US20230404914A1 - Oral thin film - Google Patents

Oral thin film Download PDF

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Publication number
US20230404914A1
US20230404914A1 US18/036,025 US202118036025A US2023404914A1 US 20230404914 A1 US20230404914 A1 US 20230404914A1 US 202118036025 A US202118036025 A US 202118036025A US 2023404914 A1 US2023404914 A1 US 2023404914A1
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Prior art keywords
thin film
ketamine
polyvinyl alcohol
oral thin
film according
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US18/036,025
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English (en)
Inventor
Markus Müller
Mario FICKER
Michael Linn
Florian HAMMES
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LTS Lohmann Therapie Systeme AG
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LTS Lohmann Therapie Systeme AG
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Priority claimed from DE102021120937.4A external-priority patent/DE102021120937A1/de
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Assigned to LTS LOHMANN THEREAPIE-SYSTEME AG reassignment LTS LOHMANN THEREAPIE-SYSTEME AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MÜLLER, MARKUS, FICKER, MARIO, DR., HAMMES, FLORIAN, DR., LINN, MICHAEL, DR.
Publication of US20230404914A1 publication Critical patent/US20230404914A1/en
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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to an oral thin film containing at least one pharmaceutically active agent, a method for producing same, and the use of such an oral thin film as a medicament, especially in the treatment of pain and/or depression.
  • Oral thin films are thin films containing at least one pharmaceutically active agent that are placed directly in the oral cavity or against the oral mucosa and dissolve or macerate there and in so doing deliver the active agent.
  • These films are, especially, thin active agent-containing polymer-based films which, when applied to a mucous membrane, especially the oral mucosa, can deliver the active agent directly into same.
  • the very good blood supply to the oral mucosa ensures a rapid transfer of the active agent into the bloodstream.
  • This dosage system has the advantage that the active agent is resorbed for the most part by the mucous membrane, thus avoiding the first-pass effect, which occurs in the case of the conventional dosage form of an active agent in tablet form.
  • the active agent may be dissolved, emulsified or dispersed in the film.
  • the oral thin film according to the invention preferably contains ketamine as pharmaceutically active agent and is preferably used for the treatment or prevention of pain.
  • Ketamine has proven to be effective in the treatment of moderate to severe pain and represents a useful alternative to opioid analgesia. Ketamine has also been found to reduce hyperalgesia (increased sensitivity to feeling pain), which occurs in many pain conditions, more specifically also by the long-term ingestion of opioids. In combination with opioids, ketamine also has the effect of reducing the dosage amount of opioids, which is necessary for achieving this analgesia.
  • the NMDA receptor antagonism of ketamine offers a “non-opioid” treatment option for the treatment of pain, which satisfies the unfulfilled requirements of the current therapy (for example reduced severe side effects in conjunction with opioids).
  • (S)-ketamine in comparison to the racemate, has approximately twice the analgesic effect as well as an anti-depressive effect.
  • the lethal dose of (S)-ketamine is very high (lethal dose averaged at 4.2 g/70 kg, for example lethal dose of fentanyl 2 mg/70 kg, oxycodone 40 mg/70 kg).
  • known oral thin films with high active agent load have the disadvantage that the maximum area density and thus the amount of contained pharmaceutically active agent is determined by the drying of the oral thin film during production thereof.
  • the aim of the present invention lies in overcoming the above-mentioned disadvantages of the prior art.
  • the aim of the present invention lies in providing an oral thin film for administering a high amount of at least one pharmaceutically active agent, wherein the oral thin film has an acceptable disintegration time, and wherein the pharmaceutically active agent is distributed relatively homogeneously in the oral thin film.
  • the oral thin film will have a preferably pleasant and soft texture and therefore preferably will not trigger a sensation of a foreign body for the patient.
  • the oral thin film according to the invention will also allow the greatest possible bioavailability of, for example, more than 10% or more than 20% or more than 30% or more than 40% or more than 50% or more than 60% or more than 70% or more than 80% or more than 90% of the pharmaceutically active agent.
  • the oral thin film according to the invention preferably has a bioavailability of 20 to 30% of the pharmaceutically active agent.
  • oral thin film according to the invention will be designed such that approximately 40 to 60% of the contained pharmaceutically active agent can be released within the first minute following application, or approximately 75 to 90% of the contained pharmaceutically active agent can be released after the first two minutes following application.
  • the at least one pharmaceutically active agent will comprise ketamine.
