Biodegradable ocular implant

ES 2 384 875 T3

DESCRIPTION

Biodegradable eye implant.

FIELD OF THE INVENTION

The present invention relates to the field of ophthalmology. In particular, biodegradable implants and methods for treating diseases of the eye are provided.

BACKGROUND OF THE INVENTION

Immunosuppressive agents are used routinely for the treatment of uveitis of various etiologies. For example, topical or oral glucocorticoids are often included in therapeutic treatment; however, a major problem with these routes of administration is the inability to achieve an adequate intraocular drug concentration of the glucocorticoid. In fact, difficulties in treating uveitis due to poor intraocular penetration of topical medications in the posterior segment are known (Bloch-Michel E. (1992). Opening address: intermedíate uveitis, En Intermedíate Uveitis, Dev. Ophthalmol. WRF Boke et al, eds., Basel: Karger, 23: 1-2, Pinar, V. Intermediate uveitis. Massachusetts Eye and Ear Nursing Immunology Service at <http://www.immunology.meei.harvard.edu/imed.htm> (accessed 1998); Rao, NA et al. (1997). Intraocular inflammation and uveitis, In Basic and Clinical Science Course. Section 9 (1997-1998). San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Boke, W. (1992). Clinical picture of intermediate uveitis, En Intermediate Uveitis, Dev Ophthalmol. WRF Boke et al. eds., Basel: Karger, 23: 20-7 and Cheng CK et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36: 442-53).

Systemic glucocorticoid administration can be used alone or in addition to topical glucocorticoids for the treatment of uveitis. Prolonged exposure to high plasma concentrations (administration of 1 mg / kg / day for 2-3 weeks) of steroid is often necessary for therapeutic levels to be achieved in the eye (Pinar, V. Intermediate uveitis, Massachusetts Eye and Ear Nursing Immunology Service at <http://www.immunology.meei.harvard.edu/imed.htm> (accessed 1998).

However, these high plasma drug levels commonly lead to systemic side effects such as high blood pressure, hyperglycemia, increased susceptibility to infection, peptic ulcers, psychosis, and other complications (Cheng CK et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36: 442-53; Schwartz, B. (1966). The response of ocular pressure to corticosteroids, Ophthalmol. Clin. North Am. 6: 929-89; Skalka, HW et al. (1980). Effect of corticosteroids on cataract formation, Arch Ophthalmol 98: 1773-7 and Renfro, L. et al. (1992). Ocular effects of topical and systemic steroids, Dermatologic Clinics 10: 505-12).

Furthermore, total drug delivery to the eye may be poor for drugs with short plasma half-lives since their exposure to intraocular tissues is limited. Therefore, the most effective way to deliver a drug to the posterior segment is to place it directly into the vitreous (Maurice, DM (1983). Micropharmaceutics of the-eye, Ocular Inflammation Ther. 1: 97-102; Lee, VHL et al. . (1989). Drug delivery to the posterior segment Chapter 25 on Retina. TE Ogden and AP Schachat eds., St. Louis: CV Mosby, Vol. 1, pages 483-98 and Olsen, TW et al. (1995). Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36: 1893-1,903).

Techniques such as intravitreal injection have shown promising results, but due to the short intraocular half-life of glucocorticoids (approximately 3 hours), intravitreal injections must be repeated to maintain drug levels. In turn, this repetitive procedure increases the potential for side effects such as retinal detachment, endophthalmitis, and cataracts (Maurice, DM (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther. 1: 97-102; Olsen, TW et al. (1995). Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36: 1893-1.903 and Kwak, HW and D'Amico, DJ (1992). Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection, Arch. Ophthalmol. 110: 259-66).

One of the alternatives to intravitreal injection for drug delivery is the placement of biodegradable implants under the sclera or in the subconjunctival or suprachoroidal space, as described in US Patent 4,863,457 to Lee; WO 95/13765 to Wong et al .; WO 00/37056 to Wong et al .; European Patent EP 430,539 to Wong; in Gould et al., Can. J. Ophthalmol: 29 (4): 168-171 (1994) and in Apel et al., Curr. Eye Res. 14: 659-667 (1995).

Furthermore, controlled drug release of polylactide / polyglycolide copolymers (PLGA) into the vitreous has been described, for example, in US Patent 5,501,856 to Ohtori et al., And European Patent EP 654,256 to Ogura .

International patent WO-A-9638174 describes compositions and methods for biodegradable implants formulated to provide controlled, prolonged drug release. The release rate is modulated by combining the hydrophobic and hydrophilic agents of the implant. The release modulator can act

ES 2 384 875 T3 to accelerate or retard the release rate.

