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(12) Patent Application Publication (10) Pub. No.: US 2009/0186832 A1 Franklin Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0186832 A1 Franklin Et Al US 200901 86832A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0186832 A1 Franklin et al. (43) Pub. Date: Jul. 23, 2009 (54) AMINO ACID PEPTIDE PRO-DRUGS OF Publication Classification PHENOLIC ANALGESCS AND USES 51) int. C THEREOF (51) Int. Cl. A638/05 (2006.01) C07C 27L/50 (2006.01) (75) Inventors: Richard Franklin, Hampshire C07D 22.3/04 (2006.01) (GB); Bernard T. Golding, A6II 3/55 (2006.01) Newcastle upon Tyne (GB); Robert C07D 489/08 (2006.01) G. Tyson, Durham (GB) A63L/485 (2006.01) A63L/4355 (2006.01) Correspondence Address: (52) U.S. Cl. ...... 514/19:560/160; 540/611; 514/212.01; DARBY & DARBY P.C. 546/45; 514/282: 514/279 P.O. BOX 770, Church Street Station (57) ABSTRACT New York, NY 10008-0770 (US) Prodrugs of meptazinol and other phenolic analgesics exhib (73) Assignee: SHIRE LLC, Florence, KY (US) iting low oral bioavailability with amino acids or lower pep tides, pharmaceutical compositions containing Such prodrugs (21) Appl. No.: 12/356,028 and a method for providing pain relief with Such prodrugs are provided. In addition, the present invention relates to methods Filed: Jan. 19, 2009 for increasing the oral bioavailability of a phenolic analgesic. (22) e - 19 The method comprises orally administering a phenolic anal O O gesic prodrug, wherein the phenolic analgesic is bound to an Related U.S. Application Data amino acid or peptide via a carbamate linkage, to a subject in (60) Provisional application No. 61/022,044, filed on Jan. need thereof. Prodrugs having side chains of valine, leucine, 18, 2008, provisional application No. 61/022,159, isoleucine and glycine amino acids and mono-, di- and trip filed on Jan. 18, 2008. eptides thereof are preferred. 30 S 25 - s S20 - Compound Administered O -0-Meptazinol 15 - -A-Meptazinol valine carbamate 10 - CD55 O O Time (h) Patent Application Publication Jul. 23, 2009 Sheet 1 of 3 US 2009/0186832 A1 Figure 1 30 - 25 - S. S20 - Compound Administered f SC 15 -0-Meptazinol vu 2 -A-Meptazinol valine carbamate SN 3 10 a3.5 CD 5 O O Time (h) Patent Application Publication Jul. 23, 2009 Sheet 2 of 3 US 2009/0186832 A1 Figure 2 30 28 - 26 - 24 22 20 Compound administered 18 -- Oxymorphone 16 - - A - Oxymorphone valine carbamate 14 12 1 Patent Application Publication Jul. 23, 2009 Sheet 3 of 3 US 2009/0186832 A1 Figure 3 Compound administered -0-Buprenorphine -A - Buprenorphine valine carbamate conjugate Time (h) US 2009/0186832 A1 Jul. 23, 2009 AMINO ACID PEPTIDE PRO-DRUGS OF analgesics, including sublingual or transdermal drug delivery PHENOLIC ANALGESICS AND USES of buprenorphine. For meptazinol, a suppository formulation THEREOF was developed in an attempt to effect absorption from the superior hemorrhoidal veins, with the goal of avoiding the RELATED APPLICATIONS hepatic portal transfer to the liver. Withoxymorphone, no oral 0001. This application claims the benefit of U.S. Provi formulation was available until 2006, despite the drug being sional Application Nos. 61/022,044 and 61/022,159, both originally introduced to the U.S. market in 1959. Presently filed Jan. 18, 2008. These prior applications are hereby incor available oral formulations of oxymorphone now include a porated by reference. sustained release preparation, but still have a poor oral bio availability of 10%. This poor oral bioavailability is associ FIELD OF THE INVENTION ated with considerable variation in achieved plasma drug 0002 The present invention relates to the utilization of levels. amino acid and small peptide prodrugs of meptazinol, oxy 0007 Thus, despite their pharmacological merits, the use morphone, buprenorphine and other phenolic analgesics, to of phenolic analgesics can be compromised by inadequate oral bioavailability. The merits and pharmacokinetic short increase the oral availability of the respective analgesic, and comings of three representative phenolic opioid analgesics— to reduce or eliminate pain. meptazinol, oxymorphone and buprenorphine are discussed BACKGROUND OF THE INVENTION in more detail below. 0003) Inadequate pain relief continues to represent a major 0008 Meptazinol is a mixed agonist-antagonist analgesic problem for both patients and healthcare professionals. Opti with specificity for the u opioid receptor and displays both mal pharmacologic management of pain requires selection of opioid (Spiegel and Pasternak (1984). J Pharmacol Exp Ther the appropriate analgesic drug that achieves rapid efficacy 228, 414B) and cholinergic properties (Ennis et al. (1986). J with minimal side effects. Pharm Pharmacol 38, 24-27). As such, it is capable of reliev 0004 Mild analgesics are readily available, both over the ing moderate to moderately severe pain (Siegel et al. (1989). counter (OTC) and by prescription. These include the non J Clin Pharmacol 29, 1017-1025). Meptazinol exists in two steroidal anti inflammatory drugs (NSAIDs) such as aspirin enantiomeric forms, and is used as its racemate. The chemical and ibuprofen, which are well established for the treatment of structure of meptazinol is given below. mild pain. However, while offering effective pain relief they also have side effects such as gastric ulceration and potential CH3 for hemorrhage. The other widely used drug for the treatment M of mild pain is acetaminophen (paracetamol) but this, in N excessive doses, can lead to liver toxicity. 