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(12) Patent Application Publication (10) Pub. No.: US 2003/0095995 A1 Wong Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0095995 A1 Wong Et Al US 2003009.5995A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0095995 A1 Wong et al. (43) Pub. Date: May 22, 2003 (54) FORMULATION FOR CONTROLLED Related U.S. Application Data RELEASE OF DRUGS BY COMBINING HYDROPHILIC AND HYDROPHOBC (63) Continuation of application No. 09/160,635, filed on AGENTS Sep. 24, 1998, which is a continuation of application No. 08/459,134, filed on Jun. 2, 1995, now Pat. No. (76) Inventors: Vernon Wong, Rockville, MD (US); 5,869,079. Frank Kochinke, San Jose, CA (US) Publication Classification Correspondence Address: Mika Mayer (51) Int. Cl." ....................................................... A61K 9/00 Morrison & Foerster LLP (52) U.S. Cl. .............................................................. 424/426 755 Page Mill Road (57) ABSTRACT Palo Alto, CA 94.304-1018 (US) Combinations of hydrophilic and hydrophobic entities in a (21) Appl. No.: 10/327,018 biodegradable Sustained release implant are shown to modu late each other's rate of release. Formulations of a thera peutically active agent and modulator provide Substantially (22) Filed: Dec. 20, 2002 constant rate of release for an extended period of time. Patent Application Publication May 22, 2003 Sheet 1 of 4 US 2003/0095995 A1 Figure 1 | Patent Application Publication May 22, 2003. Sheet 2 of 4 US 2003/0095995 A1 Figure 2 a RT20-XTO32-40/40420 RT16-XTO29-50/50 . RRapp. 04 ugld per 100ug DDS B Time (d) Patent Application Publication May 22, 2003. Sheet 3 of 4 US 2003/0095995 A1 Figure 2 Time (hours) Patent Application Publication May 22, 2003. Sheet 4 of 4 US 2003/0095995 A1 st oo t CO () va lf S.N d an S. o US 2003/0095995 A1 May 22, 2003 FORMULATION FOR CONTROLLED RELEASE SUMMARY OF THE INVENTION OF DRUGS BY COMBINING HYDROPHILIC AND 0011 Compositions and methods are provided for bio HYDROPHOBC AGENTS degradable implants formulated to provide a controlled, Sustained drug release. The release rate is modulated by TECHNICAL FIELD combining in the implant hydrophobic and hydrophilic 0001 Biodegradable implants formulated for controlled, agents. The release modulator may act to accelerate or retard Sustained drug release. the rate of release. Optionally, the modulator will be a therapeutically active agent. The invention provides a Sus BACKGROUND OF THE INVENTION tained release implant having a combination of active agents with a defined release profile. 0002 Solid pharmaceutically active implants that pro vide Sustained release of an active ingredient are able to BRIEF DESCRIPTION OF THE DRAWINGS provide a relatively uniform concentration of active ingre dients in the body. Implants are particularly useful for 0012 FIG. 1A shows the release profile of a hydrophobic providing a high local concentration at a particular target Site drug from an extended release drug delivery System. FIG. for extended periods of time. These Sustained release forms 1B shows the release profile of the same drug when formu reduce the number of doses of the drug to be administered, lated in a drug delivery System with a release modulator. and avoid the peaks and troughs of drug concentration found 0013 FIG. 2A shows the release profile of dexametha with traditional drug therapies. Use of a biodegradable drug Sone in the absence or presence of the release modifier, delivery system has the further benefit that the spent implant ciproflaxacin HC1. FIG. 2B shows the release of ciprofloxa need not be removed from the target Site. cin in the presence of dexamethasone. FIG. 2C shows the release of ciprofloxacin in the absence of a release modifier. 0003. Many of the anticipated benefits of delayed release FIG. 2D shows the releae profile from a drug delivery implants are dependent upon Sustained release at a relatively System having combined hydrophilic and hydrophobic constant level. However, formulations of hydrophobic drugs drugs, and further having a pharmaceutically inactive with biodegradable matrices may have a release profile release modifier. which shows little or no release until erosion of the matrix occurs, at which point there is a dumping of drug. 0014 FIG. 3 shows a cross-sectional view of an eye. 0004. The eye is of particular interest when formulating DESCRIPTION OF THE SPECIFIC implantable drugs, because one can reduce the amount of EMBODIMENTS Surgical manipulation required, and provide effective levels of the drug specifically to the eye. When a solution is 0015. A controlled drug release is achieved by an injected directly into the eye, the drug quickly washes out or improved formulation of Slow release biodegradable is depleted from within the eye into the general circulation. implants. The release rate of a drug from an implant is From the