Recent experimental work has shown that unprotected PLGA degrades faster than protected (end protected) PLGA (Park et al., J. Control. Rel. 55: 181-191 (1998); Tracy et al. , Biomaterials 20: 1,057-1,062 (1999) and Jong et al., Polymer 42: 2,795-2,802 (2001). Accordingly, implants containing mixtures of unprotected and protected PLGA have been formed to modulate drug release. For example, US Patent 6,217,911 to Vaughn et al. ('911) and US Patent 6,309,669 to Setterstrom et al. ('669) describe drug delivery of a blend of unprotected and protected PLGA copolymer to reduce the initial burst of drugs. In the '911 patent, the composition delivers non-steroidal anti-inflammatory drugs from PLGA microspheres made by a solvent extraction process or PLGA microcapsules prepared by a solvent evaporation process for a duration of 24 hours to 2 months. In the '669 patent, the composition delivers various PLGA microcapsule pharmaceuticals for a duration of 1-100 days. PLGA microspheres or microcapsules are administered orally or as an injectable aqueous formulation. As mentioned above, there is poor drug delivery in the eye with oral administration. Furthermore, the use of an aqueous injectable drug composition (for injection into the eye) should be avoided since the eye is a closed space (limited volume) with intraocular pressure ranges that are strictly maintained. Administration of an injectable can increase intraocular volume to a point where intraocular pressures then become pathological.

Accordingly, a biodegradable implant for delivering a therapeutic agent to an ocular region can provide significant medical benefit for patients afflicted with an eye disease.

SUMMARY OF THE INVENTION

Biodegradable implants and methods of this invention are typically used to treat diseases of the eye. Accordingly, the implants are shaped so as to be suitable for implantation in the desired ocular region.

The bioerodible implant for treating eye diseases includes an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant has a cumulative release profile in the rabbit eye in vivo where less than about 15 percent of the active agent is released about one day after implantation of the bioerodible implant and more than about 80 percent of the agent. active is released approximately 28 days after implantation of the bioerodible implant and in which the biodegradable polymer matrix comprises a mixture of end-group PLGA hydrophilic and hydrophobic end group PLGA.

The bioerodible implant for treating diseases of the eye includes an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant is formed by an extrusion method and wherein the bioerodible implant has a cumulative release profile in the eye. in vivo rabbit in which more than about 80 percent of the active agent is released about 28 days after implantation of the bioerodible implant.

The bioerodible implant for treating eye diseases includes an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant exhibits a cumulative release profile in which more than about 80 percent of the active agent is released approximately 28 days after implantation of the bioerodible implant and wherein the cumulative release profile is approximately sigmoidal in shape for approximately 28 days after implantation.

The bioerodible implant for treating diseases of the eye includes an active agent dispersed within a biodegradable polymer matrix, wherein the biodegradable polymer matrix comprises a mixture of PLGA with hydrophilic end groups and PLGA with hydrophobic end groups. Examples of hydrophilic end groups include carboxyl, hydroxyl, and polyethylene glycol. Examples of hydrophobic end groups include alkyl esters and aromatic esters.

The bioerodible implant for treating eye diseases includes an active agent dispersed within a biodegradable polymer matrix, wherein the bioerodible implant has a cumulative release profile in the rabbit eye in vivo in which less than about 15 percent of the active agent is released about one day after implantation of the bioerodible implant and more than about 80 percent of the agent. The active ingredient is released approximately 28 days after implantation of the bioerodible implant.

Various active agents can be incorporated into bioerodible implants. In a variation, anti-inflammatory agents can be used, including, but not limited to, non-steroidal anti-inflammatory agents and steroidal anti-inflammatory agents. In another variation, the active agents that can be used in bioerodible implants are: ace inhibitors, endogenous cytokines, agents that influence the basement membrane, agents that influence endothelial cell growth, adrenergic agonists or blockers, or agonists. cholinergic blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics,

ES 2 384 875 T3 antibacterials, antihypertensives, vasopressors, antiprotozoal agents, antiviral agents, antifungal agents, anti-infective agents, antitumor agents, antimetabolites and antiangiogenic agents.

The implants can be used to treat diseases of the eye in mammalian individuals, eg, human individuals. Examples of such diseases include, but are not limited to, uveitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (VRP), Sympathetic ophthalmia, Vogt Koyanagi-Harada syndrome (VKH), histoplasmosis, uveal diffusion, vascular occlusion, and the like.

Furthermore, upon implantation in an ocular region of the individual, bioerodible implants deliver the active agent such that the resulting concentration of active agent in vivo in rabbit aqueous humor is approximately 10 times lower than in rabbit vitreous humor. The active agent is delivered such that a therapeutic amount of active agent is delivered to the ocular region of interest. In general, the therapeutic amount of active agent in an ocular region can be modified by varying the size of the bioerodible implant.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the in vivo concentration of dexamethasone in the vitreous of rabbit eyes over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 350 pg dexamethasone in the posterior segment of rabbit eyes.

Figure 2 shows the percentage of cumulative in vivo release of dexamethasone in the vitreous of rabbit eyes during a period of 42 days after implantation of compressed and extruded biodegradable implants containing 350 pg dexamethasone and 700 pg dexamethasone in the segment. back of rabbit eyes.

Figure 3 shows the in vivo concentration of dexamethasone in the aqueous humor of rabbit eyes over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 350 pg dexamethasone in the posterior segment of rabbit eyes.

Figure 4 shows the in vivo plasma concentration of dexamethasone (from a rabbit blood sample) over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 350 pg dexamethasone in the posterior segment of the eyes. rabbit.

Figure 5 shows the in vivo concentration of dexamethasone in the vitreous of rabbit eyes over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 700 pg dexamethasone in the posterior segment of rabbit eyes.

Figure 6 shows the in vivo concentration of dexamethasone in the aqueous humor of rabbit eyes over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 700 pg dexamethasone in the posterior segment of rabbit eyes.

