|Publication number||US20050244463 A1|
|Application number||US 10/836,911|
|Publication date||Nov 3, 2005|
|Filing date||Apr 30, 2004|
|Priority date||Apr 30, 2004|
|Also published as||CA2565067A1, CA2565067C, CN1950067A, EP1758552A1, EP1758552B1, EP2305261A1, US8293741, US8506986, US8580292, US20050244476, US20080118547, US20080118548, US20080118549, WO2005110368A1, WO2005110368A8|
|Publication number||10836911, 836911, US 2005/0244463 A1, US 2005/244463 A1, US 20050244463 A1, US 20050244463A1, US 2005244463 A1, US 2005244463A1, US-A1-20050244463, US-A1-2005244463, US2005/0244463A1, US2005/244463A1, US20050244463 A1, US20050244463A1, US2005244463 A1, US2005244463A1|
|Inventors||Glenn Huang, Brittany Jackson, James Burke, Ton Lin, Patrick Hughes, Larry Wheeler, Rosy Donn|
|Original Assignee||Allergan, Inc.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (99), Referenced by (22), Classifications (14), Legal Events (3)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention generally relates to devices and methods to treat an eye of a patient, and more specifically to intraocular implants that provide extended release of a therapeutic agent to an eye in which the implant is placed, and to methods of making and using such implants, for example, to treat ocular vasculopathies, or to generally improve vision.
Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline, is an alpha-2-selective adrenergic receptor agonist that is effective in the treatment of open-angle glaucoma by decreasing aqueous humor production and increasing uveoscleral outflow. Brimonidine is available in two chemical forms, brimonidine tartrate and brimonidine free base. Brimonidine tartrate (Alphagan® P) is publicly available by Allergan for treating glaucoma. Topical ocular brimonidine formulation, 0.15% Alphagan® P (Allergan, Irvine, Calif.), is currently commercially available for treatment of open-angle glaucoma. The solubility of brimonidine tartrate in water is 34 mg/mL, while the solubility of brimonidine freebase is negligible in water.
Recent studies have suggested that brimonidine can promote survival of injured retinal ganglion nerve cells by activation of the alpha-2-adrenoceptor in the retina and/or optic nerve. For example, brimonidine can protect injured neurons from further damage in several models of ischemia and glaucoma.
Glaucoma-induced ganglion cell degeneration is one of the leading causes of blindness. This indicates that brimonidine can be utilized in a new therapeutic approach to glaucoma management in which neuroprotection and intraocular pressure reduction are valued outcomes of the therapeutic regimen. For brimonidine to protect the optic nerve, however, it must have access to the posterior segment of the eye at therapeutic levels. Currently available techniques for administering brimonidine to the posterior chamber of the eye are not sufficient to address this issue.
Biocompatible implants for placement in the eye have been disclosed in a number of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493.
It would be advantageous to provide eye implantable drug delivery systems, such as intraocular implants, and methods of using such systems, that are capable of releasing a therapeutic agent at a sustained or controlled rate for extended periods of time and in amounts with few or no negative side effects.
The present invention provides new drug delivery systems, and methods of making and using such systems, for extended or sustained drug release into an eye, for example, to achieve one or more desired therapeutic effects. The drug delivery systems are in the form of implants or implant elements that may be placed in an eye. The present systems and methods advantageously provide for extended release times of one or more therapeutic agents. Thus, the patient in whose eye the implant has been placed receives a therapeutic amount of an agent for a long or extended time period without requiring additional administrations of the agent. For example, the patient has a substantially consistent level of therapeutically active agent available for consistent treatment of the eye over a relatively long period of time, for example, on the order of at least about one week, such as between about two and about six months after receiving an implant. Such extended release times facilitate obtaining successful treatment results.
Intraocular implants in accordance with the disclosure herein comprise a therapeutic component and a drug release sustaining component associated with the therapeutic component. In accordance with the present invention, the therapeutic component comprises, consists essentially of, or consists of, an alpha-2 adrenergic receptor agonist. The alpha-2 adrenergic receptor agonist may be an agonist or agent that selectively activates alpha-2 adrenergic receptors, for example by binding to an alpha-2 adrenergic receptor, relative to other types of adrenergic receptors, such as alpha-1 adrenergic receptors. The selective activation can be achieved under different conditions, but preferably, the selective activation is determined under physiological conditions, such as conditions associated with an eye of a human or animal patient. The drug release sustaining component is associated with the therapeutic component to sustain release of an amount of the alpha-2 adrenergic receptor agonist into an eye in which the implant is placed. The amount of the alpha-2 adrenergic receptor agonist is released into the eye for a period of time greater than about one week after the implant is placed in the eye and is effective in preventing or reducing occular vasculopathies, such as vascular occlusions.
In one embodiment, the intraocular implants comprise an alpha-2 adrenergic receptor agonist and a biodegradable polymer matrix. The alpha-2 adrenergic receptor agonist is associated with a biodegradable polymer matrix that degrades at a rate effective to sustain release of an amount of the agonist from the implant for a time sufficient to reduce or prevent an ocular vascular occlusion. The intraocular implant is biodegradable or bioerodible and provides a sustained release of the alpha-2 adrenergic receptor agonist in an eye for extended periods of time, such as for more than one week, for example for about three months or more and up to about six months or more. In certain implants, the alpha-2 adrenergic receptor agonist is released for about 30-35 days or less. In other implants, the alpha-2 adrenergic receptor agonist is released for 40 days or more.
The biodegradable polymer component of the foregoing implants may be a mixture of biodegradable polymers, wherein at least one of the biodegradable polymers is a polylactic acid polymer having a molecular weight less than 64 kiloDaltons (kD). Additionally or alternatively, the foregoing implants may comprise a first biodegradable polymer of a polylactic acid, and a different second biodegradable polymer of a polylactic acid. Furthermore, the foregoing implants may comprise a mixture of different biodegradable polymers, each biodegradable polymer having an inherent viscosity in a range of about 0.3 deciliters/gram (dl/g) to about 1.0 dl/g.
The alpha-2 adrenergic receptor agonist of the implants disclosed herein may include quinoxaline derivatives, or other agonists that are effective in treating ocular conditions. One example of a suitable quinoxaline derivative is brimonidine or brimonidine tartrate. In addition, the therapeutic component of the present implants may include one or more additional and different therapeutic agents that may be effective in treating an ocular condition.
A method of making the present implants involves combining or mixing the alpha-2 adrenergic receptor agonist with a biodegradable polymer or polymers. The mixture may then be extruded or compressed to form a single composition. The single composition may then be processed to form individual implants suitable for placement in an eye of a patient.
The implants may be placed in an ocular region to treat a variety of ocular conditions, including conditions such as ocular vasculopathies that affect an anterior region or posterior region of an eye. For example, the implants may be used to treat many conditions of they eye, including, without limitation, conditions associated with vascular occlusion.
Kits in accordance with the present invention may comprise one or more of the present implants, and instructions for using the implants. For example, the instructions may explain how to administer the implants to a patient, and types of conditions that may be treated with the implants.
Each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present invention provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention.
Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying drawings.
As described herein, controlled and sustained administration of a therapeutic agent through the use of one or more intraocular implants may improve treatment of undesirable ocular conditions. The implants comprise a pharmaceutically acceptable polymeric composition and are formulated to release one or more pharmaceutically active agents, such as alpha-2 adrenergic receptor agonists, over an extended period of time. The implants are effective to provide a therapeutically effective dosage of the agent or agents directly to a region of the eye to treat or prevent one or more undesirable ocular conditions. 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.
An intraocular implant in accordance with the disclosure herein comprises a therapeutic component and a drug release sustaining component associated with the therapeutic component. In accordance with the present invention, the therapeutic component comprises, consists essentially of, or consists of, an alpha-2 adrenergic receptor agonist. The drug release sustaining component is associated with the therapeutic component to sustain release of a therapeutically effective amount of the alpha-2 adrenergic receptor agonist into an eye in which the implant is placed. The therapeutic amount of the alpha-2 adrenergic receptor agonist is released into the eye for a period of time greater than about one week after the implant is placed in the eye.
For the purposes of this description, we use the following terms as defined in this section, unless the context of the word indicates a different meaning.
As used herein, an “intraocular implant” refers to a device or element that is structured, sized, or otherwise configured to be placed in an eye. Intraocular implants are generally biocompatible with physiological conditions of an eye and do not cause adverse side effects. Intraocular implants may be placed in an eye without disrupting vision of the eye.
As used herein, a “therapeutic component” refers to a portion of an intraocular implant comprising one or more therapeutic agents or substances used to treat a medical condition of the eye. The therapeutic component may be a discrete region of an intraocular implant, or it may be homogenously distributed throughout the implant. The therapeutic agents of the therapeutic component are typically ophthalmically acceptable, and are provided in a form that does not cause adverse reactions when the implant is placed in an eye.