  • an oral thin film according to claim 1 which has at least one matrix layer, wherein the at least one matrix layer comprises at least one pharmaceutically active agent, especially ketamine, at least one polyvinyl alcohol, and at least one polyvinyl alcohol-polyethylene glycol graft copolymer.
  • a polyvinyl alcohol-polyethylene glycol graft copolymer can absorb a high amount of active agent.
  • Films based on a polyvinyl alcohol-polyethylene glycol graft copolymer alone have a softer texture since the polymer itself forms softer films. These films, however, are not quite so stable.
  • the polyvinyl alcohol-polyethylene glycol graft copolymer preferably forms the basic structure and decisively determines the film properties, and the polyvinyl alcohol acts as an additional stabiliser.
  • a high active agent load with layer thicknesses and film sizes in acceptable ranges can thus be achieved.
  • the dissolving times also lie in an acceptable range, the acceptable range preferably comprising values of less than 1 min.
  • such an oral thin film is agreeable to the patient and can be produced easily and economically.
  • the oral thin film according to the invention has at least one matrix layer, wherein the at least one matrix layer comprises at least one pharmaceutically active agent, especially ketamine, at least one polyvinyl alcohol, and at least one polyvinyl alcohol-polyethylene glycol graft copolymer.
  • the at least one matrix layer comprises at least one pharmaceutically active agent, especially ketamine, at least one polyvinyl alcohol, and at least one polyvinyl alcohol-polyethylene glycol graft copolymer.
  • the at least one pharmaceutically active agent is not subject in principle to any limitation, but is preferably selected from all pharmaceutically active agents that are suitable for oral and/or transmucosal application.
  • Active agents are preferably selected from the group comprising the active agent classes of analgesics, hormones, hypnotics, sedatives, antiepiletics, analeptics, psychoneurotropic drugs, neuro-muscle blockers, antspasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumour active agents, antibiotics, chemotherapeutics and narcotics, however, this group is not conclusive.
  • Polyvinyl alcohols (abbreviated to PVA or PVAL, sometimes also PVOH) are polymers of the general structure
  • polyvinyl alcohols which are offered in the form of white-yellow powder or granules, generally have a degree of hydrolysis of 98 to 99 or 87 to 89 mol %, that is to say also contain a residual content of acetyl groups.
  • the polyvinyl alcohols are characterised by the manufacturer by a specification of the degree of polymerisation of the starting polymers or the mean molecular weight, the degree of hydrolysis, the saponification number or the solution viscosity.
  • Graft copolymers are branched polymers that contain different monomer units in the main chain and the branched chain.
  • graft copolymers is a common term.
  • the polyvinyl alcohol-polyethylene glycol graft copolymer provided here preferably has a main chain, comprising polyethylene glycol, onto which the polyvinyl alcohol units are grafted.
  • the oral thin film according to the invention is preferably also characterised in that the at least one pharmaceutically active agent comprises ketamine, preferably (S)-ketamine or a pharmaceutically acceptable salt thereof.
  • the oral thin film according to the invention in another embodiment is preferably characterised in that the at least one pharmaceutically active agent comprises ketamine, preferably R-ketamine or a pharmaceutically acceptable salt thereof.
  • Ketamine is preferably provided in the form of an HCl salt or in the form of a free base.
  • ketamine is understood to mean (S)-( ⁇ )-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-( ⁇ )-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, and the racemate (RS)-( ⁇ )-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.
  • ketamine is metabolised to norketamine, hydroxynorketamine and further substances.
  • both (S)-ketamine and R-ketamine as well as a racemic mixture of these two can be contained in the matrix layer of the oral thin film according to the invention.
  • (S)-ketamine in the form of a free base or a pharmaceutically acceptable salt thereof, especially (S)-ketamine HCl is especially preferably present as a single stereoisomer of ketamine, since the analgesic and anaesthetic potency of (S)-ketamine is approximately three times higher than that of the (R) form.
  • the oral thin film according to the invention is also preferably characterised in that the at least one pharmaceutically active agent, preferably ketamine, is provided in the matrix layer in an amount of 45 to 70 wt. %, preferably of 50 to 65 wt. %, or of 55 to 65 wt. %, or of 55 to 60 wt. %, or of 60 to 65 wt. %, in relation to the total weight of the matrix layer.
  • the at least one pharmaceutically active agent preferably ketamine
  • the oral thin film according to the invention is preferably also characterised in that the at least one pharmaceutically active agent, preferably ketamine, is present in the matrix layer in an amount of 60 wt. %, in relation to the total weight of the matrix layer.