Figure 7 shows the in vivo concentration of dexamethasone in plasma (from a rabbit blood sample) over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 700 pg dexamethasone in the posterior segment of the eyes of rabbit.

Figure 8 shows the in vivo concentration of dexamethasone in the vitreous of rabbit eyes over a period of 42 days after implantation of compressed and extruded biodegradable implants containing 350 pg dexamethasone and 700 pg dexamethasone in the posterior segment of eyes of rabbit.

Figure 9 shows the percentage of total in vitro cumulative release of dexamethasone in a saline solution at 37 ° C of 60/40 w / w dexamethasone / PLGA implants with a 40: 0 weight ratio of hydrophobic end to end PLGA. hydrophilic (312-140-2), 30:10 weight ratio of hydrophobic end to hydrophilic end (312-140-4) PLGA, 20:20 weight ratio of hydrophobic end to hydrophilic end PLGA (312-140-3) and 0:40 weight ratio of hydrophobic end to hydrophilic end PLGA (312-140-1).

Figure 10 compares the percentage of in vitro cumulative release of dexamethasone in a saline solution at 37 ° C for six batches of implants extruded with 60% by weight of dexamethasone, 30% by weight of hydrophilic end PLGA and 10% by weight of Hydrophobic end PLGA.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides biodegradable eye implants and methods for treating diseases of the eye, as claimed in claim 1. Typically, the implants are formed to be monolithic, that is, the active agent particles are distributed throughout the polymer matrix. biodegradable. Furthermore, implants are formed to release an active agent in an ocular region of the eye for various periods of time. The active agent can be released over a period of time that includes, but is not limited to, about six

ES 2 384 875 T3 months, approximately three months, approximately a month or less than a month.

Definitions

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, the term "ocular region" refers generally to any area of ​​the eyeball, including the anterior and posterior segment of the eye and generally includes, but is not limited to, any functional tissue (eg, for vision) or structural found in the eyeball or tissues or cell layers that partially or completely cover the inside or outside of the eyeball. Specific examples of areas of the eyeball in an ocular region include the anterior chamber, posterior chamber, vitreous cavity, choroid, suprachoroidal space, conjunctiva, subconjunctival space, episcleral space, intracorneal space, epicorneal space, the sclera, pars plana, surgically induced avascular regions, the macula, and the retina.

By individual is meant mammalian individuals, preferably humans. Mammals include, but are not limited to, primates, farm animals, sporting animals, eg, horses (including racehorses), cats, dogs, rabbits, mice, and rats.

As used herein, the term "treating or treating or treating" refers to the resolution, reduction, or prevention of an eye disease or the sequelae of an eye disease.

As used herein, the terms "active agent" and "drug" are used interchangeably and refer to any substance used to treat an eye disease.

As used herein, the term "disease" refers to conditions that are generally treated non-invasively, eg, with drugs, as well as conditions that are generally treated using a surgical procedure.

By therapeutic amount is meant a concentration of active agent that has been delivered locally to a region of the eye that is appropriate to safely treat an eye disease.

As used herein, the term cumulative release profile refers to the total cumulative percentage of agent released from the implant or posterior segment in vivo in rabbit eyes over time or in the specific release medium in vitro. over time.

Biodegradable Implants To Treat Eye Diseases

The implants of the invention include an active agent dispersed within a biodegradable polymer. Implant compositions typically vary according to the preferred drug release profile, the particular active agent used, the condition being treated, and the medical history of the patient. Active agents that may be used include, but are not limited to, ace inhibitors, endogenous cytokines, agents that influence the basement membrane, agents that influence endothelial cell growth, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory, antihypertensive, vasopressor, antibacterial, antiviral, antifungal, antiprotozoal agents, anti-infectives, anti-tumor agents, anti-metabolites, and anti-angiogenic agents.

In a variation the active agent is methotrexate. In another variation, the active agent is retinoic acid. In a preferred variation, the anti-inflammatory agent is a non-steroidal anti-inflammatory agent. Non-steroidal anti-inflammatory agents that may be used include, but are not limited to, aspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. In a more preferred variation, the anti-inflammatory agent is a steroidal anti-inflammatory agent.

Steroidal anti-inflammatory agents

Steroidal anti-inflammatory agents that can be used in ocular implants include, but are not limited to, 21-acetoxypregnolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, cloteronecortolone, corticosteroid, clobetasone, cloteronecortolone, cortivazole, deflazacort, desonide, deoxymethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, Fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halogenated hydrobondyl acetaminophen, halogenated hydrobondyl acetate, halogenated halidecortone propionate, hydrobondyl acetaminophen, halogenated halidecortone propionate, hydrobondyl acetate , mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, Prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide and any of its derivatives.

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In a variation, cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone, and their derivatives, are preferred steroidal anti-inflammatory agents. In another preferred variation, the steroidal anti-inflammatory agent is dexamethasone. In another variation, the biodegradable implant includes an association of two or more steroidal anti-inflammatory agents.

The steroidal anti-inflammatory agent can make up from about 10% to about 90% by weight of the implant. In a variation, the agent is from about 40% to about 80% by weight of the implant. In a preferred variation, the agent comprises about 60% by weight of the implant.