As used herein, a “drug release sustaining component” refers to a portion of the intraocular implant that is effective to provide a sustained release of the therapeutic agents of the implant. A drug release sustaining component may be a biodegradable polymer matrix, or it may be a coating covering a core region of the implant that comprises a therapeutic component.
As used herein, “associated with” means mixed with, dispersed within, coupled to, covering, or surrounding.
As used herein, an “ocular region” or “ocular site” refers generally to any area of the eyeball, including the anterior and posterior segment of the eye, and which generally includes, but is not limited to, any functional (e.g., for vision) or structural tissues found in the eyeball, or tissues or cellular layers that partly or completely line the interior or exterior of the eyeball. Specific examples of areas of the eyeball in an ocular region include the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sciera, the pars plana, surgically-induced avascular regions, the macula, and the retina.
As used herein, an “ocular condition” is a disease, ailment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball.
An anterior ocular condition is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior ocular condition primarily affects or involves the conjunctiva, the cornea, the anterior chamber, the iris, the posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site.
Thus, an anterior ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases;, corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma can also be considered to be an anterior ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. reduce intraocular pressure).
A posterior ocular condition is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site.
Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as fungal or viral-caused infections; macular degeneration, such as acute macular degeneration, non-exudative age related macular degeneration and exudative age related macular degeneration; edema, such as macular edema, cystoid macular edema and diabetic macular edema; multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease; sympathetic opthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can be considered a posterior ocular condition because the therapeutic goal is to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e. neuroprotection).
The term “biodegradable polymer” refers to a polymer or polymers which degrade in vivo, and wherein erosion of the polymer or polymers over time is occurs concurrent with or subsequent to release of the therapeutic agent. Specifically, hydrogels such as methylcellulose which act to release drug through polymer swelling are specifically excluded from the term “biodegradable polymer”. The terms “biodegradable” and “bioerodible” are equivalent and are used interchangeably herein. A biodegradable polymer may be a homopolymer, a copolymer, or a polymer comprising more than two different polymeric units.
The term “treat”, “treating”, or “treatment” as used herein, refers to reduction or resolution or prevention of an ocular condition, ocular injury or damage, or to promote healing of injured or damaged ocular tissue.
The term “therapeutically effective amount” as used herein, refers to the level or amount of agent needed to treat an ocular condition, or reduce or prevent ocular injury or damage without causing significant negative or adverse side effects to the eye or a region of the eye.
Intraocular implants have been developed which can release drug loads over various' time periods. These implants, which when inserted into an eye, such as the vitreous of an eye, provide therapeutic levels of an alpha-2 adrenergic receptor agonist for extended periods of time (e.g., for about 1 week or more). The implants disclosed are effective in treating ocular conditions, such as posterior ocular conditions.
In one embodiment of the present invention, an intraocular implant comprises a biodegradable polymer matrix. The biodegradable polymer matrix is one type of a drug release sustaining component. The biodegradable polymer matrix is effective in forming a biodegradable intraocular implant. The biodegradable intraocular implant comprises an alpha-2 adrenergic receptor agonist associated with the biodegradable polymer matrix. The matrix degrades at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist for a time greater than about one week from the time in which the implant is placed in ocular region or ocular site, such as the vitreous of an eye.
The alpha-2 adrenergic receptor agonist of the implant is typically an agent that selectively activates alpha-2 adrenergic receptors relative to alpha-1 adrenergic receptors. In certain implants, the alpha-2 adrenergic receptor agonist is selectively activates a subtype of the alpha-2 adrenergic receptors. For example, the agonist may selectively activate one or more of the alpha-2a, the alpha-2b, or the alpha-2c receptors, under certain conditions, such as physiological conditions. Under other conditions, the agonist of the implant may not be selective for alpha-2 adrenergic receptor subtypes. The agonist may activate the receptors by binding to the receptors, or by any other mechanism.
In certain implants, the alpha-2 adrenergic receptor agonist is a quinoxaline derivative. The quinoxaline derivatives useful in the present implants are those quinoxaline derivatives having the formula,
In at least one implant, R1 is H and R2 is selected from alkyl radicals containing 1 to 4 carbon atoms. R3 may advantageously be in the 5-position of the quinoxaline nucleus and be selected from H and alkyl radicals containing 1 to 3 carbon atoms. All stereoisomers, tautomers and mixtures thereof which comply with the constraints of one or more of the presently useful compounds are included within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of the invention are those formed from acids which form non-toxic addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulphonate salts.
In more specific implants, the quinoxaline derivative has the formula
In additional implants, the alpha-2 adrenergic receptor agonist is provided as a salt having the formula
The foregoing salt is known as brimonidine tartrate (AGN 190342-F, 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline tartrate), and is publicly available from Allergan, Inc. under the tradename Alphagan®-P. Brimonidine, an organic base, is publicly available as either brimonidine tartrate salt or as brimonidine freebase. The tartrate salt is more soluble than the freebase in various aqueous media. Since both the tartrate salt and the freebase are chemically stable and have melting points higher than 200° C., both forms are suitable in forming the present implants.
Thus, the implant may comprise a therapeutic component which comprises, consists essentially of, or consists of a brimonidine salt, such as brimonidine tartrate, a brimonidine free base, or mixtures thereof.
The alpha-2 adrenergic receptor agonist may be in a particulate or powder form and entrapped by the biodegradable polymer matrix. Usually, alpha-2 adrenergic receptor agonist particles will have an effective average size less than about 3000 nanometers. In certain implants, the particles may have an effective average particle size about an order of magnitude smaller than 3000 nanometers. For example, the particles may have an effective average particle size of less than about 500 nanometers. In additional implants, the particles may have an effective average particle size of less than about 400 nanometers, and in still further embodiments, a size less than about 200 nanometers.
The alpha-2 adrenergic receptor agonist of the implant is preferably from about 10% to 90% by weight of the implant. More preferably, the alpha-2 adrenergic receptor agonist is from about 20% to about 80% by weight of the implant. In a preferred embodiment, the alpha-2 adrenergic receptor agonist comprises about 20% by weight of the implant (e.g., 15%-25%). In another embodiment, the alpha-2 adrenergic receptor agonist comprises about 50% by weight of the implant.
Suitable polymeric materials or compositions for use in the implant include those materials which are compatible, that is biocompatible, with the eye so as to cause no substantial interference with the functioning or physiology of the eye. Such materials preferably are at least partially and more preferably substantially completely biodegradable or bioerodible.
Examples of useful polymeric materials include, without limitation, such materials derived from and/or including organic esters and organic ethers, which when degraded result in physiologically acceptable degradation products, including the monomers. Also, polymeric materials derived from and/or including, anhydrides, amides, orthoesters and the like, by themselves or in combination with other monomers, may also find use. The polymeric materials may be addition or condensation polymers, advantageously condensation polymers. The polymeric materials may be cross-linked or non-cross-linked, for example not more than lightly cross-linked, such as less than about 5%, or less than about 1% of the polymeric material being cross-linked. For the most part, besides carbon and hydrogen, the polymers will include at least one of oxygen and nitrogen, advantageously oxygen. The oxygen may be present as oxy, e.g. hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester, and the like. The nitrogen may be present as amide, cyano and amino. The polymers set forth in Heller, Biodegradable Polymers in Controlled Drug Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which describes encapsulation for controlled drug delivery, may find use in the present implants.
Of additional interest are polymers of hydroxyaliphatic carboxylic acids, either homopolymers or copolymers, and polysaccharides. Polyesters of interest include polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof. Generally, by employing the L-lactate or D-lactate, a slowly eroding polymer or polymeric material is achieved, while erosion is substantially enhanced with the lactate racemate.
Among the useful polysaccharides are, without limitation, calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being water insoluble, a molecular weight of about 5 kD to 500 kD, for example.
Other polymers of interest include, without limitation, polyvinyl alcohol, polyesters, polyethers and combinations thereof which are biocompatible and may be biodegradable and/or bioerodible.
Some preferred characteristics of the polymers or polymeric materials for use in the present invention may include biocompatibility, compatibility with the therapeutic component, ease of use of the polymer in making the drug delivery systems of the present invention, a half-life in the physiological environment of at least about 6 hours, preferably greater than about one day, not significantly increasing the viscosity of the vitreous, and water insolubility.
The biodegradable polymeric materials which are included to form the matrix are desirably subject to enzymatic or hydrolytic instability. Water soluble polymers may be cross-linked with hydrolytic or biodegradable unstable cross-links to provide useful water insoluble polymers. The degree of stability can be varied widely, depending upon the choice of monomer, whether a homopolymer or copolymer is employed, employing mixtures of polymers, and whether the polymer includes terminal acid groups.
