Classifications

• • 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
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • 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 a sheet-like pharmaceutical preparation for the transmucosal administration of oxycodone or a pharmacologically comparable active substance in the area of the oral cavity, and to the use of such a pharmaceutical preparation in pain therapy and in substitution therapy for the treatment of opiate and cocaine dependency.
• the invention relates to sheet-like medicinal preparations of the type mentioned which are disintegrable in aqueous media and are in the form of foils, films, papers or wafers.
• the invention further encompasses methods which are suitable for producing such pharmaceutical preparations.
• the use of opiates in pain therapy places special demands on the dosage forms used for this.
• the main difficulty is to adjust the dose to the individual patient's subjective pain experience, ie as needed. It is important to avoid that the patient is exposed to unacceptable pain conditions and that tolerance development and possibly dependency develop as a result of overdosing. For this reason, it is desirable and necessary that suitable active ingredients and administration forms are available which enable a rapidly occurring analgesic effect in order to rapidly bring about a dose adjustment that is necessary if required. Therefore, the active ingredient or the dosage form should be characterized by the shortest possible flooding time. In addition, such a dosage form should be such that it can be applied by the patient himself in an uncomplicated and at the same time reliable manner.
• flat dosage forms such as. B. film or wafer-like preparations
• the small thickness compared to the surface results in a short diffusion path when such a dosage form is applied to the oral mucosa, for example. This leads to a rapid dissolution of the preparation under the influence of saliva and to a correspondingly quick release of the active ingredient, which can be quickly and directly absorbed through the oral mucosa.
• DE-OS 27 46 414 which describes a film-like band of active ingredient, binder and other auxiliaries, can be regarded as fundamental for this dosage form. Due to the homogeneous thickness, density and width, there is a direct relationship between a unit length of the strip and the dose of active ingredient contained therein. The advantages of Continuous meterability was also recognized by other applicants and described in special individual variants. So DE-PS 36 30 603 describes a flat carrier material, for. B. in the form of a release paper with an active ingredient-containing coating, the latter being pre-divided in dosage units from the carrier material in a dose.
• DE-OS 196 52 188 AI describes a flat medicinal preparation which is suitable for the application and release of the opiate anaesthetic buprenorphine in the oral cavity.
• this dosage form a large part of the amount of active ingredient contained therein is transported and metabolized via the saliva into the stomach, since this dosage form is not or not sufficiently mucoadhesive.
• the analgesic agents that are well suited for oral administration also include the opiate oxycodone, which has been used successfully in pain therapy for years. After oral administration, two thirds of it is bioavailable, i. H. it appears to a good effect in the bloodstream.
• the oral mucosa for the active ingredient has sufficient permeability, taking into account the necessary dose.
• the permeability in turn depends to a large extent on the physicochemical properties of the active ingredient.
• Oxycodone is already effective in small amounts and has good oral absorption, the average duration of action being 4-6 h.
• the flooding times for normal oral application are 15-30 min. This period is too long for dose adjustment as required and means an unnecessarily long waiting time for the patient to experience relief.
• the object of the invention was therefore to provide pharmaceutical preparations based on and with the general advantages of flat active substance carriers, which by the combination with a special active substance have additional therapeutic and / or economic advantages over pharmaceutical preparations of the same active ingredient based on conventional dosage forms.
• the active ingredient mentioned is to be released in the oral cavity in a manner without the disadvantages described in the prior art occurring.
• the object was to provide an application form for oxycodone which releases the active ingredient in the oral cavity without having the disadvantages described in the prior art.
• the dosage forms should also be safe and easy to use and meet the practical requirements in pain therapy or addiction weaning therapy.
• the object of the invention was furthermore to specify production processes for such preparations which would enable production under competitive conditions.
• the object is surprisingly achieved by a flat, film, film, paper or wafer-shaped medicinal preparation which can disintegrate in aqueous media and which contains oxycodone, or an active ingredient comparable to oxycodone, or a therapeutically suitable salt of oxycodone or the pharmacologically comparable one Has active ingredient.