  • the at least one pharmaceutically active agent preferably ketamine
  • the oral thin film according to the invention is preferably also characterised in that the at least one pharmaceutically active agent, preferably ketamine, is present in the form of microcrystals.
  • Suitable mean crystal sizes of these microcrystals lie preferably in the range of 1 to 1000 ⁇ m or in the range of 5 to 500 ⁇ m or in the range of 10 to 200 ⁇ m.
  • the mean crystal size especially preferably lies in the range of 15 to 25 ⁇ m, especially in the range of 20 to 22 ⁇ m.
  • the crystal size can be determined, for example, by means of light microscopy or by means of micro computer tomography X-ray (micro-CT).
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol comprises a polyvinyl alcohol with a mean molecular weight of approximately 25,000 to approximately 250,000 g/mol.
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol comprises a polyvinyl alcohol with a mean molecular weight of approximately 25,000 to approximately 35,000 g/mol and/or a polyvinyl alcohol with a mean molecular weight of approximately 200,000 to 210,000 g/mol.
  • polyvinyl alcohols with a mean molecular weight of approximately 31,000 (4-88) to approximately 205,000 (40-88) g/mol are especially suitable.
  • polyvinyl alcohols with a mean molecular weight with approximately 31,000 (4-88) to approximately 205,000 (40-88) g/mol are especially suitable.
  • polyvinyl alcohols with a viscosity of 3.4 to 4.6 mPas (4-88) to 34 to 46 mPas (40-88) mPas in a 40 g/I aqueous solution, determined by the “falling ball method” (Ph.Eur. 2.2.49), are also especially suitable, or mixtures of two or more different ones of these PVA types.
  • polyvinyl alcohols with a viscosity of 3.4 to 4.6 mPas (4-88) or of 34 to 46 mPas (40-88) mPas in a 40 g/I aqueous solution, determined by the “falling ball method” (Ph.Eur. 2.2.49), are also especially suitable, or mixtures of two or more different ones of these PVA types.
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol main chain onto which there are grafted polyvinyl alcohol units.
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol main chain onto which there are grafted polyvinyl alcohol units, wherein the molar ratio of polyethylene glycol to polyvinyl alcohol is 1:3.
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol main chain onto which there are grafted polyvinyl alcohol units, wherein the polyvinyl alcohol-polyethylene glycol graft copolymer has a mean molecular weight in the range of 40,000 to 50,000 g/mol, preferably of approximately 45,000 g/mol.
  • a suitable and preferred polyvinyl alcohol-polyethylene glycol graft copolymer is known by the trade name Kollicoat IR (BASF).
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 40 wt. %, preferably of 5 to 20 wt. %, of 5 to 19 wt. %, of 5 to 18 wt. %, of 5 to 17 wt. %, of 5 to 16 wt. %, of 5 to 15 wt. %, of 5 to 14 wt. %, of 5 to 13 wt. %, of 5 to 12 wt. %, of 5 to 11 wt. % or of 5 to 10 wt. %, in relation to the total weight of the matrix layer.
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 15 to 45 wt. %, preferably of 17 to 40 wt. %, or 20 to 30 wt. %, in relation to the total weight of the matrix layer.
  • the oral thin film according to the invention is also preferably characterised in that the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 10 to 30 wt. %, preferably of 15 to 25 wt. %, of 17.5 to 22.5 wt. % or of 19 to 21 wt. %, especially of approximately 19.5 to 20.5 wt. %, and especially preferably of approximately 20 wt. % or of 20.1 wt. %, in relation to the total weight of the matrix layer.
  • the oral thin film according to the invention is also preferably characterised in that the matrix layer also comprises at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, softeners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants.
  • auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, softeners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants.
  • Each of these auxiliary substances is preferably contained in each case in an amount of 0.1 to 15 wt. %, preferably of 0.1 to 10 wt. %, or of 0.1 to 5 wt. %, in relation to the total weight of the matrix layer.
  • Sweeteners such as saccharin Na and/or sucralose are preferably contained in the matrix layer in a total amount of 2 to 5 wt. %, especially approximately 3 wt. %, in relation to the total weight of the matrix layer.
  • flavourings are preferably contained in the matrix layer in a total amount of 2 to 5 wt. %, especially approximately 3 wt. %, in relation to the total weight of the matrix layer.
  • Colouring agents are preferably contained in the matrix layer in a total amount of 0.1 to 1 wt. %, especially approximately 0.4 wt. %, in relation to the total weight of the matrix layer.
