US 20080317666A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0317666 A1 Fattal et al. (43) Pub. Date: Dec. 25, 2008 (54) COLONIC DELIVERY OF ACTIVE AGENTS Publication Classification (51) Int. Cl. (76) Inventors: Elias Fattal, Paris (FR); Antoine A6IR 9/00 (2006.01) Andremont, Malakoff (FR); A61R 49/00 (2006.01) Patrick Couvreur, A6II 5L/12 (2006.01) Villebon-sur-Yvette (FR); Sandrine A6IPI/00 (2006.01) Bourgeois, Lyon (FR) (52) U.S. Cl. .......................... 424/1.11; 424/423; 424/9.1 (57) ABSTRACT Correspondence Address: Drug delivery devices that are orally administered, and that David S. Bradlin release active ingredients in the colon, are disclosed. In one Womble Carlyle Sandridge & Rice embodiment, the active ingredients are those that inactivate P.O.BOX 7037 antibiotics, such as macrollides, quinolones and beta-lactam Atlanta, GA 30359-0037 (US) containing antibiotics. One example of a Suitable active agent is an enzyme Such as beta-lactamases. In another embodi ment, the active agents are those that specifically treat colonic (21) Appl. No.: 11/628,832 disorders, such as Chrohn's Disease, irritable bowel syn drome, ulcerative colitis, colorectal cancer or constipation. (22) PCT Filed: Feb. 9, 2006 The drug delivery devices are in the form of beads of pectin, crosslinked with calcium and reticulated with polyethylene imine. The high crosslink density of the polyethyleneimine is (86). PCT No.: PCT/GBO6/OO448 believed to stabilize the pectin beads for a sufficient amount of time such that a Substantial amount of the active ingredi S371 (c)(1), ents can be administered directly to the colon. Advanta (2), (4) Date: Mar. 3, 2008 geously, the amount of polyethyleneimine is sufficient to allow a Substantial portion of the pectin beads to pass through Related U.S. Application Data the gastrointestinal tract to the colon without releasing the active agent, and is also sufficient Such that the pectin beads (60) Provisional application No. 60/651,342, filed on Feb. are sufficiently degraded in the colon to release an effective 9, 2005. amount of the active agent. 12 PE) 0% 0.60% a 0.70% E 0.80% is 0.90% 1% Gastric Medium Intestinal medium PBS 001M pH 7.4 Media Patent Application Publication Dec. 25, 2008 Sheet 1 of 8 US 2008/0317666 A1 |eun61 au,L Patent Application Publication Dec. 25, 2008 Sheet 2 of 8 US 2008/0317666A1 Z?un61 Spt:0.8910?AA spe98yno Patent Application Publication Dec. 25, 2008 Sheet 3 of 8 US 2008/0317666 A1 eunôl9 Patent Application Publication Dec. 25, 2008 Sheet 4 of 8 US 2008/0317666 A1 : yG) : 5,y 3 E 3 2 is C sO &O Go () al r G t - e. Vo s N B 9 O Jty / -X w lO N C C d o e O C c ce C. O S Vo f w r N cs Patent Application Publication Dec. 25, 2008 Sheet 5 of 8 US 2008/0317666 A1 spe08310?AA Geinfil Patent Application Publication Dec. 25, 2008 Sheet 6 of 8 US 2008/0317666 A1 eun619 Patent Application Publication Dec. 25, 2008 Sheet 7 of 8 US 2008/0317666 A1 speagatoqAA /.e.Infil Patent Application Publication Dec. 25, 2008 Sheet 8 of 8 US 2008/0317666 A1 eunôl9 axoidod?TvNaalbayNG OO,ÇLIC) 001- OZ WNCI portuopt. Jo uopensdeou3% US 2008/0317666 A1 Dec. 25, 2008 COLONIC DELVERY OF ACTIVE AGENTS though this diarrhoea is generally not serious and quickly ceases, either spontaneously, or on completion of treatment, it FIELD OF THE INVENTION is all the same badly received by patients and adds to the discomfort of the base illness for which the antibiotic was 0001. The present invention is in the area of oral drug prescribed: delivery devices that administer active agents to the colon. 0007 2. perturbation of the functions of resistance to colo nization by exogenic bacteria (or “barrier effect”) with pos BACKGROUND OF THE INVENTION sibilities of risk from infection, for example, alimentary sal 0002 Drug delivery devices that specifically deliver active monella intoxication (Holmberg S. D. et al. (1984) Drug agents to the colon have been recognized as having important resistant Salmonella from animals fed antimicrobials, New therapeutic advantages. A large number of colonic conditions England Journal of Medicine, 311, 617); could effectively be treated more efficaciously if the active 0008. 3. selection of microorganisms resistant to the anti ingredient is released locally. Examples of Such colonic dis biotic. The latter can be of various types: orders include Crohn's disease, ulcerative colitis, colorectal 0009 a) first they can be pathogenic bacteria such as for cancer and constipation. example, Clostridium difficile, a species capable of secreting 0003 Colonic release can also benefit patients when, from toxins causing a form of colitis known as pseudomembranous atherapeutic point of view, a delay in absorption is necessary. (Bartlett J. G. (1997) Clostridium difficile infection: patho Examples include the treatment of disorders such as noctur physiology and diagnosis, Seminar in Gastrointestinal Dis nal asthma or angor (Kinget R. et al. (1998), Colonic Drug ease, 8, 12); Targeting, Journal of Drug Targeting, 6, 129). 