WO2013171146A1 - Film oral contenant un résinate d'opiate à libération entérique - Google Patents

Film oral contenant un résinate d'opiate à libération entérique Download PDF

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Publication number
WO2013171146A1
WO2013171146A1 PCT/EP2013/059784 EP2013059784W WO2013171146A1 WO 2013171146 A1 WO2013171146 A1 WO 2013171146A1 EP 2013059784 W EP2013059784 W EP 2013059784W WO 2013171146 A1 WO2013171146 A1 WO 2013171146A1
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Prior art keywords
release
film dosage
oral film
controlled
oral
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PCT/EP2013/059784
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English (en)
Inventor
Michael Hsin Chwen LI
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Lts Lohmann Therapie-Systeme Ag
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Publication of WO2013171146A1 publication Critical patent/WO2013171146A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • the present invention relates to muco-adhered films providing controlled enteric release of an opiate from a cation-exchange complex.
  • the present invention more specifically relates to muco-adhered films providing a controlled enteric release of a cation exchange resin-bound opioid agonist, present in therapeutic amounts, and an opioid antagonist, present at a sub-therapeutic level.
  • the search for a safe, orally ingested opiate analgesic is one of the oldest challenges known in medicinal chemistry. Opiates are incredibly well known for the treatment of acute or chronic severe pain, and are arguably one of the oldest drugs known to man.
  • the market for chronic pain treatment is a substantial one, including the treatment of chronic pain associated with fibromyalgia, arthritis, sports injuries and malignancies.
  • Current pain management protocols have resulted in a multi-billion dollar prescription market, with a pain management drug, hydrocodone/APAP, ranked number one in prescription drug sales in 2010.
  • Products are well known for treating narcotic addiction. Individuals addicted to narcotics may suffer from a serious dependence, resulting in potentially dangerous withdrawal.
  • One well known method by which to treat narcotic addiction is to provide a reduced amount of opiate, in an amount sufficient to satisfy the addict's urge for the narcotic, but not in an amount sufficient to induce euphoria, commonly referred to as a "high.”
  • a product may include a particularly potent opiate, buprenorphine, along with an antagonist, naloxone, providing both a reduced euphoric effect and potentially avoiding opiate extraction (and subsequent abuse) by addicts.
  • the narcotic antagonist binds to a receptor in the brain to block the receptor, thus reducing the effect of the opiate.
  • a product was initially developed as a tablet.
  • medicaments containing buprenorphine in tablet form have the potential for abuse.
  • Films were subsequently developed that provide direct buccal absorption of the buprenorphine in a form that could not be easily removed from the mouth once administered, thereby retarding abuse.
  • mucoadhesive film is described in United States Patent Application Publication No. 2011/0033541, hereby incorporated by reference herein.
  • the present invention thus provides a longer acting opiate drug forms for the treatment of addiction, acute pain and chronic pain.
  • inventive oral films dosages include at least one controlled-release layer formed from a controlled-release composition imparting intestinal release of a therapeutically effective amount of an opioid agonist salt, along with a muco-adhesive layer.
  • the controlled-release composition includes at least one controlled- release matrix polymer and at least one enteric-resinate dispersed within the matrix polymer.
  • the enteric-release resinate includes at least one cation exchange resin with at least one opioid agonist salt bound therein.
  • the controlled-release composition further incorporates a pH adjuster in an amount effective to adjust the composition to a pH of about 2.0 to 3.0 pH units below the pKa of the opioid agonist salt to bind the opioid to the cation exchange resin.
  • the inventive oral films further provide either buccal or intestinal release of a clinically effective amount of at least one opioid antagonist or pharmaceutically acceptable salt thereof.
  • the opioid antagonist in the form of its pharmaceutically acceptable salt, may likewise be bound within one or more cation exchange resins in a clinically effective amount.
  • the opioid antagonist is absorbed bucally, the opioid antagonist and/or its
  • the oral film dosage or controlled-release composition or layer further optionally includes one or more additives, such as additives selected from one or more of taste masking agents, emulsifiers, plasticizers, colorants, antioxidants, microbial preservatives and permeation enhancers.
  • the edible oral film dosages include buprenorphine as the opioid agonist along with naloxone as the opioid antagonist.
  • inventive aspects include methods by which to form the inventive oral film dosages, as well as their subsequent administration.
  • Figure 1 is a schematic cross-sectional view of an exemplary bi-layered inventive oral film dosage.
  • the present invention generally relates to the treatment of opioid dependence or chronic or acute pain in a patient using a dosage form that also hinders misuse of the narcotic.
  • the present invention provides a method of treating chronic/acute pain or narcotic dependence by administering an orally dissolvable, muco-adhesive film dosage (also referred to herein as an oral wafer) providing a bioequivalent effect to the known opiate tablets and films, particularly SUBOXONE ® tablets and films, but with enteric delivery of opioid agonist to provide a more prolonged efficacy.
  • the inventive film dosages further provides buccal adhesion to the user's mouth, rendering it difficult to remove after administration, and includes opiate antagonist, thereby avoiding illicit opiate extraction.
  • the inventive oral film dosage (1) generally includes at least one controlled-release layer (2) imparting enteric release of a clinically effective, i.e. therapeutic, amount of an opioid agonist, along with a muco-adhesive layer (5).
  • the composition used to form the controlled- release layer i.e. the controlled-release composition
  • the controlled-release layer generally includes at least one controlled-release matrix polymer (3) and enteric-release resinate (4) dispersed therein.
  • the enteric-release resinate refers to cation exchange resin having an opioid agonist cation salt as an active ingredient bound therein.
  • the controlled-release composition further comprises a pH adjuster in an amount effective to adjust the composition to a pH of about 2.0 to 3.0 pH units below the pKa of the opioid agonist salt to ensure that the opioid agonist salt bonds with or binds to the cation exchange resin.
  • the inventive oral film dosage further includes a clinically effective, i.e. sub-therapeutic, amount of an opioid antagonist as an active ingredient that may be included in either the muco-adhesive layer (5) and/or the controlled-release layer (2), including the enteric-release resinate (4).
  • the oral film dosage is designed to disintegrate when applied to the oral cavity to release the opiate-containing enteric-release resinate, which is then swallowed to be absorbed within the intestines, along with the opiate antagonist, which may be absorbed either bucally or enterically.
  • the inventive oral film strip disperses easily in the saliva of the oral cavity without the need for further oral liquids to release the enteric-release resinate so that the active ingredients may be absorbed within the patient's intestines.
  • the saliva dispersible and disintegrable polymers used to form the matrix of the controlled release layer(s) may be any known monographed film-forming material known in the art for use in flat-shaped or wafer-shaped administration forms for application to or in the oral region or on the mucous membranes of the mouth.
  • the inventive oral film dosages generally comprise at least one acetone-soluble, alcohol-soluble and/or water-soluble and/or water-dispersible film- forming polymer, particularly at least one saliva-soluble and/or saliva- dispersible film-forming polymer, that is capable of forming a suitably strong film upon casting in a pharmacologically acceptable solvent.
  • the controlled-release matrix polymer may thus be formed from any water, acetone and/or alcohol soluble or swellable pharmaceutical grade polymer that is either orally dissolvable/dispersible or orally consumable with gastric dissolution or swelling.
  • the controlled release matrix polymer may also be formed from a combination of two or more such water, acetone and alcohol soluble or swellable polymers.
  • the controlled-release matrix polymer provides cohesion to the dosage form during manufacture, storage and the like, but is sufficiently dissolved, swollen or disintegrated to release the enteric-release resinate containing the opioid agonist for enteric absorption subsequent to its administration.
  • Non-limiting exemplary polymers suitable for use as the controlled-release matrix polymer include one or more of cellulose and/or derivatives thereof; synthetic or natural gum, acrylic polymer and/or copolymer thereof, polyalkylene oxide, polyalkylene glycol, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, carrageanan, alginic acid and/or salts thereof, carboxyvinyl polymers, pectin and/or derivatives thereof, xanthan gum and/or derivatives thereof, and starch and/or derivatives thereof.