therapeutic Standpoint, this may be as useleSS as modulated by addition of a release modulator to the implant. giving no drug at all. Because of this inherent difficulty of Release of a hydrophobic agent is increased by inclusion of delivering drugs into the eye, Successful medical treatment an accelerator in the implant, while retardants are included of ocular diseases is inadequate. to decrease the release rate of hydrophilic agents. The release modulator may be physiologically inert, or a thera 0005 Improved sustained release formulations which peutically active agent. allow for a constant drug release rate are of considerable interest for medical and Veterinary uses. 0016. The rate of release of the therapeutically active agent will be controlled by the rate of transport through the 0006 Relevant Literature polymeric matrix of the implant, and the action of the modulator. By modulating the release rate, the agent is 0007 U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose released at a Substantially constant rate, or within a thera biocompatible implants for introducing into an anterior peutic dosage range, over the desired period of time. The chamber or posterior Segment of an eye for the treatment of rate of release will usually not vary by more than about an ocular condition. 100% over the desired period of time, more usually by not 0008 Heller, Biodegradable Polymers in Controlled more than about 50%. The agent is made available to the Drug Delivery, in: CRC Critical Reviews in Therapeutic Specific site(s) where the agent is needed, and it is main Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, Fla., tained at an effective dosage. The transport of drug through 1987, pp. 39-90, describes encapsulation for controlled drug the polymer barrier will also be affected by drug solubility, delivery. Heller in: Hydrogels in Medicine and Pharmacy, N. polymer hydrophilicity, extent of polymer cross-linking, A. Peppes ed., Vol. III, CRC Press, Boca Raton, Fla., 1987, expansion of the polymer upon water absorption So as to pp. 137-149, further describes bioerodible polymers. make the polymer barrier more permeable to the drug, geometry of the implant, and the like. 0009 Anderson et al., Contraception (1976) 13:375 and Miller et al., J. Biomed. Materials Res. (1977) 11:711, 0017. The release modulator is an agent that alters the describe various properties of poly(dL-lactic acid). U.S. Pat. release of a drug from a biodegradable implant in a defined No. 5,075,115 discloses Sustained release formulations with manner. It may be an accelerator or a retardant. Accelerators lactic acid polymers and co-polymers. will be hydrophilic compounds, which are used in combi nation with hydrophobic agents to increase the rate of 0010 Di Colo (1992) Biomaterials 13:850-856 describes release. Hydrophilic agents are those compounds which controlled drug release from hydrophobic polymers. have at least about 100 tug/ml solubility in water at ambient US 2003/0095995 A1 May 22, 2003 temperature. Hydrophobic agents are those compounds therapeutic agent. The additional agent may be an analgesic, which have less than about 100 ug/ml solubility in water at e.g. codeine, morphine, keterolac, naproxen, etc., an anes ambient temperature. thetic, e.g. lidocaine, B-adrenergic blocker or B-adrenergic agonist, e.g. ephidrine, epinephrine, etc.; aldose reductase 0.018. Therapeutically active hydrophobic agents which inhibitor, e.g. epalrestat, ponalrestat, Sorbinil, tolrestat; anti benefit from release modulation include cyclosporines, e.g. allergic, e.g. cromolyn, beclomethasone, dexamethasone, cyclosporin A, cycloSporin G, etc.; Vinca alkaloids, e.g. and flunisolide; colchicine. Anihelminthic agents, e.g. iver Vincristine and vinblastine, methotrexate, retinoic acid; cer mectin and Suramin Sodium; antiamebic agents, e.g. chlo tain antibiotics, e.g. ansamycins Such as rifampin; nitro roquine and chlortetracycline; and antifungal agents, e.g. furans Such as nifuroxazide, non-Steroidal antiinflammatory amphotericin, etc. may be co-formulated with an antibiotic drugs, e.g. diclofenac, keterolac, flurbiprofen, naproxen, and an anti-inflammatory drug. For intra-ocular use, anti Suprofen, ibuprofen, aspirin, etc. Steroids are of particular glaucomas agents, e.g. acetoZolamide, befunolol, etc. in interest, including hydrocortisone, cortisone, prednisolone, combinations with anti-inflammatory and antimicrobial prednisone, dexamethasone, medrySone, fluorometholone, agents are of interest. For the treatment of neoplasia, com eStrogens, progesterOneS, etc. binations with anti-neoplastics, particularly vinblastine, Vin 0.019 Accelerators may be physiologically inert, water cristine, interferons C, B and Y, antimetabolites, e.g. folic Soluble polymers, e.g. low molecular weight methyl cellu acid analogs, purine analogs,
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