US 20110077222A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0077222 A1 Schaefer et al. (43) Pub. Date: Mar. 31, 2011 (54) SUSTAINED-RELEASE OPIATE AND OPIATE Publication Classification DERVATIVE COMPOSITIONS (51) Int. Cl. (75) Inventors: Carl J. Schaefer, Crestwood, MO A63L/485 (2006.01) (US); Gary L. Cantrell, Troy, IL C07F 9/09 (2006.01) (US) A6IP 25/04 (2006.01) (73) Assignee: Mallinckrodt Inc., Hazelwood, (52) U.S. Cl. ............................................. 514/81: 546/23 MO (US) (21) Appl. No.: 12/894,203 (57) ABSTRACT The present invention provides Sustained-release opiate com (22) Filed: Sep. 30, 2010 positions. In particular, the present invention provides Sus tained-release opiate compositions that include an opiate Related U.S. Application Data attached to a blood albuminbinder. The present invention also (60) Provisional application No. 61/247,076, filed on Sep. relates to methods of administering an opiate with a Sustained 30, 2009. release pharmacokinetic profile. US 2011/0077222 A1 Mar. 31, 2011 SUSTAINED-RELEASE OPIATE AND OPIATE SUMMARY OF THE INVENTION DERVATIVE COMPOSITIONS 0008. One aspect of the present invention encompasses a Sustained-release opiate composition that includes an opiate, CROSS REFERENCE TO RELATED a non-peptide blood albumin binder, and a connecting bridge APPLICATIONS attached to the opiate and to the non-peptide blood albumin 0001. This application claims the benefit of U.S. Provi binder. Without being bound to any particular theory, after sional Application No. 61/247,076 filed Sep. 30, 2009, which administering the composition to a patient, the non-peptide is incorporated herein in its entirety. blood albumin binder non-covalently binds to circulating albumin protein in the bloodstream of the patient. The opiate FIELD OF THE INVENTION and binding bridge, which are attached to the non-peptide 0002 The present invention generally relates to sustained blood albumin binder, are similarly bound to the circulating release opiate compositions. In particular, the present inven albumin protein. In this bound state, the opiate is rendered tion relates to Sustained-release opiate compositions that inactive until released into the bloodstream. The bonds that include an opiate attached to a blood albumin binder. attach the opiate to the binding bridge are cleaved as a func tion of time, and the opiate is released into the bloodstream to BACKGROUND OF THE INVENTION exert its therapeutic effect. It has been discovered surprisingly that an opiate released in this manner exhibits essentially the 0003) Opiates are highly effective and widely used nar same efficacy as the same opiate administered in isolation. cotic compounds. Although these compounds have a power 0009. Without being bound to any particular theory, the ful and essentially immediate effect, the benefits of opiate elapsed time at which the opiate is released is influenced by a administration are somewhat limited by relatively short half number of factors including the chemical properties of the life of opiates due to rapid clearance by the hepatic and binding bridge and the opiate, as well as the chemical prop urinary systems. erties of the patient's bloodstream, such as pH. Because blood 0004 Existing sustained-release opiate formulations pH is actively maintained at a constant value, the pharmaco entail administering the opiate active compound as an oral kinetic release profile is highly reliable. In another aspect, the composition that includes the opiate active compounds Sustained-release opiate composition includes an opiate, a coated with a degradable coating that releases the opiate non-peptide blood albumin binder such as diphenylcyclohex active compound with a specified release profile. However, anol, and a connecting bridge Such as phosphate diester. Yet these formulations are relatively expensive to produce and are another aspect provides a sustained-release opiate composi particularly Vulnerable to tampering, posing the danger of tion that includes an opiate chosen from Oxycodone, oxymor overdose. Further, the release profile of oral sustained release phone, hydrocodone, hydromorphone, naloxone, nalbuphine, compounds are relatively unpredictable due to wide variation nalmefene, buprenorphine, and naltrexone, a non-peptide in the chemical conditions in the stomach due to the ingestion blood albumin binder Such as diphenylcyclohexanol, and a of food, alcohol, or other pharmaceutically active com connecting bridge Such as phosphate diester. pounds. 