  • the oral thin film according to the invention is not subjected to any limitations in respect of its structure.
  • the oral thin film according to the invention can thus be provided in the form of a single-layer oral thin film and thus can consist merely of the matrix layer as defined above.
  • the oral thin film according to the invention can thus be provided in the form of a multi-layer oral thin film and thus can contain further layers in addition to the matrix layer as defined above.
  • This plurality of layers can be laminated directly on top of one another or can be connected to an adhesive layer arranged in between.
  • An adhesive layer is understood to mean a layer that can act as an adhesive, as defined in DIN EN 923:2016-03. A non-adhesive layer therefore cannot act as an adhesive as defined above.
  • water-soluble adhesive layers as described in DE 10 2014 127 452 A1 are suitable as adhesive layers, and the content of that document in this regard is hereby expressly incorporated fully in the present disclosure.
  • buffer layers for setting a pH value or slowly dissolving or insoluble layers which protect the oral thin film against premature erosion can be provided as further layers.
  • further matrix layers can be provided, which contain other pharmaceutically active agents or flavourings or taste-masking agents.
  • the oral thin film according to the invention is characterised in that the matrix layer is in the form of a smooth film.
  • the matrix layer for example, is not provided in the form of a foam.
  • a smooth film is preferably characterised in that a smooth film has a volume fraction of 0 to 5%, in relation to the total volume of the matrix layer, of bubbles or cavities.
  • the cavities are filled here preferably with air or a gas, preferably with an inert gas, especially preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.
  • the diameter of the bubbles or cavities generally lies in the range of 0.01 to 350 ⁇ m.
  • the diameter of the bubbles or cavities especially preferably lies in the range of 10 and 200 ⁇ m.
  • the oral thin film according to the invention is characterised in that the matrix layer is in the form of a solidified film having cavities.
  • the infiltration of water or saliva or other bodily fluids into the interior of the dosage form is facilitates by the cavities and the associated larger surface of the films, and therefore the dissolving of the dosage form and the active agent release are accelerated.
  • the transmucosal resorption can be improved additionally by the quick dissolution of the matrix layer.
  • the wall thickness of said cavities is preferably low, since these represent, for example, solidified bubbles, and so these cavities dissolve or break down quickly.
  • a further advantage of this embodiment lies in the fact that, due to the formulation as a foam, a quicker drying can be provided than for a comparable, non-foamed composition, in spite of the comparatively high area density.
  • the multi-layer oral thin film according to the invention is preferably characterised in that the cavities are isolated from one another and are preferably provided in the form of bubbles, wherein the cavities are filled with air or a gas, preferably with an inert gas, especially preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.
  • the cavities are connected to one another preferably by forming a cohesive channel system penetrating the matrix.
  • Said cavities preferably have a volume fraction of 5 to 98%, preferably of 50 to 80%, in relation to the total volume of the matrix layer. In this way, the advantageous effect of accelerating the dissolving of the matrix layer is favourably influenced.
  • surface-active substances or surfactants can be added to the matrix layer for foam formation or to the obtained foam before or after the drying in order to improve the stability of the foam before or after the drying.
  • a further parameter that influences the properties of the dosage form according to the invention is the diameter of the cavities or bubbles.
  • the bubbles or cavities are preferably produced with the aid of a foaming machine, with which the diameter of the bubbles can be set within a wide range, almost arbitrarily.
  • the diameter of the bubbles or cavities can thus lie in the range of 0.01 to 350 ⁇ m.
  • the diameter especially preferably lies in the range of 10 and 200 ⁇ m.
  • the oral thin film according to the invention preferably has an area of 0.5 cm 2 to 10 cm 2, especially preferably of 2 cm 2 to 8 cm 2 or of 4 cm 2 to 5 cm 2.
  • the area density of the matrix layer or of a further layer possibly provided is, in each case, preferably at least 10 g/m 2 , more preferably at least 20 g/m 2 or at least g/m 2 or most preferably 50 g/m 2 , or less than or equal to 400 g/m 2 , more preferably less than or equal to 350 g/m 2 , or less than or equal to 300 g/m 2 or most preferably less than 250 g/m 2 .
  • the area density is preferably 10 to 400 g/m 2 , more preferably 20 to 350 g/m 2 , or 30 to 300 g/m 2 and most preferably 50 to 250 g/m 2 .
  • Each of the provided layers, especially the matrix layer preferably has in each case a layer thickness of preferably 10 ⁇ m to 500 ⁇ m, especially preferably of 20 ⁇ m to 300 ⁇ m.