The Biodegradable Polymer Matrix

In a variation, the active agent can be homogeneously dispersed in the biodegradable polymer matrix of the implants. The selection of the biodegradable polymer matrix to be employed will vary with the desired release kinetics, the tolerance of the patient, the nature of the disease to be treated, and the like. Characteristics of the polymer that are considered include, but are not limited to, biocompatibility and biodegradability at the implantation site, compatibility with the active agent of interest, and treatment temperatures. The biodegradable polymer matrix typically comprises at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, or at least about 90 percent by weight of the implant. In a variation, the biodegradable polymer matrix comprises about 40% by weight of the implant.

The polymers can be cross-linked or non-cross-linked. If they are cross-linked, they are typically no more than slightly cross-linked and they are less than 5% cross-linked, usually less than 1%.

Biodegradable polymeric matrices that include mixtures of PLGA with hydrophilic and hydrophobic ends are employed and are useful in modulating degradation rates of the polymeric matrix. PLGA with hydrophobic ends (also referred to as capped or capped) has an ester linkage of a hydrophobic nature at the end of the polymer. Typical hydrophobic end groups include, but are not limited to, alkyl esters and aromatic esters. Hydrophilic end PLGA (also referred to as unprotected) has a hydrophilic end group at the end of the polymer. PLGA with a hydrophilic end group at the end of the polymer degrades faster than PLGA with hydrophobic ends because it absorbs water and undergoes hydrolysis at a faster rate (Tracy et al., Biomaterials 20: 1,057-1,062 (1999 )). Examples of suitable hydrophilic end groups that can be incorporated to activate hydrolysis include, but are not limited to, carboxyl, hydroxyl, and polyethylene glycol. The specific end group will typically result from the initiator employed in the polymerization process. For example, if the initiator is water or carboxylic acid, the resulting end groups will be carboxyl and hydroxyl. Similarly, if the initiator is a monofunctional alcohol, the resulting end groups will be ester or hydroxyl.

Implants can be formed from all hydrophilic end PLGAs or all hydrophobic end PLGAs. In general, however, the ratio of hydrophilic end to hydrophobic end PLGA in the biodegradable polymer matrices of this invention ranges from about 10: 1 to about 1:10 by weight. For example, the ratio can be 3: 1, 2: 1, or 1: 1 by weight. In a preferred variation, an implant with a hydrophilic end to hydrophobic end PLGA ratio of 3: 1 w / w is used.

Additional Agents

Other agents can be employed in the formulation for a variety of purposes. For example, buffering agents and preservatives can be used. Preservatives that may be used include, but are not limited to, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methyl paraben, polyvinyl alcohol, and phenylethyl alcohol. Examples of buffering agents that may be employed include, but are not limited to, sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, and the like, as approved by the FDA for the intended route of administration. . Electrolytes such as sodium chloride and potassium chloride can also be included in the formulation.

Biodegradable eye implants can also include additional hydrophilic or hydrophobic compounds that accelerate or delay the release of the active agent. Furthermore, the authors believe that because hydrophilic end PLGA exhibits a faster degradation rate than hydrophobic end PLGA due to its ability to absorb water more easily, increasing the amount of hydrophilic end PLGA in the implant polymer matrix. will result in faster dissolution rates. Figure 9 shows that the time from implantation to significant active agent release (lag period) increases with decreasing amounts of hydrophilic end PLGA in the ocular implant. In Figure 9, the lag period for implants with 0% hydrophilic end PLGA (40% w / w hydrophobic end) is shown to be approximately 21 days. In comparison, a significant reduction in lag period was observed with implants having 10% w / w and 20% w / w hydrophilic end PLGA.

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Release Kinetics

The authors believe that the implants of the invention are formulated with particles of an active agent dispersed within a matrix of biodegradable polymer. Without being limited by theory, the authors believe that the release of the active agent is achieved by erosion of the biodegradable polymer matrix and by diffusion of the particulate agent in an ocular fluid, for example, the vitreous, with subsequent dissolution of the polymer matrix. and release of the active agent. The authors believe that factors influencing release kinetics include characteristics such as active agent particle size, active agent solubility, ratio of active agent to polymer (s), method of manufacture, surface exposed and the erosion rate of the polymer (s). The release kinetics achieved by this form of active agent release is different than that achieved by formulations that release active agents by swelling of the polymer, such as with cross-linked hydrogels. In that case, the active agent is not released by erosion of the polymer but by swelling of the polymer, which releases agent as the liquid diffuses through the exposed pathways.

The authors believe that the release rate of the active agent depends at least in part on the rate of degradation of the polymer backbone component (s) that make up the biodegradable polymer matrix. For example, condensation polymers can be degraded by hydrolysis (among other mechanisms) and therefore any change in implant composition that increases water absorption by the implant will likely increase the rate of hydrolysis, thereby increasing the rate of hydrolysis. degradation and erosion of the polymer and thus increasing the rate of release of active agent.

The release kinetics of the implants of the invention depend in part on the surface of the implants. A larger surface area exposes more polymer and active agent to ocular fluid, causing more rapid erosion of the polymeric matrix and dissolution of the active agent particles in the fluid. The size and shape of the implant can also be used to control the rate of release, the period of treatment, and the concentration of active agent at the implantation site. At equal active agent loads, larger implants will deliver a proportionally higher dose, but depending on the surface-to-mass ratio, they may have a lower release rate. For implantation in an ocular region, the total weight of the implant preferably ranges, for example, from about 100-5,000 pg, typically from about 500-1,500 pg. In a variation, the total weight of the implant is approximately 600 pg. In another variation, the total weight of the implant is approximately 1,200 pg.