  • synthetic or natural gum acrylic polymer and/or copolymer thereof, polyalkylene oxide, polyalkylene glycol, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, carrageanan, alginic acid and/or salts thereof, carboxyvinyl polymers, pectin and/or derivatives thereof, xanthan gum and/or derivatives thereof, and starch and/or derivatives thereof.
  • Exemplary cellulose derivatives suitable for use in forming the inventive oral film strips include methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and mixtures thereof.
  • the inventive oral film strips are formed from a mixture of sodium carboxymethylcellulose or hydroxypropylmethyl cellulose and/or hydroxypropylcellulose.
  • Sodium carboxymethylcellulose commonly referred to as cellulose gum, is commercially available from any of a number of suppliers, including as AQUALON ® CMC-7LF sodium carboxymethyl cellulose (“CMC”) from Ashland Inc., of Covington, Kentucky.
  • HPMC Hydroxypropylmethyl cellulose
  • HPMC Hydroxypropylmethyl cellulose
  • METHOCEL ® from Dow Chemical Company, Midland, Michigan
  • BENECEL ® from Ashland, Inc. of Covington, Kentucky
  • PHARMACOAT ® from Shin-Etsu Chemical Col, Ltd. of Tokyo, Japan
  • METOLOSE also from Shin Etsu Chemical Co. Ltd of Tokyo
  • Hydroxypropylcellulose is commercially available as KLUCEL ® from Hercules Incorporated, Wilmington, Delaware.
  • the inventive oral film dosages incorporate a controlled-release matrix based on a film-forming mixture containing both lower and higher viscosity cellulose derivatives.
  • the inventive oral film strips may incorporate a mixture of lower and higher viscosity HPMCs, for example.
  • An exemplary range for the lower viscosity cellulose derivatives is from about 1.5 to 25 mPas, such as about 2 to 20 mPas, particularly about 3 mPas.
  • An exemplary range for the higher viscosity cellulose derivative is from about greater than 25 to 100 mPas, such as from about 40 to 80 mPas, particularly about 50 mPas.
  • HPMC having a viscosity of 3 mPas is commercially available as PHARMACOAT ® 603 and HPMC having a viscosity of 50 is commercially available as METOLOSE ® 60 SH50.
  • the lower viscosity cellulose derivative is generally present within the film-forming mixture in a greater amount than the higher viscosity cellulose derivative.
  • the lower viscosity cellulose derivative may be present within the film-forming mixture in any effective weight ratio in comparison to the higher viscosity cellulose derivative, such as a weight ratio ranging from about 1.5 : 1 to 6: 1, particularly about 2.0 : 1 to 4 : 1, such as about 3 : 1 (lower viscosity cellulose derivative : higher viscosity cellulose derivative).
  • a mixture of sodium carboxymethylcellulose and hydroxypropylmethyl cellulose is used as the film-forming material or matrix, as this mixture has been determined to have both excellent film forming capabilities, oral film strip handling characteristics, beneficial mouth-feel, as well as a fast dissolution time.
  • the particular ratio of sodium carboxymethylcellulose to hydroxypropylmethyl cellulose is chosen to yield the desirable dissolution times and mouth-feel for a reasonably thin film and to further impart acceptable product handling characteristics.
  • Exemplary synthetic or natural gums for use as the controlled-release matrix polymer include xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, locust bean gum or mixtures thereof.
  • Acceptable starches for use as the inventive controlled-release matrix polymer include bean starch, pea starch or mixtures thereof.
  • Exemplary acrylic polymer and/or copolymers that may be used as the controlled- release matrix polymer include methacrylic acid polymer, methacrylic acid copolymer, acrylic acid polymers, acrylic acid copolymers, polyacrylamide or mixtures thereof.
  • the controlled-release matrix polymer is present within the controlled-release layer in an amount that typically ranges from about 30 to 70 wt %, such as from about 40 to 60 wt% and particularly from about 45 to 55 wt %, based upon the weight of controlled-release layer.
  • controlled-release layer refers to the controlled-release layer subsequent to drying, i.e.
  • controlled-release layer composition refers to a mixture that includes the controlled-release matrix polymer, the enteric-release resinate, optional additives and solvent, i.e. to the mixture prior to drying, unless indicated to the contrary.
  • the muco-adhesive layer matrix may likewise be formed from any muco-adhesive polymer, copolymer and/or interpolymer indicated to be acceptable within the U.S.
  • the muco-adhesive layer is formulated to provide sufficient bioadhesion to avoid easy removal, advantageously forming a gel-like structure following administration.
  • Exemplary mucoadhesive polymers, copolymers and/or interpolymers include one or more of synthetic polymers, such as edible silicone, polyacrylic acids, cross-linked acrylic acid polymers, polyvinyl pyrrolidone, poloxamer; natural polymers, such as chitosan and sodium alginate; and/or regenerated polymers, such as sodium carboxymethyl cellulose, methyl cellulose or hydroxypropyl cellulose.
  • Particularly advantageous polymers include polymers of cross-linked acrylic acid are commercially available as CARBOPOL ® polymer and NONEON ⁇ polymer, both from Lubrizol Corp. of Cleveland, OH.
  • CARBOPOIT polymers are high molecular weight polymers of acrylic acid chemically crosslinked with polyalkenyl alcohol
  • NOVEON® polymers are high molecular weight polymers of acrylic acid chemically crosslinked with divinyl glycol.
  • the mucoadhesive polymer may be either lightly or highly crosslinked.
  • the foregoing mucoadhesive polymers may further include free thiol groups, such as iminothiolane, cysteine, homocysteine, thiogycolic acid, and thioethylamidine.
  • the muco-adhesive layer typically dissolves or degrades moderately slowly over time, such as a period ranging from 1 minute up to several hours, particularly from about 1 to 3 minutes.
  • Exemplary biodegradable polymers include blends of polycaprolactone and aliphatic polyanhydride.
  • the muco-adhesive matrix polymer is present within the muco-adhesive layer in an amount that typically ranges from about 40 to 100 wt %, such as from about 40 to 80 wt% and particularly from about 65 to 75 wt %, based upon the weight of muco-adhesive layer.
  • the term "muco-adhesive layer" as used herein refers to the mucoadhesive layer subsequent to drying, i.e. upon removal of a significant amount (if not all) of the solvent used in forming the muco-adhesive layer, unless indicated otherwise.
  • muco-adhesive layer composition refers to a mixture that includes the muco- adhesive matrix polymer, optional opioid antagonist, optional excipients/additives and solvent, i.e. to the mixture prior to drying, unless indicated to the contrary.
  • the present dosage form is suitable for the extended release of any opioid agonist having cationic functionality indicated to be acceptable within the U.S.
  • Non-limiting exemplary opioid agonists that may be included within the controlled-release composition include one or more of alfentanil, allylprodine, alphaprodine, amfepramone, amphetamine, amphetaminil, anileridine, apocodeine, apomorphine, asimadoline, axomadol, benzylmorphine, bezitramide, bremazocine, brifentanil, buprenorphine, , butorphanol, carfentanil, clonitazene , codeine, cyclazocine, cyclorphan, cyprenorphine, cyprodime, deltorphin, desomorpine,
  • fencamfamine fenethylline, fenproporex, fentanyl, a-methylfentanyl, beta-funaltrexamine, P-hydroxy-3-methylfentanyl, heroin, hydrocodone, hydromorphone, hydromorphodone, hydroxymethylmorphinan, hydroxypethidine, isomethadone, ketobemidone, kyotorphin, levo-a-acetylmethadol , levacetylmethadol, levallorphan, levomethadone, levomethadyl acetate, levallorphan, levorphanol, levophenacylmorphan, lofentanil, Lofexidine, loperamide, malbuphine, mazindol, mefenorex, meperidine, meprobamate, meptazinol, metazocine, methadone, metopon, methyldihydromorphine, methyldihydromorphinone, me
  • the opioid agonist is present in the form of its cation salt, including the cation salt of the opioid in the form of a prodrug, ester, analog, derivative, solvate, complex, polymorph, hydrate, racemate or as an individual diastereoisomers and/or their enantiomeric isomers and their respective glucuronide dervivative.
