EP3151842A1 - Formulations à usage nasal contenant de l'huile de silicone - Google Patents

Formulations à usage nasal contenant de l'huile de silicone

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Publication number
EP3151842A1
EP3151842A1 EP15726864.0A EP15726864A EP3151842A1 EP 3151842 A1 EP3151842 A1 EP 3151842A1 EP 15726864 A EP15726864 A EP 15726864A EP 3151842 A1 EP3151842 A1 EP 3151842A1
Authority
EP
European Patent Office
Prior art keywords
rhinitis
silicone oil
nasal
nose
containing formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15726864.0A
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German (de)
English (en)
Inventor
Nowak GÖTZ
Christof Jaenicke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Inqpharm Group Sdn Bhd
Original Assignee
Inqpharm Group Sdn Bhd
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Filing date
Publication date
Application filed by Inqpharm Group Sdn Bhd filed Critical Inqpharm Group Sdn Bhd
Publication of EP3151842A1 publication Critical patent/EP3151842A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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

Definitions

  • the invention relates to a silicone oil-containing nasal formulation for the intranasal treatment of endogenous and / or exogenous causes, such as bacteria, fungi, viruses or allergens, caused diseases of the nose, in particular rhinitis.
  • Inflammatory diseases of the nasal mucosa are one of the most common causes of disease and affect several million people of all ages in Germany each year. All elderly and immunocompromised individuals may have more severe disease symptoms characterized by swelling and edema of the nasal mucous membranes, which are associated with shortness of breath and involvement. Dreaded complications are concomitant inflammation of the mucous membranes of the paranasal sinuses due to the edematous swelling of the mucosa in the immediate vicinity of the nostrils located in the openings of these air chambers, which then no longer allow pressure equalization and ignite purulent.
  • influenza viruses can also use the nasal mucous cells as virus-producing sites and lead to typical irritation and secretions.
  • viral genesis bacterial species on the mucous membranes of the nose, which frequently lead to chronic nasal inflammation ("stink nose") and are poorly treatable, are also found in immunocompromised individuals in particular.Another frequent cause of nasal irritation is allergens, for example flower pollen.
  • CONFIRMATION COPY animal epithelial and other organic dusts that may trigger immune reactions on the nasal mucosa and mucous membranes of the upper respiratory tract. There are strong swelling and irritation to find at the same time low-viscosity nasal secretions. Although this form of rhinitis is not infectious in contrast to viral and bacterial rhinitis, those affected have other common symptoms, such as headache, general fatigue and malaise. Rhinitis is a typical seasonal disease with rarely severe progression, but high cost pressures.
  • rhinitis Various forms of rhinitis are thus known: allergic rhinitis (allergic rhinitis), viral or bacterial or fungal induced (generalized infectious) rhinitis, such as rhinitis acuta, also rhinitis atrophicans ("stink nose"), rhinitis sicca, hypertrophic rhinitis (rhinitis hypertrophic), vasomotor rhinitis, pseudomembranous rhinitis, rhinitis medicamentosa or chronic rhinitis, or two or more thereof
  • the said diseases also correspond as preferred or special variants to the term "nasal diseases" or "diseases.” mentioned above and below in the definition of the invention the nose” .
  • aqueous solutions or nasal ointments as active substance carriers are intended to regenerate and moisten the mucous membranes. This should support the ciliary epithelial function and make the nose usable again as a respiratory organ.
  • nasal sprays and saline solutions are used, which restore the patency of the nose for a certain time.
  • alpha mimetics are used which contract the precapillaries of the nasal microcirculation and thus reduce the production of But antivirals, rare antibiotics, are used.
