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  Pharmaceutical Patents  

 

Title:  Method and composition for inhibiting reperfusion injury in the brain
United States Patent: 
7,332,159
Issued: 
February 19, 2008

Inventors: 
Labhasetwar; Vinod D. (Omaha, NE), Reddy; Maram K. (Omaha, NE)
Assignee: 
Board of Regents of the University of Nebraska (Omaha, NE)
Appl. No.: 
10/955,739
Filed: 
September 30, 2004


 

Covidien Pharmaceuticals Outsourcing


Abstract

The present invention relates to a method for inhibiting reperfusion injury in the brain. The method involve injecting via the carotid artery or jugular vein an antioxidant-loaded nanoparticle. A nanoparticle formulation containing an inert plasticizer is also provided for sustained release of an active agent.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention relates to a method for inhibiting reperfusion injury in the brain. The method involves administering an effective amount of an antioxidant, wherein said antioxidant is formulated in a nanoparticle and administered via the carotid artery or jugular vein to a subject in need of treatment, thereby inhibiting reperfusion injury in the brain of said subject. In certain embodiments, the antioxidant is an antioxidant enzyme (e.g., superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase hemeoxygenase, or mimetic or synthetic enzymes thereof), a small molecule antioxidant (e.g., a vitamin antioxidant, acetyl salicyclic acid, mannitol, captopril, arginine, or pyruvate) or a combination thereof. In other embodiments, the nanoparticle is composed of a biodegradable polymer such as a poly(lactide-co-glycolide), poly(lactic acid), poly(alkylene glycol), polybutylcyanoacrylate, poly(methylmethacrylate-co-methacrylic acid), poly-allylamine, polyanhydride, polyhydroxybutyric acid, or a polyorthoester or a combination thereof. In still further embodiments, the nanoparticle contains a targeting moiety or a plasticizer such as L-tartaric acid dimethyl ester, triethyl citrate, or glyceryl triacetate to facilitate sustained release of the antioxidant.

The present invention further relates to a composition for sustained release of an effective amount of an active agent. The composition contains an active agent (e.g., antioxidant, an anti-infective, an antiseptic, a steroid, a therapeutic peptide, an analgesic, an anti-inflammatory agent, an anticancer agent, a narcotic, an anesthetic, an antiangiogenic agent, a polysaccharide, a vaccine, an antigen, or a nucleic acid), at least one biodegradable polymer (e.g., a poly(lactide-co-glycolide), poly(lactic acid), poly(alkylene glycol), polybutylcyanoacrylate, poly(methylmethacrylate-co-methacrylic acid), poly-allylamine, polyanhydride, polyhydroxybutyric acid, or a polyorthoester), and an inert plasticizer (e.g., L-tartaric acid dimethyl ester, triethyl citrate, or glyceryl triacetate). In particular embodiments, the nanoparticle composition further contains a targeting moiety.

A method for effecting a sustained release of an effective amount of an active agent using a nanoparticle containing an active agent, at least one biodegradable polymer and an inert plasticizer is also provided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for inhibiting reperfusion injury in the brain using a highly effective course of therapy which combines an antioxidant formulated into a nanoparticle and injection of the nanoparticle formulation via the carotid artery or jugular vein. Using this protocol, it has now been shown that the nanoparticles can cross the blood brain barrier and inhibit ischemia in the brain. It has further been demonstrated that when the nanoparticle formulation contains an inert plasticizer such as dimethyl tartrate (DMT), sustained release of the active agent can be achieved.

As it pertains to the present disclosure, ischemia is used in the classical sense to refer to the condition suffered by tissues or organs when deprived of blood flow; reduced blood flow results in an inadequate supply of nutrients and oxygen in the tissues or organs. Reperfusion injury refers to the tissue damage inflicted when blood flow is restored after an ischemic period of more than about ten minutes.

