added and dissolved, and accurate
amount of timolol maleate (Huhtamaki OY Pharmaceuticals, Turku,
Finland) to make a 0.5% w/w concentration.
EXAMPLE 18
[0097]
7 Percentage by weight Timolol maleate 0.50 Sodium hyaluronate 1.00
Sodium alginate, high viscosity 1.00 Sodium borate, decahydrate
0.19 Glycerin 0.50 Sterile water 95.60
[0098] A medicated contact lens was prepared using a suitable glass
container in which the sodium borate, boric acid and glycerin were
dissolved to make a solution in sterile water. Sodium alginate and
sodium hyaluronate were sprinkled into this solution with
continuous stirring to form a uniform paste. To a fixed weight of
the hyaluronate-alginate mixture, there was added and dissolved an
amount of timolol maleate (Huhtamaki OY Pharmaceuticals, Turku,
Finland) to make a 0.5% w/w concentration.
[0099] An in-vitro evaluation of the contact lens of Examples 16-18
was carried out as follows: The medicated contact lens was prepared
by accurately weighing a big drop of the formulation on a glass
microscopic slide (2'.times.1"). Two drops of a 5% by weight
calcium chloride counter-ion solution was next placed on the
formula drop. After 1 minute, the excess calcium chloride was
blotted away from the now formed corneal contact lens.
[0100] The glass slide with contact lens in place was next placed
at the bottom of the 1 liter dissolution vessel containing 500 ml
of purified water, maintained at 37.degree. C. The dissolution
experiment was carried out as per method 2 (paddle) of the United
States Pharmacopoeia XXII, page 1579, The United States
Pharmacopoeial Convention, Mack Publishing Company, 1990. Paddle
stirring rate was 50 revolutions per minute.
[0101] At regular time intervals, aliquots were removed from the
vessels for analysis by High Pressure Liquid Chromatography. Six
vessels were used for each formulation (n=6).
8 TIMOLOL MXLEATE DELIVERY FROM CORNEAL LENSES n = 6 TIME
CUMULATIVE % OF TIMOLOL RELEASED (SD) Example 16 Example 17 Example
18 0 0.0 0.0 0.0 10 min 100.0 -- -- 30 min 100.0 -- -- 60 min 100.0
-- -- 120 min -- 80.3 (12.0) 77.9 (6.2) 240 min -- 90.0 (3.8) 93.9
(2.2) 360 min -- 90.1 (3.1) 94.9 (2.5) 480 min -- 95.7 (3.3) 97.5
(2.9)
[0102] It was observed that the drug is released in-vitro, by
diffusion and not by the erosion of the lens. Approximately 80% of
timolol maleate is released in 1 hour and the remaining amount
gradually diffuses out in 3 to 4 hours. The lenses remained intact
48 hours after the start of the experiment. On the other hand, when
0.9% sodium chloride was used in place of purified water as the
dissolution medium, the drug was released by both erosion and
diffusion, within the first hour. The lenses are first reduced in
size and then dissolved away within 6 hours. This erosion is
dependent on the replacement of calcium ions (in the lens) with
sodium ions (from the dissolution medium). The break up in-vivo is
expected to be slow and gradual and is dependent on the sodium
concentration in the tear fluid.
[0103] In the following examples there are described compositions
having multiple uses. For instance, they may be used as vehicles
for drug delivery by topical application or by injection or useful
as a protective corneal shield or in a process for excimer laser
keratectomy as a laser ablatable corneal mask.
[0104] The procedure for preparation and the polymeric materials
utilized in the composition are those described in Example 1. The
TRIS-hydrochloride buffer utilized in this composition was prepared
utilizing the ingredients and proportions by weight indicated
below.
9 TRIS (trcanethamine, USP) 0.6058 Concentrated hydrochloric acid
0.4123 Purified water, USP 100
[0105] The composition was found to have a pH of 7.4 and an
osmolality in mOsm/kg of 83. The procedure for preparation of this
buffer is as follows: The weighed amount of TRIS was placed in a
2-liter volumetric flask and about 1 liter of purified water was
added to the flask. The concentrated hydrochloric acid was added
and the solution was made up to volume by adding the remaining
water in the formulation.