  • Nose oils often combined with anti-inflammatory herbal agents, often reduce the mass and gas exchange at the mucosal surface and are believed to produce a protective film on the epithelia. With heavy secretion, these films can not produce the desired therapeutic effect.
  • Rhinologika with vasoconstrictive substances of advantage, but these locally acting drugs are introduced too often in the nose due to the short reaction times.
  • the chronic microcirculation leads to capillary insufficiency and microcapillary bleeding due to stasis and microthrombosis.
  • mucosal atrophy and permanent dryness of the nose are also a consequence of the chronic use of nasal therapy (rhinitis medicamentosa).
  • Dimethicone-sealed micro-lesions rapidly normalize an otherwise excessive immune response without disturbing or antagonizing it.
  • the simultaneous availability of elemental oxygen to the mucosal surface may contribute to a further enhanced anti-infective effect.
  • other rhinologically active ingredients can be incorporated, which can lead to an additive or cumulative anti-snuff effect.
  • a completely new anti- rhinitis principle and system is available, which has no side effects, is not absorbed and can have an 8-10-hour palliative or curative effect.
  • a nasal spray with this (in particular oxygen-enriched) dimethicone emulsion is suitable for prophylactic use.
  • nasal / pharyngeal mucous membrane is wetted with the monopreparation oxygen dimethicone spray before starting contact with, for example, rhinoviruses or allergens, safe prophylaxis is ensured for several (eg 12 or more) hours.
  • this prophylactic spray is also for immune-compromised or persons with intensive public contact (sales staff, nurses) provided for self-protection.
  • the invention therefore relates to a formulation containing silicone oil, in particular an emulsion of silicone oil in an aqueous medium, for the intranasal treatment of endogenous and / or exogenous causes, such as bacteria, fungi, viruses or allergens, caused diseases of the nose, in particular corresponding diseases of the
  • Nasal mucosa in a mammal, especially humans, wherein the silicone oil is preferably enriched with oxygen.
  • Another embodiment of the invention relates to the use of a silicone oil-containing nasal formulation, in particular an emulsion of silicone oil in an aqueous medium, for the preparation of a pharmaceutical formulation for intranasal use for the treatment of endogenous and / or exogenous causes, such as bacteria, fungi, viruses or Allergenic, induced diseases of the nose, in particular corresponding diseases of the nasal mucosa, in a mammal, in particular humans, wherein the silicone oil is preferably enriched with oxygen.
  • a further embodiment of the invention relates to a method or a method for the intranasal treatment of endogenous and / or exogenous causes, such as bacteria, fungi, viruses or allergens, caused diseases of the nose, in particular corresponding diseases of the nasal mucosa, comprising the nasal administration of a silicone oil-containing nasal formulation to be used, in particular an emulsion of silicone oil in an aqueous medium, to a mammal, in particular a human, in particular requiring such treatment, in an amount effective against said diseases of the nose, the silicone oil is preferably enriched specifically with oxygen.
  • An emulsion of silicone oil in an aqueous medium is in particular an oil-in-water (O / W) emulsion of liquid polydialkyl or polydiphenylsilanes, defined here as 23 ° C., in particular of polydi- (C 1 -C 4 -alkyl ) silanes, in particular of liquid at room temperature polydimethylsiloxanes (dimethicones).
  • O / W oil-in-water
  • Such siloxanes are preferred kinematic on average viscosities (as per manufacturer's instructions) at 25 ° C of 10 to 5000 mm 2 s _1, for example Dimethicone with designations MIO, M50, M100, M350, M500, M1000, M2000 and M5000, particularly MIO, M50, M100, M350 and M500, especially M1000 and M2000, GE Bayer Silicones GmbH & Co KG, Leverkusen, Germany; Wacker Chemie GmbH, Kunststoff, Germany; Caesar & Loretz GmbH, Hilden, Germany), where the numbers each indicate the kinematic viscosities in mm 2 s _1 at 25 ° C, which can be measured as follows: The viscosity of the aqueous solutions, for example, with the automatic measuring instrument AVS 3650 (Schott-Gerate GmbH, D-Hofheim), which is combined with the temperature control unit CT 1450 / CK 101.