  • the opioid agonist is a pharmaceutically acceptable cation salt of buprenorphine, particularly the hydrochloride salt of buprenorphine
  • the term "agonist" as used herein generally refers to the pharmaceutically acceptable cation salt of the opioid agonist unless stated to the contrary.
  • the opioid agonist is present within the controlled release composition in a therapeutically effective amount.
  • opioid agonist therapeutically effective amounts for inventive dosages intended for the treatment of opiate addiction include greater than 2 milligrams; such as from about 2 mg to about 16 mg per dosage, particularly from about 4 mg to about 12 mg per dosage.
  • Exemplary opioid agonist therapeutically effective amounts for dosages intended to control acute pain in non-opioid tolerant individuals range from about 100 to 400 micrograms, such as approximately 200 micrograms.
  • Exemplary opioid agonist therapeutically effective amounts for dosages intended to control chronic pain ranges from about 20 to 70 micrograms per hour per dosage.
  • the opioid agonist is thus generally present within the controlled release layer in exemplary amounts ranging from about 1 to 30 wt %, such as from about 8 to 35 wt %, particularly 16 to 18 wt %, based upon the weight of the controlled release layer.
  • Non-limiting exemplary opioid antagonists that may be included within the controlled-release composition include one or more of alazocine, amiphenazole, butorphanol, chlomaltrexamine, clocinnamox, cyclazacine, cyclazocine, cyclorphan, cyprenorphine, diprenorphine, etazocine, ⁇ -funaltrexamine, , levallorphan, meptazinol, metazocine, nadide, nalbuphine, nalide, nalmefene , nalmefendiprenorphine, nalmexone, nalorphine, , nalorphine dinicotinate, naloxone, 6-amino-naloxone, N- methylna
  • the opioid antagonist may be present in the form of its free base, or in the form of a cation salt, prodrug, ester, analog, derivative, solvate, complex, polymorph, hydrate, racemate or as an individual diastereoisomers and/or their enantiomeric isomers and their respective glucuronide dervivative.
  • the opioid antagonist is naloxone and/or a pharmaceutically acceptable cation salt thereof, particularly as naloxone hydrochloride.
  • the term "antagonist" as used herein includes both the agonist and/or its pharmaceutically acceptable salts unless stated to the contrary.
  • the opioid antagonist is generally present within the controlled release composition in a clinically effective amount.
  • clinically effective amount of opiod antagonist refers to a subtherapeutic amount of opiod antagonist when administered orally, i.e. the opiod antagonist will elicit no significant therapeutic effect via the oral route.
  • clinically effective amount of opioid antagonist more specifically means the minimum amount of opiod antagonist possible or conventionally used to effectively deter misuse of the inventive film dosages, e.g. by active ingredient extraction and subsequent intravenous injection.
  • the term "clinically effective amount of opioid antagonist” as used herein refers to an orally ineffective dose but intravenously effective dose of opioid antagonist sufficient to deter abuse of the inventive film dosages.
  • the opioid antagonist is generally present in significantly lower amounts than the opioid agonist.
  • Conventional dosages may include the opioid antagonist in a weight ratio of about 6:1 to 2:1 agonist to antagonist, such as a weight ratio of about 4:1 (agonis antagonist).
  • Exemplary opioid antagonist clinically effective amounts within the inventive dosages intended to treat opiate addiction may include greater than 0.5 milligrams antagonist per dosage, such as from about 0.5 to about 4 mg per dosage; particularly from about 1 mg to about 3 mg per dosage.
  • Exemplary opioid antagonist clinically effective amounts for dosages intended to control acute pain in non-opioid tolerant individuals ranges from about 25 to 100 micrograms per dosage, such as approximately 50 micrograms per dosage.
  • Exemplary opioid antagonist clinically effective amounts for dosages intended to control chronic pain ranges from about 5 to 17.5 micrograms per hour per dosage.
  • inventive dosages administered solely within a medical facility may contain no opioid antagonist.
  • the opioid antagonist may be present within any of one or more of the inventive film layers, i.e. in either the muco-adhesive layer or the controlled-release layer.
  • Advantageous embodiments in which the opioid antagonist is present within the muco-adhesive layer provide buccal absorption of the opioid antagonist.
  • the opioid antagonist is present within the controlled-release layer, it may be present either within the drug resinate (i.e. as an active ingredient) in its salt form or within the controlled-release polymer matrix.
  • the opioid antagonist is present within the muco-adhesive layer, it is typically present in exemplary amounts ranging from about 1 to 20 wt %, such as from about 5 to 15 wt %, particularly 9 to 11 wt %, based upon the weight of the muco-adhesive layer.
  • the inventive oral film dosages advantageously provide a bioequivalent result, e.g. a bioequivalent release, to commercially available SUBOXONE ® products, particularly for advantageous embodiments in which the agonist is buprenorphine and the antagonist is naloxone.
  • inventive oral film dosages thus advantageously exhibit an AUC value so as to provide a bioequivalent result to a commercially available SUBOXONE ® tablet.
  • the oral film dosage composition may be prepared to provide a Cmax and/or AUCinf value for each of the agonist and antagonist that provides a bioequivalent release to a commercially available SUBOXONE tablet, i.e. providing 80% to 125 % of the Cmax and AUC values for a given active within a commercial product.
  • the oral film dosages may be tailored in advantageous embodiments to provide an in vivo plasma profile having an agonist Cmax ranging from 0.624 to 0.975 ng/ml, such as an agonist Cmax of about 6.4 ng/ml, and an agonist AUC value of 5.431 to 8.486 hr*ng/ml, with a corresponding antagonist Cmax of less than about 400 pg/ml and antagonist AUCinf value of less than about 1030 hr*pg/ml.
  • an agonist Cmax ranging from 0.624 to 0.975 ng/ml, such as an agonist Cmax of about 6.4 ng/ml, and an agonist AUC value of 5.431 to 8.486 hr*ng/ml, with a corresponding antagonist Cmax of less than about 400 pg/ml and antagonist AUCinf value of less than about 1030 hr*pg/ml.
  • the opioid agonist, and optionally the opiod antagonist is present within an enteric release resinate suspended in the controlled-release matrix polymer.
  • the enteric-release resinate is cation exchange resin having at least the opiod agonist bound therein, thereby protecting the opioid agonist (and optionally the opiod antagonist) until it is released from the enteric-release resinate, e.g. within the intestine.
  • the opioid agonsist (and optionally the opioid antagonist) is initially dissolved within a pH adjusted solvent, such as water, to which the cation exchange resin, optional auxiliaries, and enteric-release polymer are subsequently added.
  • the same cation exchange resin or cation exchange resin blend is used to bind both the opioid agonist and optional opioid antagonist.
  • the opioid agonist and optional opioid antagonist may be bound using different cation exchange polymers or cation exhchange polymer blends.
  • Cation exchange resins suitable for use in the enteric-release resinate binding at least the opioid agonist include any cation exchange resin indicated to be acceptable within the U.S. Pharmacopeia/National Formulary for the gastric and/or enteric delivery of active ingredients.
  • Ion exchange resins also referred to as ion exchange polymers, are well known in the art as insoluble matrices (or support structures), normally in the form of small beads formed from organic polymer or a powder formed therefrom. Ion exchange resins have a highly developed structure of pores containing sites with easily trapped and released ions.
  • Cation exchange resins are ion exchange resins having negatively charged radicals attached to its' polymer chain that can attract and hold active ingredient cations present in a surrounding solution.
  • Cation exchange resins are generally categorized as either strong acid cation exchange resins or weak acid cation exchange resins. Strong acid cation exchange resins typically contain sulfonic or phosphonic acid functionalities, while weak acid cation exchange resins typically contain carboxylic acid or phenolic acid groups.
  • An exemplary strong acid cation exchange resin is formed from a styrene-divinylbenzene polymer matrix having a strong acid functionality of - S0 3 " , commercially available as AMBERLITE ® IRP69 (compendial name sodium polystyrene sulfonate) from Rohm and Haas, a subsidiary of Dow Chemical, Midland, Michigan.