[0106] The calcium based counter-ion solution utilized to gel the
inventive drug delivery compositions of Examples 19-22 was prepared
utilizing the following proportion of ingredients in proportions by
weight.
10 Calcium chloride, dehydrate 1.2 Calcium gluconate, anhydrous
3.0
[0107] The composition had a pH of 6.88 and an osmolality in
mOsm/kg of 299. The calcium based counter-ion solution was prepared
as follows: The Calcium gluconate and calcium chloride in the
required amount were placed in a 200 ml volumetric flask.
Approximately 100 ml of water were added to partially dissolve the
salts. The solution was, thereafter, warmed to 80.degree. C. to
facilitate dissolution. The solution was cooled and the remaining
water was added to make up to 200 ml volume.
EXAMPLE 19
[0108] A composition containing both sodium alginate and sodium
hyaluronate was prepared for use as a vehicle for drug delivery, a
laser ablatable corneal mask, a protective corneal shield, or a
composition for use in preventing post-surgical adhesions. The
proportions by weight are as follows:
11 Sodium hyaluronate 0.5 Sodium alginate 1.0 Sodium chloride 0.54
TRIS-hydrochloride Buffer 97.96
[0109] The composition was found to have a pH of 7.6 and an
osmolality of 297 mosm/kg prior to treatment with calcium ions by
the addition of the previously described calcium based counter-ion
solution. After treatment with calcium ions the osmolality was 302
mosm/kg.
[0110] The product was further characterized by measuring the
average penetration in millimeters as determined using a precision
penetrometer with a 1/4 size (9.38 grams, ASTM D-1043) cone and
plunger. The penetration in millimeters prior to treatment of the
composition of Example 19 with calcium ions was greater than 20 mm.
After treatment with calcium ions the penetration was 4.77 mm.
EXAMPLE 20
[0111] composition containing polyvinyl pyrrolidone and sodium
alginate was prepared which is useful for the same applications as
that formulation described in Example 19. The proportions in
percent by weight of the ingredients of the composition are as
follows:
12 Polyvinyl pyrrolidone 0.8 Sodium alginate 1.0 Sodium chloride
0.62 TRIS-hydrochloride buffer 97.58
[0112] The composition had a pH of 7.59 and as osmolality in
mOsm/kg prior to treatment with calcium ions of 320 and after
treatment with calcium ions of 289.
[0113] The penetration utilizing a precision penetrometer as
further described in Example 19 was greater than 20 prior to
treatment of the composition with calcium ions and 6.57 after
treatment with calcium ions.
EXAMPLE 21
[0114] A composition useful for the same uses as stated in Example
19 containing a combination of sodium alginate and chondroitin
sulfate was prepared.
[0115] The proportions of ingredients in percent by weight are as
follows:
13 Sodium Chondroitin sulfate 2.0 Sodium alginate 1.0 Sodium
chloride 0.35 TRIS-hydrochloride buffer 96.65
[0116] The composition had a pH of 7.9 and an osmolality expressed
in mOsm/kg of 301 prior to treatment with calcium ions and 272
after treatment with calcium ions.
[0117] The penetration utilizing a precision penetrometer as
further described in Example 19 was found to be greater than 20 mm
prior to treatment with calcium counter-ions and 4.57 upon
treatment with calcium ions utilizing the calcium counter-ions
solution prepared above.
EXAMPLE 22
[0118] A composition useful for the same uses as stated in Example
19 containing a combination of hydroxypropyl methyl cellulose, and
sodium alginate was prepared. The proportions of ingredients and
their percent by weight are as follows:
14 Hydroxypropyl methyl cellulose 2.0 Sodium alginate 1.0 Sodium
chloride 0.6 TRIS-hydrochloride buffer 96.7
[0119] The composition had a pH of 7.59 and an osmolality expressed
in mOsm/kg of 326 prior to treatment with calcium ions and 301
after treatment with calcium ions.
[0120] While this invention has been described with reference to
certain specific embodiments, it will be recognized by those
skilled in the art that many variations are possible without
departing from the scope and spirit of the invention, and it will
be understood that it is intended to cover all changes and
modifications of the invention, disclosed herein for the purposes
of illustration, which do not constitute departures from the spirit
and scope of the invention.
* * * * *