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 certain implants, the relative average molecular weight of the polymer will range from about 9 to about 64 kD, usually from about 10 to about 54 kD, and more usually from about 12 to about 45 kD.
In some implants, copolymers of glycolic acid and lactic acid are used, where the rate of biodegradation is controlled by the ratio of glycolic acid to lactic acid. The most rapidly degraded copolymer has roughly equal amounts of glycolic acid and lactic acid. Homopolymers, or copolymers having ratios other than equal, are more resistant to degradation. The ratio of glycolic acid to lactic acid will also affect the brittleness of the implant, where a more flexible implant is desirable for larger geometries. The % of polylactic acid in the polylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%, preferably about 15-85%, more preferably about 35-65%.
In some implants, a 50/50 PLGA copolymer is used. The biodegradable polymer matrix of the intraocular implant may comprise a mixture of two or more biodegradable polymers. For example, the implant may comprise a mixture of a first biodegradable polymer and a different second biodegradable polymer. One or more of the biodegradable polymers may have terminal acid groups.
Release of a drug from an erodible polymer is the consequence of several mechanisms or combinations of mechanisms. Some of these mechanisms include desorption from the implants surface, dissolution, diffusion through porous channels of the hydrated polymer and erosion. Erosion can be bulk or surface or combination of both. As discussed herein, the matrix of the intraocular implant may release drug at a rate effective to sustain release of an amount of the alpha-2 adrenergic receptor agonist for more than one week after implantation into an eye. In certain implants, therapeutic amounts of the alpha-2 adrenergic receptor agonist are released for no more than about 30-35 days after implantation. For example, an implant may comprise brimonidine tartrate, and the matrix of the implant degrades at a rate effective to sustain release of a therapeutically effective amount of brimonidine tartrate for about one month after being placed in an eye. As another example, the implant may comprise brimonidine tartrate, and the matrix releases drug at a rate effective to sustain release of a therapeutically effective amount of brimonidine tartrate for more than forty days, such as for about six months.
One example of the biodegradable intraocular implant comprises an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer matrix, which comprises a mixture of different biodegradable polymers. At least one of the biodegradable polymers is a polylactide having a molecular weight of about 63.3 kD. A second biodegradable polymer is a polylactide having a molecular weight of about 14 kD. Such a mixture is effective in sustaining release of a therapeutically effective amount of the alpha-2 adrenergic receptor agonist for a time period greater than about one month from the time the implant is placed in an eye.
Another example of a biodegradable intraocular implant comprises an alpha-2 adrenergic receptor agonist associated with a biodegradable polymer matrix, which comprises a mixture of different biodegradable polymers, each biodegradable polymer having an inherent viscosity from about 0.16 dl/g to about 1.0 dl/g. For example, one of the biodegradable polymers may have an inherent viscosity of about 0.3 dl/g. A second biodegradable polymer may have an inherent viscosity of about 1.0 dl/g. The inherent viscosities identified above may be determined in 0.1% chloroform at 25° C.
One particular implant comprises brimonidine tartrate associated with a combination of two different polylactide polymers. The brimonidine tartrate is present in about 20% by weight of the implant. One polylactide polymer has a molecular weight of about 14 kD and an inherent viscosity of about 0.3 dl/g, and the other polylactide polymer has a molecular weight of about 63.3 kD and an inherent viscosity of about 1.0 dl/g. The two polylactide polymers are present in the implant in a 1:1 ratio. Such an implant provides for release of the brimonidine for more than two months in vitro, as described herein. The implant is provided in the form of a rod or a filament produced by an extrusion process.
The release of the alpha-2 adrenergic receptor agonist from the intraocular implant comprising a biodegradable polymer matrix may include an initial burst of release followed by a gradual increase in the amount of the alpha-2 adrenergic receptor agonist released, or the release may include an initial delay in release of the alpha-2 adrenergic receptor agonist followed by an increase in release. When the implant is substantially completely degraded, the percent of the alpha-2 adrenergic receptor agonist that has been released is about one hundred. Compared to existing implants, the implants disclosed herein do not completely release, or release about 100% of the alpha-2 adrenergic receptor agonist, until after about one week of being placed in an eye.
It may be desirable to provide a relatively constant rate of release of the alpha-2 adrenergic receptor agonist from the implant over the life of the implant. For example, it may be desirable for the alpha-2 adrenergic receptor agonist to be released in amounts from about 0.01 μg to about 2 μg per day for the life of the implant. However, the release rate may change to either increase or decrease depending on the formulation of the biodegradable polymer matrix. In addition, the release profile of the alpha-2 adrenergic receptoragonist may include one or more linear portions and/or one or more non-linear portions. Preferably, the release rate is greater than zero once the implant has begun to degrade or erode.
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. In addition, the therapeutic component, including the alpha-2 adrenergic receptor agonist, may be distributed in a non-homogenous pattern in the matrix. For example, the implant may include a portion that has a greater concentration of the alpha-2 adrenergic receptor agonist relative to a second portion of the implant.
The intraocular implants disclosed herein may have a size of between about 5 μm and about 2 mm, or between about 10 μm and about 1 mm for administration with a needle, greater than 1 mm, or greater than 2 mm, such as 3 mm or up to 10 mm, for administration by surgical implantation. The vitreous chamber in humans is able to accommodate relatively large implants of varying geometries, having lengths of, for example, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod) with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be a cylindrical pellet with a length of about 7 mm to about 10 mm, and a diameter of about 0.75 mm to about 1.5 mm.
The implants may also be at least somewhat flexible so as to facilitate both insertion of the implant in the eye, such as in the vitreous, and accommodation of the implant. The total weight of the implant is usually about 250-5000 μg, more preferably about 500-1000 μg. For example, an implant may be about 500 μg, or about 1000 μg. For non-human individuals, the dimensions and total weight of the implant(s) may be larger or smaller, depending on the type of individual. For example, humans have a vitreous volume of approximately 3.8 ml, compared with approximately 30 ml for horses, and approximately 60-100 ml for elephants. An implant sized for use in a human may be scaled up or down accordingly for other animals, for example, about 8 times larger for an implant for a horse, or about, for example, 26 times larger for an implant for an elephant.
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.
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×0.5 mm, usually about 3-10 mm×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 may be in the range of 0.5 μm 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.
The proportions of alpha-2 adrenergic receptor agonist, polymer, and any other modifiers may be empirically determined by formulating several implants with varying proportions. A USP approved method for dissolution or release test can 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 implant is added to a measured volume of a solution containing 0.9% NaCl in water, where the solution volume will be such that the drug concentration is after release is less than 5% of saturation. The mixture is maintained at 37° C. 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. until the absorbance becomes constant or until greater than 90% of the drug has been released.
In addition to the alpha-2 adrenergic receptor agonist or alpha-2 adrenergic receptor agonists included in the intraocular implants disclosed herein, the intraocular implants may also include one or more additional ophthalmically acceptable therapeutic agents. For example, the implant may include one or more antihistamines, one or more antibiotics, one or more beta blockers, one or more steroids, one or more antineoplastic agents, one or more immunosuppressive agents, one or more antiviral agents, one or more antioxidant agents, and mixtures thereof.
Pharmacologic or therapeutic agents which may find use in the present systems, include, without limitation, those disclosed in U.S. Pat. No. 4,474,451, columns 4-6 and U.S. Pat. No. 4,327,725, columns 7-8.
Examples of antihistamines include, and are not limited to, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, and derivatives thereof.
Examples of antibiotics include without limitation, cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine, cefuroxime, ampicillin, amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin V potassium, piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin, aziocillin, carbenicillin, methicillin, nafcillin, erythromycin, tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol, ciprofloxacin hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin, tobramycin, vancomycin, polymyxin B sulfate, colistimethate, colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim, and derivatives thereof.
Examples of beta blockers include acebutolol, atenolol, labetalol, metoprolol, propranolol, timolol, and derivatives thereof.
Examples of steroids include corticosteroids, such as cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone, prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, triamcinolone, derivatives thereof, and mixtures thereof.
Examples of antineoplastic agents include adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxol and derivatives thereof, taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, and flutamide, and derivatives thereof.
Examples of immunosuppresive agents include cyclosporine, azathioprine, tacrolimus, and derivatives thereof.
Examples of antiviral agents include interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir, and derivatives thereof.
Examples of antioxidant agents include ascorbate, alpha-tocopherol, mannitol, reduced glutathione, various carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin, cryotpxanthin, astazanthin, lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba extract, tea catechins, bilberry extract, vitamins E or esters of vitamin E, retinyl palmitate, and derivatives thereof.
Other therapeutic agents include squalamine, carbonic anhydrase inhibitors, alpha agonists, prostamides, prostaglandins, antiparasitics, antifungals, and derivatives thereof.