Antioxidants which can be formulated in a nanoparticle of the present invention to inhibit reperfusion injury include antioxidant enzymes, small molecule antioxidants, or combinations thereof. Antioxidants are substances which inhibit oxidation or suppress reactions promoted by reactive oxygen species such as oxygen itself, oxygen free radicals, or peroxides. Antioxidants can be absorbed into the cell membrane to neutralize oxygen radicals and thereby protect the membrane. As used herein, antioxidant enzymes are generally proteins, or their fragments, that scavenge oxygen free radicals or H.sub.2O.sub.2 (hydrogen peroxide). Suitable antioxidant enzymes include, but are not limited to superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase or hemeoxygenase, or mimetic or synthetic enzymes thereof. See, U.S. Pat. No. 5,994,339 for mimetic enzymes.

Small molecule antioxidants include scavengers of .O.sub.2.sup.- (superoxide), .OH (hydroxyl) or NO (nitric oxide) radicals (e.g., acetyl salicylic acid, a scavenger of .O.sub.2.sup.-; mannitol or captopril which are scavengers of .OH); molecules that inhibit the generation of these radicals (e.g., arginine derivatives, inhibitors of nitric oxide synthase which produce NO; pyruvate which attenuates the rate of H.sub.2O.sub.2-- induced generation of reactive oxygen species); or vitamin antioxidants. Vitamin antioxidants include lycopene; lutein; xeaxanthine; all forms of Vitamin A including retinal and 3,4-didehydroretinal; all forms of carotene (e.g., alpha-carotene, beta-carotene, gamma-carotene, delta-carotene); all forms of Vitamin C (e.g., D-ascorbic acid, L-ascorbic acid); all forms of Vitamin E such as tocopherol (e.g., alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol), tocoquinone, tocotrienol, and Vitamin E esters which readily undergo hydrolysis to Vitamin E such as Vitamin E acetate and Vitamin E succinate, and pharmaceutically acceptable Vitamin E salts such as Vitamin E phosphate; prodrugs of Vitamin A, carotene, Vitamin C, and Vitamin E; pharmaceutically acceptable salts of Vitamin A, carotene, Vitamin C, and Vitamin E, and the like, and mixtures thereof. Analogues of Vitamin E such as TROLOX.RTM., a compound which is more hydrosoluble than natural forms of Vitamin E and which could reach intracellular sites more rapidly, is also contemplated.

Antioxidants for use in the formulations of the present invention can be isolated from a natural source or wholly or partially synthetically- or recombinantly-produced. Methods for isolating or producing antioxidants or antioxidant extracts are well-established in the art, see, e.g., U.S. Pat. Nos. 6,737,552; 6,660,320; 6,656,358; 6,653,530; 6,623,743; RE 38,009; 6,429,356; 6,436,362; 6,262,279; 6,410,290; 6,231,853; and 5,714,362 and WO 91/04315.

An effective amount of antioxidant present in a nanoparticle formulation of the present invention is an amount which prevents and/or reduces injury of mammalian brain tissue due to ischemic conditions. Such ischemic conditions can arise from acute head trauma, surgical occlusion of blood flow, stroke, cardiac arrest and the like. The exact amount of antioxidant will vary according to factors such as the antioxidant being used as well as the other ingredients in the composition. Typically, the amount of antioxidant can vary from about 1 unit/kg to about 30,000 units/kg of body weight or from about 500 units/kg to about 20,000 units/kg. In particular embodiments, the antioxidant is given at a dose of about 10,000 units/kg. The effectiveness of the antioxidant treatment can be determined by monitoring the mammals neurological status, infarct volume or plasma glucose levels as disclosed herein.

When the antioxidant is a mimetic, it has been demonstrated that the in vivo oxidoreductase activity of the mimetic is such that an effective dose will be low enough to avoid problems of toxicity (Faulkner, et al. (1994) J. Biol. Chem. 269:23471); therefore, doses that can be used include those in the range of 1 to 50 mg/kg.

