Title: Composition and method for treating glaucoma
United States Patent: 6,369,116
Inventors: Wong; Vernon (Menlo Park, CA); Peng; Lin (San Jose, CA)Assignee: Oculex Pharmaceuticals, Inc. (Sunnyvale, CA)
Appl. No.: 221002Filed: December 23, 1998
Implants and methods are provided for modulating wound healing and controlling infection to improve the success of glaucoma filtration surgery. Formulations of one or more therapeutically active agents and a biodegradable polymer provide a substantially constant rate of release for an extended period of time.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
As shown herein, the success rate of GFS can be improved
dramatically by the controlled and sustained administration of appropriate
therapeutic agents to the episcleral-subconjunctival interface proximal to
the surgical site, using an improved formulation of biodegradable
implants. The implants comprise a pharmaceutically acceptable polymeric
composition and are formulated to release one or more pharmaceutically
active agents over an extended period of time and at a substantially
constant rate of release, to provide a therapeutically effective dosage of
the agent or agents directly to the surgical site to inhibit the
inflammatory response. Thus, with a single administration therapeutic
agents will be made available at the site where they are needed and will
be maintained for an extended period of time, rather than subjecting the
patient to repeated injections or, in the case of self-administered drops,
ineffective treatment with only limited bursts of exposure to the active
agent or agents.
Pharmaceutically acceptable biodegradable polymeric compositions that may
be employed in the implants of the present invention may be polymers of
hydroxyaliphatic carboxylic acids, either homo- or copolymers, and
polysaccharides. Included among the polyesters of interest are polymers of
D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. By employing the L-lactate or
D-lactate, a slowly biodegrading polymer is achieved, while degradation is
substantially enhanced with the racemate. In a particularly preferred
embodiment, copolymers of glycolic and lactic acid are used, where the
rate of biodegradation is controlled by the ratio of glycolic to lactic
acid. The most rapidly degraded copolymer has roughly equal amounts of
glycolic and lactic acid. Homopolymers, or copolymers having ratios other
than equal, are more resistant to degradation.
Equally important to controlling the biodegradation of the polymer and
hence the extended release profile of the implant is the relative average
molecular weight of the polymeric composition employed in the implant.
Different molecular weights of the same or different polymeric
compositions may be included in the implant to modulate the release
profile. In the preferred embodiment, the relative average molecular
weight of the polymer will range from about 9 to about 60 kD, usually from
about 10 to about 54 kD, more usually from about 12 to about 45 kD, and
most preferably from about 15 to about 40 kD. The implant is formulated to
release the active agent(s) over a period of at least about three weeks,
more usually at least about four to six weeks, and usually not more than
about one year, more usually not more than about three to six months. The
formulation also provides for a substantially constant and uniform rate of
release, which will usually not vary by more than about 100% over the
desired period of time, more usually by not more than about 50%.
The release of drug from the implant can also be modulated by the addition
of a release modulator. The release modulator is an agent that alters the
release of a drug from a biodegradable implant in a defined manner.
Release of a hydrophobic agent is increased by inclusion of an accelerator
in the implant, while retardants are included to decrease the release rate
of hydrophilic agents. Hydrophilic agents are those compounds which have
at least about 100 .mu.g/ml solubility in water at ambient temperature.
Hydrophobic agents are those compounds which have less than about 100 .mu.g/ml
solubility in water at ambient temperature. The release modulator may be
physiologically inert, or may also be a therapeutically active agent.
With this embodiment of the invention, the rate of release of the
therapeutically active agent is controlled by the rate of transport
through the polymeric matrix of the implant, and by the action of the
modulator. The transport of drug through the polymer barrier is also
affected by drug solubility, polymer hydrophilicity, extent of polymer
cross-linking, expansion of the polymer upon water absorption so as to
make the polymer barrier more permeable to the drug, geometry of the
implant, and the like. At high drug loadings, i.e. at a loading
concentration above the theoretical percolation threshold, percolation
theory predicts the potential for drug leaching from the drug delivery
system matrix. In such cases release modulators are useful to slow down
the leaching process.