The amount of active agent or agents 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.
In addition to the therapeutic component, the intraocular implants disclosed herein may include effective amounts of buffering agents, preservatives and the like. Suitable water soluble buffering agents include, without limitation, alkali and alkaline earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate and the like. These agents advantageously present in amounts sufficient to maintain a pH of the system of between about 2 to about 9 and more preferably about 4 to about 8. As such the buffering agent may be as much as about 5% by weight of the total implant. Suitable water soluble preservatives include sodium bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and the like and mixtures thereof. These agents may be present in amounts of from 0.001 to about 5% by weight and preferably 0.01 to about 2% by weight. In at least one of the present implants, a purite preservative is provided in the implant, such as when the alpha-2 adrenergic receptor agonist is brimonidine. Thus, these implants may contain a therapeutically effective amount of Alphagan®-P.
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.
Additionally, release modulators such as those described in U.S. Pat. No. 5,869,079 may be included in the implants. The amount of release modulator employed will be dependent on the desired release profile, the activity of the modulator, and on the release profile of the alpha-2 adrenergic receptor agonist in the absence of modulator. Electrolytes such as sodium chloride and potassium chloride may also be included in the implant. Where the buffering agent or enhancer is hydrophilic, it may also act as a release accelerator. Hydrophilic additives act to increase the release rates through faster dissolution of the material surrounding the drug particles, which increases the surface area of the drug exposed, thereby increasing the rate of drug bioerosion. Similarly, a hydrophobic buffering agent or enhancer dissolve more slowly, slowing the exposure of drug particles, and thereby slowing the rate of drug bioerosion.
In certain implants, an implant comprising brimonidine or brimonidine tartrate and a biodegradable polymer matrix is able to release or deliver an amount of brimonidine between about 0.1 mg to about 0.5 mg for about 3-6 months after implantation into the eye. The implant may be configured as a rod or a wafer. A rod-shaped implant may be derived from filaments extruded from a 720 μm nozzle and cut into 1 mg size. A wafer-shaped implant may be a circular disc having a diameter of about 2.5 mm, a thickness of about 0.127 mm, and a weight of about 1 mg.
The proposed 3-month release formulations may be sterile, and bioerodible in the form of a rod, a wafer or a microsphere containing brimonidine tartrate within a PLA matrix or POE matrix. The implants are designed to delay the clearance of the drug and reduce the need for repeated implantation over 3-month period, thereby lowering the risk of complications.
Various techniques may be employed to produce the implants described herein. Useful techniques include, but are not necessarily limited to, solvent evaporation methods, phase separation methods, interfacial methods, molding methods, injection molding methods, extrusion methods, co-extrusion methods, carver press method, die cutting methods, heat compression, combinations thereof and the like.
Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusion methods may be 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 85 degrees Celsius. Extrusion methods use temperatures of about 25 degrees C. to about 150 degrees C, more preferably about 65 degrees C. to about 130 degrees C. An implant may be produced by bringing the temperature to about 60 degrees C. to about 150 degrees C for drug/polymer mixing, such as about 130 degrees C, for a time period of about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, a time period may be about 10 minutes, preferably about 0 to 5 min. The implants are then extruded at a temperature of about 60 degrees C to about 130 degrees C, such as about 75 degrees C.
In addition, the implant may be coextruded so that a coating is formed over a core region during the manufacture of the implant.
Compression methods may be used to make the implants, and typically yield implants with faster release rates than extrusion methods. Compression methods may use pressures of about 50-150 psi, more preferably about 70-80 psi, even more preferably about 76 psi, and use temperatures of about 0 degrees C. to about 115 degrees C, more preferably about 25 degrees C.
The implants of the present invention may be inserted into the eye, for example the vitreous chamber of the eye, by a variety of methods, including placement by forceps or by trocar following making a 2-3 mm incision in the sclera. One example of a device that may be used to insert the implants into an eye is disclosed in U.S. Patent Publication No. 2004/0054374. The method of placement may influence the therapeutic component or drug release kinetics. For example, delivering the implant with a trocar may result in placement of the implant deeper within the vitreous than placement by forceps, which may result in the implant being closer to the edge of the vitreous. The location of the implant may influence the concentration gradients of therapeutic component or drug surrounding the element, and thus influence the release rates (e.g., an element placed closer to the edge of the vitreous may result in a slower release rate).
The present implants are configured to release an amount of alpha-2 adrenergic receptor agonist in an eye for a period of time to minimize an ocular vascular occlusion, such as a retinal vascular occlusion. Retinal vascular occlusion may result from a variety of diseases such as retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, hemi-retinal vein occlusion, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (cad), eales disease and vasculopathies associated with diabetes. By implanting the alpha-2 adrenergic receptor agonist-containing implants into the vitreous of an eye, it is believed that the agonist is effective to reduce occlusion within blood vessels located in the eye.
In addition, the present implants may be configured to release an alpha-2 adrenergic receptor agonist in a therapeutically effective amount for a period of time effective to treat glaucoma of a patient.
The implants disclosed herein may also be configured to release additional therapeutic agents, as described above, which may be effective in treating diseases or conditions, such as the following:
MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age Related Macular Degeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD), Choroidal Neovascularization, Diabetic Retinopathy, Acute Macular Neuroretinopathy, Central Serous Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema.
UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid Pigment Epitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada Syndrome.
VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease, Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle Cell Retinopathy and other Hemoglobinopathies, Angioid Streaks, Familial Exudative Vitreoretinopathy.
TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow Transplant Retinopathy.
PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy and Epiretinal Membranes, Proliferative Diabetic Retinopathy.
INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular Toxocariasis, Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis, Toxoplasmosis, Retinal Diseases Associated with HIV Infection, Choroidal Disease Associated with HIV Infection, Uveitic Disease Associated with HIV Infection, Viral Retinitis, Acute Retinal Necrosis, Progressive Outer Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, Ocular Tuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis.
GENETIC DISORDERS: Retinitis Pigmentosa, Systemic Disorders with Accosiated Retinal Dystrophies, Congenital Stationary Night Blindness, Cone Dystrophies, Stargardt's Disease and Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy, pseudoxanthoma elasticum.
RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant Retinal Tear.
TUMORS: Retinal Disease Associated with Tumors, Congenital Hypertrophy of the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma, Choroidal Metastasis, Combined Hamartoma of the Retina and Retinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.
MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal Degeneration, Acute Retinal Pigment Epithelitis and the like.
In one embodiment, an implant, such as the implants disclosed herein, is administered to a posterior segment of an eye of a human or animal patient, and preferably, a living human or animal. In at least one embodiment, an implant is administered without accessing the subretinal space of the eye. For example, a method of treating a patient may include placing the implant directly into the posterior chamber of the eye. In other embodiments, a method of treating a patient may comprise administering an implant to the patient by at least one of intravitreal injection, subconjuctival injection, sub-tenon injections, retrobulbar injection, and suprachoroidal injection.
In at least one embodiment, a method of reducing retinal vascular occlusion in a patient comprises administering one or more implants containing one or more alpha-2 adrenergic receptor agonists, as disclosed herein to a patient by at least one of intravitreal injection, subconjuctival injection, sub-tenon injection, retrobulbar injection, and suprachoroidal injection. A syringe apparatus including an appropriately sized needle, for example, a 27 gauge needle or a 30 gauge needle, can be effectively used to inject the composition with the posterior segment of an eye of a human or animal. Repeat injections are often not necessary due to the extended release of the alpha-2 adrenergic receptor agonists from the implants.
In another aspect of the invention, kits for treating an ocular condition of the eye are provided, comprising: a) a container comprising an extended release implant comprising a therapeutic component including an alpha-2 adrenergic receptor agonist, such as brimonidine free base or brimonidine tartrate (e.g., Alphagan-P), and a drug release sustaining component; and b) instructions for use. Instructions may include steps of how to handle the implants, how to insert the implants into an ocular region, and what to expect from using the implants.
Biodegradable implants were made by combining brimonidine tartrate or brimonidine freebase with a biodegradable polymer composition in a stainless steel mortar. The combination was mixed via a Turbula shaker set at 96 RPM for 15 minutes. The powder blend was scraped off the wall of the mortar and then remixed for an additional 15 minutes. The mixed powder blend was heated to a semi-molten state at specified temperature for a total of 30 minutes, forming a polymer/drug melt.
Rods were manufactured by pelletizing the polymer/drug melt using a 9 gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into the barrel and extruding the material at the specified core extrusion temperature into filaments. The filaments were then cut into about 1 mg size implants or drug delivery systems. The rods had dimensions of about 2 mm long×0.72 mm diameter. The rod implants weighed between about 900 μg and 1100 μg.