0010 b) they can also be microorganisms that are rela 0004 Colonic release can also be used to administer thera tively weakly pathogenic, but whose multiplication can lead peutically active polypeptides. Polypeptides are typically to an associated infection (vaginal Candidosis or Escherichia administered by injection, because they are degraded in the coli resistant cystitis). stomach. Because injection is painful, research efforts have 0011 c) they can finally be non-pathogenic commensal focused on using the colon as a site of absorption for active drug resistant bacteria whose multiplication and fecal elimi polypeptides, including analgesics, contraceptives, vaccines, nation is going to increase dissemination in the environment. insulin, and the like. The absorption of polypeptides in the Now, these resistant commensal bacteria can constitute an colon appears effectively better than in other sites in the important source of mechanisms of drug resistance for patho digestive tract. This is particularly due to the relatively weak genic species. This risk is currently considered seminal in proteolytic activity in the small intestine and the absence of terms of the disquieting character of the evolution towards peptidasic activity associated with the membrane of the drug multiresistance by numerous species pathogenic for colonic epithelial cells. humans. 0005. During administration of antibiotics by mouth, they 0012) Numerous strategies exploiting the diverse physi pass through the stomach and are then absorbed in the Small ological parameters of the digestive tract have thus been intestine to diffuse in the whole organism and treat the infec envisioned with the aim of releasing active ingredients in the tious outbreak site for which they have been administered. All colon. These strategies have focused on drug delivery systems the same, a fraction of antibiotics ingested (whereof the based on (1) using polymers that are sensitive to variations in importance varies with the characteristics of each type of pH, (2) time-dependent drug release forms, (3) prodrugs or antibiotics) is not absorbed and continues its progress to the polymers degradable by bacteria in the intestinal flora. colon before being eliminated in the stool. These residual 0013. It would be advantageous to have additional drug antibiotics are reunited, in the large intestine, by a fraction of delivery devices which can administer active agents to the the antibiotics absorbed, but which are re-excreted in the colon. It would also be desirable to have drug delivery devices digestive tract by means of biliary elimination. This fraction for reducing the quantity of residual antibiotics arriving at the is of variable importance as a function of metabolism and colon after oral or parenteral antibiotic therapy. The present ways of elimination of each antibiotic. Finally, for certain invention provides such drug delivery devices. antibiotics, a fraction of the dose absorbed is eliminated directly via intestinal mucous in the lumen of the digestive SUMMARY OF THE INVENTION tract. Thus, since the antibiotics had been administered orally or parenterally, a residual active fraction is generally found in 0014 Oral drug delivery devices that release active agents the colon. This is true, to varying degrees, for the greater in the colon, are disclosed. In one embodiment, the active majority of families of antibiotics utilized in therapeutics, the agents are those that inactivate antibiotics, such as mac sole notable exception being the family of amino-glycosides rolides, quinolones and beta-lactam containing antibiotics. for which intestinal excretion is negligible. For other antibi One example of a Suitable active agent is an enzyme such as otics, intestinal excretion of a residual antibiotic activity is beta-lactamases. In another embodiment, the active agents going to have different consequences, all harmful. In effect, in are those that specifically treat colonic disorders, such as the colon there is a complex and very dense bacterial ecosys ulcerative colitis, colorectal cancer, Chrohn's Disease, irri tem (several hundreds of different bacterial species; more table bowel syndrome, and constipation. The active ingredi than 10' bacteriaper gram of colonic content) which is going ents can be hydrosoluble or liposoluble. Depending on the to be affected by the arrival of active antibiotic residues. The active agent, the drug delivery devices can be used in thera following can be observed: peutics or in diagnostics. 0006 1. Imbalance inflora which would be the main cause 0015 The drug delivery devices are in the form of beads of of banal diarrhoea at time following taking antibiotics (Bar pectin, crosslinked with calcium or other metal cations and tlett J. G. (2002) Clinical practice. Antibiotic associated diar reticulated with polyethyleneimine. The high crosslink den rhoea, New England Journal of Medicine, 346,334).