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(12) Patent Application Publication (10) Pub. No.: US 2003/0069170 A1 Soltero Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0069170 A1 Soltero Et Al US 2003OO6917OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0069170 A1 Soltero et al. (43) Pub. Date: Apr. 10, 2003 (54) PHARMACEUTICAL COMPOSITIONS OF Related U.S. Application Data DRUG-OLIGOMER CONJUGATES AND METHODS OF TREATING DSEASES (60) Provisional application No. 60/318,193, filed on Sep. THEREWITH 7, 2001. Provisional application No. 60/377,865, filed on May 3, 2002. (76) Inventors: Richard Soltero, Holly Springs, NC Publication Classification (US); Nnochiri N. Ekwuribe, Cary, NC 5 1. Int.nt. Cl."Cl. ......................... A61K 38/23 ; A61K 31/56;5 (US); Foyeke Opawale, Raleigh, NC A61K 31/202; A61K 38/00 (US); Bruce Rehlander, Chapel Hill, NC (US); Anthony Hickey, Chapel (52) U.S. Cl. ................ 514/2; 514/12; 514/171; 514/560 Hill, NC (US); Bovet Li Li, Chapel Hill, NC (US) (57) ABSTRACT Pharmaceutical compositions that include a drug-oligomer Correspondence Address: conjugate, a fatty acid component, and a bile Salt component MYERS BIGELSIBLEY & SAJOVEC are described. The drug is covalently coupled to an oligo PO BOX 37428 meric moiety. The fatty acid component and the bile Salt RALEIGH, NC 27627 (US) component are present in a weight-to-weight ratio of between 1:5 and 5:1. Methods of treating diseases in a (21) Appl. No.: 10/235,284 Subject in need of Such treatment using Such pharmaceutical compositions are also provided, as are methods of providing (22) Filed: Sep. 5, 2002 Such pharmaceutical compositions. Patent Application Publication Apr. 10, 2003 Sheet 1 of 13 US 2003/0069170 A1 InáHI9 s (p16u) GSO3nS eu Sal Patent Application Publication Apr. 10, 2003 Sheet 3 of 13 US 2003/0069170 A1 (P/5u) escone eused Elec Patent Application Publication Apr. 10, 2003 Sheet 5 of 13 US 2003/0069170 A1 l G) s C) e y-uoou00:z?uidoo: Patent Application Publication Apr. 10, 2003 Sheet 6 of 13 US 2003/0069170 A1 Delta Plasma Insulin (IU/mL) (p16u) esoons eused Bied Patent Application Publication Apr. 10, 2003. Sheet 7 of 13 US 2003/0069170 A1 OZ (eueSegoueole) eSoon pool Patent Application Publication Apr. 10, 2003 Sheet 8 of 13 US 2003/0069170 A1 O ~~~~~);50EdW ***:»?EdWd 08 09 OZ (eueSegoueojed) eSoonio pools [90]]-06090€0 US 2003/0069170 A1 (eueSego Ueole) eSoons poog Patent Application Publication Apr. 10, 2003 Sheet 10 of 13 US 2003/0069170 A1 4000 3600 3200 2800 - - - LLOQ: 150pg/mL - - - - - - - - ULOQ: 3200 pg/mL 2400 - - LLOQ: 200pg/mL, Dog 23 2000 1600 1200 800 400 O 15 30 45 60 75 90 105 120 Time (minutes) Figure 10 Patent Application Publication Apr. 10, 2003 Sheet 11 of 13 US 2003/0069170 A1 g 7000 Dog 1 N-1 Dog 2 6000 Dog 3 Dog 4 5000 LLOQ:150pg/mL. ULOQ:3200pg/mL 4OOO 3000 2000 1000 Time (minutes) Figure 11 Patent Application Publication Apr. 10, 2003 Sheet 12 of 13 US 2003/0069170 A1 O 15 30 45 60 75 90 105 120 Time (minutes) Figure 12 Patent Application Publication Apr. 10, 2003. Sheet 13 of 13 US 2003/0069170 A1 20 O 10 20 30 40 50 60 Time (minutes) -0- Each Points Represents Meant SD, n = 5 Figure 13 US 2003/0069170 A1 Apr. 10, 2003 PHARMACEUTICAL COMPOSITIONS OF 0007 U.S. Pat. No. 5,283,236 to Chiou proposes com DRUG-OLIGOMER CONJUGATES AND METHODS positions for Systemic delivery of insulin through the eyes OF TREATING DSEASES THEREWITH where the drug passes into the nasolacrimal duct and becomes absorbed into circulation. The composition RELATED APPLICATION includes insulin and an enhancing agent. The enhancing agents proposed include, either alone or in combination, 0001) This application claims the benefit of U.S. Provi Surfactants Such as polyoxyethylene ethers of fatty acids, sional Application No. 60/318,193, filed Sep. 7, 2001 and and bile Salts and acids Such as cholic acid, deoxycholic U.S. Provisional Application No. 60/377,865, filed May 3, acid, glycocholic acid, glycodeoxycholic acid, taurocholic 2002, the disclosures of which are incorporated herein by acid, taurodeoxycholic acid, Sodium cholate, Sodium glyco reference in their entireties. cholate, glycocholate, Sodium deoxycholate, Sodium tauro FIELD OF THE INVENTION deoxycholate, chenodeoxycholic acid, and urSodeoxycholic acid. The enhancer is present in a concentration ranging 0002 The present invention relates to pharmaceutical from 0.1% to 5% (w/v). compositions and methods of treating diseases there with. 0008 U.S. Pat. No. 5,853,748 to New proposes enteric BACKGROUND OF THE INVENTION coated compositions for oral administration of insulin. The composition includes insulin, a bile Salt or bile acid, and 0.003 Fatty acids have been proposed as excipients in carbonate or bicarbonate ions, which are used to adjust the pharmaceutical compositions of unconjugated drug mol pH of the gut to a pH of from 7.5 to 9. ecules. For example, U.S. Pat. No. 4,338,306 to Kitao