US 2010O209499A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0209499 A1 Cumming et al. (43) Pub. Date: Aug. 19, 2010 (54) SOLID ORAL DOSAGE FORM CONTAINING A 6LX 3L/727 (2006.01) AN ENHANCER A638/24 (2006.01) A638/28 (2006.01) (76) Inventors: Kenneth I. Cumming, Dublin (IE): A638/08 (2006.01) Zebunnissa Ramtoola, Dublin (IE) A6II 3/66 (2006.01) A638/3 (2006.01) Correspondence Address: A6IR 9/22 (2006.01) MYERS BIGELSIBLEY & SAJOVEC A 6LX 9/52 (2006.01) POBOX37428 A6IP 43/00 (2006.01) RALEIGH, NC 27627 (US) (52) U.S. Cl. ............. 424/456; 514/784: 514/54: 514/12: (21) Appl. No.: 12/768,008 514/2: 514/56; 514/8: 514/3: 514/15: 514/108; 514/11; 424/468; 424/457 (22) Filed: Apr. 27, 2010 (57) ABSTRACT Related U.S. Application Data The invention relates to a solid oral dosage form comprising (63) Continuation of application No. 12/172,707, filed on a pharmaceutically active ingredient in combination with an Jul. 14, 2008. enhancer which enhances the bioavailability and/or the absorption of the active ingredient. Accordingly, a Solid oral Publication Classification dosage form comprises a drug and an enhancer wherein the (51) Int. C. enhancer is a medium chain fatty acid ester, ether or salt or a A6 IK 9/64 (2006.01) derivative of a medium chain fatty acid, which is, preferably, A6 IK 47/12 (2006.01) Solid at room temperature and which has a carbon chain A 6LX 3L/75 (2006.01) length of from 6 to 20 carbonatoms. Preferably, the solid oral A6 IK 38/16 (2006.01) dosage form is controlled release dosage form Such as a A6 IK 38/02 (2006.01) delayed release dosage form. Patent Application Publication Aug. 19, 2010 Sheet 1 of 15 US 2010/0209499 A1 s en E e en Sir co de as5 9O C9- O- O- O- O- ; : g - f ve O - O yard varia 1. CD E s NuYE .S. CD E s O un CO (9 (uo (5) su! useuo. RIGIHL 9/, Patent Application Publication Aug. 19, 2010 Sheet 2 of 15 US 2010/0209499 A1 C8) so --w -6g --- (N .S. 2 CIO is Ge. s OIO isgld d 8) IO-ILIOo f en lin sess l? CD ea ves CO so IX oos/uo) ia Aa dra Patent Application Publication Aug. 19, 2010 Sheet 5 of 15 US 2010/0209499 A1 ———OZL(štuSº)0JOEN+(n-10001)u?edaH (õu01)DIOEN+(n-10001)u?uedaH—w—00|| co O O O CO CO vs. CN (es) Lidw Patent Application Publication Aug. 19, 2010 Sheet 6 of 15 US 2010/0209499 A1 i i 2 O O 9 N 1N ND S. C CD CD s - C c) CD s S f m CN w d (u/n) Ape eXO3 e-uw Patent Application Publication US 2010/0209499 A1 | L0.In??I D Patent Application Publication Aug. 19, 2010 Sheet 8 of 15 US 2010/0209499 A1 HSp??eo0un)sjæIqe,G,qo?eg• (n100006u?uedaq+010eN ex-UW Patent Application Publication Aug. 19, 2010 Sheet 9 of 15 US 2010/0209499 A1 9.O. (b { { } { i + - 69.InáI ueeW Patent Application Publication Aug. 19, 2010 Sheet 10 of 15 US 2010/0209499 A1 Patent Application Publication Aug. 19, 2010 Sheet 11 of 15 US 2010/0209499 A1 -- O -- E 1) c - C/O - O OO m ym la d S . CD S Y CN I-I-I-I- O Lo N. L. co La Cn La V - Lo O r Cy) CN v- d Sewel . ex Jooey!) uw eused ueeW Patent Application Publication Aug. 19, 2010 Sheet 12 of 15 US 2010/0209499 A1 Patent Application Publication Aug. 19, 2010 Sheet 13 of 15 US 2010/0209499 A1 Patent Application Publication Aug. 19, 2010 Sheet 14 of 15 US 2010/0209499 A1 Patent Application Publication Aug. 19, 2010 Sheet 15 of 15 US 2010/0209499 A1 US 2010/0209499 A1 Aug. 19, 2010 SOLID ORAL DOSAGE FORM CONTAINING caprate has been reported to enhance intestinal and colonic AN ENHANCER drug absorption by the paracellular route (Pharm. Res. (1993) 10,857-864; Pharm. Res. (1988), 5,341-346). U.S. Pat. No. FIELD OF THE INVENTION 4,656,161 (BASF AG) discloses a process for increasing the enteral absorbability of heparin and heparinoids by adding 0001. The present invention relates to a solid oral dosage non-ionic Surfactants such as those that can be prepared by form containing enhancers. In particular the invention relates reacting ethylene oxide with a fatty acid, a fatty alcohol, an to a solid oral dosage form comprising a pharmaceutically alkylphenol or a sorbitan or glycerol fatty acid ester. U.S. Pat. active ingredient in combination with an enhancer which No. 5.229,130 (Cygnus Therapeutics Systems) discloses a enhances the bioavailability and/or the absorption of the composition which increases the permeability of skin to a active ingredient and which is a controlled release dosage transdermally administered pharmacologically active agent form such as a delayed release dosage form. formulated with one or more vegetable oils as skin perme ation enhancers. Dermal penetration is also known to be BACKGROUND OF THE INVENTION enhanced by a range of sodium carboxylates Int. J. of Phar 0002 The epithelial cells