Bioerodible implants are typically solid and can be shaped as particles, sheets, patches, plates, films, discs, fibers, rods, and the like or they can be of any size or shape compatible with the selected implantation site, as long as the implants exhibit kinetics. of desired release and deliver an amount of active agent that is therapeutic for the desired eye disease. The upper limit for implant size will be determined by factors such as desired release kinetics, tolerance for the implant at the implantation site, size limitations on insertion, and ease of manipulation. For example, the vitreous chamber can accommodate relatively large rod-shaped implants, generally with diameters of about 0.05mm to 3mm and a length of about 0.5 to about 10mm. In a variation, the rods have diameters from about 0.1mm to about 1mm. In another variation, the rods have diameters from about 0.3mm to about 0.75mm. In yet another variation, other implants with varying geometries but roughly similar volumes can also be used.

As previously discussed, the release of an active agent from a biodegradable polymer matrix can also be modulated by varying the ratio of hydrophilic end PLGA to hydrophobic end PLGA in the matrix. Release rates can be further manipulated by the method used to fabricate the implant. For example, as illustrated in Examples 4-7, 3: 1 dexamethasone / PLGA 60/40 w / w implants, compared to compressed tablet implants, demonstrate a different drug release profile and agent concentration in the vitreous for about a period of one month. Overall, less abrupt agent release and more consistent agent level in the vitreous are demonstrated with extruded implants.

As shown in Figure 2 and Examples 4 and 5, a more abrupt release of initial active agent occurs on day one post implantation with the 350 pg dexamethasone compressed tablet implant (350T) compared to the implant ( 350E) of extrudate of 350 pg dexamethasone. A more abrupt initial active agent release also occurs with the 700 pg dexamethasone compressed implant (700T) compared to the extruded 700 pg dexamethasone implant (700E) on day 1, as shown in Figure 2 and the Examples 6 and 7.

The proportions of active agent, biodegradable polymer matrix and any other additives can be determined empirically by formulating various implants with varying proportions and determining the release profile in vitro or in vivo. A USP approved method for dissolution or release assay can be used to measure the rate of release in vitro (USP 24; NF 19 (2,000) pp. 1941-1951). For example, a weighed sample of the implant is added to a measured volume of a solution containing 0.9% NaCl in water, in the case that the volume of solution is such that the concentration of active agent after release is less than 20% saturation. The mixture is kept at 37 ° C and shaken or shaken slowly to keep the implants in suspension. The release of the dissolved active agent as a function of time is

ES 2 384 875 T3 can then be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy and the like, until the concentration of the solution becomes constant or until more than 90% of the solution has been released. active agent.

In a variation, the extruded implants described with this (ratio of hydrophilic end PLGA to hydrophobic end PLGA of 3: 1) can have cumulative percent release profiles in vivo with the following described characteristics, as shown in Figure 2 , where the release profiles are for release of the active agent in vivo after implantation of the implants in the vitreous of rabbit eyes. The volume of rabbit eyes is about 60-70% of human eyes.

On day one after implantation, the percentage of cumulative release in vivo can be between about 0% and about 15% and more usually between about 0% and about 10%. On day one after implantation, the percent cumulative release in vivo may be less than about 15% and more usually less than about 10%.

On day three after implantation, the percentage of cumulative release in vivo can be between about 0% and about 20% and more usually between about 5% and about 15%. On day three after implantation, the percent cumulative release in vivo may be less than about 20% and more usually less than about 15%.

On day seven after implantation, the percentage of cumulative release in vivo can be between about 0% and about 35%, more usually between about 5% and about 30%, and more usually still between about 10% and about 25%. On day seven after implantation, the percentage of cumulative release in vivo can be greater than about 2%, more usually greater than about 5%, and more usually still greater than about 10%.

On the fourteenth day after implantation, the percentage of cumulative release in vivo may be between about 20% and about 60%, more usually between about 25% and about 55%, and more usually still between about 30% and about 50%. On the fourteenth day after implantation, the percent cumulative release in vivo can be greater than about 20%, more usually greater than about 25%, and more usually still greater than about 30%.

On day twenty-one after implantation, the percentage of cumulative release in vivo can be between about 55% and about 95%, more usually between about 60% and about 90%, and more usually still between about 65% and about 85%. On the twenty-first day after implantation, the percent cumulative release in vivo can be greater than about 55%, more usually greater than about 60%, and more usually still greater than about 65%.

On the twenty-eighth day after implantation, the percentage of cumulative release in vivo can be between about 80% and about 100%, more usually between about 85% and about 100%, and more usually still between about 90% and about 100%. On the twenty-eighth day after implantation, the percent cumulative release in vivo can be greater than about 80%, more usually greater than about 85%, and more usually still greater than about 90%.

On day thirty-five after implantation, the percentage of cumulative release in vivo can be between about 95% and about 100% and more usually between about 97% and about 100%. On day thirty-five after implantation, the percent cumulative release in vivo can be greater than about 95% and more usually greater than about 97%.