et al. proposes pharmaceutical compositions for rectal adminis 0009. In at least one instance, a mixture of a low deter tration of insulin. The pharmaceutical compositions include gent bile Salt, Such as urSodeoxycholate, and a C to C. insulin and fatty acids having 8 to 14 carbon atoms and fatty acid, Such as linoleic or oleic acid, has been proposed nontoxic Salts thereof. as excipients in a pharmaceutical composition of orally acitve pharmaceutically active agents that need to be pro 0004 U.S. Pat. No. 5,658,878 to Bäckström et al. pro tected from the acidic and enzymatic environment of the poses a therapeutic preparation for inhalation that includes Stomach and for which the gastrointestinal mucosa should be insulin and a Substance which enhances the absorption of protected from adverse effects of the drug. The proposed insulin in the lower respiratory tract. The enhancer is pref pharmaceutical composition is proposed to be particularly erably a Sodium Salt of a Saturated fatty acid of carbon chain length 10 (i.e., Sodium caprate), 12 (Sodium laurate), or 14 Suitable for the non-Steroidal anti-inflammatory drug (Sodium myristate). Potassium and lysine salts of capric acid indomethacin. are also proposed. Bäckström et al. note that if the carbon 0010. It is desirable to provide pharmaceutical composi chain length is shorter than about 10, the Surface activity of tions for administration of drug-oligomer conjugates. the Surfactant may be too low, and if the chain length is longer than about 14, decreased Solubility of the fatty acid SUMMARY OF THE INVENTION in water limits its usefulness. AS an alternative to the proposed fatty acid enhancers, Bäckström et al. propose the 0011 Pharmaceutical compositions according to embodi use of the following bile Salts-Sodium urSOdeoxycholate, ments of the present invention use a mixture of bile Salts and Sodium taurocholate, Sodium glycocholate, and Sodium tau fatty acids in a particular ratio that appears to provide rodihydrofusidate. Synergistic effects in the administration of drug-oligomer conjugates that may not be achieved with bile Salts or fatty 0005 U.S. Pat. No. 6,200,602 to Watts et al. proposes acids alone. For example, in Some embodiments of the drug delivery compositions for colonic delivery of insulin. present invention, using mixtures of bile Salts and fatty acids The drug delivery compositions include insulin, an absorp in a particular ratio alters the precipitation characteristics of tion promoter which (a) includes a mixture of fatty acids the bile salt so that the bile salt more readily re-solubilizes having 6 to 16 carbon atoms or a Salt thereof and a dispersing if it happens to precipitate out of the pharmaceutical com agent, or (b) comprises a mixture of mono/diglycerides of position (e.g., upon encountering an acidic environment in medium chain fatty acids and a dispersing agent, and a the gut). As another example, in Some embodiments of the coating to prevent the release of the insulin and absorption present invention, using mixtures of bile Salts and fatty acids promoter until the tablet, capsule or pellet reaches the in a particular ratio lowers the precipitation point of the bile proximal colon. Salt in the pharmaceutical composition, providing additional 0006 Bile salts have been proposed as excipients in buffering capacity for the pharmaceutical composition. pharmaceutical compositions of unconjugated drug mol 0012. According to embodiments of the present inven ecules. For example, U.S. Pat. No. 4,579,730 to Kidron et al. tion, a pharmaceutical composition includes a drug-oligo proposes pharmaceutical compositions for the oral admin mer conjugate that includes a drug covalently coupled to an istration of insulin. The pharmaceutical compositions oligomeric moiety, a fatty acid component that includes a include insulin, a bile acid or alkali metal Salt thereof, the fatty acid, and a bile Salt component that includes a bile Salt. bile acid being Selected from the group consisting of cholic The fatty acid component and the bile Salt component are acid, chenodeoxycholic acid, taurocholic acid, taurocheno present in a weight-to-weight ratio of between 1:5 and 5:1. deoxycholic acid, glycocholic acid, glycochenocholic acid, The fatty acid component is present in an amount Sufficient 3.f3-hydroxy-12-ketocholic acid, 12C-3?-dihydrocholic acid, to lower the precipitation point of the bile Salt compared to and urSodeSOXycholic acid, and a protease inhibitor. The a precipitation point of the bile Salt if the fatty acid com composition is provided with an enterocoating to assure ponent were not present in the pharmaceutical composition. passage through the Stomach and release in the intestine. The bile Salt component is present in an amount Sufficient to US 2003/0069170 A1 Apr. 10, 2003 lower the solubility point of the fatty acid compared to a 0021 FIG.
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