As disclosed herein, it has been found that an antioxidant-containing nanoparticle formulation can exert its effect via any route of administration; however, intracarotid administration is particularly effective at delivering a therapeutic amount of the active agent to the brain. Accordingly, it is contemplated that an antioxidant-containing nanoparticle formulation of the present invention can be administered via intravenous, intracerebral, intracarotid, intramuscular or intrajugular routes, wherein intracarotid or intrajugular routes are suitable. In particular embodiments, intracarotid administration is advantageously used. The antioxidant-containing nanoparticle formulation of the present invention can be administered to a subject in need of such treatment including a subject at risk of reperfusion injury (e.g., in the case of surgery-induced ischemia) or a subject that has experienced an ischemic event (e.g., stroke) to prevent, inhibit and/or reduce reperfusion injury.

As one of skill in the art will appreciate, a nanoparticle in accordance with the methods and compositions of the present invention can be composed of a variety of injectable biodegradable polymers. Nanoparticles are said to be biodegradable if the polymer of the nanoparticle dissolves or degrades within a period that is acceptable in the desired application (usually in vivo therapy), usually less than five years, and desirably less than one year, upon exposure to a physiological solution of pH 6-8 having a temperature of between 25.degree. C. and 37.degree. C. As such, a nanoparticle for use in accordance with the methods and compositions of the present invention can be composed homopolymers or copolymers prepared from monomers of polymers disclosed herein, wherein the copolymer can be of diblock, triblock, or multiblock structure. Suitable polymers include, but are not limited to, poly(lactide-co-glycolides), poly(lactic acid), poly(alkylene glycol), polybutylcyanoacrylate, poly(methylmethacrylate-co-methacrylic acid), poly-allylamine, polyanhydride, polyhydroxybutyric acid, or polyorthoesters and the like. In particular embodiments, a nanoparticle is composed of a copolymer of a poly(lactic acid) and a poly(lactide-co-glycolide). Particular combinations and ratios of polymers are well-known to the skilled artisan and any suitable combination can be used in the nanoparticle formulations of the present invention. Generally, the resulting nanoparticle typically ranges in size from between 1 nm and 1000 nm, or more desirably between 1 nm and 100 nm.

A nanoparticle of the present invention can further contain a polymer that affects the charge or lipophilicity or hydrophilicity of the particle. Any biocompatible hydrophilic polymer can be used for this purpose, including but not limited to, poly(vinyl alcohol).

To further enhance delivery of a therapeutically effective amount of an active agent, a nanoparticle of the present invention can further contain a targeting moiety (e.g., a protein transduction domain). As used herein, a targeting moiety is any molecule which can be operably attached to a nanoparticle of the present invention to facilitate, enhance, or increase the transport of the nanoparticle into target tissue. Such a moiety can be a protein, peptide or small molecule. For example, a variety of protein transduction domains, including the HIV-1 Tat transcription factor, Drosophila Antennapedia transcription factor, as well as the herpes simplex virus VP22 protein have been shown to facilitate transport of proteins into the cell (Wadia and Dowdy (2002) Curr. Opin. Biotechnol. 13:52-56). Further, an arginine-rich peptide (Futaki (2002) Int. J. Pharm. 245:1-7), a polylysine peptide containing Tat PTD (Hashida, et al. (2004) Br. J. Cancer 90(6):1252-8), Pep-1 (Deshayes, et al. (2004) Biochemistry 43(6):1449-57) or an HSP70 protein or fragment thereof (WO 00/31113) is suitable for targeting a nanoparticle of the present invention. Not to be bound by theory, it is believed that such transport domains are highly basic and appear to interact strongly with the plasma membrane and subsequently enter cells via endocytosis (Wadia, et al. (2004) Nat. Med. 10:310-315). Animal model studies indicate that chimeric proteins containing a protein transduction domain fused to a full-length protein or inhibitory peptide can protect against ischemic brain injury and neuronal apoptosis; attenuate hypertension; prevent acute inflammatory responses; and regulate long-term spatial memory responses (Blum and Dash (2004) Learn. Mem. 11:239-243; May, et al. (2000) Science 289:1550-1554; Rey, et al. (2001) Circ. Res. 89:408-414; Denicourt and Dowdy (2003) Trends Pharmacol. Sci. 24:216-218).