  • An exemplary weak acid cation exchange resin is formed from a methacrylic acid and divinylbenzene polymer matrix having a weak acid functionality of
  • AMBERLITE ® IRP64 (compendial name polacrilex resin) from Rohm and Haas, a subsidiary of Dow Chemical, Midland, Michigan.
  • the term enteric-release resinate includes cation exchange polymers releasing active ingredient in fluids below a pH of about 5, e.g. polymers soluble at the pH of stomach fluids, solely for ease of discussion, as these cation exchange resins are generally used as a component within an overall enteric-release polymer blend intended to release at least the majority of the active ingredients within the intestines.
  • the cation exchange resin is a blend or mixture, such as a blend or mixture containing one or more cation exchange resins that release the active ingredient at a lower pH and one or more cation exchange resins that release the active ingredient at a higher pH.
  • the cation exchange resin releasing active ingredient at a lower pH may release active ingredient in fluids below a pH of about 5, such as a pH of less than about 4.5, particularly a pH ranging from about 1 to 2 (e.g. the pH of stomach fluids).
  • the cation exchange resin releasing active ingredient at higher pHs may release active ingredieint in fluids having pH of greater than about 5.5, such as a pH of greater than about 6.0, and particularly a pH of greater than about 7.0 up to about 8.5, (e.g. the pH of intestinal fluids).
  • the cation exchange resin releasing at a lower pH delivers active ingredient within the stomach fluid, thereby protecting the active ingredients during manufacture and ingestion and providing an early onset of relief via rapid release.
  • the cation exchange resin releasing at a higher pH then releases a portion of the active ingredient, such as majority, within the intestines providing more prolonged release.
  • Cation exchange resins suitable for releasing at a lower pH, and hence more rapid release include weak acid cation exchange resins.
  • lower amounts of crosslinking and small particle size favor more rapid delivery.
  • Strong acid cation exchange resins are expected to limit ion exchange within the gastric milieu, thereby providing delayed, i.e. enteric, release.
  • higher crossliriking and larger particle size favors more prolonged release.
  • Exemplary weight ratios of blends containing cation exchange resin releasing at a lower pH and cation exchange resin releasing at a higher pH typically range from 1 : 10 to 10:1 (weight of cation exchange resin releasing at lower pH : weight of cation exchange resin releasing at a higher pH), such as about 1 :5 to 5 : 1 , and particularly 1:1.
  • Preferred cation exchange resins include, but are not limited to, sytrenic strongly acidic cation exchange resins with sulfonic or phosphonic acid funcitonalities having a weight capacity of 0.1 to 8 meq/g; and styrenic weakly acidic cation exchange resins with carboxylic or phenolic acid functionalities having a weight capacity of 0.1 to 8.5 meq/g; and acrylic or methacrylic weakly acidic cation exchange resins with a carboxylic or phenolic acid functionality with a weight capacity of 0.1 to 14 meq/g.
  • Cation exchange resins include, but are not limited to, styrenic weakly acidic cation exchange resin with a phenolic functionality with a weight capacity of 0.1 to 8.5 meq/g; and a styrenic strongly acidic cation exchange resin with a sulfonic acid functionality with a weight capacity of 0.1 to 8 meq/g, or a methacrylic weakly acidic cation exchange resin with a carboxylic acid functionality with a weight capacity of 0.1 to 12 meq/g.
  • Ion exchange resins may have a moisture content ranging between 0 % and the water retention capacity of the resin, and may further be in powder or whole bead form. Strongly acidic and weakly acidic cation exchange resins useful in the invention may be in the acid form or salt form or partial salt form.
  • enteric-release polymers suitable for use in coating/encapsulating the cation exchange resin include one or more of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, and polymethacrylate copolymer.
  • the controlled release layer may additionally include cation exchange resin that does not contain active ingredient, i.e. cation exchange resin that is not loaded with active ingredient, to provide for even more constant release of the active ingredient over a prolonged time.
  • cation exchange resin that does not contain active ingredient
  • Exemplary weight ratios of loaded to unloaded to loaded resin ranges from 3 : 1 to 1:1, such as 1.5 : 1.
  • the cation exchange resin may be present within the controlled release layer in exemplary amounts ranging from about 10 to 20 wt %, such as 12 to 15 wt %, based upon the weight of the controlled release layer.
  • the enteric-release resinate is typically in the form of either powder or whole beads that may advantageously have a target size of up to 2.5 mm (i.e. average diameter) with no more than 10 percent variation over this size, to a maximum size of 2.8 mm, in conformance with FDA general recommendations.
  • the FDA has indicated that beads having the foregoing size allow for patient swallowing without stimulating the urge to chew.
  • the enteric-release resinate and/or cation exchange resin powder or beads are quite small, ranging in size from about 5 to 500 microns, such as from about 10 to 250 microns, in diameter or width.
  • the enteric-release resinate releases the majority, if not all, of the active ingredients within the intestinal fluids.
  • the enteric release resinate release at least 50 wt %, such as at least 75 wt % and preferably 100 wt % of the active ingredient within about 5 minutes in an aqueous solution at a pH of 7.4, i.e. a pH reflecting conditions found in intestinal fluid.
  • the enteric release resinate releases significantly less active ingredients within lower pHs, such as less than 50 wt %, preferably less than 25 wt % and particularly preferably less than about 20 wt % within about 5 minutes in an aqueous solution at a pH of 4.5.
  • the enteric release resinate releases minimal or no active ingredients within the extremely low pHs found in the stomach, i.e.
  • pHs ranging from about 1 to 2, such as a release of less than 5 wt %, preferably less than 2 wt % and more preferably less than about 1 wt % within about 5 minutes in an aqueous solution at a pH of 2.
  • enteric-release formulations could be formed to provide a release of a portion, even the majority or up to the entirety, of the active ingredients within the stomach, should a need for such embodiment ever arise.
  • the controlled release layer also includes at least one pH adjuster to lower the pH of the controlled release composition to between about 2.0 to 3.0 units below the pKa of the opioid agonists (and optionally the opioid antagonists) to effect binding of the opiod agonists (and optionally opioid antagonists) to the cation exchange resin.
  • the amount of pH adjuster suitable for incorporation into the controlled release composition may be readily determined by one skilled in the art, for example using the Henderson Hasselbalch equation.
  • the pKa for buprenorphine, an exemplary opioid agonist is understood to be
  • the pH adjuster is generally present in an amount effective to impart a pH ranging from about 4.94 to 6.31, such as a pH of from about 5.0 to 6.0, to the controlled release composition and/or controlled release layer.
  • the pH adjuster is present in an amount ranging from about 3.0 to 10.0 wt %, such as from 4 to 9 wt%, particularly from about 4.5 to 8 wt %, based upon the weight of the controlled release layer.
  • Exemplary pH adjusters include any monographed pH adjuster suitable for use in pharmaceuticals, such as one or more of sodium citrate, citric acid, tartaric acid, sodium tartrate, acetic acid, sodium acetate and the like.
  • the muco-adhesive layer may likewise contain pH adjuster within the foregoing amounts.
  • the inventive film dosages i.e. the controlled release layer and/or the muco-adhesive layer (and the compositions used to form them), may further include optional additives selected from one or more of taste masking ingredients, emulsifiers or sufactants, plasticizers, colorants, antioxidants, microbial preservatives, permeation enhancers.
  • the taste masking ingredients completely block any residual unpleasant taste associated with the active ingredients.
  • exemplary taste masking ingredients include one or more of sweetener(s), flavouring agents, cooling sensation agent(s), and taste receptor blocker(s).
  • multiple components are contained within the secondary taste masking composition or blend.
  • Exemplary sweeteners include any monographed sweetener, including dextrose, lactose, fructose, mannitol, sucrose, trehalose, sucralose, xylitol, mannitol, aspartame, saccharin, sorbitol, sodium saccharin, sodium cyclamate, acesulfame, honey, isomalt, maltodextrin, dextrin, dextrates and mixtures thereof.
  • monographed sweetener including dextrose, lactose, fructose, mannitol, sucrose, trehalose, sucralose, xylitol, mannitol, aspartame, saccharin, sorbitol, sodium saccharin, sodium cyclamate, acesulfame, honey, isomalt, maltodextrin, dextrin, dextrates and mixtures thereof.