  • each of the layers provided as a foam has, in each case, a layer thickness of preferably 10 ⁇ m to 3000 ⁇ m, especially preferably of 90 ⁇ m to 2000 ⁇ m.
  • the oral thin film according to the invention is also preferably characterised in that the at least one pharmaceutically active agent is present in the matrix layer in a total amount of 25 mg to 150 mg, preferably of 25 mg to 125 mg, especially of approximately 50 mg to 150 mg.
  • the oral thin film according to the invention is especially characterised in that the at least one pharmaceutically active agent is present in the matrix layer in a total amount of 50 mg to 100 mg, preferably of approximately 50 mg or approximately 100 mg.
  • the oral thin film according to the invention is also preferably characterised in that the at least one pharmaceutically active agent comprises ketamine, preferably in the form of a free base or ketamine HCl, in a total amount of 25 mg to 150 mg, preferably of 25 mg to 125 mg, especially of approximately 50 mg to 150 mg.
  • the at least one pharmaceutically active agent comprises ketamine, preferably in the form of a free base or ketamine HCl, in a total amount of 25 mg to 150 mg, preferably of 25 mg to 125 mg, especially of approximately 50 mg to 150 mg.
  • the oral thin film according to the invention is especially characterised in that the at least one pharmaceutically active agent ketamine, preferably in the form of a free base or ketamine HCl, is present in the matrix layer in a total amount of 50 mg to 100 mg, preferably of approximately 50 mg or approximately 100 mg.
  • the oral thin film according to the invention is also preferably characterised in that the at least one pharmaceutically active agent is present as ketamine, preferably in the form of a free base or ketamine HCl, is present in the matrix layer in a total amount of 25 mg to 150 mg, preferably of 25 mg to 125 mg, especially of approximately 50 mg to 150 mg.
  • the at least one pharmaceutically active agent is present as ketamine, preferably in the form of a free base or ketamine HCl, is present in the matrix layer in a total amount of 25 mg to 150 mg, preferably of 25 mg to 125 mg, especially of approximately 50 mg to 150 mg.
  • the oral thin film according to the invention is especially characterised in that the at least one pharmaceutically active agent as ketamine, preferably in the form of a free base or ketamine HCl, is present in the matrix layer in a total amount of 50 mg to 100 mg, preferably of approximately 50 mg or approximately 100 mg.
  • the oral thin film according to the invention is also preferably characterised in that the at least one pharmaceutically active agent as ketamine, preferably in the form of a free base or ketamine HCl, is present in the matrix layer in a total amount of 2 mg or 5 mg or 7 mg or 10 mg or 15 mg or 20 mg or 25 mg or 30 mg or 35 mg or mg or 45 mg or 50 mg or 55 mg or 60 mg or 65 mg or 70 mg or 80 mg or 90 mg or 95 mg or 100 mg or 105 mg or 110 mg or 115 mg or 120 mg or 125 mg or 130 mg or 135 mg or 140 mg or 145 mg or 150 mg.
  • the at least one pharmaceutically active agent as ketamine preferably in the form of a free base or ketamine HCl
  • the oral thin film according to the invention is also preferably characterised in that the puncture strength is at least 0.15 N/mm 2 , preferably at least 0.18 N/mm 2 , especially preferably 0.20 N/mm 2 or more.
  • the area density here is preferably 150 to 250 g/m 2 , especially preferably 180 to 220 g/m 2 .
  • the puncture strength is preferably determined as follows:
  • Test area round test area of diameter 5 mm.
  • the force gauge is fixed and a 10 cm 2 laminate specimen is placed centrally on the test area of the device (round test area of diameter 5 mm).
  • the laminate specimen is fixed at the edges and a force is exerted in the direction of the test specimen, which force is increased until the laminate specimen is punctured.
  • the resultant maximum value of the force that was applied to the specimen until puncture is measured.
  • the oral thin film according to the invention is also preferably characterised in that the bioavailability of the at least one pharmaceutically active agent, especially the ketamine, preferably in the form of a free base or ketamine HCl, is at least 5% or at least 10% or at least 15% or at least 20% or at least 25% or at least 30% or at least 35% or at least 40% or at least 45% or at least 50% or at least 55% or at least 60% or at least 65% or at least 70% or at least 75% or at least 80% or at least 85% or at least 90% or at least 95% or at least 97% or at least 99%
  • the oral thin film according to the invention is also preferably characterised by the following release rates, wherein the release rate relates to the release of the at least one pharmaceutically active agent, preferably the ketamine, after a certain time following application of the oral thin film according to the invention.
