'US 200600030101 «i» United States « Echanagorria et al. (6!) PHARMACEUTICAL FORMULATIONS FOR THE SAFE ADMINISTRATION OF DRUGS USED IN THE TREATMENT OF DRUG ADDICTION AND PROCESSES FOR OBTAINING THE SAME (75) Inventors: Angel Mateo Echanagorria, Segrite (11); Luigi Brambilla, Lodi (1D), Giovanni Taeehett, Codogno (IT) Correspondence Address: ABELMAN, FRAYNE & SCI 666 Third Ave., 10th Floor New York, NY 10017-5621 (US) WAR, (73) Assignee: (21) Appl. No: 170,314 ISA INSTITUT BIOCHIMIQUE S.A. Patent Application Publication co Pub. No: US 2006/0003010 Al (43) Pub. Date: Jan. 5, 2006 (22) Filed un. 28, 2005 Go Foreign Application Priority Data Jun. 30, 2004 (IT) MI2004A001317 Publication Classification 61) Inc. AGIK '9)14 (2006.01) 62) US. C1, 424/488 6 ABSTRACT The present invention provides safe pharmaceutical formu Iations for drugs used in the treatment of drug addiction, ‘namely formulations which render the abusive administra: ‘ion ofthe drug contained in these formulations not feasible, together with processes for oblaining sl formulations.US 2006/0003010 AI PHARMACEUTICAL FORMULATIONS FOR THE SAFE ADMINISTRATION OF DRUGS USED IN ‘THE TREATMENT OF DRUG ADDICTION AND PROCESSES FOR OBTAINING THE SAME. FIELD OF THE INVENTION [0001] The present invention concerns pharmaceutical formulations for drugs used in the iecatment of drug uddic- tion and processes for obtaining the same. PRIOR ART [0002] Maintenance treatment is widely known throwgh= ‘out the world 38-3 drug addiction treatment, enabling. an, ‘opiate dependent person to lead a normal and productive Iife. Maintenance treatment involves the long term thera- peutic administration of measured doses of replacement hurcotie drugs (preferably methadone, a synthetic narcotic analgesic with long half life) so as to detoxify the addicted individuals fom opiates (often heroin) by stopping or reuc- ing the use ofthis latter, and in particular by stabilizing drug Adicts with the replacement narcotic drug for the entire time necessary for them to re-establish their lives and avoid relapsing into previous deug addition patterns. [0003] With regard wo the specie case of methadone maintenance treatment (MMT), by far the most practised maintenance WorldWide, ts usefulness has been recognised by hhundteds of scientific studies; negative health conse- ‘quences atributable to this maintenance treatment hardly exist, even when continved for more than twenty or thirty years. On the olher hand, maintenance treatment requires Adherence to a very strict administration egimen, necessi- lating the distribution of a moderate numberof daly doses to be taken by the patents as well as rigid patient compli ance with self-administration insirictions. This is because, though replacement narcotic drugs used in maintenance treatments (paticulsely methadone) do not possess intoxi- cating. characteristics’ when administered by prescribed methods, the abusive selfadminstration thereof, specili- cally by intravenous means, resuls instead in a so-called “flash” Le. the euphoric effect caused by the high plasma peaks attained within a short period, this being totally ‘counteepreductive to the aims of the therapy. ‘The risk therefore exists that the patients will aempt to intrave- nosy self-administer the replacement narcotics offered 10 ‘hem (in particular methadone) [0004] Currently, to reduce the possibility of self-admin- ‘stration to 4 minimum, the daily doses destined for ind Vidal consumption within the seope of the methadone ‘maintenance treatment are distributed inthe form of single ‘dose ampoules of syrup containing between 5 mg and 100, img of methacone hydrochloride in 20 ml of liguid per dose. Said syrups have been developed with the purpose of rendering impossible abusive intravenous self-administa- tion, often achieved by dissolving the tablets or emptying (ollowed by dissolving) the contents of the formerly used ‘capsules, The syrups in current use have the advantage of being too dilute for abusive intravenous sef-administration and can be charged by the manufacturer with large quantities ‘of water-soluble excipients, such as sugars, thus rendering ‘iffcult any attemps by the deug addict to separate mothae ‘done hydrochloride from the rest of the dilute formulation, Given the lange volumes of daly doses, said syrups ae also Jan. 5, 2006 secure from another aspect, in that they are unsuitable for husive administration to third parties without theis knowl- edge, ie, in cases whece criminal individuals attempt 10 coraly adminiser methadone preparations, previously pro- ‘cured on the Black market, 10. unknowing_ persons, for example by adding them to « drink with the iit intent of| ‘drugging their victims. Whilst the curently used syeups are cllective for the aforementioned purposes and have been established on the market for decides as prefered fornni- lations