  • the sweeteners may be included in the controlled release and/or muco-adhesive layer in any effective amount, such as from about 0 to 3 wt %, such as from about 0.5 to 1.5 wt %, based upon the weight of the layer in which it is present.
  • flavouring agents include any flavouring agent indicated to be acceptable within the U.S. Pharmacopeia/National Formulary, including various essential oils or extracts of menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, butterscotch, chocolate, cinnamon, clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit, strawberry, grape, pineapple, vanilla, peppermint, peach, kiwi, papaya, mango, coconut, tutti fruitti, apple, coffee, plum, watermelon, nuts, green tea, grapefruit, banana, butter, chamomile, masking flavour, and mixtures thereof.
  • the controlled release layer incorporates one or more flavouring agents selected from lime, tutti frutti, cherry, wintergreen, spearmint, peppermint, and orange.
  • Suitable pharmaceutical grade flavouring agents may by acquired from any of a number of suppliers.
  • several of the foregoing flavouring agents may serve as cooling agents, as well.
  • the flavouring agents may be included within the controlled release and/or muco- adhesive layer in any effective amount, such as from about 1.0 to 5.0 weight %, particularly from about 2.0 to 3.0 wt %, based upon the weight of the layer in which it is present.
  • a masking flavour may also be incorporated within the controlled release and/or muco-adhesive layer, particularly in combination with further flavouring agents.
  • Masking flavours are commercially available from a number of suppliers, including Firmenich of Geneva, Switzerland.
  • the masking flavouring may be included in any effective amount, such as from about 0 to about 2.5 wt %, based upon the weight of the layer in which it is present.
  • One or more cooling sensation agents may also be included within controlled release and/or muco-adhesive layer to diminish or altogether eliminate any burning sensation, particularly any residual burning sensation, associated with the active ingredients.
  • Exemplary cooling sensation agents include essential oils or extracts of menthol, wintergreen, peppermint, sweet mint, spearmint, and mixtures thereof.
  • the cooling sensation agent may be included in any effective amount, such as from about 0 to about 5.0 weight %, such as from about 1.0 to 3.0 weight %, based upon the weight of the layer in which it is present.
  • One or more taste receptor blockers may also advantageously be included within the controlled release and/or muco-adhesive layer.
  • Exemplary taste receptor blockers include any monographed taste receptor blocker.
  • the inventive oral film strips include PEG-40 hydrogenated castor oil as taste receptor blocker. PEG-40
  • Hyrdrogenated Castor Oil is commercrially available as CREMOPHOR ® from BASF SE of Ludwigshafen, Germany.
  • the taste receptor blockers may be included within the controlled release layer in any effective amount, such as from about 0.0 to about 6.5 weight %, and particularly from about 0.30 to 4.50 wt %, based upon the weight of the layer in which it is present.
  • the controlled release and/or muco-adhesive layer can additionally beneficially include at least one emulsifier.
  • Any well-known water-soluble monographed emulsifier is suitable for use in the inventive oral film strips.
  • suitable emulsifying agents include, but are not limited to, castor oil derivatives, cetyl and palmityl alcohol, ethanol, hydrogenated vegetable oils, polyvinyl alcohol, simethicone, sorbitan ester, glyceryl monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer, polyethylene sorbitan fatty acid esters and mixtures thereof.
  • the emulsifier may be included within the controlled release and/or muco-adhesive layer in any amount effective, such as in amounts ranging from about 0 to 2.25 wt %, particularly from 0.50 to 1.50 wt %, based on the weight of the layer in which it is present.
  • the controlled release layer and/or muco-adhesive layer can additionally beneficially include at least one surfactant.
  • Any well-known water-soluble monographed surfactant is suitable for use in the inventive oral film strips.
  • the surfactant may be included in exemplary amounts ranging from 0 to 7 wt %, such as from 1 to 5 wt %, based upon the weight of the layer in which it is present.
  • Additional ancillary components suitable for incorporation within the controlled release and/or muco-adhesive layer include, but are not limited to one or more of the following pharmaceutically-acceptable excipients, coloring agents, stabilizing agents, antioxidants, fillers, permeation enhancers, plasticizers and microbial preservatives.
  • Such ancillary components are included within the inventive oral film strips in amounts considered conventional by one skilled in the art for the given component.
  • suitable colorants include approved edible pigments, dyes, natural food colors, and synthetic colorants such as FD&C coloring agents and mixtures thereof.
  • Suitable stabilizers and/or antioxidants include chelating agents, such as ethylenediaminetetraacetic acid (“EDTA”), ethylene glycol tetraacetic acid (“EGTA”), sodium bisulfite, sodium metabisulfite, ascorbic acid, ascorbyl palmitate and mixtures thereof.
  • EDTA ethylenediaminetetraacetic acid
  • EGTA ethylene glycol tetraacetic acid
  • sodium bisulfite sodium metabisulfite
  • ascorbic acid ascorbyl palmitate and mixtures thereof.
  • Exemplary fillers include any water soluble inert filler.
  • Suitable water soluble inert fillers for incorporation in the inventive oral film dosages include mannitol, xylitol, glucose, fructose, sucrose, sucralose, lactose, trehalose, maltodextrin, dextran, dextrin, modified starches, dextrose, sorbitol, dextrates and mixtures thereof.
  • the inventive film dosage i.e. the controlled release layer and/or muco-adhesive layer, may also contain natural or synthetic permeation enhancers.
  • a "permeation enhancer" is a natural or synthetic compound which facilitates the absorption of an active agent through a mucosal surface, such as the surface of the intestines.
  • exemplary permeation enhancers include anionic surfactants, such as sodium lauryl sulfate and sodium laurate; cationic surfactants, such as cetylpyridium chloride; non-ionic surfactants, such as poloxamer, Brij, Span, Myrj, and Tween; bile salts; sodium
  • glycodeoxycholate sodium glycocholate, sodium taurodeoxycholate, sodium taurocholate, Azone®
  • fatty acids such as oleic and caprylic acid
  • cyclodextrins such as ⁇ -, ⁇ -, ⁇ - cyclodextrin, methylated ⁇ -cylcodextrins
  • chelators such as EDTA, sodium citrate and poly acrylates
  • polymers such as chitosan, trimethyl chitosan and cationic amino acids, such as poly-L-arginine and L-lysine.
  • Brij is the tradename for a family of nonionic polyoxyethylene commercially available from a number of suppliers.
  • Span is the tradename for a family of sorbitan surfactants, suchas sorbitan trioleate (Span 85) and sorbitan tristearate (Span 65) and the like, commercially available from a number of suppliers.
  • Myrj is a tradename for a family of polyethoxylated fatty acid commercially available from a number of suppliers, such as polyoxyethylene monostearate (Myrj 49) and the like.
  • Tween is the tradename for a family of polyoxyethylene sorbitan or polysorbate surfactants, such as polyoxyethylene sorbitan trioleate (Tween 85) and polysorbate 80 (Tween 80) commercially available from a number of suppliers.
  • Azone is a tradename for l-Dodecylhexahydro-2h-Azepin-2-One.
  • Suitable plasticizers for incorporation into the controlled release and/or muco- adhesive layer include any monographed plasticizer.
  • Exemplary plasticizers include, but not limited to, alkylene glycols, polyalkylene glycols, glycerol, triacetin, deacetylated
  • the plasticizer may be included in exemplary amounts ranging from 0 to 15 wt %, such as from 3 to 7 wt %, based upon the weight of the layer in which it is present.
  • the controlled release and/or muco-adhesive layer may also contain microbial preservatives, such as butylated hydroxyanisol, butylated hydroxyltoluene, parabens, parabens derivatives, sorbic acids and derivatives, benzoic acid and derivatives, propionic acid and derivatives, acetic acid and derivatives and mixtures thereof.
  • microbial preservatives such as butylated hydroxyanisol, butylated hydroxyltoluene, parabens, parabens derivatives, sorbic acids and derivatives, benzoic acid and derivatives, propionic acid and derivatives, acetic acid and derivatives and mixtures thereof.
