EP3151842A1

EP3151842A1 - Silicone oil-containing formulations for nasal application

Info

Publication number: EP3151842A1
Application number: EP15726864.0A
Authority: EP
Inventors: Nowak GÖTZ; Christof Jaenicke
Original assignee: Inqpharm Group Sdn Bhd
Current assignee: Inqpharm Group Sdn Bhd
Priority date: 2014-06-03
Filing date: 2015-05-28
Publication date: 2017-04-12
Also published as: CA2950343A1; US20170196904A1; CN106659734A; JP2017516831A; DE102014009164A1; KR20170008765A; WO2015185195A1

Abstract

The invention relates to a silicone oil-containing formulation for nasal application for use in a method for the intranasal treatment of diseases of the nose brought on by endogenous and/or exogenous causes, e.g. of the kind caused by bacteria, fungi, viruses and/or allergens. According to the invention, the silicone oil or the formulation is, if desired, enriched with oxygen, preferably in the presence of emulsifiers, and optionally in the presence of further active substances, such as α-sympathomimetic drugs, e.g. oxymetazoline or xylomethazoline. The invention also relates to related subject matter according to the invention.

Description

Silicone oil containing nasal formulations

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. The most common cause is rhinoviruses or other viral vectors during the cold season, but influenza viruses can also use the nasal mucous cells as virus-producing sites and lead to typical irritation and secretions. In addition to the 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. 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" .

Various local therapeutic principles are used to restore the physiological tasks of 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. In acute rhinitis drug-containing nose drops, nasal sprays and saline solutions are used, which restore the patency of the nose for a certain time. Essentially, 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. Here are the 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. However, mucosal atrophy and permanent dryness of the nose are also a consequence of the chronic use of nasal therapy (rhinitis medicamentosa). Although there is a broad market presence of blast agents used in the various types of sprout, due to the varying genesis, causal healing or prophylaxis is not yet possible.

It is known that oxygen-containing silicone oil emulsions can be used for the treatment of gastrointestinal diseases, as described in EP 2 151 242 A1. described. Corresponding compositions without oxygen content are also described in the dissertation by Katja Presselt, "Production and Characterization of Silicone Oil Emulsions and Studies on their Therapeutic Potential in Inflammatory Bowel Diseases", Faculty of Biology and Pharmacy, Friedrich Schiller University Jena, 2010.

It has now surprisingly been found that (in particular oxygen-enriched) emulsions of silicone oils in an aqueous base are already suitable without further active substances for the treatment of nasal diseases. This is probably due above all to the creeping ability of oil emulsions, which, due to the surface tension-reducing effect in aqueous solutions, are able to infiltrate perfectly mucus deposits of nasal cells and detach them from their underlay. Particularly suitable for this purpose are water-in-oil emulsions of silicone oils, as described in more detail below. The curative effect of the dimethicone macro- molecules is presumably due to interactions by means of hydrophobic bonds with protein sugar structures of the broken paracellular TJ. 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. In the dimethicone emulsion, other rhinologically active ingredients can be incorporated, which can lead to an additive or cumulative anti-snuff effect. As a result, 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. Furthermore, a nasal spray with this (in particular oxygen-enriched) dimethicone emulsion is suitable for prophylactic use. If the 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. Thus, this prophylactic spray is also for immune-compromised or persons with intensive public contact (sales staff, nurses) provided for self-protection.

The above and below stated mechanisms of action are intended not to be understood as limiting.

In first applications of such new nasal sprays, an oxygen-containing 10% dimethicone emulsion was tested with or without oxymetazoline or xylomethazine in patients with acute rhinitis. The application of the combination of active ingredients showed a marked additive curative effect. After a single application, nasal breathing in patients was often ensured for up to 10 hours. After repeated administration, an acute cold was cured after, for example, 3-4 days. Within a few hours the affected persons were symptom free and were able to survive the limited duration of aerogen allergen exposure with 1-2 times daily spray application without disease symptoms. In cell experiments with a laryngeal cell line, one could prevent the ingress of Despite the extreme exposure of the nasal cavity to external noxae such as allergens and pathogens (eg, viruses, bacteria) there is thus a positive effect - it is also surprising that despite the presence of oxygen in the air with oxygenated emulsions can be found to have a stronger effect than with oxygen-free emulsions The effect could, without this being limiting, be due to a masking action which also helps against viruses.

