US 20080145439A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0145439 A1 LOblet al. (43) Pub. Date: Jun. 19, 2008 (54) NANOPARTICLE DRUG FORMULATIONS Related U.S. Application Data (75) Inventors: Thomas J. Lobl, Valencia, CA (60) Provisional application No. 60/820,931, filed on Jul. (US); John V. Schloss, Saugus, CA 31, 2006. (US); Anna Imola Nagy, Valencia, CAPasadena, (US); JacobCA (US) E. Pananen, Publication Classification (51) Int. Cl. Correspondence Address: A 6LX 9/5 (2006.01) BANNER & WITCOFF, LTD. A63L/4535 (2006.01) 1100 13th STREET, N.W., SUITE 1200 BOIF II/00 (2006.01) WASHINGTON, DC 20005-4051 (73) Assignee: NEUROSYSTEC (52) U.S. Cl. .......... 424/498; 424/501: 514/326; 366/108 CORPORATION, Valencia, CA (US) (57) ABSTRACT (21) Appl. No.: 11/831,230 A suspension of nanoparticles in a liquid medium provides a mechanism for delivery ofgacyclidine base or other drug that (22) Filed: Jul. 31, 2007 is substantially insoluble in the liquid medium. CH3 CH3 H : Ha- N H -- S S s -- gacyclidine gacyclidine conjugate acid conjugate base solubility > 0.5M solubility < 2 uM DECOMPOSITION SOLID (piperidine formation) (precipitation/crystallization) Patent Application Publication Jun. 19, 2008 Sheet 1 of 3 US 2008/O145439 A1 FIG. 1 Patent Application Publication Jun. 19, 2008 Sheet 2 of 3 US 2008/O145439 A1 37 35 36 42 - 32 43 ke is 45 46 33 FIG 3 30 FIG. 4 Patent Application Publication Jun. 19, 2008 Sheet 3 of 3 US 2008/O145439 A1 CH3 CH3 H 4N 4-Ns gacyclidine gacyclidine Conjugate acid conjugate base solubility > 0.5 M solubility < 2 uM DECOMPOSITION SOLID (piperidine formation) (precipitation/crystallization) FIG. 6 US 2008/O 145439 A1 Jun. 19, 2008 NANOPARTICLE DRUG FORMULATIONS 0010 FIG. 6 shows structure and solution chemistry of gacyclidine. CROSS-REFERENCE TO RELATED APPLICATIONS DETAILED DESCRIPTION 0001. This application claims the benefit of U.S. Provi Targeted Delivery of Gacyclidine sional Application Ser. No. 60/820,931, filed Jul. 31, 2006 0011 Gacyclidine is an NMDA receptor antagonist useful and titled “Nanoparticle Drug Formulations and Delivery in treating tinnitus. In addition to tinnitus therapy, gacyclidine Thereof hereby incorporated by reference herein. has other potential therapeutic uses. NMDA receptor antago nists such as gacyclidine can preventapoptosis of traumatized neurons and can protect neurons from intraoperative trau BACKGROUND matic stress. Gacyclidine can therefore be used as an adjunct therapy for cochlear implant Surgery, retinal implant Surgery, 0002. It is well known that drugs work most efficiently in neuromuscular implant Surgery, or for other neurological Sur the body of a human or animal if they are delivered locally gery and/or in connection with other neurological implants. where needed. When delivered systemically there is a much Numerous other uses for gacyclidine and formulations greater chance for side effects, as all tissues are exposed to thereofare described in one or more of the commonly-owned large quantities of the drug. Tissue-specific drug delivery can U.S. patent applications having Ser. Nos. 1 1/337,815 (titled present challenges, however. In many cases, a target tissue Apparatus and Method for Delivering Therapeutic and/or (i.e., the tissue to be treated with a drug) is difficult to reach. Other Agents to the Inner Ear and to Other Tissues” and Injecting a drug to Such a target tissue may require a signifi published as U.S. Pat. Pub. No. 2006/0264897), 11/759,387 cant medical procedure which is both costly and unpleasant to (titled “Flow Induced Delivery from a Drug Mass' and filed the patient. If a drug treatment regimen requires delivery of on Jun. 7, 2007), 11/780,853 (titled “Devices, Systems and Small doses over a prolonged period, tissue-specific drug Methods for Ophthalmic Drug Delivery' and filed on Jul. 20. delivery may be impractical. 2007), and 11/367,720 (titled “Improved Gacyclidine Formu lations” and published as U.S. Pat. Pub. No. 2006/0205789). 0012. Although gacyclidine has numerous therapeutic SUMMARY benefits when appropriately delivered, systemic delivery would expose all body tissues to effective doses, potentially 0003. This Summary is provided to introduce a selection resulting in undesirable side effects. It is therefore highly of concepts in a simplified form that are further described desirable to deliver gacyclidine directly to a cochlea, eye, below in the Detailed Description. This Summary is not brain region or other target tissue to be treated. To further intended to identify key features or essential features of the reduce the potential for side effects, it may also be desirable to claimed Subject matter, nor is it intended to be used as an aid deliver gacyclidine in very Small doses over a prolonged in determining the scope of the claimed Subject matter. period (particularly when treating a chronic condition). As 0004 Forms of gacyclidine which are substantially described in more detail