In one variation, the percentage of cumulative release in vivo exhibits the following characteristics: one day after implantation it is less than about 15%; three days after implantation it is less than about 20%; seven days after implantation is greater than about 5%; fourteen days after implantation is greater than about 25%; twenty-one days after implantation is greater than about 60% and twenty-eight days after implantation is greater than about 80%. In another variation, the percentage of cumulative release in vivo exhibits the following characteristics: one day after implantation it is less than about 10%; three days after implantation it is less than about 15%; seven days after implantation is greater than about 10%; fourteen days after implantation is greater than about 30%; twenty-one days after implantation is greater than about 65%; twenty-eight days after implantation is greater than about 85%.

In yet another variation, the extruded implants described in this patent can present profiles of cumulative release percentages in vitro, in saline solution, at 37 ° C, with the following characteristics, as further described below and as shown in the Figure 10.

ES 2 384 875 T3

The percentage of cumulative release in vitro on day one can be between about 0% and about

5% and more typically between about 0% and about 3%. The percent cumulative release in vitro on day one may be less than about 5% and more usually less than about

3%.

The percent cumulative release in vitro on day four can be between about 0% and about 7% and more typically between about 0% and about 5%. The percent cumulative release in vitro on day four may be less than about 7% and more usually less than about 5%.

The percent cumulative release in vitro on day seven can be between about 1% and about 10% and more typically between about 2% and about 8%. The percent cumulative release in vitro on day seven can be greater than about 1% and more usually greater than about 2%.

The percent cumulative release in vitro on day 14 can be between about 25% and about 65%, more usually between about 30% and about 60%, and more usually still between about 35% and about 55%. The percent cumulative release in vitro on day 14 may be greater than about 25%, more usually greater than about 30%, and more usually still greater than about 35%.

The percent cumulative release in vitro on day 21 can be between about 60% and about 100%, more usually between about 65% and about 95%, and more usually still between about 70% and about 90%. The percent cumulative release in vitro on day 21 can be greater than about 60%, more usually greater than about 65%, and more usually still greater than about 70%.

The percent cumulative release in vitro on day 28 can be between about 75% and about 100%, more usually between about 80% and about 100%, and more usually still between about 85% and about 95%. The percent cumulative release in vitro on day 28 may be greater than about 75%, more usually greater than about 80%, and more usually still greater than about 85%.

The percent cumulative release in vitro on day 35 can be between about 85% and about 100%, more usually between about 90% and about 100%, and more usually still between about 95% and about 100%. The percent cumulative release in vitro on day 35 may be greater than about 85%, more usually greater than about 90%, and more usually still greater than about 95%.

In a variation, the percentage of cumulative release in vitro exhibits the following characteristics; after one day it is less than about 1%; after four days it is less than about 7%; after seven days it is greater than about 2%; after 14 days it is greater than about 30%; after 21 days it is greater than about 65%; after 28 days it is greater than about 80% and after 35 days it is greater than about 90%. In another variation, the percentage of cumulative release in vitro exhibits the following characteristics: after one day it is less than about 3%; after four days it is less than about 5%; after seven days it is greater than about 2%; after 14 days it is greater than about 35%; after 21 days it is greater than about 70%; after 28 days it is greater than about 85% and after 35 days it is greater than about 90%.

In addition to demonstrating a less sudden release effect for extruded implants, Figures 2 and 10 also demonstrate that after 28 days in vivo in rabbit eyes or in vitro in a saline solution at 37 ° C, respectively, almost all the agent active has been released from the implants. Furthermore, Figures 2 and 10 show that the active agent release profiles for extruded implants in vivo (from the time of implantation) and in vitro (from the time of placement in a saline solution at 37 ° C) are substantially similar. and follow approximately a sigmoidal curve, releasing substantially all of the active agent over 28 days. From day one to about day 17, the curves show approximately an upward curvature (that is, the derivative of the curve increases as time increases) and from about day 17 onwards the curves show approximately an upward curvature. down (that is, the derivative of the curve decreases as time increases).

In contrast, the graphical representations shown in Figure 2 for the 350 pg and 700 pg dexamethasone compressed tablet implants exhibit a greater initial burst agent release generally followed by a gradual increase in release. Furthermore, as shown in Figures 1 and 5, implantation of a compressed implant results in different concentrations of active agent in the vitreous at various times since the implants have been extruded. For example, as shown in Figures 1 and 5, with extruded implants there is a gradual increase, plateau, and gradual decrease in intravitreal agent concentrations. By

In contrast, for compressed tablet implants, there is a greater initial active agent release followed by an approximately constant decrease over time. Consequently, the intravitreal concentration curve for extruded implants results in longer levels of active agent in the ocular region.

In addition to the previously described implants, which release substantially all of the therapeutic agent within 35 days, with the implant components varying including, but not limited to, the composition of the biodegradable polymer matrix, implants can also be formulated to deliver a therapeutic agent to any desirable length of time, for example, for about a week, for about two weeks, for about three weeks, for about four weeks, for about five weeks, for about six weeks, for about seven weeks, for about eight weeks, for about nine weeks, for about ten weeks, for about eleven weeks, for about twelve weeks, or for more than 12 weeks .