Thus, even against the background of the effects in EP 2 151 242 A1, which concerned only the gastrointestinal tract with much lower exposures to pathogens (the nasal space acts as a kind of prefilter), a surprising activity is given. In a first embodiment, 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.

The following definitions make it possible to replace more general terms with more specific terms, and in the embodiments of the invention, one or more or all of the more general terms can be replaced by specific terms, resulting in more specific, preferred embodiments of the invention. 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).

Examples are polydimethylsiloxanes of the formula I,

(H ₃ C) 3-Si-0 [-Si _(CH3) 2-0] _n -Si (CH ₃₎ ₃ (D having (on average, based on the number of molecules) n = 1 to 1000 (the Formula is primarily illustrative), preferably n = 1 to 500.

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, Munich, 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. Various Ubbelohde capillary viscometers are used to measure the samples at 20 ° C and 25 ° C (Table 3-9).

Tab. 3-9: Overview of the Ubbelohde capillary viscometers used (capillary type, classification according to Ph. Eur., Device number, capillary constant) Capillary type according to Ph. Eur. App. Number constant [mm ² / s ^-1 ]:

53200 0 97953 0, 001038

53201 0a 91414 0, 004872

53213 Ic 96276 0, 02933

53213 Ic 96277 0, 2910

53710 I 1008446 0, 009970

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.

Particularly preferred is 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. To stabilize the emulsion, 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);

Mixtures of partial fatty acid esters of sorbitol and its anhydrides with oleic acid, e.g. Span® 80 (Sigma-Aldrich Chemie GmbH, D-Steinheim);

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);

Silicone surfactants in the form of copolymers

Polydimethylsilanes and organic glycols such as Belsil® (acker-Chemie GmbH, D-Munich) or a form thereof obtained by methanol fractionation (referred to as HSY 115);

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;

or mixtures of two or more thereof, eg Tween® 80 and Span® 80 (mixture referred to as HLB 8.5),

or particulate solids, e.g. modified

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 .-%.

As 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 .-%.

Further possible 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 in amounts of from 0 to 40% by weight. %, for example from 0.1 to 10 wt .-%. 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.

It is advantageous to set a particle size of the silicone oil emulsions in the range of an average in the range of 0.3 and 15 μm, for example from 2 to 10 μm, or a D99 in the range from 0.5 to 200 μm, for example from 5 to 50 μm. 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 (polarization Intensity Differential Scattering Technology) allows the measurement of widely distributed samples with particles in the size range from 40 nm to 2000 μιη. 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: Wissenschaftliche 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.

(Ed.) Particle and Surface Characterizing Methods: Scientific Publishers Stuttgart; 1997, Chapter 3, 27-56). The calculation of the particle size distribution from the raw data was carried out using the Mie theory and assuming a spherical shape of the particles. For the silicone oil emulsions, a real refractive index of the particles of 1.40

(Wacker-Chemie GmbH, product information - Wacker Silicone Oils AK, 2006). The samples to be characterized were diluted with demineralised water for measurement. In each case, 6-8 measurements were carried out over a period of 90 seconds, the values of which were then averaged. The mean (arithmetic mean), the median (D50 value, central value) and the D99 value (diameter at 99% of the throughput) were used as the measurement parameters for the volume-related distribution.

Preferably 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.

Mixed forms with endogenous and exogenous components are also included.

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.

The preparation of 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 an annular gap homogenizer, eg MicroLab 40 homogenizer (APV-Gaulin, D-Lübeck) or Microfluidizer ™ (Microfluidics, USA) by pressing through a narrow annular gap, preferably under a pressure of 100 up to 1400 bar and if desired under multiple, eg 3 to 10-fold repetition.

If desired or if required for durability, 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. For this ent ^¬ Speaking equipped applicators are suitable, for example, which uses the drug packaging gas cartridge with automatic dosage.

When using surface-activated dimethicone, which is encased in gas-tight containers, 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. However, 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. It should be ensured that the emulsification is carried out under an oxygen atmosphere. This ensures that a maximum physical binding of oxygen into the Dimeticonketten takes place. The content of oxygen should preferably be at least 2%, calculated on the polysiloxane content of the solution. The maximum binding is achieved at about 7-8% by weight of oxygen based on the oil content. Thus, 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.

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.

Already the silicone oil emulsion as such enables a treatment of nasal diseases, but it may additionally contain one or more active ingredients customary for the treatment of nasal diseases (= diseases of the nose, in particular the nasal mucosa).