Exemplary peptide-based targeting moieties are presented in Table 1 (see Original Patent).

Suitable small molecules targeting moieties which can be operably attached to a nanoparticle of the present invention include, but are not limited to, nonpeptidic polyguanidylated dendritic structures (Chung, et al. (2004) Biopolymers 76(1):83-96) or poly[N-(2-hydroxypropyl) methacrylamide] (Christie, et al. (2004) Biomed. Sci. Instrum. 40:136-41).

To conjugate or operably attach the targeting moiety to a nanoparticle of the present invention, standard methods such as the epoxy activation method can be employed. The nanoparticle surface is contacted with an epoxy compound (e.g., DENACOL.RTM., Nagase America Co., CA) which reacts with the hydroxyl functional group of, e.g., the PVA associated with the nanoparticle surface. The epoxy activation of the nanoparticle creates multiple sites for reaction with a ligand and also serves as a linkage between the nanoparticle surface and the peptide to avoid steric hindrance for interaction of the peptide with the cell membrane (Labhasetwar, et al. (1998) J. Pharm. Sci. 87:1229-34). The epoxy groups can react with many functional groups including amine, hydroxyl, carboxyl, aldehyde, and amide under suitable pH and buffer conditions; therefore increasing the number of possible targeting moieties which can be employed.

A nanoparticle formulation of the present invention can further contain a plasticizer to facilitate sustained release of the encapsulated active agent by maintaining the structure of the nanoparticle. Release of molecules (e.g., proteins, DNA or oligonucleotides) from nanoparticles formulated from block copolymers is, in general, not continuous. Typically, there is an initial release followed by a very slow and insignificant release thereafter. Not to be bound by theory, it is contemplated that the release profile may be as a result of the rapid initial drop in the molecular weight of the polymer which reduces the glass transition temperature of the polymer to below body temperature (37.degree. C.); the glass transition temperature of copolymers prior to release is above body temperature (.about.45 to 47.degree. C.). Moreover, with degradation, these polymers become softer thereby closing the pores which are created during the initial release phase (due to the release of active agent from the surface). Therefore, an inert plasticizer is added to a nanoparticle formulation disclosed herein to maintain the glass transition temperature above 37.degree. C. despite a decline in molecular weight of the polymer with time. In this manner, the pores remain open and facilitate a continuous release of the encapsulated active agent. Suitable plasticizers are generally inert and can be food/medical grade or non-toxic plasticizers including, but not limited to, triethyl citrate (e.g., CITROFLEX.RTM., Morflex Inc., Greensboro, N.C.), glyceryl triacetate (e.g., Triacetin, Eastman Chemical Company, Kingsport, Tenn.), L-tartaric acid dimethyl ester (i.e., dimethyl tartrate, DMT) and the like. A particularly suitable plasticizer is L-tartaric acid dimethyl ester.

The amount of plasticizer employed in a nanoparticle composition can range from about 5 to 40 weight percent of the nanoparticle, more desirably from about 10 to 20 weight percent of the nanoparticle. In particular embodiments, the plasticizer encompasses about 10 weight percent of the nanoparticle composition.

By enhancing the release profile of an active agent, a plasticizer-containing nanoparticle has utility in the delivery of a variety of active agents to a variety of tissues or organs. Accordingly, the present invention further relates to a composition for sustained or continuous release of an effective amount of an active agent, wherein said composition contains an active agent, at least one biodegradable polymer, and an inert plasticizer. As used herein, controlled release, sustained release, or similar terms are used to denote a mode of active agent delivery that occurs when the active agent is released from the nanoparticle formulation at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon application or injection. Controlled or sustained release can extend for hours, days or months, and can vary as a function of numerous factors. For the composition of the present invention, the rate of release will depend on the type of the plasticizer selected and the concentration of the plasticizer in the composition. Another determinant of the rate of release is the rate of hydrolysis of the linkages between and within the polymers of the nanoparticle. Other factors determining the rate of release of an active agent from the present composition include particle size, acidity of the medium (either internal or external to the matrix) and physical and chemical properties of the active agent in the matrix.