• a medicinal preparation according to the invention as claimed in claim 1 is, as will be explained in the following, far superior to a conventional dosage form for the administration of oxycodone both from an economic and therapeutic point of view and is particularly suitable on the one hand for analgesia in severe pain conditions and on the other hand also for the therapy of Addiction to opiate or cocaine in the sense of substitution therapy or a weaning program.
• the pharmaceutical preparation according to claim 1 can be brought directly into contact with the oral mucosa during application. Due to the flat design, at least about half of the already large surface of the dosage form is immediately on the mucosa immediately after application. The oxycodone released from the preparation therefore finds two particularly favorable factors for entry into the body, namely a short diffusion path and a large diffusion area.
• the disintegration time being a few minutes after application or after introduction into an aqueous medium
• the superiority of an oxycodone-containing film over an oxycodone-containing tablet will therefore become apparent.
• the advantageous properties of the preparations according to the invention appear so clearly because oxycodone is effective even in small doses.
• the present invention combines the high effectiveness of the oxycodone with the advantageous release and release characteristics of sheet-like transmucosal dosage forms.
• the invention thus provides pharmaceutical preparations which are capable of making a highly effective analgesic available in the body in an efficient and rapid manner.
• the invention makes use of the fact that the oral mucosa has a good permeability for this active substance due to the physicochemical characteristics of the oxycodone, which is why it is particularly well suited for buccal or sublingual application.
• the pharmaceutical preparation according to the invention is preferably used for the transmucosal administration of oxycodone or its pharmaceutically acceptable salts or other pharmacologically acceptable derivatives of oxycodone.
• oxycodone possibly in the form of one of its therapeutically acceptable salts - is the most preferred active ingredient
• the invention also includes active ingredients which are pharmacologically similar or comparable to oxycodone, since the advantages of the invention described, albeit to different degrees , can also come into play here.
• active ingredients which are pharmacologically similar or comparable to oxycodone” are understood in particular to be those which are attributable to the opiates or opioids, since many of them have not only pharmacodynamic but also pharmacokinetic similarities to oxycodone, ie. H. Efficacy at a relatively low dose, good membrane permeability and high first-pass effect. From this group of active substances, morphine or dihydromorphine derivatives and substances from the methadone and fentanyl groups are particularly preferred.
• the active ingredient is released by permeation through the oral mucosa.
• the prerequisite for this is that the flat preparation is in close contact with the mucosa during the application period, that is, until the dissolution or disintegration of the preparation has taken place.
• the pharmaceutical preparation contains an adhesion-promoting auxiliary or an auxiliary mixture which imparts bio- or mucoadhesive properties to the preparation.
• Certain pharmaceutically customary, orally administrable auxiliaries are known to have mucosal properties.
• mucoadhesive substances examples include polyacrylic acid, carboxymethyl cellulose, hydroxymethyl cellulose, methyl cellulose, tragacanth, alginic acid, gelatin and gum arabic.
• various non-mucoadhesive substances are known to also form mucoadhesive properties in certain mixing ratios.
• An example of such a mixture is glycerol monooleate / water in the ratio 84:16 (Engström et al., Pharm. Tech. Eur. 7 [1995], No. 2, pp. 14-17).
• a two- or multi-layer structure of the dosage form of the preparation according to the invention is preferred.
• Preferred embodiments are therefore constructed in two or more layers, one of the two layers or, in the case of a multilayer structure, one of the layers having bio- or mucoadhesive properties.
• the latter are preferably designed such that they have or have a lower permeability for the active substance than the bio- or mucoadhesive layer. In this way it can be avoided that active substance is released into the saliva of the oral cavity, which would lead to loss of active substance.
• the present invention also includes those preparations which, in addition to oxycodone or a comparable active ingredient, contain at least one further active ingredient for transmucosal application.