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). In addition or alternatively, direct, for example, antimicrobial effects may also play a role. If oxygen is used in addition, a further improved effect of the silicone oils, without this being a final interpretation, 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.

An improved effect of conventional drugs for the treatment of nasal diseases is possible by 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.

Examples of possible active ingredients:

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,

Antipyretics,

antibiotics,

vasodilators,

Enzymes,

Antibody,

Secretolytica,

mucolytics, -Sympathicometica (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;

β ₂ -sympathomimetics;

Mast cell stabilizers, such as cromolyn sodium or its salts, in particular sodium cromoglycate,

Essential oils,

or similar,

pharmaceutically acceptable salts 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 α-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.

The invention also relates to those in the claims and the Summary of the invention, which are incorporated herein by reference.

The following examples serve to illustrate the invention without limiting its scope:

Example 1: Preparation of a nasal formulation:

Preparation of an oxygenated silicone oil emulsion:

To 75 ml distilled water 20 ml of silicone oil M 500 MC (Wacker Chemie GmbH) and 500 ml Poloxamer 188 (Lutrol.RTM., BASF, Ludwigshafen, Germany) are coarsely homogenized in an Ultraturrax.RTM. 4 × at stage 8 for 5 minutes and then in a high-pressure homogenizer (Yonekura K Hayakawa K, Kawaguchi M, Kato T. Langmuir 1998; 14: 3145-3148) prepared into a stable silicone oil emulsion ready for use. After one hour of storage and quality control (droplet size, surface activity), the emulsion is placed in a sterile 100 ml glass bottle. 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

Remove foreign gas admixtures. Subsequently, the oxygenated silicone oil emulsion is ready for further use.

Preparation of a stock solution of oxymetazoline or xylomethazoline: 500 mg oxymetazoline or xylomethacin (sigma Aldrich, Munich, Germany) in 250 ml distilled water. dissolved and filled with gentle warming and intensive stirring in sterile 25 ml glass vials and sealed. Until use, the bottles are stored at 4 ° C.

Preparation of the Bovine Therapeutic A for the following applications:

Pipet 5 ml of the oxygenated silicone oil solution and 0.25 ml of the stock OX / XTZ stock into a 1 ml nasal application unit (drop bottle or spray bottle) and make up to 4.75 ml of l, 8% NaCl solution. After intensive shaking mixing phase, the application units are sealed and released for use.

Production of the antipyretic B for the following applications:

100 ml Dimeticon SE 2 MC (Wacker Chemie AG, Munich, Germany) are filled into a glass pressure bottle as described above and gassed with oxygen according to the method described above. They are processed analogously to the steps described above to a snuff treatment.

Example 2: Application to Patients

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

(Drop dispenser or pressure sprayer) in each nostril (2-3 sprays or 3-4 drops) entered with briefly merging the nostrils with two fingers. After 10 - 15 sec the application is finished. If necessary, it is repeated until the secretion outflow is permanently stopped.

It means:

SE-2: Silicone Oil Emulsion Base = Dimeticon SE 2 MC (Wacker Chemie GmbH) (Snuff Therapeutic B)

XMZ = xylomethazine

OX = oxymetazoline

Data in mg (ml refer to the final concentration of OX or XMZ in the antiemetic agent.

(A) The following patients were treated with oxygen-saturated SE 2 emulsion in various types of colds:

Patient 1.

J. O. 39 years old female Diagnosis: acute influenza infection with cold, chronic rhinitis patient with dependency potential):

1st day 4-5 ml / h aqueous-slimy discharge

Application:

1st day of treatment: every 2 hours 2 sprays SE-2 / 0.5 mg / ml plus OX. 3 puffs before sleep

2nd day of treatment: every 6 to 7 hours for every 2 sprays

3rd day of treatment: every 2 hours, 2 sprays each

4th day of treatment: in the morning every 2 sprays

5th day: symptom-free without the otherwise occurring tidal discharge.

Self-evaluation from the decades-long use of aqueous nasal sprays with 0.8-1 mg / ml OX: faster healing without residuals, free nasal cavities, no nasal discharge ("red nose") Patient would use the SE-2 emulsion again and again when shivering.

Patient 2.

J. N. 23 years old male

Diagnosis: Rhinitis vasomotorica (allergy to hops protein) massive aqueous nasal discharge 10-20 min after ingestion of the allergen (2-3 temp touches!)

