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(12) United States Patent (10) Patent No.: US 7.691,873 B2 Duncalfetal

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(12) United States Patent (10) Patent No.: US 7.691,873 B2 Duncalfetal US007691873B2 (12) United States Patent (10) Patent No.: US 7.691,873 B2 Duncalfetal. (45) Date of Patent: Apr. 6, 2010 (54) PREPARATION OF PHARMACEUTICAL (56) References Cited FORMULATIONS U.S. PATENT DOCUMENTS (75) Inventors: David John Duncalf, Little Neston 6,207,674 B1 3/2001 Smith (GB); Steven Paul Rannard, Mickle 2004/0180089 A1 9, 2004 Plachetka et al. Trafford (GB); James Long, Oxton 2006/0105038 A1 5, 2006 Lai et al. (GB); DongWang, Prenton (GB); FOREIGN PATENT DOCUMENTS Andrew James Elphick, Long EP 1598 066 A1 11/2005 Hanborough (GB); John Staniforth, WO WO97, 13503 A1 4f1997 Chippenham (GB); Daniele Chauvin, WO WO 97.35562 A1 10, 1997 WO WO97/38678 A1 10, 1997 Chippenham (GB); Alison Jayne Foster, WO WOOOf 72827 A2 12/2000 Higher Bebington (GB) WO WO 01.00243 A1 1, 2001 WO WOO1 (13889 A1 3, 2001 (73) Assignee: Conopco, Inc., Englewood Cliffs, NJ WO WOO1,39836 A1 6, 2001 (US) WO WOO1,89484 A2 11/2001 WO WO O2/O3955 A1 1, 2002 *) Notice: Subject to anyy disclaimer, the term of this WO WO O2/O98352 A2 12/2002 patent is extended or adjusted under 35 WO WO 2004/091665 A1 10, 2004 U.S.C. 154(b) by 0 days. WO WO 2005,117837 A1 12/2005 OTHER PUBLICATIONS (21) Appl. No.: 12/309,341 Palmierietal. (2001) "Spray-drying as a method for microparticulate controlled release systems preparation: advantages and limits. I. (22) PCT Filed: Jul. 13, 2007 Water-soluable drugs.” Drug Development and Industrial Pharmacy, 27(3): 195-204. (86). PCT No.: PCT/GB2OOTAOSO409 Raffa (2001) “Pharmacology of oral combination analgesics: Ratio nal therapy for pain.” Journal of Clinical Pharmacy and Therapeu S371 (c)(1), tics, 26(4): 257-264. (2), (4) Date: Jan. 13, 2009 Vermeire and Remon (1999) “Compatibility and stability of ternary admixtures of morphine with haloperidol or midazolam and dexamethasone or methylprednisolone.” International Journal of (87) PCT Pub. No.: WO2008/007152 Pharmaceutics, 177(1): 53-67. Weuts et al. (2005) “Study of the physicochemical properties and PCT Pub. Date: Jan. 17, 2008 stability of solid dispersions of loperamide and PEG6000 prepared by spray drying.' European Journal of Pharmaceutics and (65) Prior Publication Data Biopharmaceutics, 59(1): 119-126. US 2009/0325995 A1 Dec. 31, 2009 Primary Examiner Raymond J Henley, III (74) Attorney, Agent, or Firm Ellen Plotkin (30) Foreign Application Priority Data (57) ABSTRACT Jul. 13, 2006 (GB) ................................. O613925.7 Jun. 29, 2007 (WO) ................ PCT/EP2007/056560 A process for the production of a composition comprising a water-insoluble opioid which comprises the steps of: a) pro (51) Int. Cl. viding a mixture comprising: i) a water-insoluble opioid, ii) a A6 IK 3/44 (2006.01) water soluble carrier, and iii) a solvent for each of the opioid A6 IK 3/445 (2006.01) and the carrier, and b) spray-drying the mixture to remove the (52) U.S. Cl. ....................................... 514/282; 514/330 or each solvent and obtain a Substantially solvent-free nano (58) Field of Classification Search ................. 514/282, dispersion of the opioid in the carrier. 514/330 See application file for complete search history. 23 Claims, No Drawings US 7.691,873 B2 1. 2 PREPARATION OF PHARMACEUTICAL ous phase. The beads are formed by dropping the HIPE emul FORMULATIONS sion into a low temperature fluid such as liquid nitrogen, then freeze-drying the particles formed to remove the bulk of the The subject application is a US National Stage of PCT/ aqueous phase and the dispersed phase. This leaves behind GB2007/050409 filed Jul. 13, 2007, and claims priority to and the polymer in the form of a “skeletal structure. The beads benefit of GB application 0613925.7 filed Jul. 13, 2006 and dissolve rapidly in water and have the remarkable property PCT/EP2007/056560 filed Jun. 29, 2007. that a water-insoluble component dispersed in the dispersed phase of the emulsion prior to freezing and drying can also be FIELD OF THE INVENTION dispersed in water on solution of the polymer skeleton of the 10 beads. The present invention relates to improvements relating to WO 2005/01 1636 discloses a non-emulsion based spray pharmaceutical compositions. In particular it relates to phar drying process for forming “solidamorphous dispersions of maceutically active compositions and precursors therefor drugs in polymers. In this method a polymer and a low which fall within the group of so-called “opioids”. solubility drug are dissolved in a solvent and spray-dried to 15 form dispersions in which the drug is mostly present in an BACKGROUND OF THE INVENTION amorphous form rather than in a crystalline form. Unpublished co-pending applications (GB 0501835 of 28 Opioids are therapeutically active agents that have a mor Jan. 2005 and GB 0613925 filed on 13 Jul. 2006) describe phine-like action in the body. Their main use is as analgesics how materials which will form a nano-dispersion in water can for treating moderate