• a preparation can be advantageous in several ways. For one thing, it is a recognized method of treating multiple symptoms or conditions that occur at the same time to administer a fixed combination of active ingredients in a single medication.
• any therapeutically useful active ingredients can be incorporated into the preparation according to the invention.
• the combination of an opiate active ingredient with another substance which is provided in a further embodiment of the invention and which can reduce the specific risks of opiate administration is particularly useful and advantageous.
• opiate antagonists - or also partial opiate antagonists - such as B.
• the medicinal preparation according to the invention is preferably pre-divided in doses and separated from one another in suitable packaging so that each dose unit can be removed, for example in the form of a blister pack, in which each dose unit is individually sealed in a deep-drawing bowl.
• the dosage may have to be adjusted.
• the analgesic single dose will be 5 to 20 mg, but may be significantly higher for use in addiction therapy or substitution therapy.
• the pharmaceutical preparations are produced in several steps.
• Two basic process variants are suitable for producing a web-shaped starting material, from which either the individual cans or entire packaging units are finally divided by cutting or punching.
• the first group of processes includes those in which with aqueous or solvent-containing liquids, some of which are increased Can have viscosity, a tape or a process film coated evenly and then subjected to a drying process.
• the coating composition is first produced, for which purpose at least one water-soluble polymer capable of film formation, as well as the active ingredient (s) and a suitable, vaporizable liquid must be mixed intimately.
• the sheet-like starting material can be produced by thermoplastic molding, ie without the use of liquids. This includes all hot melt coating processes and all extrusion processes. A prerequisite in this case is that the polymer or polymer mixture capable of film formation is thermoplastic.
• the required ingredients are mixed and shaped under the action of pressure and / or heat by extrusion, blowing or by coating tapes or foils and, after solidification, passed on for further processing.
• Appropriately modified methods are suitable for the production of preparations according to the invention with a multilayer structure, it being irrelevant whether a plurality of sheet-like materials are produced and joined together at the same time or in succession.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Addiction (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Emergency Medicine (AREA)
• Pain & Pain Management (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Psychiatry (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (3)

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• 1999
  • 1999-12-14 DE DE19960154A patent/DE19960154A1/de not_active Withdrawn
• 2000
  • 2000-12-01 EP EP00993377A patent/EP1239847A1/de not_active Withdrawn
  • 2000-12-01 PL PL00355816A patent/PL355816A1/xx not_active Application Discontinuation
  • 2000-12-01 HU HU0203733A patent/HUP0203733A2/hu unknown
  • 2000-12-01 CA CA002393838A patent/CA2393838A1/en not_active Abandoned
  • 2000-12-01 US US10/149,980 patent/US20040024003A1/en not_active Abandoned
  • 2000-12-01 AU AU28392/01A patent/AU781946B2/en not_active Ceased
  • 2000-12-01 CZ CZ20022063A patent/CZ20022063A3/cs unknown
  • 2000-12-01 RU RU2002115277/15A patent/RU2002115277A/ru unknown
  • 2000-12-01 WO PCT/EP2000/012093 patent/WO2001043728A1/de active IP Right Grant
  • 2000-12-01 CN CN00816787A patent/CN1407889A/zh active Pending
  • 2000-12-01 JP JP2001544667A patent/JP2003516961A/ja active Pending
  • 2000-12-01 BR BR0016504-2A patent/BR0016504A/pt not_active Application Discontinuation
  • 2000-12-01 IL IL15012700A patent/IL150127A0/xx unknown
  • 2000-12-01 KR KR1020027007565A patent/KR100597806B1/ko not_active IP Right Cessation
  • 2000-12-01 MX MXPA02005857A patent/MXPA02005857A/es unknown
  • 2000-12-13 AR ARP000106618A patent/AR027902A1/es unknown
• 2002
  • 2002-05-28 ZA ZA200204225A patent/ZA200204225B/en unknown

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