  • inventive oral film dosages are in the form of a two or more layered film, specifically one or more non-mucoadhesive controlled release layer(s) in combination with a layer formed from muco-adhesive polymer.
  • Each of the individual layers within the inventive films may contain either identical or different additives and/or ancillary
  • film layers may be formulated to exhibit differing dissolution times or contain various active ingredient loadings, for example.
  • the inventive oral film dosages are prepared in thicknesses conventional with wafer or thin film-based oral pharmaceutical films, such as thicknesses ranging from 50 to 120 microns, particularly about 60 to 115 microns.
  • the muco-adhesive layer generally forms from about 1 to 50 % of the total thickness, such as form about 10 to 25 % of the overall film thickness.
  • inventive oral film dosages may have any shape known in the art for
  • the oral film dosages may have a a round, oval, square, rectangular or other irregular geometric shape.
  • the inventive oral film dosages may further have any dimensions known in the art as suitable for oral film strips, oral wafers or oral film dosages.
  • Suitable solvents suitable for use in forming the inventive film dosages, including the enteric-release resinate, controlled release layer and/or muco-adhesive layer, include one or more of purified water, acetone, ethanol or other pharmacologically acceptable alcohol that is 4 carbons or less in length.
  • the pharmacologically acceptable solvents may be used in any combination and any solvent ratio, unless indicated to the contrary.
  • Solvents are generally used in amounts effective to dissolve and/or suspend the entirety of the ingredients within the enteric-release resinate, controlled release layer and/or muco-adhesive layer into a liquid mass prior to oral film dosage formation, particularly during the casting, coating or extrusion of the film layers.
  • the resulting liquid mass has a moderately elevated viscosity, as is conventional for film-forming blends used to form edible oral film strips or wafer thin film dosages.
  • the solvent may be present in amounts of up to 95 % within the liquid mass, such as an amount ranging from about 60 to 90 %, based on the weight of the casting/coating/extrusion composition. The solvent is then removed after casting, coating or extruding the various wet film layers in subsequent drying steps during oral film dosage production.
  • the present invention further provides methods for preparing the edible oral film dosages.
  • the oral film dosages are prepared by any methods known in the art for preparing multi-layered pharmaceutical films.
  • the inventive methods specifically include forming the controlled-release layer containing the enteric-release resinate, similarly by any of the methods known in the art.
  • a typical method for loading ionizable substances onto an ion exchange resin is to dissolve an acidic or basic ionizable substance in water, and then mix it with ion exchange resin.
  • the inventive methods thus include forming a controlled-release composition by incorporating one or more cation exchange resins into a pH adjusted solution containing the active ingredient(s). Optional excipients and auxiliaries are then added, along with the controlled- release matrix polymer, and the resulting controlled-release composition is
  • controlled-release layer which is subsequenlty dried.
  • a muco-adhesive layer is then formed and cast/coated/extruded onto the controlled release layer, thereby forming the inventive film dosages.
  • the controlled-release composition is advantageously formed by charging water into a vessel under mixing and adjusting the pH of the water to about 2 to 3 units below the opioid agonist pKa by admixing pH adjuster into the aqueous solution.
  • Opiod agonist salt and optional opiod antagonist are then added and stirred until dissolved.
  • Cation exchange resin is then added under continued stirring.
  • This intermediate solution containing the opioid agonist, optional opioid antagonis, and cation exchange resin may then be stirred or shaken for a considerable amount of time, such as for about 12 hours.
  • plasticizers may subsequently be added under continued stirring.
  • Further optional auxiliary components, including flavor, cooling agents and surfactants may then be added to the aqueous solution, either individually or as a pre-mix, with stirring continued until the solution is uniform.
  • the enteric-release polymer(s) may then be slowly added to the uniform solution under continuous mixing until a homogeneous coating mass, i.e. the controlled release composition, is obtained.
  • the viscous homogenous coating mass Prior to film formation, the viscous homogenous coating mass can be sonicated, aspirated and/or vacuumed to remove air entrapped within the film forming composition.
  • one or more antifoaming agents e.g. insoluble oils, dimethyl polysiloxanes and other silicones, alcohol-based defoamers, stearate-based defoamers or glycol-based defoamers, can be added.
  • the optionally deareated film forming composition is subsequently formed into a thin film having a defined wet thickness using processes well known in the art, such as by casting, coating or extrusion. More particularly, the inventive film forming composition may be cast, coated or extruded onto a suitable casting substrate, e.g.
  • the muco-adhesive composition is formed in a similar manner.
  • the exemplary method that follows describes advantageous embodiments in which the muco-adhesive layer incorporates opiate antagonist.
  • the muco-adhesive composition can be formed by charging water into a vessel under mixing and adjusting the pH of the water to about 2 to 3 units below the opioid antagonist pKa by admixing pH adjuster into the aqueous solution.
  • Opiod antagonist particularly in its salt form, is then added and stirred until dissolved.
  • Optional sweeteners and plasticizers may subsequently be added under continued stirring.
  • Further optional auxiliary components, including flavor, cooling agents and surfactants, may then be added to the aqueous solution, either individually or as a pre-mix, with stirring continued until the solution is uniform.
  • the muco-adhesive polymer(s) may then be slowly added to the uniform solution under continuous mixing until a homogeneous coating mass, i.e. the muco-adhesive composition, is obtained.
  • the viscous homogenous coating mass Prior to muco-adhesive layer formation, the viscous homogenous coating mass can be sonicated, aspirated and/or vacuumed to remove air entrapped within the film forming composition.
  • one or more antifoaming agents e.g. insoluble oils, dimethyl polysiloxanes and other silicones, alcohol-based defoamers, stearate-based defoamers or glycol-based defoamers, can be added.
  • the optionally deareated film forming composition is subsequently formed into a thin film having a defined wet thickness using processes well known in the art, such as by casting, coating or extrusion onto the controlled-release layer to form a wet film having a defined wet thickness.
  • This wet film may then be dried, such as with a uniform laminar flow heating oven or other suitable dryers, using conventional process equipment and conditions well known to those skilled in the art, such as a drying temperature ranging from 30 to 60 °C for a drying time of 5 to 30 minutes.
  • the dried bi-layered film may then be removed from the coating substrate and subsequently be cut into various geometric shapes and sizes using a suitable cutting method, such as, die cutting, punching, knife, or rotary cutting machine.
  • the inventive oral film dosages may have any geometric shape, including round, oval, square, rectangular, or any other irregular geometric shape.
  • Methods of administering the inventive oral film dosages are also provided herein.
  • the inventive methods of administering generally comprise either dispensing the oral film dosage to a patient or medical professions who applies the oral film dosage to the oral cavity of the patient and allowing the oral film to dissolve or disintegrate, advantageously without additional water or oral liquids other than saliva, for subsequent absorption of at least the opioid agonist in the intestinal tract of the patient.
  • the inventive oral film strips have a dissolution time of less than 15 minutes, such as dissolution time of less than 5 minutes, and most preferably a dissolution time of less than 1 minute, based upon a 10 cm oral film strip submerged in physiological fluids or an artificial simulation of such fluids.
  • exemplary oral mucosal membranes to which the oral film dosages may adhere include surfaces of the cheek, palate or tongue.
  • the inventive methods of administration relates to the use of the inventive oral film dosages to administer a clinically effective dose of
  • buprenorphine and naloxone to an individual for its subsequent absorption in the intestinal tract to alleviate symptoms associated with acute pain, chronic pain or suffering from addition, such as opiate addiction.
  • the advantageous binding of the active ingredients to the enteric-release polymer, particularly via pH adjustment allows release of the active ingredient, e.g. buprenorphine and naloxone, within the intestinal tract to provide for an extended efficacy.
  • an individual oral film dosage provides a bioequivalent effect to a single dosage of SUBOXONE ® in tablet form.
  • inventive oral film strips may be used to treat symptoms associated with any of a number of disease states or conditions, including acute or chronic pain from chronic arthritis, osteoarthritis, acute tendonitis, bursitis, headaches, migraines, chronic neuropathic pains, shingles, premenstrual symptoms, sports injuries, malignancy pain, or substance abuse syndromes, particularly opiate addiction.