Another important feature of extruded implants is that different levels of active agent concentration can be established in the vitreous using different doses of the active agent. As illustrated in Figure 8, the agent concentration in the vitreous is significantly higher with the 700 pg dexamethasone extruded implant than with the 350 pg dexamethasone extruded implant. Different concentrations of active agent are not demonstrated with the compressed tablet implant. Thus, by using an extruded implant, it is possible to more easily control the concentration of active agent in the vitreous. In particular, specific dose-response relationships can be established since implants can be shaped to deliver a predetermined amount of active agent.

Applications

Examples of eye diseases that can be treated by the implants and methods of the invention include, but are not limited to, uveitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy. , proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt Koyanagi-Harada syndrome (VKH), histoplasmosis, uveal diffusion and vascular occlusion. In a variation, the implants are particularly useful in the treatment of diseases such as: uveitis, macular edema, occlusive vascular conditions, proliferative vitreoretinopathy (PVR) and various other retinopathies.

Implantation method

Biodegradable implants can be inserted into the eye by a variety of methods, including forceps, trocar, or other types of applicators, after making an incision in the sclera. In some cases, a trocar or applicator can be used without creating an incision. In a preferred variation, a portable applicator is used to insert one or more biodegradable implants into the eye. The portable applicator typically comprises an 18-30 GA stainless steel needle, a lever, an actuator, and a plunger.

The implantation method in general involves first accessing the target area within the ocular region with the needle. Once inside the target area, eg, the vitreous cavity, the lever on the portable device is depressed to cause the actuator to drive the plunger forward. As the plunger advances, it pushes the implant into the target area.

Extrusion Methods

The use of extrusion methods allows large scale fabrication of implants and results in implants with a homogeneous dispersion of the drug within the polymer matrix. When extrusion methods are used, the polymers and the active agents that are enclosed are stable at the required temperatures during manufacture, typically at least about 50 ° C. Extrusion methods use temperatures from about 25 ° C to about 150 ° C, more preferably about 60 ° C to about 130 ° C.

Different extrusion methods can provide implants with different characteristics, including but not limited to, homogeneity of the dispersion of the active agent within the polymeric matrix. For example, using a piston extruder, a single screw extruder will generally produce implants with progressively more homogeneous dispersion of the active agent. When using an extrusion method, extrusion parameters such as temperature, extrusion speed, die geometry, and die surface finish will have an effect on the release profile of the implants produced.

In a variation of implant production by extrusion methods, the drug and polymer are first mixed at room temperature and then heated to a temperature range of about 60 ° C to about 150 ° C, more usually about 130 ° C. for a period of time from about 0 to about 1 hour, more usually from about 0 to about 30 minutes, more usually still from about 5 minutes to about 15 minutes and most usually for about 10 minutes. The implants are then extruded at a temperature of about 60 ° C to about 130 ° C, preferably at a temperature of about 75 ° C.

ES 2 384 875 T3

In a preferred extrusion method, the active agent powder and PLGA mixture is added to a preset twin screw or single screw extruder at a temperature of about 80 ° C to about 130 ° C and extruded directly as a filament. or rod with minimum residence time in the extruder. The extruded filament or extruded rod is then cut into small implants with the appropriate active agent loading dose to treat the disease of its intended use.

Examples

The following examples serve to more fully describe the manner of using the invention already described. It is understood that these examples do not serve in any way to limit the scope of this invention, but rather are presented for illustrative purposes.

Example 1 (Reference example)

Manufacture of Compressed Tablet Implants

Micronized dexamethasone (Pharmacia, Peapack, NJ) and PLGA 50/50 with micronized hydrophobic end (Birmingham Polymers, Inc., Birmingham, AL) were weighed accurately and placed in a stainless steel mixing container. The container was sealed, placed in a Turbula mixer and mixed at a prescribed intensity, eg, 10 rad / s (96 rpm) and time, eg, 15 minutes. The resulting powder mixture was loaded one dose at a time into a single cavity tablet press. The press was activated at a preset pressure, for example, 172 kPa (25 psi) and a duration, for example, 6 seconds, and the tablet was formed and expelled from the press at room temperature. The ratio of dexamethasone to PLGA was 70/30 w / w for all compressed tablet implants.

Example 2

Manufacture of Extruded Implants

Micronized dexamethasone (Pharmacia, Peapack, NJ) and non-micronized PLGA were accurately weighed and placed in a stainless steel mixing container. The container was sealed, placed in a Turbula mixer and mixed at a prescribed intensity, eg, 10 rad / s (96 rpm) and time, eg, 10-15 minutes. The non-micronized PLGA composition comprised a 30/10 w / w mixture of hydrophilic end PLGA (Boehringer Ingelheim, Wallingford, CT) and hydrophobic end PLGA (Boehringer Ingelheim, Wallingford, CT). The resulting powder mixture was fed into a DACA Micromixer-Extruder (DACA, Goleta, CA) and subjected to a preset temperature, for example, 115 ° C and screw speed, for example, 1.26 rad / s (12 rpm). The filament was extruded on a guide mechanism and cut into exact lengths corresponding to the designated implant weight. The ratio of dexamethasone to total PLGA (hydrophilic and hydrophobic end) was 60/40 w / w for all extruded implants.