Start of the SE 2 emulsion at 0.5 mg / ml plus OX / seawater hourly; within 2-3 h significant reduction of aqueous outflow, 3 times per 12 h applied, complete cessation without cold-typical reddening of the mucous membranes and swelling, no laying of the tubes, no paranasal sinus involvement.

Self-assessment: perfect immediate antagonization of the common cold allergy, SE-2 NT will reapply immediately, "pleasant remedy".

Patient 3.

P. L. 37 years old male

Diagnosis: chronic cold, at least 3 attacks per month, mixed rhinitis viral allergic, NT mandatory: OX / seawater therapeutics, nasal oils, nasal creams;

Treatment for 4 months with SE-2 OX emulsion:

first 2 months: combination with 0.5 mg / ml OX seawater; since 2 months SE-2 with 0.25 mg / ml OX-seawater in the last month only two subacute attacks of sputum, each with 1 x 8 hours of spraying, significantly reduced disease episodes: max. 2 days duration.

Self-assessment: very good effectiveness with ever-rarer attacks of colds, clear superiority over standard OTC products. Patient 4.

E. N. 71 years female

Diagnosis: severe acute cold in tracheobronchitis subchronica

1st day: Immediately within 7-8 hours of strong purulent-aqueous nasal mucus with paranasal sinus involvement, trigeminal neuralgia and severe left-sided headache, commercial nasal sprays and drops ineffective.

2. -4. Day Neo application of SE-2 / OX-saline nasal spray first every 3 h, then applied after 12 h only twice a day, significantly reduced spray volume and rapid healing of the accompanying signs of inflammation.

Self-assessment: very good activity, the first time "noticed" Cure ^¬ trend.

Patient 5:

MR. 42 years old male

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.

Begin with first three times two bursts of SE-2 / 0.5 mg / ml XMZ in the first hour, then stopping the acute secretory phase for more than 4 hours.

Re-enter SE-2 / 0.5 mg / ml XMZ, then only need 3 drops of nasal drops per 16 hours, after 4 days

Healing without further sense of smell.

Self-assessment: good efficacy in initially still existing secretion of reduced thin nasal mucus, but stopped 4 hours after the first spray application. Patient 6:

C. L. 6 years old male

Diagnosis: chronic runny nose with frequent feverish colds

Immediate application of SE-2 / 0.125 mg / ml XMZ in seawater at the first symptoms, application (1 spray into each nostril early, noon and evening). Result: No cold, no mucosal redness in the nasopharynx, no pain.

Review by the parents: perfect snuff prophylaxis, seen in no other child-friendly cold spray so, is often used again in next infection.

Patient 7:

S.N. 44 years female

Diagnosis: Allergic vasomotor cold during pollen exposure with general symptoms such as headache, subfebrile temperatures and joint complaints.

After severe mucosal swelling in the nose and sinus-pressure sensation onset of a purulent-slimy

Cold and "nose pain", significantly increasing.

Using SE-2 / 0.25 XMZ several times a day and 2-3 times at night because of dry mouth and impossibility of Na ^¬ senate determination.

After 3 days significantly less spray applications needed

(twice / day), healed after 5 days.

Self-assessment: rapid reduction of the otherwise 7-10-day allergy episodes, very good effect.

Patient 8: CS. 69 y.

Diagnosis: Immunodeficiency syndrome with chronic runny nose involvement, almost permanent runny nose with phases of nasal dryness and mucoid nasal discharge.

Use of SE-2 / 0.25 mg / ml XMZ 2 times a day and once in the evening before bedtime.

Clear, rapid "healing" of the nasal spaces without the occurrence of attacks of the nose; Application over 14 days, then 4-6 weeks without discomfort.

Self-assessment: very good effect, pleasant "soft"

Spray quality, it will use again and again.

Example 3: Comparison of oxygenated and non-oxygenated dimethicone emulsion - antibacterial action on laryngeal cells:

Abbreviations: DIM: Dimeticone emulsion

OxiDIM: oxygenated dimethicone emulsion

HEp2 cells Human epithelial cell line from the larynx (epithelioma)

In the studies on the effectiveness of dilute OxiDIM emulsions with different dimeticon chain lengths on the attachment and internalization of E. coli on HEp-2 cells, the non-oxygenated 3% DIM emulsions were also investigated. The most striking finding was that these DIM dilutions invariably showed only minimal inhibition of internalization already at 1: 3000.