Active agents which may find use in the present invention to improve the
post-operative success of glaucoma filtration surgery include, but are not
limited to, the following therapeutic classes: Ace-inhibitor; endogenous
cytokines that influence basement membrane; agents that influence growth
of endothelial cells; adrenergic agonist or blocker; aldose reductose
inhibitor; analgesic; anesthetic; antiallergic; antibacterial;
antifibrotic; antifungal, e.g. amphoteracin B; antiglaucoma; antihyper- or
hypotensive; anti-inflammatory; antineoplastic; antiprotozoal; antitumor;
antimetabolites, e.g., folic acid analogs, purine analogs, and pyrimidine
analogs; antiviral; carbonic anhydrase inhibitor; chelating agents;
cholinergic; cholinesterase inhibitor; CNS stimulant; contraceptive;
dopamine receptor agonist or antagonist; estrogen; glucocorticoid;
glucosidase inhibitor; releasing factor; growth hormone inhibitor; growth
stimulant; hemolytic; heparin antagonist; immunomodulator;
immunosuppressant; LH-RH agonist; antimitotics; NSAID; anti-glaucoma
agents, e.g acetozolamide (dimox), befunolol, .beta.-blockers,
Ca-blockers, etc.; anti-neoplastics, e.g., vinblastine, vincristine,
interferons .alpha., .beta., and .gamma.; progesterone; thrombolytic;
vasodilator; vasopressor; and vitamin.
Among hydrophobic drugs, which typically have a slow release profile and
therefore benefit from formulation with a release accelerator, are
cyclosporines, e.g. cyclosporin A, cyclosporin G, etc.; vinca alkaloids,
e.g. vincristine and vinblastine; methotrexate; retinoic acid; certain
antibiotics, e.g. ansamycins such as rifampin; nitrofurans such as
nifuroxazide; non-steroidal anti-inflammatory drugs, e.g. diclofenac,
keterolac, flurbiprofen, naproxen, suprofen, ibuprofen, aspirin; etc.
Steroids are of specific interest, in particular steroidal compounds with
anti-inflammatory activity, i.e. glucocorticoids. Glucocorticoids include
the following:
21-acetoxypregnenolone
alclometasone
algestone
amcinonide
beclomethasone
betamethasone
budesonide
chloroprednisone
clobetasol
clobetasone
cloprednol
clocortolone
corticosterone
cortisone
cortivazol
deffazacort
desonide
desoximetasone
dexamethasone
diflucortolone
diruprednate
enoxolone
fluazacort
flucloronide
flumethasone
flunisolide
fluocinolone acetonide
fluocinonide
fluocortinbutyl
fluocortolone
fluorometholone
fluperoloneacetate
fluprednidene acetate
fluprednisolone
flurandrenolide
formocortal
halcinonide
halometasone
halopredone acetate
hydrocortamate
diflorasone
hydrocortisone
hydrocortisone acetate
hydrocortisone phosphate
hydrocortisone 21-sodium succinate
hydrocortisone tebutate
mazipredone
medrysone
meprednisone
methylprednisolone
mometasone furoate
prednisolone sodium 21-m-sulfobenzoate
prednisolone 21-stearoylglycolate
prednisolone tebutate
prednisolone 21-trimethylacetate
prednisone
prednival
paramethasone
prednylidene
prednicarbate
prednylidene 21-diethylaminoacetate
prednisolone
prednisolone 21-diethylaminoacetate
tixocortol
triamcinolone
prednisolone sodium phosphate
triamcinolone acetonide
prednisolone sodium succinate
triamcinolone benetonide
triamcinolone hexacetonide.
These hydrocortisone derivatives have been recognized as having
significant therapeutic effects that are beneficial in the treatment of
ocular inflammatory diseases, varying in their potency and biotolerability
as a function of their chemical substitutions.The following are examples of glucocorticoids that have been used in the treatment of ocular inflammation, and are of interest for use in the subject invention: dexamethasone sodium phosphate; prednisolone sodium phosphate; prednisolone acetate; fluorometholone acetate; dexamethasone; fluoromethalone; and medrysone. Of these, dexamethasone is thought to be the most potent, and is therefore a good candidate for use in a GFS drug delivery system, because a small drug release rate is sufficient to establish therapeutic concentration levels at the surgical site.
Accelerators may be physiologically inert, water soluble polymers, e.g. low molecular weight methyl cellulose or hydroxypropyl methyl cellulose (HPMC); sugars, e.g monosaccharides such as fructose and glucose, disaccharides such as latose, sucrose, or polysaccharides, usually neutral or uncharged, such as cellulose, amylose, dextran, etc. Alternatively, the accelerator may be a physiologically active agent, allowing for a combined therapeutic formulation. The choice of accelerator in such a case will be determined by the desired combination of therapeutic activities.