  • the at least one pharmaceutically active agent preferably the ketamine
  • the at least one pharmaceutically active agent preferably the ketamine
  • 100 mg (S)-ketamine can be administered here in one dose or by means of two doses of 50 mg each of (S)-ketamine.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following administration of a dose of 50 mg of (S)-ketamine lies at 50 to 200 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following administration of a dose of 50 mg of (S)-ketamine lies at 200 to 400 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following administration of a dose of 50 mg of (S)-ketamine lies at 50 to 150 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following administration of a dose of 100 mg of (S)-ketamine lies at 100 to 200 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following administration of a dose of 100 mg of (S)-ketamine lies at 300 to 500 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following administration of a dose of 100 mg of (S)-ketamine lies at 100 to 250 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following administration of a dose of 50 mg of (S)-ketamine lies at 70 to 120 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following administration of a dose of 50 mg of (S)-ketamine lies at 200 to 300 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following administration of a dose of 50 mg of (S)-ketamine lies at 70 to 120 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following administration of a dose of 100 mg of (S)-ketamine lies at 120 to 160 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following administration of a dose of 100 mg of (S)-ketamine lies at 300 to 350 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following administration of a dose of 100 mg of (S)-ketamine lies at 150 to 220 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following sublingual administration of a dose of 50 mg of (S)-ketamine lies at 70 to 120 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following sublingual administration of a dose of 50 mg of (S)-ketamine lies at 200 to 300 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following administration of a dose of 50 mg of (S)-ketamine lies at 70 to 120 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following sublingual administration of a dose of 100 mg of (S)-ketamine lies at 120 to 160 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following sublingual administration of a dose of 100 mg of (S) ketamine lies at 300 to 350 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following sublingual administration of a dose of 100 mg of (S)-ketamine lies at 150 to 220 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following buccal administration of a dose of 50 mg of (S)-ketamine lies at 80 to 160 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following buccal administration of a dose of 50 mg of (S)-ketamine lies at 200 to 280 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following buccal administration of a dose of 50 mg of (S)-ketamine lies at 60 to 100 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of (S)-ketamine following buccal administration of a dose of 100 mg of (S)-ketamine lies at 120 to 200 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-norketamine following buccal administration of a dose of 100 mg of (S)-ketamine lies at 400 to 500 ng/mL.
  • the oral thin film according to the invention is preferably characterised in that the maximum plasma concentration of the ketamine metabolite (S)-hydroxynorketamine following buccal administration of a dose of 50 mg of (S)-ketamine lies at 120 to 200 ng/mL.
  • the oral thin film according to the invention is also preferably characterised in that the matrix layer comprises 60 wt. % of (S)-ketamine HCl, 10 wt. % of the polyvinyl alcohol 40-88 as defined previously, and 20 wt. % or 20.1 wt. % of a polyvinyl alcohol-polyethylene glycol graft copolymer as defined previously.
  • the oral thin film according to the invention is also preferably characterised in that the matrix layer comprises 60 wt. % of (S)-ketamine HCl, 10 wt. % of the polyvinyl alcohol 40-88 as defined previously, and 20.1 wt. % of a polyvinyl alcohol-polyethylene glycol graft copolymer, preferably as defined previously, 1.0 wt. % of saccharin Na, 2.0 wt. % of sucralose, 3.5 wt. % of glycerol, 3.0 wt. % of a pharmaceutically acceptable flavouring and 0.4 wt. % of a pharmaceutically acceptable colouring agent. Pure water is preferably used here as solvent.
  • the oral thin film has a formulation according to formulation 15 in Table 3.
  • the oral thin film according to the invention can be produced by conventional methods.
  • a method for producing the oral thin film according to the invention preferably comprises the steps of:
  • step a1) is necessary only if the matrix layer is to be provided in the form of a solidified foam having cavities.
  • the bubbles or cavities are preferably produced with the aid of a foaming machine, with which the diameter of the bubbles can be set within a wide range, almost arbitrarily.
  • the present invention also relates to an oral thin film obtainable by the method described above.
  • the present invention relates to an oral thin film, as described above or obtainable by the above-described method, as a medicament.
  • the present invention relates to an oral thin film, as described above or obtainable by the above-described method, as a medicament for sublingual and/or buccal administration.
  • the present invention relates to an oral thin film, as described above or obtainable by the above-described method, as a medicament for use in the treatment of pain and/or depression.