Wafers were formed by flattening the polymer melt with a Carver press at a specified temperature and cutting the flattened material into wafers, each weighing about 1 mg. The wafers had a diameter of about 2.5 mm and a thickness of about 0.13 mm. The wafer implants weighed between about 900 μg and 1100 μg.
The in-vitro release testing was performed on each lot of implant (rod or wafer) in six replicates initially, and later in four replicates. Each implant was placed into a 24 mL screw cap vial with 10 mL of Phosphate Buffered Saline solution at 37° C. and 1 mL aliquots were removed and replaced with equal volume of fresh medium on day 1, 4, 7, 14, 28, and every two weeks thereafter.
The drug assays were performed by HPLC, which consists of a Waters 2690 Separation Module (or 2696), and a Waters 2996 Photodiode Array Detector. An Ultrasphere, C-18 (2), 5 μm; 4.6×150 mm column heated at 30° C. was used for separation and the detector was set at 264 nm. The mobile phase was (10:90) MeOH—buffered mobile phase with a flow rate of 1 mL/min and a total run time of 12 min per sample. The buffered mobile phase comprised of (68:0.75:0.25:31) 13 mM 1-Heptane Sulfonic Acid, sodium salt—glacial acetic acid—triethylamine—Methanol. The release rates were determined by calculating the amount of drug being released in a given volume of medium over time in μg/day.
The polymers chosen for the implants are were obtained from Boehringer Ingelheim. The polymers were: RG502, RG752, R202H, R203 and R206, and Purac PDLG (50/50). RG502 is (50:50) poly(D,L-lactide-co-glycolide), RG752 is (75:25) poly(D,L-lactide-co-glycolide), R202H is 100% poly(D, L-lactide) with acid end group or terminal acid groups, R203 and R206 are both 100% poly(D, L-lactide). Purac PDLG (50/50) is (50:50) poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502, RG752, R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3, 1.0, and 0.2 dL/g, respectively. The average molecular weight of RG502, RG752, R202H, R203, R206, and Purac PDLG are, 11700, 11200, 6500, 14000, 63300, and 9700 daltons, respectively.
A total of 53 formulations were prepared, 31 rods and 22 wafers. Of the rod formulations, 4 had release periods longer than 3 months and 3 had release periods longer than 6 months. Of the wafer formulations, 7 had release periods longer than 3 months and 4 had release periods longer than 4 months.
A list of the rod formulations is shown in Table 1, and a list of wafer formulations is shown in Table 2.
TABLE 1 Brimonidine Rod Formulations Formulation Lot BT (w/w) BFB (w/w) Polymer I.V. (dL/g) Core Extr T 1 295-123 50% RG752 0.2 104° C. 2 295-124 50% RG752 0.2 105° C. 3 295-126 50% RG502 0.2 108° C. 4 295-127 50% RG502 0.2 112° C. 5 295-167 50% R203 0.3 98° C. 6 295-168 50% R203 0.3 101° C. 7 295-169 50% R206 1.0 118° C. 8 295-170 50% R206 1.0 104° C. 9 295-171 25% R206 1.0 98° C. 10 295-172 25% R203 0.3 96° C. 11 453-3 10% 40% R203 0.3 98° C. 12 453-4 5% 20% R203 0.3 96° C. 13 453-6 10% 40% R206 1.0 105° C. 14 453-7 5% 20% R206 1.0 104° C. 15 453-8 5% 45% R206 1.0 102° C. 16 453-9 15% R206 1.0 102° C. 17 453-10 20% (1:1) R203/R206 N/A 98° C. 18 453-11 20% (3:1) R203/R206 N/A 96° C. 19 453-12 10% 40% RG752 0.2 108° C. 20 453-13 5% 20% RG752 0.2 104° C. 24 453-50 20% R206 1.0 100° C. 25 453-51 17% (1:1) R203/R206 N/A 98° C. 26 453-52 40% (1:1) RG752/RG502 N/A 105° C. 27 453-53 40% (3:1) RG752/RG502 N/A 103° C. 28 453-54 40% (1:1) R203/RG502 N/A 103° C. 29 453-55 50% R202H 0.2 96° C. 30 453-56 50% R202H 0.2 98° C. 31 453-73 20% RG752 0.2 98° C. 32 453-74 20% Purac (Mw 9700) N/A 95° C. 33 453-75 20% Purac (Mw 9700) N/A 92° C. 53 453-95 20% (2:1) R203/R206 N/A 97° C.
BT = Brimonidine Tartrate
BFB = Brimonidine Free Base
I.V. = Inherent Viscosity
TABLE 2 Brimonidine wafer Formulations BT BFB I.V. Formulation Lot (w/w) (w/w) Polymer (dL/g) 21 453-47 25% R206 1.0 22 453-48 20% (1:1) R203/R206 N/A 23 453-49 20% (3:1) R203/R206 N/A 34 453-76 20% (1:1) R203/R206 N/A 35 453-77 25% R206 1.0 36 453-78 20% (3:1) R203/R206 N/A 37 453-79 25% R203 0.3 38 453-80 50% R203 0.3 39 453-81 50% R206 1.0 40 453-82 15% R206 1.0 41 453-83 40% (1:1) RG752/RG502 N/A 42 453-84 40% (2:1) RG752/RG502 N/A 43 453-85 40% (1:1) R203/RG502 N/A 44 453-86 50% R202H 0.2 45 453-87 50% (1:1) RG752/RG502 N/A 46 453-88 10% (1:1) R203/R206 N/A 47 453-89 15% (1:1) R203/R206 N/A 48 453-90 10% (3:1) R203/R206 N/A 49 453-91 15% (3:1) R203/R206 N/A 50 453-92 10% R206 1.0 51 453-93 10% (2:1) R203/R206 N/A 52 453-94 15% (2:1) R203/R206 N/A
BT = Brimonidine Tartrate
BFB = Brimonidine Free Base
I.V. = Inherent Viscosity
The first 10 formulations were prepared with the five different polymers, RG752, RG502, R203, R206, and R202H each at 50% w/w drug load for both brimonidine tartrate and brimonidine free base. The release profiles are shown in
In most cases, formulations prepared with brimonidine tartrate had a faster initial burst than those prepared from brimonidine freebase using the same polymer, except for RG502. The data also show that brimonidine freebase had a lag time of approximately 30 days when formulated in poly(D, L-lactide) matrix (R203, R206, and R202H), while brimonidine tartrate was released completely on the first day (F5 and F7). This may be due to the quick dissolution of brimonidine tartrate on the surface of the implant.
Several formulations using R203 and R206 with drug doses lower than 50% were prepared, and the release profiles are shown in
With 20% brimonidine tartrate in R206 (F24), a 14 day lag time is present before it started releasing and eventually reaching 89.5% release after 134 days. At 15% brimonidine tartrate in R206 (F16), the lag time increased to 28 days before it started releasing and eventually reaching 97.6% after 175 days.
The release profiles of formulation #9 and #10 behaved in an opposite but complementary way, in that one polymer exhibits early release while the other exhibits a delayed release, but both reached the same end point at the same time. When both polymers were combined with a lower drug load, a more linear and longer release profile would be obtained, as shown in
The data show that formulation # 17, 20% brimonidine tartrate/(1:1) R203/R206, has a desirable in-vitro release profile for a six month release implant. It released approximately 90% of the brimonidine tartrate after 175 days. It was also shown that by varying the proportion of R203 and R206, even with the same drug load (Formulation # 17, #18, and # 53), different release profiles would result.
Brimonidine freebase formulations with polymer blends were also prepared to see if a more linear release profile could be obtained. Knowing its low solubility in aqueous media and its release characteristics in each polymer, different combinations of RG502-RG752, and RG502-R203 were prepared, and the release profiles are shown in
The duration of release for all three formulations was approximately 2 months, but all three exhibited a lag time between 1 to 2 weeks. Two formulations (F32 and F33) were prepared with Purac polymer, PDLG (50/50)-Mw 9700, one with brimonidine tartrate and the one with brimonidine freebase. Both formulations had fast release with high standard of deviation; therefore, the release tests were stopped after 7 days.
The first set of wafer formulations was prepared from 3 existing rod formulations. Specifically, formulations # 9, # 17 and # 18, with release reaching 89.4% after 105 days, 89.2% after 175 days, and 102% after 175 days, respectively. The release profiles of the first three wafer formulations are shown in
These three formulations had release periods lasting only two to three weeks, while their rod counterparts had release periods lasting three to four months. This may be due to the increased surface area of the wafer compared to that of a rod. In the wafer configuration, drug load also determines the duration of drug release. Therefore, drug load was reduced from 20-25% down to 15% and 10% and the release profiles are shown in
At 15% drug load, formulation # 7 had a cumulative release 51.4% after 35 days, while formulation # 47, 49, and 52 had cumulative releases of 93.2%, 92.8% and 88.5%, respectively, after 99 days. The latter three formulations may be effective as a 4-month drug delivery system.
