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(12) Patent Application Publication (10) Pub. No.: US 2003/0144207 A1 Bentley Et Al US 2003O144207A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0144207 A1 Bentley et al. (43) Pub. Date: Jul. 31, 2003 (54) POLYMER STABILIZED NEUROPEPTIDES (60) Provisional application No. 60/157,503, filed on Oct. 4, 1999. Provisional application No. 60/166,589, filed (75) Inventors: Michael David Bentley, Huntsville, AL on Nov. 19, 1999. (US); Michael James Roberts, Madison, AL (US) Publication Classification Correspondence Address: ALSTON & BIRD LLP BANK OF AMERICA PLAZA (51) Int. Cl." .......................... C07K 14770; A61K 38/24 101 SOUTH TRYON STREET, SUITE 4000 (52) U.S. Cl. .............................................. 514/12; 530/399 CHARLOTTE, NC 28280-4000 (US) (73) Assignee: Shearwater Corporation (57) ABSTRACT (21) Appl. No.: 10/354,683 (22) Filed: Jan. 30, 2003 A Substantially hydrophilic conjugate is provided having a Related U.S. Application Data peptide that is capable of passing the blood-brain barrier covalently linked to a water-Soluble nonpeptidic polymer (60) Continuation of application No. 09/956,440, filed on Such as polyethylene glycol. The conjugate exhibits Sep. 19, 2001, which is a division of application No. improved solubility and in vivo stability and is capable of 09/678,997, filed on Oct. 4, 2000. passing the blood-brain barrier of an animal. Patent Application Publication Jul. 31, 2003. Sheet 1 of 6 US 2003/0144207 A1 Figure 1 Analgesia of mPEG2K-DPDPE in Mice (I.C.V) 100 E Morphine (10ug) 90 -e-DPDPE (50ug) 80 AmPEG2K-DPDPE (50ug) TO 60 s 50 30 2O 10 O 30 60 90 120 150 18O Time (minutes) Patent Application Publication Jul. 31, 2003 Sheet 2 of 6 US 2003/0144207 A1 Figure 2 Analgesia of mPEG2K-DPDPE in Mice (I.V.) 100 E. Morphine (20ug) 9 DPDPE (400ug) ArmPEG2K-DPDPE (400ug) Time (minutes) Patent Application Publication Jul. 31, 2003. Sheet 3 of 6 US 2003/0144207 A1 Figure 3 PEG MW Dependence on Biphalin Analgesia in Mice (I.V.) Morphine (20ug) "A Biphalin (20ug) ---O-. (mSPA-1K)2 Biphalin (20ug) -o- (mSPA-2K)2 Biphalin (20ug) mAr (mSPA-5K)2 Biphalin (20ug) "O" (mSPA-12K)2 Biphalin (20ug) s (mSPA-20K)2 Biphalin (20ug) 500 Time (minutes) Patent Application Publication Jul. 31, 2003 Sheet 4 of 6 US 2003/0144207 A1 Figure 4 Analgesia of mPEG2K-Biphalin Analogs --- Morphine (20ug) rArr Biphalin (20ug) 80 As a A----,A. - - - - - Asa "TimSPA-2K Biphalin (20ug) 70 \, (mSPA-2K)2 Biphalin (10ug) (r. 60 a ------A" (mSPA-2K)2 Biphalin (20ug) 50 Y.y & 40 s 30 O 50 100 150 200 250 300 350 400 450 500 Time (minutes) Patent Application Publication Jul. 31, 2003 Sheet 5 of 6 US 2003/0144207 A1 Figure 5 Analgesia of (mPEG2K)2-Biphalin in Rats at Various Doses (mPEG2K)2-Biphalin (175ug i.v.) 9 (mPEG2K)2-Biphalin (80 ug i.v.) s (mPEG2K)2-Biphalin (40 ug iv) O 30 60 90 120 150 180 210 240 270 Time (min) Patent Application Publication Jul. 31, 2003. Sheet 6 of 6 US 2003/0144207 A1 Figure 6 S.C. and I.M. Injection of Biphalin and PEG-Biphalin in Rats OO Biphalin (4.8 mg/kg, s.c.) 90 Biphalin (4.8 mg/kg, i.m.) 80 (mPEG2K)2-Biphalin (4.8 mg/kg, s.c.) (InPEG2K)2-Biphalin (4.8 mg/kg, im) O 30 60 90 20 50 18O 210 240 270 Time (min) US 2003/O144207 A1 Jul. 31, 2003 POLYMER STABILIZED NEUROPEPTIDES to transferrin, insulin, insulin-like growth factor I and II, low-density lipoprotein and atrial natriuretic factor. See CROSS REFERENCE TO RELATED Friden, P. M., J. Controlled Rel, (1996) 46:117-128. U.S. APPLICATIONS Pat. No. 5,833,988 to Friden describes a method for deliv 0001. This application is related to commonly owned ering a neuropharmaceutical or diagnostic agent across the copending Provisional Applications Serial No. 60/157,503, blood-brain barrier employing an antibody against the trans filed Oct. 4, 1999, and Serial No. 60/166,589, filed Nov. 19, ferrin receptor. A nerve growth factor or a neurotrophic 1999, and claims the benefit of their earlier filing dates under factor is conjugated to a transferrin receptor-specific anti 35 U.S.C. Section 119(e). body. The resulting conjugate is administered to an animal and is capable crossing the blood-brain barrier into the brain FIELD OF THE INVENTION of the animal. 