0005 Treatment of more severe pain with opioid analge sics such as oxymorphone may also have their limitations. OH Unwanted effects can include sedation, respiratory depres HC-CH sion, chronic constipation and abuse liability. Many of the stronger opioid analgesics possess a phenolic or hydroxylic function. Such drugs include butorphanol, buprenorphine, codeine, dezocine, dihydrocodeine, hydromorphone, levor phanol, meptazinol, morphine, nalbuphine, oxycodone, oxy Meptazinol-3-(3-Ethyl-1-methyl-azepan-3-yl)-phe morphone, and pentazocine. As a consequence of the pres nol ence of either a phenolic or hydroxylic function, many of these compounds are subject to extensive metabolism during 0009. The preparation of a meptazinol hydrobromide salt the initial passage through the liver after oral dosing, limiting is taught in U.S. Pat. No. 3,729,465. Preparation of the free the amount of unchanged drug which can reach the systemic base form of meptazinol is taught in U.S. Pat. No. 4,197.241, circulation. This high first pass effect results in poor oral both of which are incorporated by reference herein in their bioavailability. For example, meptazinol, oxymorphone and entireties. buprenorphine all have oral bioavailabilities less than 10%. A (0010 Meptazinol is a potent inhibitor of acetylcholine direct consequence of such low bioavailability is consider esterase, and the consequential cholinergic properties are able variability in attained blood levels within and between thought to contribute to its anti-nociceptive effects (Bill et al. subjects. For example, with meptazinol, the range of (1983). BrJ Pharmacol 79, 191-199). Additionally, this activ observed oral bioavailabilities extends from 2-20% (Norbury ity may counter the typical side effects associated with the et al., (1983) Eur. J. Clin Pharmacol 25, 77-80). This inevita more traditional opioid therapeutics (Li et al. (2005). Acta bly results in a variable analgesic response requiring subjects Pharmacol Sin 26,334-338). Meptazinol has also been shown to be individually titrated to achieve adequate pain relief. to have a negligible clinical dependency liability from both Dose titration can be tedious and time consuming and make formal clinical investigation and the lack of reported effective treatment of subjects extremely difficult. In any instances of street use/abuse (Johnson and Jasinski (1987). event, the treatment of moderate to severe pain demands Clin. Pharm. Ther. 41, 426-33). This negligible clinical urgent relief and subjects may not be prepared to tolerate a dependency distinguishes meptazinol from other opioid anal protracted period of dose titration. This inevitably leads to gesics such as fentanyl (DuragesicR), pentazocine, oxyc compliance issues among subjects. odone (Oxycontin(R), Percocet(R), and morphine, which are 0006. Several different approaches have been examined to all classified as “Controlled Drugs' and, consequently, have overcome the problems of poor oral bioavaibilities of opioid prescription/dispensation restrictions. US 2009/01 86832 A1 Jul. 23, 2009 0011 Meptazinol has many other clinical advantages over Oxymorphone has little affinity for the K (kappa) receptor (ten the more conventional opioid analgesics, including lower fold less than L or Ö) which may explain the drug's decreased respiratory depression (Verborgh and Camu (1990). Eur. J. sedative properties (Sinatra and Harrison (1989). Clin Pharm. Clin Pharmacol 38, 437-42), minimal sedation (Bradley and 8,541-544). Nicholson (1987). Eur. J. Clin Pharmacol 32, 135-139), and 0016 Despite these pharmacological advantages, oxy lack of a constipating effect (Price and Latham (1982). Curr morphone displays poor pharmacokinetics. The absolute oral Ther Res 31, 807-812). bioavailability of the drug is only 10% (Sloan et al. (2005). 0012 However, despite these clinical advantages, use of Supp Care Cancer 13, 57-65), and as a consequence, there is meptazinol has been restricted by the major disadvantage of much variability in the attained plasma concentrations and its low oral bioavailability, with reported mean bioavailability potentially, subject response. This variability is reflected in values lying between 4-9% (Norbury et al. (1983) Eur J. Clin C. values, which after a single 5 mg dose, is associated with Pharmacol 25, 77-80). The low bioavailability is due to exten a >50% (relative standard deviation (RSD). Further, after sive conjugation of meptazinol's metabolically Vulnerable multiple dosing, the RSD is only reduced to ~36% (Opana(R) phenolic function with glucuronic acid (Franklin (1988). FDA labeling). Total exposures, reflected in AUC values, are Xenobiotica 18, 105-112). This process can remove up to similarly variable. There is also an undesirable food effect on 98% of an oral dose of meptazinol as it passes through the the pharmacokinetics that increases C values by up 38% liver (i.e., first pass metabolism).
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