0010. An additional aspect provides a sustained-release 0005. Although the opiate may be released in a sustained opiate composition that includes a first compound and a sec release profile using an orally administered composition, the ond compound. The first compound includes a first opiate, a opiate is still rapidly cleared from circulation upon release. first non-peptide blood albumin binder, and a first connecting Thus the sustained-release period is limited to the amount of bridge attached to the first opiate and to the first non-peptide time that the oral composition is resident in a region of the blood albumin binder. The second compound includes a sec digestive tract possessing Suitable conditions for the release ond opiate, a second non-peptide blood albuminbinder, and a and absorption of the opiate active compounds. second connecting bridge attached to the second opiate and to 0006. The half-life of any active compound in circulation the second non-peptide blood albumin binder. is affected by the affinity of the compound for long-lived 0011. Another additional aspect provides a sustained-re circulating proteins such as blood albumin or blood cell Sur lease opiate composition that includes a first opiate, a second face proteins. Recent Sustained-release formulations have attempted to exploit this phenomenon by coupling active opiate, a non-peptide blood albumin binder, and a connecting compounds with antibodies, antibody fragments, and other bridge attached to the first opiate, to the second opiate, and to peptides that have a binding affinity for blood albumin or the non-peptide blood albumin binder. other circulating proteins. In addition to extending the half 0012 Still another aspect provides a method of adminis life of active compounds, the chemical properties of the tering an opiate to a human Subject with a Sustained release bloodstream such as pH are actively maintained at constant pharmacokinetic profile relative to a pharmacokinetic profile levels, resulting in a more reliable release profile than oral of the opiate administered in isolation. In this aspect, the Sustained release compositions. To date, this approach has method includes providing a Sustained-release opiate compo been limited to active compounds that are Small peptides. sition that includes an opiate, a non-peptide blood albumin 0007. A need exists in the art for a sustained-release opiate binder, and a connecting bridge attached to the opiate and to composition that incorporates a circulating protein binding the non-peptide blood albumin binder. The method further compound to extend the halt-life of the opiate in circulation includes administering the Sustained-release opiate composi and to provide a reliable pharmacokinetic release profile. tion to the human Subject. However, the efficacy of opiates and opiate derivatives are 0013. Other features and iterations of the invention are notoriously sensitive to Small changes to their chemical struc described in more detail below. tures. A need exists in the art for a Sustained-release formu lation that incorporates a circulating protein binding com DETAILED DESCRIPTION pound without compromising the efficacy of the opiate active 0014. The present invention provides sustained-release compound. opiate compositions and methods of administering the com US 2011/0077222 A1 Mar. 31, 2011 positions to a human patient. In particular, the present inven opiate compositions may include adulmine, allocryptopine, tion provides Sustained-release opiate compositions that aporphine, benzylmorphine, berberine, bicuculine, bicucine, include an opiate attached to a blood albumin binder using a bulbocapnine, buprenorphine, butorphanol, canadine, capau connecting bridge. Upon administration, the blood albumin rine, chelerythrine, chelidonine, codamine, codeine, cop binder component of the composition non-covalently binds to tisine, coreximine, corlumine, corybulbine, cory cavamine, circulating blood albumin. The connecting bridge is cleaved corycavine, corydaline, corydine, corytuberine, cularine, as a function of time, thereby releasing the opiate into circu cotamine, cryptopine, cycloartenol, cycloartenone, lation, where it exerts its therapeutic effect. It has been dis cyclolaudenol, dehydroreticuline, desomorphine, dextropro covered that administering the opiate attached to a blood poxyphene, dextrorphanol, diacetylmorphine, dicentrine, albuminbinder significantly extends the half-life of the opiate dihydrosanguinarine, dipropanoylmorphine, epiporphyroX in the blood without significantly degrading the therapeutic ine, ethylmorphine, eupaverine, fagarine, fentanyl, glaucine, homochelidonoine, hydrocodone, hydrocotamine, hydro efficacy of the opiate. morphone, hydroxythebaine, isoboldine, isocorybulbine, iso 0015 Without being bound to any particular theory, when corydine, isocorypalmine, isoquinoline, laudanidine, lauda bound to blood albumin, the Sustained-release opiate compo nine, laudanosine, levorphanol, magnoflorine, meconic