0002 The invention relates to a conjugate between a 0007 U.S. Pat. No. 4,902,505 to Pardridge et al. peptide and polyethylene glycol or a Substantially Substitut describes the use of chimeric peptides for neuropeptide able polymer and a method of use thereof. delivery through the blood-brain barrier. A receptor-specific peptide is used to carry a neuroactive hydrophilic peptide BACKGROUND OF THE INVENTION through the BBB. The disclosed carrier proteins, which are capable of crossing the BBB by receptor-mediated transcy 0003. There has been significant progress in the discov ery and development of potential neuropharmaceuticals tosis, include histone, insulin, transferrin, insulin-like (Small molecules, peptides, proteins, and antisense) for growth factor I (IGF-I), insulin-like growth factor II (IGF treating pain and brain disorderS Such as Alzheimer's and II), basic albumin, and prolactin. U.S. Pat. No. 5,442,043 to Parkinson's diseases over the last decade. However, SyS Fukuta et al. discloses using an insulin fragment as a carrier temic delivery of many newly discovered neuropharmaceu in a chimeric peptide for transporting a neuropeptide acroSS ticals has been hampered by the lack of an effective System the blood-brain barrier. for delivering them. Intravenous injection is usually inef 0008. Non-invasive approaches for delivering neurophar fective because of inadequate transport acroSS the barrier maceutical agents acroSS the BBB are typically less effective between the brain and the blood supply (the “blood-brain than the invasive methods in actually getting the agent into barrier” or “BBB”). The blood-brain barrier is a continuous the brain. High doses of the chimeric peptides are required physical barrier that separates the central nervous System, to achieve the desired therapeutic effect because they are i.e., the brain tissue, from the general circulation of an prone to degradation. The concentration of the chimeric animal. The barrier is comprised of microvascular endothe peptides in the blood circulation can be quickly reduced by lial cells that are joined together by complex tight intracel proteolysis. An acqueous delivery System is not generally lular junctions. This barrier allows the Selective eXchange of effective for delivering hydrophobic drugs. molecules between the brain and the blood, and prevents many hydrophilic drugs and peptides from entering into the 0009. Another method for delivering hydrophilic com brain. Many of the new potent neuroactive pharmaceuticals pounds into the brain by receptor-mediated transcytosis is do not cross the BBB because they have a molecular weight described by Pardridge et al. in Pharm. Res. (1998) above 500 daltons and are hydrophilic. Compounds that are 15(4):576-582. A monoclonal antibody to the transferrin non-lipophilic and have a molecular weight greater than 500 receptor (OX26 MAb) modified with streptavidin is used to daltons generally do not cross the BBB. transport the cationic protein, brain-derived neurotrophic 0004 Several strategies for delivering high molecular factor (BDNF) through the BBB. BDNF is first modified weight, non-lipophilic drugs to the brain have been devel with PEG'-biotin to form BDNF-PEG'-biotin, which is oped including intracerebroVentricular infusion, transplan then bound to the streptavidin-modified antibody OX26 tation of genetically engineered cells that Secrete the neu MAb. The resulting conjugate was shown to be able to croSS roactive compound, and implantation of a polymer matrix the BBB into the brain. containing the pharmaceutical. See Pardridge, W. M., J. 0010) Enhancing the duration of antinociceptive effects Controlled Rel, (1996) 39:281-286. However, all of these in animals may result in leSS frequently administered anal involve invasive Surgical procedures that can entail a variety gesics, which can improve patient compliance and reduce of complications. potential side effects. Maeda et al. in Chem. Pharm. Bull. 0005 Four nonsurgical transport mechanisms have been (1993) 41(11): 2053-2054, Biol. Pharm. Bull. (1994) identified for crossing the BBB, including: (i) transmem 17(6):823-825, and Chem. Pharm. Bull. (1994) 42(9): 1859 brane diffusion, (ii) receptor-mediated transport, (iii) absorp 1863 demonstrate that by attaching polyethylene glycol tive-mediated endocytosis, and (iv) carrier-mediated trans amine 4000 to the C-terminal leucine of Leu-enkephalin port. See Brownless et al., J. Neurochemistry, (1993) (distant from the tyrosine residue needed for antinocicep 60(3):793-803. Vascular permeability can be increased by tion), they could increase the potency and duration of opening the tight junctions with hyperoSmotic Saccharide Leu-enkaphalin when it was directly administered to the Solutions and analogs of bradykinin. An inherent problem in brain by intracerebroVentricular injection. this method is that undesirable compounds in the general 0011. There is a need in the art to deliver neuroactive circulation may enter the brain through the artificially agents from Systemic circulation across the blood-brain enlarged openings in the blood-brain barrier. barrier and into the brain that reduces or eliminates Some of 0006. It has been discovered that capillary endothelial the drawbacks and disadvantages associated with the prior cells in the blood-brain barrier have a high level of receptors art. US 2003/O144207 A1 Jul. 31, 2003 SUMMARY OF THE INVENTION dation and clearance, and once delivered into the brain through the blood-brain barrier, exhibit extended lifetime in 0012. This invention provides a method for delivering a the brain.
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