Experimental Procedure: In each of twelve 25 ml cell culture bottles, HEp-2 cells were incubated until complete cell lawn, then at the cell culture medium change was in the controls and the five dilution stages of the 3% Dimeticon emulsion (M500) each with prior equilibration with Conoxia (02 (+)) or without fumigation (-) per 5000 E. coli B2332 (from cryoculture, from the Institute of Medical Microbiology, University Hospital Jena, provided) in 10 ml of medium. After incubation for 24 hours, the cell lawn was rinsed with cell culture medium. Then, by means of vital staining, the dead Hep-2 cells were counted in 4 quadrants on the inverted microscope. In the same way, another two tests were carried out with 3% Dimeticon emulsion M1000 and M2000.

The results are summarized in the table: When compared to percent internalization, a significantly stronger inhibition of the internalization of the oxygenated dimethicone emulsions can be seen. The optimal chain length of the dimeticone is to be defined in the range of M 1000-2000. Table: Inhibition of internalization of E. coli (B2332) in Hep 2 cells by 3% dimethicone solutions of different chain lengths (M...) With and without oxygen:

Oil component M 500 M 1000 M 2000

Oxygen Yes No Yes No Yes No

Control 180 181 360 385 285 280

(100) (100) (100) (100) (100)

1: 2000 128 18 235 315 134 205

(71) (87) ^⁽⁶⁵⁾ (88) (47) (73)

1: 2500 132 147 140 240 85 172

(73) (82) (39) (67) (29) (61)

1: 3000 105 150 190 225 65 140

(58 ⁾ (53) (80) (23) (50)

1: 3500 95 165 145 285 100 230 (53) (81) ⁽ 40 ⁾ (80) (35) (82)

1: 4000 190 185 175 290 190 268

(106) (102) (49) (81) (67) (95)

Values in brackets: Control without oil component = 100% for the respective test (M 500, M 1000, M 2000)

Highlighted by underlining are the levels at which oxygenation provides greater inhibition than without oxygenation.

For example, the 77% inhibition found in M 2000-OxiDIM, for example in the case of the 1: 3000 dilution, was not detectable in any experiment with DIM emulsions (maximum inhibition: 54% for 1: 2000 dil. 3% M 2000 DIM emulsion ).

Result: Non-oxygenated DIM emulsions have a significantly weaker antibacterial effect than OxiDIM emulsions.

Example 4 Study on Efficacy in Human Patients

The following study design is used to demonstrate the superiority of an oxygen-enriched silicone oil-containing xylometazoline-reduced nasal formulation (Group 3) versus standard formulation xylometazoline 0.1% clinically and the superiority of oxygen-enriched versus non-oxygenated silicone oil-containing formulations:

Design :

Controlled randomized parallel group study according to GCP

Groups and group size: 4 groups of 25 participants:

1. silicone oil

2. silicone oil plus oxygen

3. silicone oil plus oxygen plus 0.01% xylometazoline

4. Standard dose xylometazoline 0.1%

Inclusion criteria / indication:

Acute rhinitis Exclusion criteria:

Drug-induced rhinitis Severe underlying diseases

Measurement parameters:

Nasal Peak Flow

Number of used handkerchiefs

symptom improvement

Measuring times:

0,3,7,10 days Destination:

Significant reduction in disease duration

Significant improvement in symptoms In case of non-inferiority of physical parameters

Safety parameters:

Large blood count and blood sedimentation beginning and end 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:

Used by a group of 5 students who completed a 12-hour intercontinental flight in October 2014 2 participants (JN male 23 years and MS male 24 years) before the start, after 4 and after 8 hours a spray application of the drug-free nasal spray (three sprays in each nostril). Both spray users had no symptoms of acute or allergic rhinitis at the end of the flight and in the next few days. The other three participants in the group trip fell ill within 24 hours of a mild flu, subfebrile temperature (37.3-37.8 degrees Celsius) and acute rhinitis. All participants used this nasal spray formulation on the return flight 3 weeks later, none of the participants subsequently showed symptoms of acute rhinitis.

Claims

claims

Silicone oil-containing nasal anz ^"tacking formulation for use in a method for intranasal treatment of endogenous and / or exogenous causes, caused diseases of the nose.

A silicone oil-containing formulation for the treatment according to claim 1, wherein the diseases of the nose are caused by bacteria, fungi, viruses and / or allergens.