Release retardants are hydrophobic compounds that slow the rate of release of hydrophilic drugs, allowing for a more extended release profile. Hydrophilic drugs of interest which may benefit from release modulation include water soluble antibiotics, e.g. aminoglycosides such as gentamycin, kanamycin, neomycin, and vancomycin; amphenicols such as chloramphenicol; cephalosporins such as cefazolin HCl; penicillins such as ampicillin, penicillin, carbenicillin, oxycillin, methicillin; lincosamides such as licomycin; polypeptide antibiotics such as polymixin and bacitracin; tetracyclines such as tetracycline; quinolones such as ciprofloxacin, etc.; sulfonamides such as chloramine T; and sulfones such as sulfanilic acid. Also of interest as active hydrophilic agents are nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine; isoflurphate; adriamycin; bleomycin; mitomycin; ara-C; actinomycin D; scopolamine; and the like.
Agents of interest as release retardants include non-water soluble polymers, e.g. high molecular weight methylcellulose and ethylcellulose, etc., low water soluble organic compounds, and pharmaceutically active hydrophobic agents, as previously described.
Co-delivery of therapeutic agents from two different therapeutic classes may be particularly beneficial for the post-operative care of GFS patients. Combinations of interest include anti-inflammatory and anti-proliferative, e.g. glucocorticoid and methotrexate, glucocorticoid and 5-fluorouracil, NSAID and methotrexate; anti-inflammatory and antiviral; e.g. glucocorticoid or NSAID in combination with vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine, acyclovir, foscarnet, or gancyclovir; anti-inflammatory and antibacterial, e.g. glucocorticoid and quinolone, NSAID and quinolone. In a particularly preferred embodiment, the implant comprises dexamethasone and 5-flourouracil or dexamethasone and ciprofloxacin. Other more specific combinations of interest include the NSAID diclofenac combined with an antibacterial such as gentamicin or vancomycin.
Antibacterial drug classes that may be advantageously combined with a suitable anti-inflammatory to improve the post-operative success of GFS include: aminoglycosides, amphenicols, ansamycins, lactams, lincosamides, macrolides, polypeptides, tetracyclines, diaminopyrimidines, nitrofurans, quinolones and analogs, sulfonamides, sulfones, etc. Where one compound does not cover the range of the bacterial infection, products may combine several antibacterial drugs in one combination product. Examples of antibiotics useful in treating ocular infections include: chloramphenicol; polymyxin b, neomycin, gramicidin; neomycin; bacitracin; sulfacetamide sodium; gentamicin; tobramycin; trimethprim sulfate; erythromycin; vancomycin; tetracycline; and chlortetracycline. Of particular interest are the quinolones, which are very potent, broad spectrum antibiotics. The high activity of these drugs allows a therapeutic concentration to be reached at low levels of the drug. Examples include ciprofloxacin; norfloxacin; ofloxacin; enoxacin, lomefloxacin; fleroxacin; temafloxacin, tosufloxacin and perfloxacin.
Combinations of anti-inflammatory agents with antiviral drugs are also of interest. These include a number of water soluble nucleotide analogs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine and dideoxycytosine.
A combined anti-inflammatory drug, and antibiotic or antiviral, may be further combined with an additional therapeutic agent. The additional agent may be an analgesic, e.g. codeine, morphine, keterolac, naproxen, etc., an anesthetic, e.g. lidocaine; b-adrenergic blocker or b-adrenergic agonist, e.g. ephidrine, epinephrine, etc.; aldose reductase inhibitor, e.g. epalrestat, ponalrestat, sorbinil, tolrestat; antiallergic, e.g. cromolyn, beclomethasone, dexamethasone, and flunisolide; colchicine. Antihelminthic agents, e.g. ivermectin and suramin sodium; antiamebic agents, e.g chloroquine and chlortetracycline; and antifungal agents, e.g. amphotericin, etc. may be co-formulated with an antibiotic and an anti-inflammatory drug. Immunosuppressants such as azathioprine, cyclosporine and mizoribine are also of interest in combinations.
The amount of active agent employed in the implant, individually or in combination, will vary widely depending on the effective dosage required and the desired rate of release from the implant. Usually the agent will be at least about 1, more usually at least about 10 weight percent of the implant, and usually not more than about 80, more usually not more than about 40 weight percent of the implant.
Where a release modulator is included, the amount employed will be dependent on the desired release profile, the activity of the modulator, and on the release profile of the active agent in the absence of modulator. An agent that is released very slowly or very quickly will require relatively high amounts of the modulator. Generally, the modulator will be at least about 10, more usually at least about 20 weight percent of the implant, and usually not more than about 50, more usually not more than about 40 weight percent of the implant.
Where a combination of active agents is to be employed, the desired release profile of each active agent is determined. If necessary, a physiologically inert modulator is added to precisely control the release profile. The drug release will provide a therapeutic level of each active agent.