to severe pain, including acute pain Such be prepared, preferably by a spray-drying process. In the first as post-operative pain and severe, chronic, disabling pain of of these applications the water insoluble materials is dis terminal conditions such as cancer. They are also frequently Solved in the solvent-phase of an emulsion. In the second, the used as anesthetics for pre-operative sedation. Some opioids water-insoluble materials are dissolved in a mixed solvent are also used to treat diarrhea. In recent years there has been system and co-exist in the same phase as a water-soluble an increased use of opioids in the management of non-malig 25 structuring agent. In both cases the liquid is dried above nant chronic pain following the recognition that dependence ambient temperature (above 20°C.). Such as by spray drying, is rare when the drug is being used for pain relief. to produce particles of the structuring agent, as a carrier, with In addition to analgesia and anaesthesia, opioids are used to the water-insoluble materials dispersed therein. When these treat or prevent cough (in particular codeine, dextromethor particles are placed in water they dissolve, forming a nano phan and hydrocodone), to treat diarrhea, anxiety (in particu 30 dispersion of the water-insoluble material with particles typi lar oxymorphone) and for detoxification and addiction (in cally below 300 nm. This scale is similar to that of virus particular methadone, buprenorphine, naloxone and naltrex particles, and the water-insoluble material behaves as though one). it were in solution. Opioids include: endogenous opioid-peptides such as In the present application the term "ambient temperature' endorphins, dynorphins and enkephalins; opium alkaloids 35 means 20° C. and all percentages are percentages by weight Such as codeine, morphine and thebaine; semisynthetic unless otherwise specified. derivatives such as diacetylmorphine (heroin), dihydroco deine, hydrocodone, hydromorphone, nicomorphine, oxyc BRIEF DESCRIPTION OF THE INVENTION odone and oxymorphone; anilidopiperidines Such as fenta nyl, alphamethylfentanyl, alfentanil, Sufentanil, remifentanil, 40 We have now determined that both the emulsion-based and carfentanyl and ohmefentanyl; phenylpiperidines such as the single-phase method can be used to produce a water nocaine, pethidine (meperidine), ketobemidone, MPPP, allyl soluble, nano-disperse form of an opioid. prodine, prodine and PEPAP; diphenylpropylamine deriva Accordingly, the present invention provides a process for tives such as propoxyphene, dextropropoxyphene, dextro the production of a composition comprising a water-insoluble moramide, bezitramide, piritramide, methadone, levo 45 opioid which comprises the steps of alphacetylmethadol (LAAM), loperamide and a) providing a mixture comprising: diphenoxylate; benzomorphane derivatives Such as pentazo i) a water-insoluble opioid, cine and phenazocine; oripavine derivatives such as ii) a water soluble carrier, and buprenorphine and etorphine; morphinan derivatives such as iii) a solvent for each of the opioid and the carrier; and butorphanol, nalbuphine, levorphanol and levomethorphan; 50 b) spray-drying the mixture to remove the or each solvent and other opioids such as dezocine, lefetamine, tilidine and and obtain a Substantially solvent-free nano-dispersion tramadol. of the opioid in the carrier. Many opioids exhibit low water solubility and are practi The preferred method of particle sizing for the dispersed cally insoluble in water. This hinders their effective use, par products of the present invention employs a dynamic light ticularly for oral delivery in base form and so water soluble 55 scattering instrument (Nano S., manufactured by Malvern salt forms are preferred, such as Sulphates (e.g. morphine Instruments, UK). Specifically, the Malvern Instruments Sulphate), citrates (e.g. fentanyl and Sufentanil Salts), tartrates Nano S uses a red (633 nm) 4 mW Helium-Neon laser to (e.g. hydrocodone bitartrate), phosphates (e.g. codeine salt), illuminate a standard optical quality UV cuvette containing a hydrobromides (e.g. dextrometorphan salt), hydrochlorides Suspension of material. The particle sizes quoted in this appli (e.g. oxycodone, oxymorphone, hydromorphone, buprenor 60 cation may be obtained with that apparatus using the standard phine and tramadol salts). protocol. Particle sizes in solid products are the particle sizes WO 2004/011537 describes the formation of solid, porous inferred from the measurement of the particle size obtained beads comprising a three dimensional open-cell lattice of a by solution of the solid in water and measurement of the water-soluble polymeric material. These are typically “tem particle size. plated materials formed by the removal of both water and a 65 Preferably, the peak diameter of the water-insoluble opioid non-aqueous dispersed phase from a high internal phase is below 1500 nm. More preferably the peak diameter of the emulsion (HIPE) which has a polymer dissolved in the aque water-insoluble opioid is below 1000 nm, most preferably US 7.691,873 B2 3 4 below 800 nm.
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