  • AVS 3650 Schott-Gerate GmbH
  • the capillary viscometers are rinsed with ethanol before each measurement and then dried by means of compressed air.
  • the kinematic viscosity of the samples is calculated from the measured flow time of a defined sample volume through the capillary.
  • the evaluation of the measurements is carried out with the help of the software VPC 38. For each sample 3-5 measurements are carried out.
  • dimethicone having a kinematic viscosity in the range of 100 to 10,000, in particular from 500 to 5000, for example from 1000 to 2000 mm 2 s _1 .
  • the proportion by weight of the siloxanes in the emulsions used according to the invention is from 0.1 to 50% by weight, for example from 0.5 to 50% by weight, for example from 5 to 25% by weight.
  • emulsifiers are required.
  • Suitable emulsifiers are ionic emulsifiers (such as sodium dodecyl sulfate) or preferably nonionic emulsifiers, e.g. low molecular weight nonionic emulsifiers or block copolymers, such as
  • Macrogolglycerol ricinoleates such as Cremophor® EL (Caesar & Loretz GmbH, D-Hilden);
  • Polyoxyethylene sorbitan fatty acid esters such as Tween® 80 (Caesar & Lorentz, D-Hilden);
  • Phospholipids such as Lipoid S100 (Lipoid GmbH, D-Ludwigshafen) (mixture with phosphatidylcholine, phosphatidylethanolamine, N-acyl-phosphatidylethanolamine, phosphatidylinositoi,
  • Lysophosphatidylcholine triglycerides, free fatty acids and DL-alpha-tocopherol
  • Block copolymer of ethylene oxide and propylene oxide units e.g. Poloxamer 188 (e.g., Lutrol®, BASF, D-Ludwigshafen)
  • Hydroxypropylmethylcellulose e.g., Metolose® from Shin-Etsu Chemical Co., Ltd., J-Toyko
  • Sucrose esters such as Ryoto® Sugar Ester (Mitsubishi-Kagaku Foods Co., J-Toyko), e.g. Esters with lauric acid (L-595), esters with myristic acid (M-1695), esters with oleic acid (O-170 or O-1570), or esters with stearic acid (S-570 or S-1570) as the predominant acyl moiety;
  • Tween® 80 and Span® 80 mixtures of two or more thereof, eg Tween® 80 and Span® 80 (mixture referred to as HLB 8.5),
  • Silica particles in question. Particular preference is given to block copolymers of ethylene oxide and propylene oxide units, such as poloxamer 188, or else sucrose esters with stearic acid as the predominant acyl moiety, such as S-570, polyoxyethylene sorbitan fatty acid esters, such as Tween® 80, alone or in admixture with mixtures of partial fatty acid esters of sorbitol and its Anhydrides with oleic acid, eg Span® 80, macrogolglycerol ricinoleates such as Cremophor® EL or phospholipids such as Lipoid S100, or mixtures of two or more thereof.
  • the weight fraction of the emulsifiers is preferably, based on the finished emulsions, in a range from 0.01 to 20 wt .-%, in particular from 1 to 10 wt .-%.
  • aqueous medium pure water, buffers (such as phosphate buffer, pH adjusted with bases such as NaOH or with phosphoric acid) or other salt solutions (eg hypotonic, isotonic or hypertonic solutions of sodium chloride or potassium chloride) dissolved in water or seawater can be used .
  • the proportion of the aqueous medium in the total composition is preferably 40 to 99.9 wt .-%, for example 60 to 99 wt .-%.
  • additives are selected from thickeners ("quasi-emulsifiers"), for example gum arabic, tragacanth, polyalkylene glycols, such as polyethylene glycol or polypropylene glycol, sugar alcohols or other substances which can serve as regulators of the osmotic activity, such as sorbitol, hexitol or mannitol, (in particular in the presence of active ingredients and / or in the absence of oxygen) preservatives such as ethylenediaminetetraacetic acid, antioxidant such as ascorbic acid, BHA or BHT, paraben, benzoic acid, cetyltrimethylammonium chloride, sorbic acid or thiomersal; Pigments or dyes, such as beta-carotene, erythrosine, yellow-orange, indigotine or the like, flavoring substances, such as fruit esters or vanillin, liquid polyols, such as glycerol, propylene glycol or ethylene glycol, preferably