At 10% drug load, formulations # 46, # 48, # 50, and # 51 had cumulative releases of 83.8%, 98.0%, 92.7% and 89.2%, respectively, after 133 days. These four formulations may be effective as 5-month drug delivery systems. Both
Three wafer formulations were prepared from three previous rod formulations # 26, # 27, and # 28, and the release profiles are shown in
Of the 15 rod formulations prepared from brimonidine tartrate, three formulations had release periods longer than 3 months (F9, F10, and F53), two formulations had release periods longer than 4 months (F24 and F25), and three formulations had release periods close to 6 months (F16, F17, and F18). Of the 8 rod formulations prepared from brimonidine freebase, 3 had release periods longer than 2 months (F26, F27, and F28).
Of the 22 wafer formulations, 11 were prepared from brimonidine tartrate and 11 were prepared from brimonidine freebase. Of the 11 wafer formulations prepared from brimonidine tartrate, 3 had release periods of about 4 months (F47, F49, and F52), and 4 had release periods between 4 and 5 months (F46, F48, F50, and F51).
Of the 11 wafer formulations prepared from brimonidine freebase, 4 had release periods between 3 and 4 months (F35, F36, F38, and F39), and 5 had release periods between one to two months (F34, F37, F41, F42, and F43).
In general, the wafer formulations prepared from brimonidine tartrate or brimonidine freebase have faster release than their rod counterparts.
Cynomologous monkeys were randomly assigned to receive either placebo (n=2) or bimonidine (n=2) formulated intravitreal implants. Baseline measures were performed 3 days prior to implantation and 10 days following implantation with intraocular pressure (IOP), mfERG, laser Doppler scanning topography/flowmetry (HRT/HRF), optical coherence tomography (OCT), indocyanine green angiography (ICG) and fluoroscein angiography (FA).
Three implants (Formulation #17 described in Example 1), each formulated with 200 μg brimonidine or placebo were implanted intravitreally into an eye through a port made with an MVR blade (OS), the port was closed with sutures. Wide angle contact lens fundus photography verified implant count and localization. Branch retinal vein occlusion (BRVO) was achieved by injecting 1 ml of 20 mg/kg Rose Bengal intravenously followed by thermal irradiation using Omni Coherent Diode laser at 532 nm, 600 mW, 50 um spot size, 0.01 sec pulse mode with a 1.6× inversion contact lens. Laser pulses were delivered until the vein segment was closed. One brimonidine treated monkey received 235 pulses and the other received 78 pulses. One placebo treated monkey received 43 pulses and the other received 31 pulses. Vascular occlusion of a vein was induced in the superior arcade approximately one disc diameter from the optic nerve head. Occlusion was verified post-laser by fundus photography.
Funduscopic observations at day 1 following BRVO showed dramatic retinopathy and vasculopathy in both monkeys with placebo implant—marked retinal edema and dot blot hemorrhages, vessel tortuosity, cotton wool spots. Fluorescein angiography verified vein occlusion and stagnate blood flow upstream from the lasered region and elucidated late phase fluorescein leak and pooling from retina capillaries. Monkeys with brimonidine implants had less than 5 small dot blot hemorrhages, some retinal edema localized to the superior retina. Fluorescein angiography in brimonidine monkeys showed reperfusion of the once occluded vein with minimal stagnate blood flow.
The brimonidine containing implants decreased the duration of vascular occlusion as shown in
Fovea thickness measurements from OCT single line scans (6 mm) show an increase in retinal edema as a result of vascular occlusion in the placebo group. Brimonidine containing implants decreased the magnitude of retinal edema associated with vascular occlusion. A series of line scans (covering 3 mm2) directly compare changes in retinal thickness in the superior region surrounding the occluded vein with thickness changes in the inferior retina. Retinal edema in placebo monkeys was so profound that fluid accumulation occurred in the inferior region of the retina. In contrast, the brimonidine group did not have a significant change in inferior retina edema compared to baseline, as shown in
Intraocular pressure (IOP) was recorded (OD and OS) in each group in triplicate post implantation and prior to all follow-up electrophysiology and retinal imaging procedures. The brimonidine implants did not significantly lower IOP in eyes prior to or during BRVO, as shown in
Laser Doppler Flowmetry (HRF) was used to measure blood flow in the fovea, superior and inferior retina regions. The graph of
Intravitreal application of three brimonidine intraocular implants has lessened the magnitude and duration of localized vascular occlusion and associated vasculopathy and retinopathy in monkeys.
In addition, the amount of laser burns needed to close the veins was higher in the brimonidine group compared to placebo (brimonidine: 157±79, n=2; placebo: 37±6, n=2). Together, these data show that the presence of brimonidine increases the difficulty of occluding retinal vasculature and decreases the duration of that occlusion.
Treatment of glaucoma with an intraocular implant containing brimonidine associated with a biodegradable polymer matrix.
A 68 year old female complains to her physician that it is becoming difficult to see. The physician determines that she has elevated intraocular pressure levels, and diagnoses her with glaucoma. An implant containing 200 μg of brimonidine tartrate and 800 μg of a combination of biodegradable polymers (R203 and R206 at a 1:1 ratio, as described above in Example 1) is placed in the vitreous of both of the woman's eyes using a trocar. After about 2 days, the woman begins to notice a change in her eyes, presumably due to a decrease in intraocular pressure. The loss of vision is prevented for about five months after the implant procedure.
An implant can be formulated with various active agents, including the agents described herein, following the procedures in the Examples above. These implants can provide an extended therapeutic treatment of an ocular condition, that is a therapeutic effect during a period of time during release of the active agent or after release of all of the active agent from the implant and during which there is no longer a therapeutic amount of the active agent present at the ocular site at which the implant was placed. Thus, an implant can be prepared containing an alpha-2 adrenergic receptor agonist, such as clonidine, apraclonidine, or brimonidine (available from Allergan, Irvine, Calif. as brimonidine tartrate ophthalmic solution, under the tradename Alphagan®-P). Thus, for example, a brimonidine extended therapeutic treatment implant can be implanted into an ocular site (i.e. into the vitreous) of a patient with an ocular condition for a desired extended therapeutic effect. The implant may contain from about 50 μg to about 500 μg of Alphagan or Alphagan-P depending on the size of the implant. The brimonidine extended therapeutic treatment implant can be implanted into an ocular region or site (i.e. into the vitreous) of a patient with an ocular condition for a desired therapeutic effect. The ocular condition can be an inflammatory condition such as uveitis or the patient can be afflicted with one or more of the following afflictions: macular degeneration (including non-exudative age related macular degeneration and exudative age related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (including cystoid macular edema and diabetic macular edema); Behcet's disease, diabetic retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlusion; uveitic retinal disease; retinal detachment; retinopathy; an epiretinal membrane disorder; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. The implant(s) can be inserted into the vitreous using the procedure such as trocar implantation. The implant can release a therapeutic amount of the active agent to provide and retain a therapeutic effect for an extended period of time to thereby treat a symptom of an ocular condition. For example, the implant may be effective to improve visual acuity, visual contract sensitivity, or both.
All references, articles, publications and patents and patent applications cited herein are incorporated by reference in their entireties.