  • inventive oral film strips may be dispensed to an individual or patient to be self- administered as needed by the patient or administered by a medical professional to alleviate symptoms associated with one or more of the foregoing disease states or conditions.
  • inventive oral film strips generally take effect beginning after about 30 to 45 minutes, with the effect lasting up to 6 hours. Consequently, the inventive oral film strips are very robust, with fast onset, low dosage amount in comparison to conventional tablets, easily transported, and easily administered with long shelf life, and further provide more extended relief in comparison to conventional oral film dosages.
  • the inventive opiate-containing enteric-release resinate may be incorporated into a wide variety of pharmacologically acceptable solid dosage forms.
  • the opiate-containing enteric-release resinate may be incorporated into an orally disintegrating tablet that rapidly disintegrates in the oral cavity and releases the active ingredient to be swallowed.
  • enteric-release bead technology described in this invention can be applied to any known dosage forms, including films, tablets, oral liquids, creams, etc.
  • any dosage form may be formed by forming a mixture of active ingredient containing enteric-release resinate, controlled release polymer(s), pH adjuster, and optional additives in the same ratios described in this invention.
  • the resulting mixtures can be either in solid or liquid form, provided that the liquid form can be lyophilized to rid of the solvents if the dosage form is intended to be compressed into tablets.
  • inventive oral film dosages are useful to deliver various active pharmaceutical ingredients contained in an enteric-release bead.
  • inventive oral film dosages may be administered without water and edible liquids to allow for easy patient adherence and compliance especially for the young and certain general and geriatric patients who have difficulty swallowing.
  • inventive oral film strips are formed at ambient temperatures, i.e. a temperature of approximately 23 °C, and atmospheric pressure, unless indicated to the contrary or otherwise obvious from the context.
  • a controlled release layer containing agonist salt, particularly Buprenorphine salt, could be produced from the advantageous exemplary composition described in Table I:
  • a muco-adhesive layer containing opioid agonist salt, particularly naloxone salt, could be produced from the advantageous exemplary composition described in Table II: Table II:
  • An at least bi-layered oral film dosage comprising at least one layer formed from a controlled-release composition imparting intestinal release of a therapeutically effective amount of an opioid agonist salt and at least one layer formed from a muco-adhesive composition
  • controlled-release composition comprising at least one controlled-release matrix polymer and enteric-release resinate dispersed within said matrix polymer, wherein
  • said enteric-release resinate comprises a cation exchange resin having said opioid agonist salt bound therein;
  • said controlled-release composition further comprises a pH adjuster in an amount effective to adjust the composition to a pH of about 2.0 to 3.0 pH units below the pKa of the opioid agonist salt,
  • said controlled-release composition and said muco-adhesive composition further optionally comprising one or more additives selected from taste masking agents, emulsifiers, plasticizers, colorants, antioxidants, microbial preservatives and permeation enhancers, and said film further comprises a clinically effective amount of opioid antagonist and/or pharmaceutically acceptable salt thereof within at least one layer.
  • said muco-adhesive composition further comprises said opioid antagonist.
  • opioid agonist is selected from one or more of alfentanil, allylprodine, alphaprodine, amfepramone, amphetamine, amphetaminil, anileridine, apocodeine, apomo ⁇ hine, asimadoline, axomadol, benzylmo ⁇ hine, bezitramide, bremazocine, brifentanil, buprenorphine, , butorphanol, carfentanil, clonitazene , codeine, cyclazocine, cyclorphan, cyprenorphine, cyprodime, deltorphin, desomorpine,
  • the opioid agonist is selected from one or more of alfentanil, allylprodine, alphaprodine, amfepramone, amphetamine, amphetaminil, anileridine, apocodeine, apomo ⁇ hine, asimadoline, ax
  • fencamfamine fenethylline, fenproporex, fentanyl, a-methylfentanyl, beta-funaltrexarnine, P-hydroxy-3-methylfentanyl, heroin, hydrocodone, hydromorphone, hydromorphodone, hydroxymethylmorphinan, hydroxypethidine, isomethadone, ketobemidone, kyotorphin, levo-a-acetyhnethadol , levacetylmethadol, levallorphan, levomethadone, levomethadyl acetate, levallorphan, levorphanol, levophenacylmorphan, lofentanil, Lofexidine,
  • loperamide malbuphine, mazindol, mefenorex, meperidine, meprobamate, meptazinol, metazocine, methadone, metopon, methyldihydromorphine, methyldihydromorphinone, methylmorphine, methylnaltrexone , methylphenidate, methyprylon, metopon, mirfentanil, modafinil, morphiceptin, , morphinan, morphine, myrophine, nabilone, , nalbuphene, nalbuphine, nalmefene, nalorphine, naloxone, naloxone benzoylhydrazone, naltrexone, naltriben, naltrindole, naltrindole isothiocyanate, narceine, natbuphine, nicomorphine, nor- binaltorphimine, norlevorphanol,
  • opioid antagonist is selected from one or more of alazocine, amiphenazole, butorphanol, chlornaltrexamine, clocinnamox, cyclazacine, cyclazocine, cyclorphan, cyprenorphine, diprenorphine, etazocine, ⁇ - funaltrexamine, , levallorphan, meptazinol, metazocine, nadide, nalbuphine, nalide, nalmefene , nalmefendiprenorphine, nalmexone, nalorphine, , nalorphine dinicotinate, naloxone, 6-amino-naloxone, N-methylnaloxone, nor-binaltorphimine, naltrendol, naltrexone , 6-amino-naltrexone , 7-benzylidenenaltrexone,
  • said controlled-release matrix polymer is a film forming polymer selected from one or more of cellulose and/or derivatives thereof; synthetic or natural gum, acrylic polymer and/or copolymer thereof, polyalkylene oxide, polyalkylene glycol, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, carrageanan, alginic acid and/or salts thereof, carboxyvinyl polymers, pectin and/or derivatives thereof, xanthan gum and/or derivatives thereof, and starch and/or derivatives thereof.
  • muco-adhesive composition comprises mucoadhesive polymer selected from one or more of edible silicone, polyacrylic acids, and cross-linked polymer of acrylic acid, polyvinyl pyrrolidone, poloxamer; chitosan, sodium alginate; sodium carboxymethyl cellulose, methyl cellulose and hydroxypropyl cellulose.
  • mucoadhesive polymer selected from one or more of edible silicone, polyacrylic acids, and cross-linked polymer of acrylic acid, polyvinyl pyrrolidone, poloxamer; chitosan, sodium alginate; sodium carboxymethyl cellulose, methyl cellulose and hydroxypropyl cellulose.
  • said sweetener is one or more of dextrose, lactose, fructose, mannitol, sucrose, trehalose, sucralose, xylitol, mannitol, aspartame, saccharin, sorbitol, sodium saccharin, sodium cyclamate, acesulfame, honey, isomalt, maltodextrin, dextrin and dextrate
  • said cooling sensation agent is menthol
  • said taste receptor blocker is one or more of polyethoxylated castor oil or ion exchange resin
  • said flavor is one or more of essential oils or extracts of menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, butterscotch, chocolate, cinnamon, clove, lemon,
  • said emulsifier is selected from one or more of castor oil derivatives, cetyl and palmityl alcohol, ethanol, hydrogenated vegetable oils, polyvinyl alcohol, simethicone, sorbitan ester, glyceryl monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer, and polyoxyethylene sorbitan fatty acid esters.
  • said film dosage further comprises one or more colorants selected from edible pigments, dyes, natural food colors and synthetic colorants.
  • An oral film dosage as in (20), wherein said chelating agents are one or more of ethylenediaminetetraacetic acid or ethylene glycol tetraacetic acid (22)
  • hydroxyltoluene parabens and derivatives thereof, sorbic acids and derivatives thereof, benzoic acid and derivatives thereof, propionic acid and derivatives thereof, and acetic acid and derivatives thereof.
  • a permeation enhancer selected from one or more of anionic surfactants, cationic surfactants, non-ionic surfactants, bile salts, sodium glycodeoxycholate, sodium glycocholate, sodium taurodeoxycholate, sodium taurocholate, fatty acids, cyclodextrins, chelators, sodium citrate, polyacrylates, polysaccharide polymers and cationic amino acids.