  • the present invention relates to an oral thin film, as described above or obtainable by the above-described method, as a medicament for use in the treatment of pain and/or depression by sublingual and/or buccal administration of the oral thin film.
  • the present invention additionally relates to an oral thin film, as described above or obtainable by the above-described method, wherein ketamine, preferably (S)-ketamine, or a pharmaceutically acceptable salt thereof, is used as pharmaceutically active agent in the matrix layer, for use in the treatment of pain and/or depression, especially to reduce the risk of suicide and/or for use as a general anaesthetic, preferably to initiate and carry out general anaesthesia, or as a supplement in the case of local anaesthesia and/or as an analgesic.
  • ketamine preferably (S)-ketamine, or a pharmaceutically acceptable salt thereof
  • the present invention relates especially to an oral thin film as described above or obtainable by the above-described method, wherein ketamine, preferably (S)-ketamine, or a pharmaceutically acceptable salt thereof is used as pharmaceutically active agent in the matrix layer, for use in the treatment of pain, preferably as defined hereinafter.
  • Pain is generally understood to mean a feeling of pain that is often caused by intense or noxious stimuli. Pain that is chronic or ongoing is understood to be long-lasting, and pain that disappears quickly is said to be acute.
  • Nociceptive pain is pain caused by the stimulation of sensory nerve fibres which respond to stimuli approaching or surpassing a noxious intensity (nociceptors) and can be classified according to the mode of the noxious stimulation. The most common categories are thermal, mechanical and chemical stimulation. Some nociceptors respond to more than one modality and are therefore termed as being polymodal.
  • Nociceptive pain can also be subdivided into “visceral”, “deep somatic” and “superficial somatic” pain.
  • Neuropathic pain is generally caused by an injury or illness affecting a part of the nervous system involved in body sensation (the somatosensory system). Neuropathic pain can be subdivided into peripheral, central or mixed (peripheral and central) neuropathic pain. Peripheral neuropathic pain is often described as “burning”, “tingling”, “electric” or “piercing”.
  • the present invention also relates to a method for treating pain and/or depression in a patient, comprising the application of an oral thin film, as described above, to a mucous membrane of the patient.
  • the method for treating pain and/or depression in a patient is preferably characterised in that the mucous membrane comprises the oral mucosa.
  • the method for treating pain and/or depression in a patient is preferably characterised in that the oral thin film according to the invention is applied sublingually or buccally.
  • the method for treating pain and/or depression in a patient is preferably characterised in that the dosing of the at least one pharmaceutically active agent, preferably ketamine, especially in the form of a free base or ketamine HCl, is approximately 50 mg to 150 mg, preferably approximately 50 mg or approximately 100 mg.
  • the at least one pharmaceutically active agent preferably ketamine, especially in the form of a free base or ketamine HCl
  • the method for treating pain and/or depression in a patient is preferably characterised in that the oral thin film preferably is applied for a period of less than 2 min, especially of 30 s to 90 s, preferably of 30 s to 60 s and preferably dissolves during this time.
  • composition 2 Based on composition 2 , further oral thin films were produced having the composition according to Table 3 and were tested.
  • Formulation 15 is stable for 9 months at 25° C./60 r.h. %-40°/r.h. 75%.
  • the residual water content of formulation 15 was determined by means of Karl Fischer titration.
  • the residual water content of 6 samples was determined.
  • the determined residual water content was 4.40 wt. %, 3.82 wt. %, 4.02 wt. %, 4.51 wt. %, 4.91 wt. % and 4.57 wt. %.
  • the disintegration time of formulation 15 in a 1 L glass beaker with 900 ml dimineralised water was determined.
  • the disintegration time of six samples was determined.
  • the determined disintegration time was 52 s, 55 s, 58 s, 56 s, 54 s and 55 s.
  • Formulation 15 thus has a good disintegration time.
  • the in vitro release of the active agent was also determined from formulation 15.
  • (S)-ketamine is released from (S)-ketamine HCl-containing oral thin films and is determined.
  • the active agent is released in phosphate buffer pH 6.8 USP and is then determined by in situ fibre optic UV system. The quantification was performed against an external standard.
  • Dissolution Apparatus 2 (Paddle over sinker) according to USP ⁇ 711>
  • FIG. 1 The results of the release study are shown and FIG. 1 and were as follows:
  • Test area round test area of diameter 5 mm.