lining the lumenal side of the maceutics (1994), 108, 141-148). Additionally, the use of GIT are a major barrier to drug delivery following oral admin essential oils to enhance bioavailability is known (U.S. Pat. istration. However, there are four recognised transport path No. 5,66,386 AvMax Inc. and others). It is taught that the ways which can be exploited to facilitate drug delivery and essential oils act to reduce either, or both, cytochrome P450 transport: the transcellular, paracellular, carrier-mediated and metabolism and P-glycoprotein regulated transport of the transcytotic transport pathways. The ability of a drug, Such as drug out of the blood stream back into the gut. a conventional drug, a peptide, a protein, a macromolecule or 0007 Often, however, the enhancement of drug absorp a nano- or microparticulate system, to “interact with one or tion correlates with damage to the intestinal wall. Conse more of these transport pathways may result in increased quently, limitations to the widespread use of GIT enhancers is delivery of that drug from the GIT to the underlying circula frequently determined by their potential toxicities and side tion. effects. Additionally and especially with respect to peptide, 0003 Certain drugs utilise transport systems for nutrients protein or macromolecular drugs, the “interaction of the GIT which are located in the apical cell membranes (carrier medi enhancer with one of the transport pathways should be tran ated route). Macromolecules may also be transported across sient or reversible, such as a transient interaction with or the cells in endocytosed vesicles (transcytosis route). How opening of tight junctions so as to enhance transport via the ever, many drugs are transported across the intestinal epithe paracellular route. lium by passive diffusion either through cells (transcellular 0008. As mentioned above, numerous potential enhancers route) or between cells (paracellular). Most orally adminis are known. However, this has not led to a corresponding tered drugs are absorbed by passive transport. Drugs which number of products incorporating enhancers. One such prod are lipophilic permeate the epithelium by the transcellular uct currently approved for use in Sweden and Japan is the route whereas drugs that are hydrophilic are restricted to the DoktacillinTM suppository Lindmarket al., Pharmaceutical paracellular route. Research (1997), 14, 930-935. The suppository comprises 0004 Paracellular pathways occupy less than 0.1% of the ampicillin and the medium chain fatty acid, Sodium caprate total surface area of the intestinal epithelium. Further, tight (C10). junctions, which form a continuous belt around the apical part 0009 Provision of a solid oral dosage form which would of the cells, restrict permeation between the cells by creating facilitate the administration of a drug together with an a seal between adjacent cells. Thus, oral absorption of hydro enhancer is desirable. The advantages of Solid oral dosage philic drugs such as peptides can be severely restricted. Other forms over other dosage forms include ease of manufacture, barriers to absorption of drugs may include hydrolysing the ability to formulate different controlled release and enzymes in the lumen brush border or in the intestinal epithe extended release formulations and ease of administration. lial cells, the existence of the aqueous boundary layer on the Administration of drugs in Solution form does not readily surface of the epithelial membrane which may provide an facilitate control of the profile of drug concentration in the additional diffusion barrier, the mucus layer associated with bloodstream. Solid oral dosage forms, on the other hand, are the aqueous boundary layer and the acid microclimate which Versatile and may be modified, for example, to maximise the creates a proton gradient across the apical membrane. extent and duration of drug release and to release a drug Absorption, and ultimately bioavailability, of a drug may also according to a therapeutically desirable release profile. There be reduced by other processes such as P-glycoprotein regu may also be advantages relating to convenience of adminis lated transport of the drug back into the gut lumen and cyto tration increasing patient compliance and to cost of manufac chrome P450 metabolism. ture associated with Solid oral dosage forms. 0005. Therefore, new strategies for delivering drugs across the GIT cell layers are needed, particularly for hydro SUMMARY OF THE INVENTION philic drugs including peptides, proteins and macromolecular 0010. According to the present invention, a solid oral dos drugs.