While this invention has been described with respect to various specific examples and embodiments, it is to be understood that the invention is not limited thereto and that it can be variously practiced within the scope of the following claims.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4008864 *||Feb 18, 1975||Feb 22, 1977||Nils Gustav Yngve Torphammar||Locking mechanism for a safety belt|
|US4014335 *||Mar 25, 1976||Mar 29, 1977||Alza Corporation||Ocular drug delivery device|
|US4052505 *||Jul 15, 1976||Oct 4, 1977||Alza Corporation||Ocular therapeutic system manufactured from copolymer|
|US4088864 *||Feb 23, 1976||May 9, 1978||Alza Corporation||Process for forming outlet passageways in pills using a laser|
|US4144317 *||Sep 21, 1977||Mar 13, 1979||Alza Corporation||Device consisting of copolymer having acetoxy groups for delivering drugs|
|US4158005 *||May 9, 1977||Jun 12, 1979||Interx Research Corporation||Intermediates useful in the synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols|
|US4186184 *||Apr 23, 1979||Jan 29, 1980||Alza Corporation||Selective administration of drug with ocular therapeutic system|
|US4190642 *||May 11, 1979||Feb 26, 1980||Alza Corporation||Ocular therapeutic system for dispensing a medication formulation|
|US4200098 *||Oct 23, 1978||Apr 29, 1980||Alza Corporation||Osmotic system with distribution zone for dispensing beneficial agent|
|US4281654 *||Apr 7, 1980||Aug 4, 1981||Alza Corporation||Drug delivery system for controlled ocular therapy|
|US4285987 *||Nov 1, 1979||Aug 25, 1981||Alza Corporation||Process for manufacturing device with dispersion zone|
|US4327725 *||Nov 25, 1980||May 4, 1982||Alza Corporation||Osmotic device with hydrogel driving member|
|US4396625 *||Apr 27, 1981||Aug 2, 1983||Sumitomo Chemical Company, Limited||Treatment of glaucoma or ocular hypertension and ophthalmic composition|
|US4425346 *||Jan 25, 1982||Jan 10, 1984||Smith And Nephew Associated Companies Limited||Pharmaceutical compositions|
|US4474451 *||Nov 1, 1982||Oct 2, 1984||Olympus Optical Co., Ltd.||Diaphragm control circuit for TTL automatic electronic flash|
|US4478818 *||Jan 5, 1984||Oct 23, 1984||Alza Corporation||Ocular preparation housing steroid in two different therapeutic forms|
|US4494247 *||Dec 28, 1981||Jan 22, 1985||Trace Athletic Corporation||Knee/elbow guard treated to increase durability and a process for producing same|
|US4521210 *||Dec 27, 1982||Jun 4, 1985||Wong Vernon G||Eye implant for relieving glaucoma, and device and method for use therewith|
|US4599353 *||May 3, 1982||Jul 8, 1986||The Trustees Of Columbia University In The City Of New York||Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma|
|US4649151 *||May 14, 1984||Mar 10, 1987||Health Research, Inc.||Drugs comprising porphyrins|
|US4656186 *||Apr 30, 1985||Apr 7, 1987||Nippon Petrochemicals Co., Ltd.||Tetrapyrrole therapeutic agents|
|US4668506 *||Aug 16, 1985||May 26, 1987||Bausch & Lomb Incorporated||Sustained-release formulation containing and amino acid polymer|
|US4675338 *||Jul 18, 1984||Jun 23, 1987||Nippon Petrochemicals Co., Ltd.||Tetrapyrrole therapeutic agents|
|US4693885 *||Apr 30, 1985||Sep 15, 1987||Nippon Petrochemicals Co., Ltd.||Tetrapyrrole therapeutic agents|
|US4853224 *||Dec 22, 1987||Aug 1, 1989||Visionex||Biodegradable ocular implants|
|US4863457 *||Apr 22, 1988||Sep 5, 1989||Lee David A||Drug delivery device|
|US4865846 *||Jun 3, 1988||Sep 12, 1989||Kaufman Herbert E||Drug delivery system|
|US4866168 *||Jul 24, 1986||Sep 12, 1989||Health Research, Inc.||Hematoporphyrin derivatives and process of preparing|
|US4932934 *||Aug 24, 1988||Jun 12, 1990||Health Research, Inc.||Methods for treatment of tumors|
|US4935495 *||Dec 21, 1984||Jun 19, 1990||Oncogen||Monoclonal antibodies to the L6 glycolipid antigenic determinant found on human non-small cell lung carcinomas|
|US4959217 *||May 22, 1986||Sep 25, 1990||Syntex (U.S.A.) Inc.||Delayed/sustained release of macromolecules|
|US4981871 *||May 15, 1987||Jan 1, 1991||Abelson Mark B||Treatment of ocular hypertension with class I calcium channel blocking agents|
|US4997652 *||May 31, 1989||Mar 5, 1991||Visionex||Biodegradable ocular implants|
|US5002962 *||Jul 20, 1988||Mar 26, 1991||Health Research, Inc.||Photosensitizing agents|
|US5017579 *||Feb 6, 1989||May 21, 1991||Sanofi||Use of aminoalkoxyphenyl derivatives for reducing and/or controlling excessive intraocular pressure|
|US5019400 *||May 1, 1989||May 28, 1991||Enzytech, Inc.||Very low temperature casting of controlled release microspheres|
|US5028621 *||May 16, 1989||Jul 2, 1991||Health Research, Inc.||Drugs comprising porphyrins|
|US5034413 *||Sep 18, 1990||Jul 23, 1991||Allergan, Inc.||Intraocular pressure reducing 9,11-diacyl prostaglandins|
|US5089509 *||Mar 20, 1989||Feb 18, 1992||Allergan, Inc.||Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity|
|US5093349 *||Oct 15, 1990||Mar 3, 1992||Health Research Inc.||Photosensitizing agents|
|US5100431 *||Sep 27, 1990||Mar 31, 1992||Allergan, Inc.||Single stitch suture needle and method|
|US5190966 *||Sep 18, 1990||Mar 2, 1993||Health Research, Inc.||Purified hematoporphyrin dimers and trimers useful in photodynamic therapy|
|US5198460 *||Jan 17, 1992||Mar 30, 1993||Health Research Inc.||Pyropheophorbides and their use in photodynamic therapy|
|US5300114 *||Aug 10, 1992||Apr 5, 1994||Allergan, Inc.||Subconjunctival implants for ocular drug delivery|
|US5314905 *||Nov 9, 1992||May 24, 1994||Health Research, Inc.||Pyropheophorbides conjugates and their use in photodynamic therapy|
|US5356629 *||Jul 12, 1991||Oct 18, 1994||United States Surgical Corporation||Composition for effecting bone repair|
|US5378475 *||Feb 21, 1991||Jan 3, 1995||University Of Kentucky Research Foundation||Sustained release drug delivery devices|
|US5385887 *||Sep 10, 1993||Jan 31, 1995||Genetics Institute, Inc.||Formulations for delivery of osteogenic proteins|
|US5438071 *||Jun 10, 1993||Aug 1, 1995||American Cyanamid Company||Stable porfimer sodium compositions and methods for their manufacture|
|US5459159 *||May 5, 1994||Oct 17, 1995||Health Research, Inc.||Pyropheophorbides and their use in photodynamic therapy|
|US5501856 *||Nov 27, 1991||Mar 26, 1996||Senju Pharmaceutical Co., Ltd.||Controlled-release pharmaceutical preparation for intra-ocular implant|
|US5504074 *||Aug 6, 1993||Apr 2, 1996||Children's Medical Center Corporation||Estrogenic compounds as anti-angiogenic agents|
|US5597897 *||Jun 22, 1992||Jan 28, 1997||Genetics Institute, Inc.||Pharmaceutical formulations of osteogenic proteins|
|US5655832 *||May 22, 1995||Aug 12, 1997||Tir Technologies, Inc.||Multiple wavelength light processor|
|US5656297 *||May 3, 1994||Aug 12, 1997||Alkermes Controlled Therapeutics, Incorporated||Modulated release from biocompatible polymers|
|US5707643 *||Jun 7, 1996||Jan 13, 1998||Santen Pharmaceutical Co., Ltd.||Biodegradable scleral plug|
|US5766242 *||Mar 13, 1996||Jun 16, 1998||Oculex Pharmaceuticals, Inc.||Biocompatible ocular implants|
|US5770589 *||Jul 27, 1994||Jun 23, 1998||The University Of Sydney||Treatment of macular degeneration|
|US5776699 *||Mar 11, 1996||Jul 7, 1998||Allergan, Inc.||Method of identifying negative hormone and/or antagonist activities|
|US5798349 *||Feb 17, 1995||Aug 25, 1998||The General Hospital Corporation||Use of green porphyrins to treat neovasculature in the eye|
|US5824074 *||Feb 2, 1995||Oct 20, 1998||Koch; Hans-Reinhard||Intraoccular lens arrangement and method for correcting astigmatism|
|US5827072 *||Aug 29, 1997||Oct 27, 1998||Neufer; David J.||Graphic, sports-related instruction board|
|US5869079 *||Jun 2, 1995||Feb 9, 1999||Oculex Pharmaceuticals, Inc.||Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents|
|US5877207 *||Jun 24, 1997||Mar 2, 1999||Allergan Sales, Inc.||Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities|
|US5882682 *||Oct 19, 1995||Mar 16, 1999||Merck & Co., Inc.||Controlled release simvastatin delivery device|
|US5906920 *||Aug 29, 1995||May 25, 1999||The Salk Institute For Biological Studies||Methods for the detection of ligands for retinoid X receptors|