The exact proportion of modulator and active agent is empirically determined by formulating several implants having varying amounts of modulator. A USP approved method for dissolution or release test will be used to measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed sample of the drug delivery device is added to a measured volume of a solution containing four parts by weight of ethanol and six parts by weight of deionized water, where the solution volume will be such that the drug concentration after release is less than 5% of saturation. The mixture is maintained at 37oC. and stirred slowly to maintain the implants in suspension. The appearance of the dissolved drug as a function of time may be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, etc. The drug concentration after 1 h in the medium is indicative of the amount of free unencapsulated drug in the dose, while the time required for 90% drug to be released is related to the expected duration of action of the dose in vivo. Normally the release will be free of larger fluctuations from some average value which allows for a relatively uniform release.
The implants may be monolithic, i.e. having the active agent or agents homogenously distributed through the polymeric matrix, or encapsulated, where a reservoir of active agent is encapsulated by the polymeric matrix. Due to ease of manufacture, monolithic implants are usually preferred over encapsulated forms. However, the greater control afforded by the encapsulated, reservoir-type implant may be of benefit in some circumstances, where the therapeutic level of the drug falls within a narrow window.
The implants may be substantially homogeneous as to composition and physical characteristics or heterogeneous. Thus, implants can be prepared where the center may be of one material and the surface may have one or more layers of the same or a different composition, where the layers may be cross-linked, or of a different molecular weight, different density or porosity, or the like. For example, where it is desirable to quickly release an initial bolus of drug, the center may be a polylactate coated with a polylactate-polyglycolate copolymer, so as to enhance the rate of initial degradation. Alternatively, the center may be polyvinyl alcohol coated with polylactate, so that upon degradation of the polylactate exterior the center would dissolve and be rapidly washed out of the eye.
Other agents may be employed in the formulation for a variety of purposes. For example, buffering agents and preservatives may be employed. Water soluble preservatives which may be employed include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol. These agents may be present in individual amounts of from about 0.001 to about 5% by weight and preferably about 0.01 to about 2%. Suitable water soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the FDA for the desired route of administration. These agents may be present in amounts sufficient to maintain a pH of the system of between 2 to 9 and preferably 4 to 8. As such the buffering agent may be as much as 5% on a weight to weight basis of the total composition. Where the buffering agent or enhancer is hydrophilic, it may also act as a release accelerator, and will have a cumulative effect with other modulator(s). Similarly, a hydrophilic buffering agent may act as a release retardant.
The implants may be of any geometry including fibers, sheets, films, microspheres, spheres, circular discs, plaques and the like. The upper limit for the implant size will be determined by factors such as toleration for the implant, size limitations on insertion, ease of handling, etc. Where sheets or films are employed, the sheets or films will be in the range of at least about 0.5 mm.times.0.5 mm, usually about 3-10 mm.times.5-10 mm with a thickness of about 0.1-1.0 mm for ease of handling. Where fibers are employed, the fiber diameter will generally be in the range of about 0.05 to 3 mm and the fiber length will generally be in the range of about 0.5-10 mm. Spheres will be in the range of 2 .mu.m to 4 mm in diameter, with comparable volumes for other shaped particles.
The size and form of the implant can also be used to control the rate of release, period of treatment, and drug concentration at the site of implantation. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The particular size and geometry of the implant are chosen to suit the site of implantation. In the methods of the present invention, wafers, rods and sheets are preferable for intrascleral or episcleral implantation.
In some situations mixtures of implants may be utilized employing the same or different pharmacological agents. In this way, a cocktail of release profiles, giving a biphasic or triphasic release with a single administration is achieved, where the pattern of release may be greatly varied.
Various techniques may be employed to produce the implants. Useful techniques include solvent evaporation methods, phase separation methods, interfacial methods, extrusion methods, molding methods, injection molding methods, heat press methods and the like. Specific methods are discussed in U.S. Pat. No. 4,997,652, herein incorporated by reference. In a preferred embodiment, extrusion methods are used to avoid the need for solvents in manufacturing. When using extrusion methods, the polymer and drug are chosen so as to be stable at the temperatures required for manufacturing, usually at least about 85oC.
Claim 1 of 19 Claims
What is claimed is:
1. A method for improving the post-operative success of glaucoma
filtration surgery, said method comprising the steps of:
introducing proximal to the surgical site an implant comprising
dexamethasone at a concentration from about 40 to 80 weight percent of the
implant and poly-lactate glycolic acid copolymer at a concentration of at
least about 20 weight percent of the implant;
wherein said therapeutically active agent is released within a therapeutic
dosage which does not vary by more than about 100% for a period of at
least about 3 weeks.
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