for precisely these reasons, ther handling during legitimate distribution is burdensome owing to the large volumes involved. This is because the distribution centres necessary fr the maintenance Ireatment of individuals being cared forgiven the unstable slat of the patients and the ever present consequent risk of the patients relapsing into drug addiction (and their consequent susceptibility 10 the undertaking of unlawful acts often associated with their illness)—are guarded and protected with a level of security ‘comparable that of banks. Consequently, provision forthe volumes required for string doses for local distribution poses the not inconsiderable problem of expense, when ‘considering tht the volume involved ia legitimate disteibu- tion in aly alone of the formulations provided by a single radhcer amounts 10 20 milion doses per year. This signilies 5 massive committed handling of materials already at the very production stage and the distibution centre supply stage, thus produetion aod supply having in their turn 10 satisfy the same very high standards of security adopted at the final delivery stage, ie. safety standards which require elective measures against raids, burglary and thelt of ans. acted narcoties, whether by outsiders or members of stall entrusted with Carying out of the necessary duties [0005] As a consequence, in view of the difeutes found ‘with conventional symips, and in particular their onerous legitimate distripution, often a burden on public expenditure, the nced exists to provide new safe pharmaccutical compo” sitions for drugs used inthe treatment of drug action (so called replacement narcotis), in pasicular methadone and/ for its salts, more particusey is hydrochlocide, as well as procedures for oblaining these formulations. In particular the requirement exists for new formulations that are hard 10 abuse. dilicul to tamper within such a way as tobe able to be sell administered intravenously. [0006] Advantageously, said new formulations. shou! also be hard o administer orally to unknowing thcd paris, ‘who are not drug dependent, by criminal individuals who intend to exploit narcotic drug elfets ia order to commit further illct acts t0 the detriment of unknowing third partes. On the other hand, the new formulations. must be tsi to handle than those used heretofore, thus facilitating theie legitimate distribution within the soope ofthe thecapy [0007] The object of the present invention is therefore to satisfy these and other needs which will become more apparent from the detailed deseription presented hereinafer ‘SUMMARY [0008] In accordance with the present invention, the dis advantages ofthe prior art have been found 10 be overcome by providing pharmaceutical compositions of drugs used in drug addiction therapy, such as methadone andior its sll, preferably is hydrochloride, in «uniform sol-gel matrix to be taken orally without chewing, whereby the uniforUS 2006/0003010 AI matrix has the shape and size of a pill or capsule, said pharmaceutical compositions comprising in the dry’ sate 30-75%, preferably 405-655, by weight of bovine, por ‘ine, chicken, turkey or fish peli, the drug used in the drug addiction therapy ina pharmaceutically effective concentra tion for this purpose, preferably 015%-20% by weight, characterised by containing in the dry state 104%-60% by ‘weight preferably 25-45% by weight of an adjuvant ‘excipient chesen from the group consisting of polyhydroxy and polyether alcohols, preferably chosen from the group ‘consisting of glycerol, sorbitol’srbitans, 1,2-prepylene gly ‘ol, polyethylene glycols, mannitol or mixtures thereof and 19-10% by weight of water. Among the adjuvant exeipien’s particularly preferred are glyeerol and 1,2-propylene glycol DETAILED DESCRIPTION OF THE INVENTION [0009] In particular the new pharmaccutical composition ‘described herein of drugs used in drug aldition therapy (Le. socalled replacement cups), in particular methadone and its sals, preferably its hydrochloride, in a uniform softgel matrix to be taken orally without chewing, (where the "uniform matex consists of thee dimensional body having the shape and size of @ normal pill or capsule intcoded for ‘oral consumption), said matrix comprising, i the dry sate, 30%-75% (preferably 40%%-65%) by weight of bovine, por ‘ine, chicken, turkey or fish gelatin, characterised by con- laining, inthe dry slate, 10-60% by weight (preferably 25%¢-45% by weight) of an adjuvant excipient chosen from the group consisting of polyhydroxy and polyether alcobols, preferably chosen from the group consisting of glycerol, sorbitolsorbitans, 1,2-propylene glycol, polyethylene gly ‘ols, mannitol or mixtures thereat and 1%-10% by weight of water, has been found to possess considerable advantages ‘compared to normal administration of known pharmaceati- ‘al forms (capsules with liquid