  • the commercially obtainable product “LISTERINE POCKETPAKS® COOL MINT ORAL CARE FRESH BREATH STRIPS” was used as comparison product. This contains pullulan, menthol, Acesulfame potassium, copper gluconate, polysorbate 80, chondrus crispus gum (Carrageenan), glyceryl oleate, thymol, eucalyptol, methyl salicylate, Ceratonia siliqua gum (locust bean gum), propylene glycol, xanthan gum, aroma (flavouring), FD&C Blue No. 1 (colouring agent) and FD&C Green No. 3 (colouring agent).
  • the force gauge was fixed and a 10 cm 2 laminate specimen (for Listerine, a 32 mm ⁇ 22 mm Listerine OTF was used) was placed centrally on the test area of the device (round test area of diameter 5 mm).
  • the laminate specimen was fixed at the edges and a force was exerted in the direction of the test specimen; the force was increased until the laminate specimen was punctured.
  • the resultant maximum value of the force that was applied to the test specimen until puncture was measured.
  • the oral thin film according to the invention is preferably characterised in that the at least one pharmaceutically active agent, preferably ketamine, is present in the form of microcrystals.
  • Suitable mean crystal sizes of these microcrystals lie preferably in the range of 1 to 1000 ⁇ m or in the range of 5 to 500 ⁇ m or in the range of 10 to 200 ⁇ m.
  • the crystal size can be determined, for example, by means of light microscopy or by means of micro computer tomography X-ray (micro-CT).
  • Micro computer tomography (micro CT) x-ray test method and measurement conditions Micro computer tomography (micro CT) x-ray test method and measurement conditions:
  • a low (S)-ketamine dose (20 mg) was administered to the test subjects intravenously.
  • a wash-out phase of at least 2 days was provided between the study days.
  • test subjects assessed their pressure pain threshold in response to an increasing pressure stimulus using an FDN 200 Algometer from Wagner Instruments.
  • test subject used a transcutaneous electrical pain model to assess the pain threshold during a fixed stimulation of the skin so that the pain value was 7 to 8.
  • the plasma concentration was measured by means of liquid chromatography coupled with QTOF-MS as detection method.
  • the lower detection limit was 6 ng/mL, 6 ng/mL and 4 ng/mL for (S)-ketamine, (S)-norketamine and (S)-hydroxynorketamine respectively.
  • the upper detection limit was 1000, 500 and 200 ng/mL for (S)-ketamine, (S)-norketamine and (S)-hydroxynorketamine respectively.
  • Bowdle questionnaire Based on the Bowdle questionnaire (Bowdle et a1 “Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations” Anesthesiology 1998 Jan; 88(1): 82-8) it is possible to deduce three factors of psychedelic effects: drug intoxication, internal perception and external perception.
  • Bond and Lader questionnaire The Bond and Lader scales are calculated from sixteen 100 mm visual analogue scales. The end points are set to antonymous word pairs, such as ‘awake-sleepy’, ‘well coordinated-clumsy’, ‘mentally slow-quickly attentive’ and ‘incompetent-professional’.
  • the plasma level of the metabolites (S)-norketamine (see FIGS. 3 , 4 and 5 ) and (S)-hydroxynorketamine ( FIGS. 6 , 7 and 8 ) are higher following administration of an OTF (see also Table 7 below) as compared to intravenous administration of 20 mg (S)-ketamine.
  • the plasma levels of ketamine are higher for intravenous administration than following administration of an OTF (see FIGS. 9 , 10 , 11 and Table 7 below).
  • the examined film formulation is suitable for the treatment of pain.
  • the oral bioavailability for (S)-ketamine OTF is 26.3% ⁇ 1.0%.
  • Tmax AUC data calculated using a PK model.
  • FOCI-I first-order conditional estimation with interaction
  • the OTF formulation according to the invention has an analgesic effect in all three pain modalities, irrespective of the localisation.
  • the analgesic effect is long-lasting and ranged from 2 to 6 hours, especially following sub-lingual administration of the OTF.
  • the psychedelic effects for the administered OTF can be considered to be very mild.
  • the active agent flux was determined below in the in vitro model.
  • the active agent flux was performed within the scope of a typical in vitro permeation by means of Franz diffusion cells (volume 10 mL) at 37° C.
  • the used acceptor medium was replaced completely for a new one at predetermined replacement times, and the content of permeated active agent amount in these acceptor solutions was determined by means of HPLC.
  • Phosphate buffer pH 7.4 was used as acceptor medium.
  • Dermatomised skin from the oesophagus of a pig with a layer thickness of 400 ⁇ m was used as skin model.

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