  • Oxygen (0 2 ) is associatively bound in very high concentrations compared to other gases (nitrogen, carbon dioxide) in emulsions used in the invention, per kg of methylpolysiloxane, for example, up to about 80 g of oxygen (0 2 ) can be bound.
  • a particle size of the silicone oil emulsions in the range of an average in the range of 0.3 and 15 ⁇ m, for example from 2 to 10 ⁇ m, or a D99 in the range from 0.5 to 200 ⁇ m, for example from 5 to 50 ⁇ m.
  • the particle sizes are determined by means of laser diffractometry with an LS 230 Particle Sizer (Small Volume Module, Beckman-Coulter GmbH, D-Krefeld).
  • the combination of laser diffractometry with the PIDS technology allows the measurement of widely distributed samples with particles in the size range from 40 nm to 2000 ⁇ .
  • the principle of the PIDS technology is the irradiation of the sample to be examined with horizontally and vertically polarized light of different wavelengths. Subsequently, the scattered light intensity is analyzed at six different angles (Müller RH, Schuhmann R. Particle Size Measurement in Laboratory Practice: Academicliche Verlagsgesellschaft mbH Stuttgart, 1996. Chapter 4, 55-99, Keck CM, Muller RH, Size analysis of submicron particles by laser diffractometry). 90% of the published measurements are false 2008; 355: 150-163; Xu R. Improvements in particle size analysis using light scattering. In: Müller RH, Mehnert W.
  • emulsions according to the invention are lecithin-free and / or free of hydrophobic silica.
  • Endogenous diseases can be, for example, diseases of the nose caused by an immunodeficiency, autoimmune reaction, or other causes that are not clearly definable.
  • Diseases caused by exogenous causes can be, for example, those caused by infections, for example by bacteria, fungi or viruses, or allergens, such as dusts or pollen.
  • rhinitis Under “Nasal Diseases” or “Diseases of the Nose” is especially rhinitis, especially allergic rhinitis (rhinitis allergica), viral or bacterial or fungal induced (generalized infectious) rhinitis, such as rhinitis acuta, or rhinitis atrophicans ("stink nose"), rhinitis sicca, hypertrophic rhinitis (rhinitis hypertrophica), vasomotor rhinitis, pseudomembranacid rhinitis, rhinitis medicamentosa, or chronic rhinitis, or two or more thereof.
  • Diseases of the nasal mucosa include all (endogenous or exogenous) rhinitis, as well as pollinosis.
  • Intranasal administration is intended in a mammal, especially a human, especially a mammal or human being in need of such treatment.
  • silicone oil emulsions which can be used according to the invention is carried out by processes known per se, for example as described in DE 103 26 188, by homogenization using high gravitational forces after addition of all constituents (if appropriate also of active ingredients), in particular after addition of the emulsifiers to the aqueous Medium in a first step dissolving or dispersing; or adding the emulsifier (eg in the case of Span® 80) to the oily phase; and in both cases subsequent combination of the aqueous and the oily phase and pre-homogenization by means of a conventional stirrer, a colloid mill, by sonication or by means of a Zahnzranzdispergiermaschine which operates on the rotor-stator principle (eg Ultra-Turrax® T8, IKA- Werke GmbH & Co KG, D-Staufen) to a preemulsion and subsequent high pressure homogenization, eg by means of a high pressure homogenizer, in particular by means of
  • the emulsions are then sterilized, for example autoclaved.
  • Corresponding production methods are described in DE 103 26 188 A1, which is incorporated herein by reference.
  • the enrichment with oxygen is carried out, if desired, as described in EP 2 151 242 A2.
  • the oxygen is physically dissolved, for example by the equilibration of the aqueous emulsion of methylpolysiloxane with gaseous oxygen immediately prior to packaging, or by gassing the use solution after the preparation or immediately before taking the preparation.
  • ⁇ Speaking equipped applicators are suitable, for example, which uses the drug packaging gas cartridge with automatic dosage.