or solid content, oF pills) ‘which instead lend themselves to abusive administration, One of the characteristics of the new pharmaceutical for- iulation described herein is the fact that in said new formulations, the drug used inthe drug addiction therapy, particular methadone hydrochloride, is eniely gelatined, {e,uniformly miero-ineoeporated within the soft-gel matrix, [0010] The now formulations in woifoem soft-gel matrices, ‘when compared withthe previously known capsules or pill, ‘do-not Tend themselves to sbusive selt-administering of the active principle contained therein, other than by slow and ‘ery difficult dissolution—assised in any ease by heating and vigorous mechanical agitation—of the sofl-gel matrix Subjected to the atempted misuse, in comparatively large volumes of water, making it impossible to attain the eon: ‘centration needed to achieve euphoria on ther entry directly into the circulation by intavenous means, Moreover, caol- ing these solutions, achieved only with the greatest difi- culty, tends fo restore the gel state Which isa characteristic ‘ofthe staring formulation, and this then renders further not feasible attempts to sel-administer intravenously [0011] These characteristics of the new softgel matix ormullations deseribed herein make its abusive adminis tion to unknowing third parties equally difficult. To deter such illicit practices, colorants andjor substances with an unpleasant flavouriodovr ean be incorporated [0012] In addition to rendering not feasible intravenous abusive selfadministering and the illicit administration to Jan. 5, 2006 thied pasties, the new formulations are also more compact and easy to handle than the syrup doses previously used ia this fel, resulting in a considerable saving along the entre supply chain of legitimate distribution, [0013] Certain characteristics of the pharmaceutical for- ‘ulation will be examined hereinafter. [0014] The term “dry state™ means preferably the state attained by the pharmaceutical formulation after dkying at a femperature between 20° C24” C. and 20% relative humia- ity with continuous change of the surrounding air until a ‘constant weight is achieved, ic until two weighings under taken 24 hours apart do not difer by more than 1%. [0015] The wniformn sol-gel matrices of the presen inven- ‘ion contain a drug used in the drug addiction therapy, preferably methadone or its salt, in particular its hydrochlo- ride, in pharmaceutically acceptable quantity, preferably (0.56.20% by weight of the deied matsx. In the softgc] ‘mateiees ofthe present invention itis particularly preferred that the content of drug used in the drug addiction therapy is 05-85% by weigh. [0016] I the case of methadone hydrochloride, the abso- Ite doses incorporated in a single soft-gel matrix in accor. dance withthe prescat invention vary between I mg ad 150 ‘mg, preferably between 5 mg and 100) mg, according to the daily dose prescribed for the scope of the maintenance therapy. [0017] Optionally, the uniform sofl-gel matrices of the preseal invention cam possess enteric layers on their exterior ormlated in accordance with known techniques in onder to substantially degrade inthe smal intestine [0018] In adttion 1 (or instead of) possible enteric layers, the uniform softgel matrices of the present invention can also have optional further external layers to facilitate inges- tion, i. being composed of excipients which reduce friction between the matrix and the oesophagus of the patent [0019] The materials used for obtaining uniform sof-gel ‘matrices ofthe resent invention are the so-called type Aor type B gelatins of bovine and porcine origin, or of avian (Chicken, turkey) of fish origin normally used in the ps ‘maceutical art Tor the production of capsules. In uniform softgel matrices of the present invention, the yelains are present in the dried produet from 30M 754 by weight Preferably the gelatins are present from 40%-65% by weight, A representative but not exclusive example of a gelatin usable for the scope of the preseot invention is a gelatin with the following amino seid profile: Glycine: 265%, Alanine: 9%, Isoleucine: 1.5%, Leucine: 34%, Valine: 2.5%, Serine: 3.5%, Threonine: 2%, Proline: 16%, Pheny lalaniae: 24%, Tyrosine: 08%, Tryptophan: Of, Merion. ine: 0.8%, Histidine: 0.8%, Arginine: 9%, Lysine: 5%, Aspartic acid: 6%, Glutamie acid: 11%, Hydroxyproline: 135% and Hydroxglysine: 1%. Preferubly, the gel usable Within the scope of the present invention have a particle size distribution between 4 and 100 mesh and a pl between 3 and 10, [0020] The adjuvant excipients usable for obtaining the ‘inifoem soft-gel matrices of the present invention are chosen Irom the group consisting of polyhydcoxy and polyether alcohols, preferably chosen from the group consisting af slyeerol, sorbitolsorbitans, 1,2-propylene glycol, polyeth-