A silicone-containing formulation for the treatment according to claim 1, wherein nose disease includes rhinitis, especially allergic rhinitis, infectious rhinitis, rhinitis atrophicans, rhinitis sicca, hypertrophic rhinitis, vasomotor rhinitis, pseudomembranacea rhinitis, rhinitis medicamentosa or chronic rhinitis, or two or more thereof to understand.

Silicone oil-containing formulation for the treatment according to claim 1 or 2 or 3, wherein the silicone oil or the formulation is enriched with oxygen.

Silicone oil-containing formulation for the treatment according to one of claims 1 to 4 in the form of an emulsion of silicone oil in an aqueous medium.

Silicone oil-containing formulation for the treatment according to one of Claims 1 to 5 in the form of an oil-in-water emulsion, comprising polydialkylsilanes which are liquid at room temperature in the presence of ionic or nonionic emulsifiers in an aqueous medium.

A silicone oil-containing formulation for the treatment according to claim 6, wherein the polydialkylsilanes are kinematic Viscosities in the range of 10 to 5000 mm ² s ^_1 have and the emulsifiers are selected from the group, the ionic emulsifiers, such as sodium dodecyl sulfate, or preferably nonionic emulsifiers, for example low molecular weight nonionic emulsifiers or block copolymers, such as

Macrogolglycerolricinoleate;

polyoxyethylene,

Mixtures of partial fatty acid esters of sorbitol and its anhydrides with oleic acid;

Phospholipids;

Block copolymers of ethylene oxide and

Propylene oxide units;

Hydroxypropylmethylcellulose;

Silicone surfactants in the form of copolymers of polydimethylsilanes and organic glycols, or a form thereof obtained by methanol fractionation; ) Sucrose ester;

or mixtures of two or more thereof,

or particulate solids, e.g. modified

silica,

in particular from block copolymers of ethylene oxide and propylene oxide units, or furthermore from sucrose esters with stearic acid as the predominant acyl fraction,

Polyoxyethylenesorbitanfettsäureestern, alone or in a mixture with mixtures of partial fatty acid esters of sorbitol and its anhydrides with oleic acid,

Macrogolglycerolricinoleates, and phospholipids, or mixtures of two or more thereof. includes.

Silicone oil-containing formulation for the treatment according to any one of claims 1 to 7, characterized in that it contains pure water, buffer or water as the aqueous medium Salt solutions, or seawater, with or without further additives.

A silicone oil-containing formulation for the treatment according to any one of claims 1 to 8, further comprising at least one active substance for the treatment of nasal diseases, preferably selected from antiphlogistics, such as

Glucocorticoids, e.g. Prednisolone, prednisone,

Methylprednisone, budesonide, flunisolide, fluocortinebutyl,

Fluticasone 17-propionate, mometasone furoate, betamethasone,

Hydrocortisone, aminosalicylates, such as sulfasalazine,

Mesalazine, olsalazine or balsalazide,

Antipyretics,

antibiotics,

vasodilators,

enzymes,

antibodies

Secretolytica,

mucolytics,

α-sympathicometica, in particular phenylephrine, ephedrine, tetryzoline, naphazoline, oxymetozoline, xylometazoline or tramazoline, or indanazoline, etilefrine, fenoxazoline, antihistamines such as azelastine, levocabastine, cetirizine, loratidine, terfenadine or fexofenadine;

Leukotriene antagonists, such as Prankulast, Zafirlukast or

montelukast;

β ₂ -sympathomimetics;

Essential oils,

pharmaceutically acceptable salts thereof,

or combinations of two or more of said active substances.

Silicone oil-containing formulation according to one of claims 1 to 9, further including oxymetazoline or especially xylomethazoline.

Silicone oil-containing formulation according to one of claims 1 to 10, preparable using a high-pressure homogenization step and, if desired, in particular with addition of oxygen.

Use of a silicone oil-containing formulation according to any one of claims 1 to 11 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 allergens, caused diseases of the nose, especially the nasal mucosa, in particular Rhinitis, especially allergic rhinitis, infectious rhinitis, atrophic rhinitis, rhinitis sicca, hypertrophic rhinitis, vasomotor rhinitis, pseudomembranacid rhinitis, rhinitis medicamentosa or chronic rhinitis, or two or more thereof.

A method or method for the treatment of diseases of the nose, in particular the nasal mucosa, comprising the nasal administration of a silicone oil-containing formulation according to any one of claims 1 to 11 to a mammal, in particular a human, in particular requires such a treatment, in a against the said diseases Nose effective amount.