  • the oxygen binding can take place even before filling in the appropriate dosage form with the oil. It is also possible to admix 0.5-2% hydrogen peroxide solution or oxygen-storing compounds, such as heme proteins or perfluorocarbons.
  • the preferred dosage form is the aqueous emulsion of the dimethicone. Already during the preparation of the emulsion, oxygen-saturated dimethicone is used.
  • the first emulsification step is associated with an intensive mixing of a preferably vegetable emulsifier with the oil phase and the subsequent incorporation into the aqueous phase, in which ultrasound applications and temperature increases are also used for emulsification improvement.
  • oxygen-containing emulsions preferably have, based on the silicone content, preferably a bound oxygen content of from 1 to 8, eg from 6 to 8 or more particularly from 7 to 8% by weight.
  • the oxygen binding in the oily phase is relatively stable and the oxygen is not exchanged with the surrounding emulsion carrier (aqueous medium).
  • the oxygen molecules are specifically associatively attached to the polysiloxane moiety.
  • the specific binding (without this being limiting) is presumably achieved in such a way that the alkyl or methyl radicals are bonded to the respective free Si valencies, forming molecule "clamps" for the oxygen molecules, since they are rigidly arranged as a weakly negative Have charge surface to which slightly positively charged oxygen molecules can dock or be attached.
  • the oxygenation can be carried out, for example, by means of oxygen (for example from pressure bottles) in pressure-resistant containers (eg 2 to 40 l or more) in which the emulsions are present, preferably under elevated pressure, for example from 2 to 10 atm, in particular at 2.5 to 5 atm, via a feed line, preferably a frit, introduced and stirred, eg for 0.5 to 2 hours, with equilibration for example at room temperature.
  • oxygen for example from pressure bottles
  • pressure-resistant containers eg 2 to 40 l or more
  • elevated pressure for example from 2 to 10 atm, in particular at 2.5 to 5 atm
  • a feed line preferably a frit
  • a method according to the invention or a method according to the invention for the treatment includes in particular the intranasal administration of a nasal formulation or Silicone oil emulsion to be used according to the invention to a mammal, in particular a human, for example as a drop or as a nasal spray or by means of an inhaler.
  • Possible dosages of the dimethicone solutions are, for example, in the range of 0.1 to 5, in particular 0.2 to 2 ml of a (eg 1 to 10 wt .-%) (in particular dimethiocon-) emulsion per day, usually at least in two aliquots from 0.1 to 1 ml or more frequently, which may contain 0.01 to 5 mg, eg 0.1 to 2 mg xylomethazonine or oxymetazoline in solution.
  • the formulations for intranasal administration may be provided as emulsions in tubes (analogously to a lotion or as nasal ointment) or other containers, preferably in the form of nose drops, for example vials with pipettes, or in particular as a nasal spray, for example in spray bottles or other packaging units, or as for example Capsules for aerosol-forming (fine nebulizing) inhalers.
  • the effect of the silicone oil emulsions without further active ingredient is, without this being intended to be a conclusive interpretation of the mechanism of action, possibly due to spreading (spreading) of the silicone oil on the nasal mucosa with film formation (formation of a thin silicone oil-based protective layer).
  • direct, for example, antimicrobial effects may also play a role.
  • a further improved effect of the silicone oils may be due to an oxidative effect of the oxygen enriched on the nasal mucosa, which can react with components of pathogens, on the one hand, and the defense mechanisms of Cells of the nasal mucosa could amplify.
  • the silicone oil emulsions used in the invention since on the one hand, the active ingredients can be kept in direct contact with the nasal mucosa through the film formation, on the other hand also in reducing the dosage of the active ingredients over the active ingredients containing conventional nasal therapeutic agents because of an enrichment (especially lipophilic) active ingredients in the silicone oil droplets of the emulsion they can be supplied in a particularly concentrated form of the nasal mucosa.