  • said anionic surfactants are sodium lauryl sul
  • said clinically effective amount of opioid antagonist is a subtherapeutic amount ranging from greater than 0.5 milligrams for opioid addiction treatment dosages; about 25 to 100 micrograms for acute pain treatment dosages and from about 5 to 17.5 micrograms per hour for chronic pain treatment dosages.
  • said film dosage is a bi- layered film.
  • a method of making an oral film dosage as in (1), said method comprising
  • a method of treatment for chronic arthritis, osteoarthritis, acute tendonitis, bursitis, headaches, migraines, chronic neuropathic pains, shingles, premenstrual symptoms, sports injuries, malignancy pain or substance abuse syndromes comprising administering an oral film dosage as in (1) by dispensing the film dosage to a patient or placing the film dosage in the mouth cavity of a patient with subsequent release of a therapeutically effective dose of opioid agonist and a clinically effective dose of opioid antagonist in the intestinal tract.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur une forme pharmaceutique de type cachet oral ou de film oral comestible pour l'administration de médicaments opiates à libération contrôlée et résistante aux abus pour traiter la douleur et l'abus de substances. La forme pharmaceutique de type cachet oral ou film oral comestible pour l'administration de médicaments comprend une couche à libération contrôlée contenant un résinate à libération entérique dispersé dans une matrice de polymère. Le résinate à libération entérique est formé à partir d'une quantité thérapeutique d'un sel d'agoniste opioïde lié dans une résine échangeuse de cations. La forme pharmaceutique de type cachet oral ou film oral comestible comprend avantageusement une quantité inférieure à la quantité thérapeutique d'un antagoniste opioïde et/ou d'un sel pharmaceutiquement acceptable de celui-ci dans une couche mucoadhésive. La matrice de polymère à libération contrôlée se dissout ou se désagrège après administration ou consommation du cachet oral ou du film oral comestible, ce qui libère le résinate àlibération entérique devant être avalé, avec absorption subséquente des principes actifs dans les intestins du patient, alors que l'antagoniste opioïde présent dans la couche mucoadhésive peut être absorbé par voie buccale.
PCT/EP2013/059784 2012-05-15 2013-05-13 Film oral contenant un résinate d'opiate à libération entérique WO2013171146A1 (fr)

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US201261647269P 2012-05-15 2012-05-15
US61/647,269 2012-05-15

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US8808740B2 (en) 2010-12-22 2014-08-19 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9149533B2 (en) 2013-02-05 2015-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9616030B2 (en) 2013-03-15 2017-04-11 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US9707180B2 (en) 2010-12-23 2017-07-18 Purdue Pharma L.P. Methods of preparing tamper resistant solid oral dosage forms
WO2018224674A1 (fr) * 2017-06-08 2018-12-13 Klaria Pharma Holding Ab Formulation pharmaceutique
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
EP3481428A4 (fr) * 2016-08-08 2019-07-10 Pharmedica Ltd. Films à dissolution orale adhésifs destinés à l'hygiène bucco-dentaire
CN110545816A (zh) * 2017-04-25 2019-12-06 久光制药株式会社 贴附剂
WO2020115497A1 (fr) 2018-12-07 2020-06-11 University Of Strathclyde Films buccaux minces
WO2021038460A1 (fr) * 2019-08-26 2021-03-04 Period Pill Bv Traitement de symptômes induits par le cycle menstruel
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11007144B2 (en) 2016-11-15 2021-05-18 Klaria Pharma Holding Ab Pharmaceutical formulation
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation

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US20060204559A1 (en) * 2000-03-23 2006-09-14 Bess William S Fast dissolving orally consumable films containing an ion exchange resin as a taste masking agent
WO2010008863A1 (fr) * 2008-06-23 2010-01-21 Biodelivery Sciences International, Inc. Dispositifs d'administration mucosale à directions multiples et leurs procédés d'utilisation
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US9375428B2 (en) 2003-03-26 2016-06-28 Egalet Ltd. Morphine controlled release system
US9884029B2 (en) 2003-03-26 2018-02-06 Egalet Ltd. Morphine controlled release system
US9005660B2 (en) 2009-02-06 2015-04-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9358295B2 (en) 2009-02-06 2016-06-07 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
US9023394B2 (en) 2009-06-24 2015-05-05 Egalet Ltd. Formulations and methods for the controlled release of active drug substances
US9861584B2 (en) 2010-12-22 2018-01-09 Purdue Pharma L.P. Tamper resistant controlled release dosage forms
US9750703B2 (en) 2010-12-22 2017-09-05 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US11911512B2 (en) 2010-12-22 2024-02-27 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US10966932B2 (en) 2010-12-22 2021-04-06 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
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US11590082B2 (en) 2010-12-22 2023-02-28 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
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US9744136B2 (en) 2010-12-22 2017-08-29 Purdue Pharma L.P. Encased tamper resistant controlled release dosage forms
US9895317B2 (en) 2010-12-23 2018-02-20 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
US9707180B2 (en) 2010-12-23 2017-07-18 Purdue Pharma L.P. Methods of preparing tamper resistant solid oral dosage forms
US9579389B2 (en) 2013-02-05 2017-02-28 Purdue Pharma L.P. Methods of preparing tamper resistant pharmaceutical formulations
US11576974B2 (en) 2013-02-05 2023-02-14 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9662399B2 (en) 2013-02-05 2017-05-30 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9149533B2 (en) 2013-02-05 2015-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9655971B2 (en) 2013-02-05 2017-05-23 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9545448B2 (en) 2013-02-05 2017-01-17 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10792364B2 (en) 2013-02-05 2020-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10478504B2 (en) 2013-02-05 2019-11-19 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10195152B2 (en) 2013-03-15 2019-02-05 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US9616030B2 (en) 2013-03-15 2017-04-11 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10517832B2 (en) 2013-03-15 2019-12-31 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11000473B2 (en) 2016-08-08 2021-05-11 Pharmedica Ltd. Adhesive oral dissolved films in managing oral care
EP3481428A4 (fr) * 2016-08-08 2019-07-10 Pharmedica Ltd. Films à dissolution orale adhésifs destinés à l'hygiène bucco-dentaire
US11007144B2 (en) 2016-11-15 2021-05-18 Klaria Pharma Holding Ab Pharmaceutical formulation
CN110545816A (zh) * 2017-04-25 2019-12-06 久光制药株式会社 贴附剂
CN110545816B (zh) * 2017-04-25 2023-04-11 久光制药株式会社 贴附剂
WO2018224674A1 (fr) * 2017-06-08 2018-12-13 Klaria Pharma Holding Ab Formulation pharmaceutique
EP3932399A1 (fr) * 2017-06-08 2022-01-05 Klaria Pharma Holding AB Formulation pharmaceutique
US11219600B2 (en) 2017-06-08 2022-01-11 Klaria Pharma Holding Ab Pharmaceutical formulation
US11904049B2 (en) 2017-06-08 2024-02-20 Klaria Pharma Holding Ab Pharmaceutical formulation
CN110831575A (zh) * 2017-06-08 2020-02-21 卡里亚制药控股有限公司 药物制剂
US12005140B2 (en) 2018-05-23 2024-06-11 Klaria Pharma Holding Ab Pharmaceutical formulation
WO2020115497A1 (fr) 2018-12-07 2020-06-11 University Of Strathclyde Films buccaux minces
JP2022510470A (ja) * 2018-12-07 2022-01-26 ユニバーシティ オブ ストラスクライド 経口シン・フィルム
CN113490485A (zh) * 2018-12-07 2021-10-08 斯特拉斯克莱德大学 口腔用薄膜
JP7524185B2 (ja) 2018-12-07 2024-07-29 ユニバーシティ オブ ストラスクライド 経口シン・フィルム
US11559502B2 (en) 2019-08-26 2023-01-24 Period Pill Bv Treatment of menstrual cycle-induced symptoms
WO2021038460A1 (fr) * 2019-08-26 2021-03-04 Period Pill Bv Traitement de symptômes induits par le cycle menstruel

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