below, prolonged small-dose deliv insoluble can be delivered as a Suspension of nanoparticles in ery can be achieved with a device which is wholly or partially a liquid medium. In some embodiments, nanoparticles are implanted within a patient. By implanting all or part of the formed from a polymer or other material to which gacyclidine drug delivery device, the patient is able to avoid repeated (and/or one or more other drugs) absorbs/adsorbs. In other medical procedures. embodiments, nanoparticles can be formed from gacyclidine 0013 Delivery of gacyclidine in such a manner presents (and/or one or more other drugs) in pure form, as a homoge numerous challenges, however. Various characteristics of neous mixture of gacyclidine (and/or one or more other gacyclidine are discussed in more detail below. Notably, how drugs) and a polymer or other non-drug Substance, or as a core ever, many forms of gacyclidine that can be dissolved in a of gacyclidine (and/or one or more other drugs) having a fluid medium for delivery to a targettissue are unstable. Other polymeric coating. Such nanoparticles and/or Suspensions forms are more stable, but are highly insoluble and suffer loss thereof can be formed in various manners, used for treatment (e.g., adsorption) to Surfaces of catheters and other compo of a variety of conditions, and delivered using various tech nents. Specifically, catheters, drug reservoirs, pumps, anti niques. bacterial filters and other components of drug delivery sys tems are typically fabricated from polymers approved for BRIEF DESCRIPTION OF THE DRAWINGS human implantation. Gacyclidine will bind to many of these polymeric materials. Silicone, one of the most commonly 0005. The following detailed description of certain used materials for human implantation, binds gacyclidine. At embodiments is better understood when read in conjunction room temperature and in a gacyclidine Solution at pH 6. with the accompanying drawings, which are included by way silicone can retain up to 60% of 100 micromolar (uM) gacy of example and not by way of limitation. clidine (depending on the time and temperature of exposure). Replacing all polymeric components of a drug delivery sys 0006 FIG. 1 shows a mixer according to at least some tem with materials having little or no affinity for gacyclidine embodiments. base can avoid drug loss to the delivery device, but this may 0007 FIG. 2 is a cross-sectional view of the mixer of FIG. not always be practical, and it will not necessarily resolve 1 with tubing omitted. problems of drug stability. 0008 FIGS. 3 and 4 show a turbulence generator from the 0014. In at least some embodiments, these challenges are mixer of FIG. 1. addressed through the use of nanoparticles. As used herein 0009 FIG. 5 shows an example of a drug delivery system. (including the claims), "nanoparticle' refers to particles gen US 2008/O 145439 A1 Jun. 19, 2008 erally having a size of 200 nanometers (nm) or less, exclusive can produce nanoparticles able to pass through a 0.22 um oftemporary aggregation of such particles that might occurat filter. The size of nanoparticles produced by this method is high particle concentrations, Because of their size, Brownian sensitive to the concentration of polymer in the organic Sol motion will keep nanoparticles Suspended in a fluid medium vent, to the rate of mixing, and to the Surfactant employed in for a very long (or even indefinite) amount of time, and they the process. Although use of the solvent displacement method can thus be used to carry forms of gacyclidine which are with the surfactant sodium dodecyl sulfate (SDS) has yielded difficult to dissolve. Nanoparticles can also address problems small nanoparticles (<100 nm), SDS is not ideal for a phar caused by gacyclidine binding to device components. In par maceutical formulation. However, similar natural Surfactants ticular, nanoparticles can be formed from materials that have (e.g., cholic acid or taurocholic acid salts) can be substituted a high affinity for gacyclidine and thus successfully compete for SDS to obtain similarly sized nanoparticles. Taurocholic with polymeric device Surfaces for gacyclidine binding. For acid, the conjugate formed from cholic acid and taurine, is a example, nanoparticles can tightly bind the stable basic form fully metabolizable sulfonic acid with very similar amphip ofgacyclidine and increase its thermal stability; a stable basic athic solution chemistry to SDS. An analog of taurocholic form of gacyclidine can be encapsulated Such that less than acid, tauroursodeoxycholic acid (TUDCA), is not toxic and is 10% decomposition occurs in one year at 37° C. Nanopar actually known to have neuroprotective and anti-apoptotic ticles can also maintain gacyclidine in a mobile phase that is properties. TUDCA is a naturally occurring bile acid and is a capable of passing through an anti-bacterial filter that blocks conjugate of taurine and urSodeoxycholic acid (UDCA).