In addition to delivery of antioxidants to the brain, a sustained release nanoparticle formulation containing a plasticizer can be used to deliver any natural or synthetic, organic or inorganic molecule or mixture thereof in an amount which is sufficient to effect prevention or treatment of a disease or condition in a subject. As used herein, an active agent includes any compound or mixture of compounds which produces a beneficial or useful result. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. Examples of active agents are pharmaceutical, agricultural or cosmetic agents. Suitable pharmaceutical agents include locally or systemically acting pharmaceutically active agents which can be administered to a subject according to standard methods of delivering nanoparticles (e.g., topical, intralesional, injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection, and the like) Examples of these agents include, but not limited to, anti-infectives (including antibiotics, antivirals, fungicides, scabicides or pediculicides), antiseptics (e.g., benzalkonium chloride, benzethonium chloride, chlorohexidine gluconate, mafenide acetate, methylbenzethonium chloride, nitrofurazone, nitromersol and the like), steroids (e.g., estrogens, progestins, androgens, adrenocorticoids, and the like), therapeutic polypeptides (e.g. insulin, erythropoietin, morphogenic proteins such as bone morphogenic protein, and the like), analgesics and anti-inflammatory agents (e.g., aspirin, ibuprofen, naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors, and the like), cancer chemotherapeutic agents (e.g., mechliorethamine, cyclophosphamide, fluorouracil, thioguanine, carmustine, lomustine, melphalan, chlorambucil, streptozocin, methotrexate, vincristine, bleomycin, vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin, tamoxifen, and the like), narcotics (e.g., morphine, meperidine, codeine, and the like), local anesthetics (e.g., the amide- or anilide-type local anesthetics such as bupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and the like), antiangiogenic agents (e.g., combrestatin, contortrostatin, anti-VEGF, and the like), polysaccharides, vaccines, antigens, nucleic acids (e.g., DNA and other polynucleotides, antisense oligonucleotides, and the like), etc.

As will be appreciated by the skilled artisan, the nanoparticle compositions of the present invention can further contain additional fillers, excipients, binders and the like depending on, e.g., the route of administration and the active agents used. A generally recognized compendium of such ingredients and methods for using the same is Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, editor, 20th ed. Lippingcott Williams & Wilkins: Philadelphia, Pa., 2000.

By way of illustration, the compositions and methods of the present invention were employed in a rat model of reperfusion injury wherein delivery of the active agent was targeted to the brain. Localization of DMT-containing nanoparticles in the brain, when administered via different routes, was demonstrated using a formulation of nanoparticles loaded with the fluorescent dye 6-coumarin (0.05%). In this manner, the dye acts as a marker and can be used to quantitatively determine the uptake of nanoparticles in cells or tissues (Panyam, et al. (2003) Int. J. Pharm. 262:1-11). Formulations containing rat serum albumin and 50 .mu.g of dye were prepared as disclosed herein for BSA. The dye was dissolved in the polymer solution prior to emulsification. A suspension of nanoparticles in saline was infused (a 35 mg/kg dose dispersed in 500 .mu.L of saline using water bath sonication) at the rate of 200 .mu.L/minute either via the intracarotid, intrajugular vein, or intravenous route. These studies were carried out in animals in which no cerebral ischemia was induced. One hour after nanoparticle administration, rats were euthanized, transcardially perfused with 200 mL of heparanized saline, and the brains collected for quantitative analysis of nanoparticle uptake. To analyze nanoparticle levels, brain samples were homogenized in 100 .mu.L saline, lyophilized for 48 hours, and the dry weight was measured. To extract the dye from the nanoparticles localized in the tissue, 10 mL of methanol was added to each sample and incubated on an orbital shaker for 48 hours. After 48 hours, one milliliter of solution was taken from the tissue bottle and centrifuged at 14,000 rpm for 15 minutes. The supernatant was collected and the dye concentration in the sample was determined using high performance liquid chromatography (HPLC). A standard plot using nanoparticles was prepared using identical conditions to determine the amount of nanoparticles localized in the brain.