Example 3

Method to Place Implants in the Vitreous

The implants were placed in the posterior segment of the right eye of New Zealand Bank Rabbits by excising the conjunctiva and sclera between exact positions 10 and 12 with a 20 gauge microvitreoretinal sheet (MVR). Fifty out of 100 pl of vitreous humor with a 1 cc syringe fitted with a 27 gauge needle. A sterile trocar, preloaded with the appropriate implant (Drug Delivery System, DDS), was inserted 5 mm through the sclerotomy and then retracted with the push wire in place, leaving the implant in the posterior segment. The sclera and conjunctiva were then closed using a 7-0 Vicril suture.

Example 4

In vivo Release of Dexamethasone From 350 ug Dexamethasone Tablet Implants

Example 4 demonstrates the high initial release but generally lower intravitreal concentration of dexamethasone from compressed tablet implants when compared to extruded implants. The 350 pg compressed tablet implant (350T) was placed in the right eye of New Zealand White Rabbits as described in Example 3. Vitreous samples were taken periodically and evaluated by LC / MS / MS to determine delivery performance. dexamethasone in vivo. As seen in Figure 1, dexamethasone reached detectable mean intravitreal concentrations from day 1 (142.20 ng / ml) to day 35 (2.72 ng / ml) and the intravitreal concentration of dexamethasone gradually decreased throughout the weather.

In addition to the vitreous samples, aqueous humor and plasma samples were also taken. The 350T showed a gradual decrease in aqueous humor dexamethasone concentrations over time, presenting a detectable average dexamethasone aqueous humor concentration from day 1 (14.88 ng / ml) to day 21 (3.07 ng / ml), as demonstrated in Figure 3. Dexamethasone levels in aqueous humor are correlated

ES 2 384 875 T3 fully with the levels of dexamethasone in the vitreous humor, but at a much lower level (approximately 10 times lower). Figure 4 shows that only trace amounts of dexamethasone were found in plasma.

Example 5

In vivo Dexamethasone Release From Extruded 350 ug Dexamethasone Implants

Example 5 demonstrates the lower initial release and generally longer intravitreal concentration of dexamethasone from extruded implants. The extruded 350 pg implant (350E) was placed in the right eye of New Zealand White Rabbits as described in Example 3. Vitreous samples were periodically taken and evaluated by LC / MS / MS to determine delivery performance of dexamethasone in vivo. Referring to Figure 1, 350E showed detectable mean vitreous concentrations on day 1 (10.66 ng / ml) to day 28 (6.99 ng / ml). The 350T implant had statistically significant higher dexamethasone concentrations on day 1 (p = 0.037) while the 350E had a statistically significant higher dexamethasone level on day 21 (p = 0.041).

In addition to the vitreous samples, aqueous humor and plasma samples were also taken. In Figure 3, 350E showed detectable mean dexamethasone aqueous humor concentrations on day 1 (6.67 ng / ml) to day 42 (2.58 ng / ml) except for day 35 when the values ​​were below the limit of quantification. In general, aqueous dexamethasone levels fully correlate with vitreous dexamethasone levels, but at a much lower level (approximately 10 times lower). Figure 4 demonstrates that only a trace amount of dexamethasone was found in plasma.

Example 6

In vivo Release of Dexamethasone From 700 ug Dexamethasone Tablet Implants

Example 6 also shows the high initial release and generally lower intravitreal concentration of dexamethasone from compressed tablet implants. The dosage form (700 T) of 700 pg compressed tablets was put into the right eye of New Zealand White Rabbits as described in Example 3. Vitreous samples were periodically taken and evaluated by LC / MS / MS to determine the conducting dexamethasone delivery in vivo. As seen in Figure 5, 700T achieved detectable mean dexamethasone vitreous concentrations from day 1 (198.56 ng / ml) to day 42 (2.89 ng / ml) and a gradual decrease in concentration. intravitreal dexamethasone over time.

In addition to the vitreous samples, aqueous humor and plasma samples were also obtained. As seen in Figure 6, 700T exhibited a gradual decrease in aqueous dexamethasone concentrations over time and reached detectable mean dexamethasone aqueous humor concentrations on day 1 (25.90 ng / mL). at day 42 (2.64 ng / ml) except for day 35 when the values ​​were below the limit of quantification. Dexamethasone levels in aqueous humor fully correlated with dexamethasone levels in vitreous humor, but at a much lower level (approximately 10 times lower). Figure 7 demonstrates that only a trace amount of dexamethasone was found in plasma.

Example 7

In vivo Dexamethasone Release From Extruded 700 ug Dexamethasone Implants

Example 7 also illustrates the lower initial release and generally higher intravitreal concentration of dexamethasone from extruded implants. The extruded 700 pg implant (700E) was placed in the right eye of New Zealand White Rabbits, as described in Example 3. Vitreous samples were periodically taken and evaluated by LC / MS / MS to determine delivery performance. dexamethasone in vivo. As seen in Figure 5, 700E exhibited a mean, detectable vitreous concentration of dexamethasone from day 1 (52.63 ng / ml) to day 28 (119.70 ng / ml).

In addition to the vitreous samples, aqueous humor and plasma samples were also taken. As seen in Figure 6, 700E reached a detectable mean aqueous humor concentration on day 1 (5.04 ng / ml) to day 28 (5.93 ng / ml). Dexamethasone levels in aqueous humor fully correlated with dexamethasone levels in vitreous humor, but at a much lower level (approximately 10 times lower). Figure 7 demonstrates that only a trace amount of dexamethasone was found in plasma.