  • Anti-inflammatory agents such as glucocorticoids, for example prednisolone, Pred ⁇ nison, methylprednisolone, budesonide, flunisolide, fluocortin butyl, fluticasone 17-propionate, mometasone furoate, beta methasone, hydrocortisone, aminosalicylates, such as sulfasalazine, mesalazine, olsalazine or balsalazide,
  • glucocorticoids for example prednisolone, Pred ⁇ nison, methylprednisolone, budesonide, flunisolide, fluocortin butyl, fluticasone 17-propionate, mometasone furoate, beta methasone, hydrocortisone, aminosalicylates, such as sulfasalazine, mesalazine, olsal
  • mucolytics especially phenylephrine, ephedrine, tetryzoline, naphazoline, oxymetozoline, xylometazoline or tramazoline), or indanazoline, etilefrin, fenoxazoline,
  • Antihistamines such as azelastine, levocabastine, cetirizine, loratidine, terfenadine or fexofenadine;
  • Leukotriene antagonists such as Prankulast, Zafirlukast or Montelukast;
  • Mast cell stabilizers such as cromolyn sodium or its salts, in particular sodium cromoglycate,
  • compositions thereof if salt-forming groups are present, or combinations of two or more of said active ingredients.
  • Particularly preferred are oxymetazoline and especially xylometazoline.
  • Salts are primarily common pharmaceutically acceptable salts, eg (in the case of the presence of basic salt-forming groups such as primary, secondary or tertiary amino groups) acid addition salts; or (in the case of the presence of acidic groups such as -COOH or -SO 3 H, salts with bases such as Particularly preferred are ⁇ -Sympathicometica, especially oxymetazoline (most preferably), xylomethazoline (most preferably) or naphazoline, individually or The proportion by weight of such active ingredients is, for example, based on the total formulation, from 0.01 to 10% by weight, preferably from 0.05 to 4% by weight.
  • Example 1 Preparation of a nasal formulation:
  • Screw cap which carries a PE plastic capillary (inner diameter 5 mm) of 5 cm in length, introduced and sealed gas-tight.
  • the capillary is connected with a PTE tube to a Conoxia® pressure bottle (Linde AG, Pullach, Germany) with reducing valve and for 60 min at 4 atm. fumigated at room temperature. During fumigation, a small amount of the supernatant gas dome is drained two to three times via screw cap, in order to avoid all possibly remaining of the silicone oil there
  • Example 1 The formulation of Example 1 was used as an example on patients as follows:
  • the snuff remedy is after external cleaning of the nose as soon as possible by means of applicator unit
  • XMZ xylomethazine
  • OX oxymetazoline
  • Data in mg (ml refer to the final concentration of OX or XMZ in the antiemetic agent.
  • Rhinitis vasomotorica allergy to hops protein
  • Diagnosis chronic cold, at least 3 attacks per month, mixed rhinitis viral allergic, NT mandatory: OX / seawater therapeutics, nasal oils, nasal creams;
  • Diagnosis rhinitis acuta in viral infection; at the first "clogged nose” by mucous membrane swelling on the first day suddenly aqueous nasal discharge with up to ten sneezing attacks per hour.
  • Diagnosis Allergic vasomotor cold during pollen exposure with general symptoms such as headache, subfebrile temperatures and joint complaints.
  • Diagnosis Immunodeficiency syndrome with chronic runny nose involvement, almost permanent runny nose with phases of nasal dryness and mucoid nasal discharge.
  • Example 3 Comparison of oxygenated and non-oxygenated dimethicone emulsion - antibacterial action on laryngeal cells:
  • OxiDIM oxygenated dimethicone emulsion
  • HEp2 cells Human epithelial cell line from the larynx (epithelioma)
  • Control without oil component 100% for the respective test (M 500, M 1000, M 2000)
  • Non-oxygenated DIM emulsions have a significantly weaker antibacterial effect than OxiDIM emulsions.
  • Groups and group size 4 groups of 25 participants:
  • Example 5 Application of oxygenated silicone oil emulsion 2 MC 0.5 plus "seawater” salt solution 0.5 for the prophylaxis of acute viral rhinitis:

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  • Dispersion Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Ophthalmology & Optometry (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une formulation à usage nasal contenant de l'huile de silicone, destinée à être utilisée dans un procédé de traitement par voie intranasale de maladies du nez endogènes et/ou provoquées par des causes exogènes telles que des bactéries, des champignons, des virus et/ou des allergènes. L'huile de silicone ou la formulation peut être enrichie en oxygène, de préférence en présence d'émulsifiants, et éventuellement en présence d'autres substances actives telles que des sympathomimétiques alpha, comme l'oxymétazoline ou la xylométazoline. Des objets connexes sont également décrits.
EP15726864.0A 2014-06-03 2015-05-28 Formulations à usage nasal contenant de l'huile de silicone Withdrawn EP3151842A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102014009164.3A DE102014009164A1 (de) 2014-06-03 2014-06-03 Silikonölhaltige nasal anzuwendende Formulierungen
PCT/EP2015/001091 WO2015185195A1 (fr) 2014-06-03 2015-05-28 Formulations à usage nasal contenant de l'huile de silicone

Publications (1)

Publication Number Publication Date
EP3151842A1 true EP3151842A1 (fr) 2017-04-12

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP15726864.0A Withdrawn EP3151842A1 (fr) 2014-06-03 2015-05-28 Formulations à usage nasal contenant de l'huile de silicone

Country Status (8)

Country Link
US (1) US20170196904A1 (fr)
EP (1) EP3151842A1 (fr)
JP (1) JP2017516831A (fr)
KR (1) KR20170008765A (fr)
CN (1) CN106659734A (fr)
CA (1) CA2950343A1 (fr)
DE (1) DE102014009164A1 (fr)
WO (1) WO2015185195A1 (fr)

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EP3725311A1 (fr) 2014-02-10 2020-10-21 Respivant Sciences GmbH Procédés de traitement de maladies pulmonaires à l'aide de stabilisateurs de mastocytes
US20150224077A1 (en) 2014-02-10 2015-08-13 Patara Pharma, LLC Methods for the Treatment of Systemic Disorders Treatable with Mast Cell Stabilizers, including Mast Cell Related Disorders
WO2017027402A1 (fr) 2015-08-07 2017-02-16 Patara Pharma, LLC Méthodes de traitement de troubles systémiques aptes à être traités par des stabilisateurs de mastocytes, y compris de troubles liés aux mastocytes
EP3331522A1 (fr) 2015-08-07 2018-06-13 Patara Pharma LLC Méthodes de traitement de troubles liés aux mastocytes par des stabilisateurs de mastocytes
CA3035528A1 (fr) 2016-08-31 2018-03-08 Respivant Sciences Gmbh Compositions de cromolyne pour le traitement de la toux chronique due a une fibrose pulmonaire idiopathique
JP2019531308A (ja) 2016-10-07 2019-10-31 レシュピファント サイエンシス ゲゼルシャフト ミット ベシュレンクター ハフトゥングＲｅｓｐｉｖａｎｔ Ｓｃｉｅｎｃｅｓ Ｇｍｂｈ 肺線維症の治療のためのクロモリン組成物
CN108201525A (zh) * 2017-12-14 2018-06-26 重庆西南医院 一种促进孟鲁司特钠经鼻吸收促进剂及其使用方法
CN110200915A (zh) * 2019-05-14 2019-09-06 扬子江药业集团江苏紫龙药业有限公司 一种富马酸卢帕他定乳剂型鼻腔喷雾剂及其制备方法

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US8211448B2 (en) * 2003-07-07 2012-07-03 Nares Ab Microemulsions and its use for preventing airway diseases
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Also Published As

Publication number Publication date
KR20170008765A (ko) 2017-01-24
US20170196904A1 (en) 2017-07-13
WO2015185195A1 (fr) 2015-12-10
CN106659734A (zh) 2017-05-10
DE102014009164A1 (de) 2015-12-03
CA2950343A1 (fr) 2015-12-10
JP2017516831A (ja) 2017-06-22

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