The results of this analysis indicated that comparable uptake of nanoparticles into the brain could be achieved via intravenous or intrajugular administration. With intracarotid administration, the nanoparticle brain levels were 20-fold higher (.about.600 .mu.g/gram of tissue) than that with intravenous or intrajugular administration. The brain uptake of DMT-containing nanoparticles via intracarotid route was about 1.7% of the total dose that was administered, indicating that a significant amount of DMT-containing nanoparticles can be localized to the brain when administered via the intracarotid artery. Further, total brain uptake was independent of the condition of the brain as uptake of dye-loaded nanoparticles following ischemia was found to be comparable to that in the normal brain via intravenous route of administration.

To demonstrate the effect of SOD on inhibition of ischemia in the brain, saline (n=4), SOD in solution (10,000 U/kg, n=2), low dose SOD-containing nanoparticles (10,000 U/kg, n=4) or high dose SOD-containing nanoparticles (20,000 U/kg, n=5) were administered to rats via intracarotid route at the time of reperfusion. The nanoparticles employed (40 mg/kg) were dispersed in 500 .mu.L of saline and infused via the carotid artery at the rate of 100 .mu.L/minute. It was found that SOD in solution had no effect on infarct volume. Conversely, animals treated with SOD-containing nanoparticles exhibited a significant 60% reduction in total infarct volume (low dose, .about.180 mm.sup.3; high dose, .about.130 mm.sup.3) as compared to that of saline control (.about.345 mm.sup.3).

Behavioral data demonstrated that the motor and somatosensory functions were impaired by the ischemic insult. Neurological deficit scores were significantly higher for animals administered saline control (deficit score.apprxeq.11) and SOD in solution (deficit score.apprxeq.12) as compared to that animals administered SOD-containing nanoparticles (deficit score.apprxeq.2-3). As animals receiving control nanoparticles demonstrated similar results as the saline control group, these data demonstrate that the beneficial outcome imparted by SOD-containing nanoparticles was due to the sustained delivery of SOD to the brain by the nanoparticles.

The integrity of the blood-brain barrier was also assessed in animals administered SOD-containing nanoparticles. Cerebral ischemia was developed by occlusion of the middle cerebral artery for 60 minutes. A solution of Evans blue dye (0.3 mL of 4% solution; Sigma, St. Louis, Mo.) was injected through the tail vein of the animals and immediately a suspension of SOD-containing nanoparticles (SOD dose=20,000 U/kg) was infused through the carotid artery prior to reperfusion. Six hours after reperfusion, rats were sacrificed, transcardially perfused to remove blood and the brains were collected and photographed. A saline control animal showed intense coloration of the brain due to extravasation of the dye into the brain, indicating disruption of the blood-brain barrier. In contrast, brains of animals infused with SOD-containing nanoparticles showed significantly lower extravasation of the dye. It is believed that the SOD-containing nanoparticles protected the endothelium thereby maintaining the integrity of the blood-brain barrier and preventing damage to the brain.
 

Claim 1 of 2 Claims

1. A nanoparticle composition for sustained release of an effective amount of a therapeutically active agent, said composition comprising a therapeutically active polypeptide as said active agent, at least one biodegradable polymer, a plasticizer, and a targeting moiety, wherein said biodegradable polymer is selected from the group consisting of a poly(lactide-co-glycolide), poly(lactic acid), poly(alkylene glycol), polybutylcyanoacrylate, poly(methylmethacrylate-co-methacrylic acid), poly-alkylamine, polyanhydride, polyhydroxybutyric acid, and a polyorthoester, wherein said targeting moiety comprises SEQ ID NO: 2, and wherein said plasticizer comprises L-tartaric acid dimethyl ester.

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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