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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to liquid, preserved pharmaceutical preparations for the application of various active substances to or in or over the nose of a patient in the form of a solution, their preparation and the use of a special buffer system for and in the preparations mentioned.
• nasal pharmaceutical preparations can either be used for the treatment or prevention of diseases on the nose itself or should lead to the absorption of active substances in the bloodstream so that they develop their effects elsewhere in the body.
• Medicines are primarily agents or active substances against runny nose, such as allergy agents, e.g. Cromoglicic acid, or sympathomimetics, e.g. Xylometazoline, tetrazoline,
• Oxymetazoline Naphazolin, Phenylephrin, to name.
• peptide Q preparations e.g. those with desmopressin as an active ingredient, which is an effective
• Nose drops contain at least one active ingredient
• Substances for setting a certain osmotic pressure e.g. NaCl
• / or 5 wetting or surface-active substances e.g. Cremophore
• auxiliaries for stabilizing the active ingredient or for maintaining a certain physiologically acceptable pH in the nose.
• phosphate or phosphate / citrate or citrate buffers and, under certain circumstances, acetate buffers are used. Furthermore, they contain in 0 most cases
• Benzalkonium chloride abbreviated BAC
• BAC Benzalkonium chloride
• benzalkonium chloride is widely used in mouth and throat disinfectants as well as wound and vaginal irrigation. Due to its good antimicrobial effectiveness and good tolerability, it is the most frequently used preservative that is used in nasal sprays and eye drops in conjunction with a large number of active pharmaceutical ingredients.
• the present invention thus relates to a new nasally applicable pharmaceutical preparation based on an aqueous, at least one per se known mucous membrane-absorbable and / or locally acting pharmaceutical active ingredient, at least one preservative formed by benzalkonium chloride alone or together with other preservatives, at least one buffer keeping the pH value at 4 to 6 or at about 5 and furthermore at least one osmotic and / or at least one wetting agent containing solution, emulsion or the like, which is characterized in that the preparation has a significantly improved compatibility with cilia in that in the same or in the underlying solution, emulsion or the like.
• the case per se in the field of pharmaceutical preparations is not so frequent that the essence of the same does not consist in a new active ingredient and its use in a pharmaceutical, but rather in the apparently much less spectacular area of a routine that has long since become routine
• Accompanying substance that has become established and has long proven itself in practice such as the buffer system contained in a pharmaceutical preparation and decisive for its effectiveness and durability, or in an unexpectedly positive change away from proven and widely used buffer systems for liquid pharmaceutical preparations to another buffer that is used much less frequently in medicinal products.
• composition ratios of the other components including the active ingredients in the various tried and tested pharmaceutical preparations can take place, while costly changes and administrative procedures can be saved.
• malic acid buffers in compositions for pharmaceutical and possibly also diagnostic purposes, reference is made, for example, to WO 98/47490 relating to the lyophilisates of biomolecules, in which, in addition to a larger number of different buffers based on organic acids, malic acid is also mentioned is, the buffers mentioned there serve to adjust the pH, but the main task of which is the formation of Use to prevent disruptive arginine-phosphate or citrate-protein aggregates that occur in known phosphate or citrate buffers.
• racemic is the simplest and quite effective embodiment Malic acid as a pH stabilizer and the ciliary-damaging effects are largely suppressing agents. However, enantiomerically pure malic acid can also be used instead of racemic malic acid.
• the A n s p r u c h 4 names NaCI as a particularly proven osmosis-active ingredient in connection with the cily-friendly effect of the new pharmaceutical preparations.
• Another essential object of the present invention is the method for producing the new nasally administrable pharmaceutical preparation, the details of which are given in claim 6, the essential ⁇ l Characteristic of this production process is the targeted replacement of the previously used - and in the course of the investigations of the present invention as - in the presence of benzalkonium chloride - buffer systems which prove to be very dangerous for the cilia activity by a malic acid buffer. 5
• claims 7 and 8 which are subordinate to production claim 6 and referenced to it, are analogous to the features of claims 2 to 6 already explained above.
• Another essential objective of the invention is to -As described above - surprisingly discovered and previously nowhere about only ⁇ ⁇ suggestively mentioned use of based on malic acid as an essential component buffer system instead of usual buffers for the preparation of cilienver juxtaposen, nasally administrable pharmaceutical preparations, the details are not cited here and are disclosed in claim 9. 5
• the beat frequency of the cilia is reduced significantly less by solution 1 with malic acid buffer than by solution 2 with the usual buffer. Then the self-cleaning of the nasal mucosa is simulated by washing out the respective solutions and adding Ringer's solution over 45 minutes. Afterwards, a clear recovery of the cilia beat frequency is achieved in solution 1 with the malic acid buffer, increased from 48 to 74%.
• Example 2 In a 5 liter beaker, 4900 g of aqua dest. submitted and in it
• Phenylephrine hydrochloride dissolved with stirring. The pH is adjusted to 5 with 1 N NaOH. It is made with aqua dest. made up to 5 l and the solution obtained becomes
• Nasal drops or processed into a nasal spray Nasal drops or processed into a nasal spray.
• the beat frequency of the cilia is reduced significantly less by the sample solutions with malic acid buffer than by the reference solutions. Then the self-cleaning of the nasal mucosa is simulated by washing out the test solutions and adding a Ringer's solution over 45 min.
• a significantly better recovery of the ciliac impact is achieved, which reaches up to over% of the initial impact (of 100%). This is a very good value, especially since even if the cilia are incubated in physiological saline after 45 min, only 55% of the cilia initial beat frequency is obtained.

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Otolaryngology (AREA)
• Epidemiology (AREA)
• Neurology (AREA)
• Immunology (AREA)
• Biomedical Technology (AREA)
• Pulmonology (AREA)
• Neurosurgery (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2002
  • 2002-10-10 AT AT0154002A patent/AT413078B/de active
• 2003
  • 2003-10-09 WO PCT/AT2003/000306 patent/WO2004032896A1/de not_active Ceased
  • 2003-10-09 AU AU2003266811A patent/AU2003266811A1/en not_active Abandoned
  • 2003-10-09 JP JP2004542079A patent/JP2006503868A/ja not_active Withdrawn
  • 2003-10-09 US US10/530,969 patent/US20060127317A1/en not_active Abandoned
  • 2003-10-09 EP EP03747695A patent/EP1549288A1/de not_active Withdrawn
  • 2003-10-09 PL PL03375762A patent/PL375762A1/xx not_active Application Discontinuation
  • 2003-10-09 CA CA002501760A patent/CA2501760A1/en not_active Abandoned
• 2005
  • 2005-05-09 NO NO20052251A patent/NO20052251L/no not_active Application Discontinuation

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