|US5913884 *||Oct 31, 1996||Jun 22, 1999||The General Hospital Corporation||Inhibition of fibrosis by photodynamic therapy|
|US5919970 *||Apr 24, 1997||Jul 6, 1999||Allergan Sales, Inc.||Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity|
|US5922773 *||Dec 4, 1992||Jul 13, 1999||The Children's Medical Center Corp.||Glaucoma treatment|
|US5958954 *||Dec 24, 1997||Sep 28, 1999||Allergan Sales, Inc.||Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities|
|US6051576 *||Jan 29, 1997||Apr 18, 2000||University Of Kentucky Research Foundation||Means to achieve sustained release of synergistic drugs by conjugation|
|US6066675 *||Sep 8, 1997||May 23, 2000||The Regents Of The University Of California||Method for treatment of retinal diseases|
|US6074661 *||Sep 10, 1998||Jun 13, 2000||Allergan Sales, Inc.||Sterile bioerodible occular implant device with a retinoid for improved biocompatability|
|US6217869 *||Sep 5, 1997||Apr 17, 2001||Neorx Corporation||Pretargeting methods and compounds|
|US6217895 *||Mar 22, 1999||Apr 17, 2001||Control Delivery Systems||Method for treating and/or preventing retinal diseases with sustained release corticosteroids|
|US6225303 *||Jul 6, 1999||May 1, 2001||Massachusetts Eye And Ear Infirmary||Use of green porphyrins to treat neovasculature in the eye|
|US6258319 *||Sep 4, 1998||Jul 10, 2001||Cerus Corporation||Device and method for photoactivation|
|US6270492 *||Sep 7, 1999||Aug 7, 2001||Cardiofocus, Inc.||Phototherapeutic apparatus with diffusive tip assembly|
|US6270749 *||Jun 10, 1999||Aug 7, 2001||Pharmacyclics, Inc.||Use of Texaphyrin in ocular diagnosis and therapy|
|US6271220 *||Mar 11, 1998||Aug 7, 2001||Allergan Sales, Inc.||Anti-angiogenic agents|
|US6274614 *||Oct 2, 1997||Aug 14, 2001||Qlt Inc.||Methods, compositions and articles for reducing or preventing the effects of inflammation|
|US6290713 *||Aug 24, 1999||Sep 18, 2001||Thomas A. Russell||Flexible illuminators for phototherapy|
|US6294361 *||Oct 26, 1997||Sep 25, 2001||New York Blood Center, Inc.||Processes for photoreactive inactivation of a virus in blood cell or coagulation factor containing compositions and use thereof for preparing compositions useful for transfusion|
|US6306426 *||Jun 5, 2000||Oct 23, 2001||Allergan Sales, Inc.||Implant device with a retinoid for improved biocompatibility|
|US6357568 *||Sep 27, 2000||Mar 19, 2002||Shou Mao Chen||Structure for protecting a luggage shell|
|US6369116 *||Dec 23, 1998||Apr 9, 2002||Oculex Pharmaceuticals, Inc.||Composition and method for treating glaucoma|
|US6403649 *||Mar 6, 2000||Jun 11, 2002||Allergan Sales, Inc.||Non-acidic cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl derivatives as therapeutic agents|
|US6455062 *||Aug 21, 2001||Sep 24, 2002||Allergan, Inc.||Implant device with a retinoid for improved biocompatibility|
|US6537568 *||Oct 17, 2001||Mar 25, 2003||Allergan, Inc.||Implant device with a retinoid for improved biocompatibility|
|US6548078 *||Dec 14, 2000||Apr 15, 2003||Control Delivery Systems||Method for treating and/or preventing retinal diseases with sustained release corticosteroids|
|US6565871 *||Aug 31, 2001||May 20, 2003||Elan Drug Delivery Ltd.||Solid dose delivery vehicle and methods of making same|
|US6573280 *||Jan 2, 2002||Jun 3, 2003||Allergan, Inc.||Calcium blockers to treat proliferative vitreoretinopathy|
|US6595945 *||Jan 9, 2001||Jul 22, 2003||J. David Brown||Glaucoma treatment device and method|
|US6699493 *||Nov 28, 2001||Mar 2, 2004||Oculex Pharmaceuticals, Inc.||Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor|
|US6713081 *||Mar 15, 2001||Mar 30, 2004||The United States Of America As Represented By The Department Of Health And Human Services||Ocular therapeutic agent delivery devices and methods for making and using such devices|
|US6726918 *||Oct 20, 2000||Apr 27, 2004||Oculex Pharmaceuticals, Inc.||Methods for treating inflammation-mediated conditions of the eye|
|US6765012 *||Sep 27, 2002||Jul 20, 2004||Allergan, Inc.||3-(Arylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors|
|US20020032201 *||Jul 10, 2001||Mar 14, 2002||Allergan Sales, Inc.||Compositions containing alpha-2-adrenergic agonist components|
|US20040151753 *||Nov 4, 2003||Aug 5, 2004||Guohua Chen||Controlled release depot formulations|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US8293741||Oct 23, 2012||Allergan, Inc.||Intraocular implants and methods for improving vision|
|US8506986||Jan 31, 2008||Aug 13, 2013||Allergan, Inc.||Sustained release intraocular implants and methods for treating ocular vasculopathies|
|US8529927||Mar 31, 2006||Sep 10, 2013||Allergan, Inc.||Alpha-2 agonist polymeric drug delivery systems|
|US8580292||Jan 31, 2008||Nov 12, 2013||Allergan, Inc.||Sustained release intraocular implants and methods for treating ocular vasculopathies|
|US8663194||Nov 12, 2010||Mar 4, 2014||University Of Utah Research Foundation||Intraocular drug delivery device and associated methods|
|US8821870||Jul 18, 2008||Sep 2, 2014||Allergan, Inc.||Method for treating atrophic age related macular degeneration|
|US9011857||Nov 26, 2012||Apr 21, 2015||The Regents Of The University Of California||Methods of treating cancer by administering EMP2 antibodies|
|US9089478||Aug 19, 2014||Jul 28, 2015||Allergen, Inc.||Peripherally administered viscous formulations|
|US9095404||Aug 16, 2011||Aug 4, 2015||University Of Utah Research Foundation||Intraocular drug delivery device and associated methods|
|US9095506||Nov 17, 2008||Aug 4, 2015||Allergan, Inc.||Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof|
|US9101583||Mar 27, 2014||Aug 11, 2015||Allergan, Inc.||Microparticles manufactured in an oil-in-water process comprising a prostamide|
|US9110064||Dec 28, 2011||Aug 18, 2015||The Regents Of The University Of California||Methods for diagnosis and treatment of endometrial cancer|
|US20050244476 *||Apr 29, 2005||Nov 3, 2005||Allergan, Inc.||Intraocular implants and methods for improving vision|
|US20140341968 *||Aug 1, 2014||Nov 20, 2014||Allergan, Inc.||Intraocular Drug Delivery Systems|
|US20150065474 *||Oct 30, 2014||Mar 5, 2015||Warsaw Orthopedic, Inc.||Dexamethasone formulations in a biodegradable material|
|EP2218424A1||Nov 9, 2007||Aug 18, 2010||Allergan, Inc.||Intraocular drug delivery systems|
|EP2664347A1||Jul 13, 2009||Nov 20, 2013||Allergan, Inc.||Method for treating atrophic age related macular degeneration|
|WO2008144399A1 *||May 15, 2008||Nov 27, 2008||Bausch & Lomb||COMPLEXES COMPRISING α2-ADRENERGIC RECEPTOR AGONISTS AND COMPOSITIONS|
|WO2010056598A2||Nov 6, 2009||May 20, 2010||Allergan, Inc.||Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof|
|WO2011091225A2||Jan 21, 2011||Jul 28, 2011||Allergan, Inc.||Alpha-2 adrenergic agonist having long duration of intraocular pressure-lowering effect|
|WO2012067941A1||Nov 10, 2011||May 24, 2012||Allergan, Inc.||Pharmaceutical compositions comprising (3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl)methanol|
|WO2013081981A1||Nov 26, 2012||Jun 6, 2013||Allergan, Inc.||Pharmaceutical compositions comprising 7-(1h-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline for retinal neuroprotection|
|U.S. Classification||424/427, 514/249|
|International Classification||A61K9/00, A61K31/498|
|Cooperative Classification||A61K31/498, A61K9/0051, C08L67/04, A61L31/16, A61K9/204, A61L27/58, A61L2300/436, A61L31/148, A61L2300/604|
|Sep 13, 2004||AS||Assignment|
Owner name: ALLERGAN, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HUANG, GLENN T.;JACKSON, BRITTANY;BURKE, JAMES A.;AND OTHERS;REEL/FRAME:015794/0262;SIGNING DATES FROM 20040826 TO 20040902
|Jan 7, 2005||AS||Assignment|
Owner name: ALLERGAN, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HUANG, GLENN T.;JACKSON, BRITTANY;BURKE, JAMES A.;AND OTHERS;REEL/FRAME:016137/0410;SIGNING DATES FROM 20040427 TO 20040902
|Dec 14, 2006||AS||Assignment|
Owner name: ALLERGAN, INC., CALIFORNIA
Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF CONVEYING PARTIES;ASSIGNORS:HUANG, GLENN T.;JACKSON, BRITTANY;BURKE, JAMES A.;AND OTHERS;REEL/FRAME:018633/0964;SIGNING DATES FROM 20040826 TO 20040902