EP2714005A1 - Nasal pharmaceutical formulation - Google Patents

Nasal pharmaceutical formulation

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Publication number
EP2714005A1
EP2714005A1 EP12745769.5A EP12745769A EP2714005A1 EP 2714005 A1 EP2714005 A1 EP 2714005A1 EP 12745769 A EP12745769 A EP 12745769A EP 2714005 A1 EP2714005 A1 EP 2714005A1
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EP
European Patent Office
Prior art keywords
formulation according
nasal
fluticasone
formulation
treatment
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Withdrawn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
EP12745769.5A
Other languages
German (de)
French (fr)
Inventor
Annegret Hildebrand-Cyrener
Joachim Maus
Ullrich Munzel
Hans Tritschler
Mario Weingart
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.)
Meda Pharma GmbH and Co KG
Original Assignee
Meda Pharma GmbH and Co KG
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Publication date
Application filed by Meda Pharma GmbH and Co KG filed Critical Meda Pharma GmbH and Co KG
Publication of EP2714005A1 publication Critical patent/EP2714005A1/en
Withdrawn legal-status Critical Current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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K9/08—Solutions
    • 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
    • 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 present invention relates to a nasal formulation containing as active ingredient an intranasal corticosteroid.
  • the invention relates to a nasal formulation comprising fluticasone or its pharmaceutically usable esters or salts.
  • the invention relates to a nasal formulation containing fluticasone propionate.
  • the present invention further relates to a method for prophylaxis or
  • nasal Formulation containing as active ingredient an intranasal corticosteroid, preferably fluticasone or its pharmaceutically usable ester or salts.
  • the invention relates to a method for the prophylaxis or treatment of seasonal or perennial allergic rhinitis and rhinoconjunctivitis with a nasal formulation containing fluticasone propionate.
  • the present invention furthermore relates to a process for the preparation of a nasal formulation containing as active ingredient an intranasal corticosteroid, preferably fluticasone or its pharmaceutically usable esters or salts.
  • the invention relates to a method for
  • Allergic rhinitis is a global health problem with increasing prevalence. At present, about 500 million people worldwide are affected. Symptoms of allergic rhinitis affect social life, sleep, and learning
  • intranasal corticosteroids are the treatment of choice (LaForce J Allergy Clin Immunol 1999; 103: S388-S94; Brozek et al., J Allergy Clin Immunol 2010; 126: 466-76, Wallace J Allergy Clin Immunol. 2008 Aug; 122 (2 Suppl): S1-84).
  • Fluticasone is an active ingredient in the class of corticosteroids and is becoming
  • Formulations for nasal application in the market are, for example, Flutide, Flonase or Fluticasone Propionate Nasal Spray 50 pg (Roxane Laboratories).
  • the active ingredient fluticasone is microfine dispersed in the liquid.
  • the object of the present invention is to provide a corticosteroid-containing drug for the treatment of allergic rhinitis with improved efficacy.
  • the object is achieved by a nasal formulation of fluticasone, in particular fluticasone propionate, containing as excipients microcrystalline cellulose +
  • Na carboxymethylcellulose (Avicel CL 61 1), disodium edetate, polysorbate 80, glycerol, benzalkonium chloride, phenylethyl alcohol.
  • the nominal dose of fluticasone propionate is 50 pg.
  • a key parameter for the efficiency of locally applied and locally acting substances is the nominal dose of the drug being administered. In general, it is assumed that medicinal products with the same nominal dose of the same active substance show comparable effects. (Le Souef, Allergy 1999, 54, S93-96)
  • the formulation according to the invention has the advantage that the corticoid futicasone is better available locally in the nose despite the same nominal dose (Derendorf, et al., 2012 Br J Clin Pharmacol accepted) and can exert a stronger effect there:
  • Table 1 shows the comparison between the formulation according to the invention according to Example 1 and a formulation of the prior art (Fluticasone Propionate Nasal Spray 50 mg (Roxane Laboratories)) with the same nominal dose. The results are given as the baseline difference, if not otherwise
  • iTNSS Instantaneous Total Nasal Symptom Score
  • TOSS Total Ocular Symptom Score
  • Fluticasone values in [pg / ml] are plotted over time in Figure 1 and show the extent of improvement in availability:
  • inventions comprise, instead of fluticasone or one of its pharmaceutically usable esters or salts, one or more active substances from the group of intranasal corticosteroids, budesonides,
  • Beclomethasone mometasone, triamcinolone, dexamethasone, ciclesonide or their pharmaceutically acceptable salts or esters.
  • the formulation optionally contains one or more excipients from the group of suspending agents / thickeners, such as carboxymethylcellulose, hydroxymethylcellulose, methylcellulose, gelatin, polyvinylpyrrolidone,
  • Na carboxymethylcellulose (Avicel CL 61 1), chelating agents, preferably disodium edetate, wetting agents, such as polyoxyethylene derivatives of fatty acids or
  • Polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides preferably polysorbate 80, osmotically active substances, such as sucrose, glucose, sorbitol, Propylene glycol, NaCl preferably glycerol and preservatives, such as thiomersal, benzyl alcohol, alkonium and benzalkonium salts, Chlorhexidinglukonat, preferably benzalkonium chloride and phenylethyl alcohol.
  • the preparation of the formulation according to the invention is carried out, for example, by tempering purified water to 30-40.degree. Become one after another
  • Disodium edetate and glycerol added and each about 5 min. mixed.
  • Microcrystalline cellulose and Na carboxymethyl cellulose are passed through
  • Phenylethyl alcohol is added and mixed with stirring for about 10 minutes. After addition of purified water, the suspension for about 30 min.
  • the formulation is administered via spray bottles with commercially available pumps, such as those from the companies Aptar or MeadWestvaco
  • the formulation according to the invention is applied with a droplet size of not more than 150 ⁇ m, preferably between 50 ⁇ m and 100 ⁇ m, more preferably between 75 ⁇ m and 95 ⁇ m, in half of the droplets in the administered dosage unit.
  • a dosage unit contains between 10 and 200 g, preferably between 25 and 100 g, more preferably between 40 and 60 pg of the intranasal corticosteroid.
  • one unit dose contains 50 pg fluticasone propionate.
  • the dosage unit of the intranasal corticosteroid is administered in a volume between 50 and 250 ⁇ , preferably between 100 and 150 ⁇ .
  • one unit dose of fluticasone propionate is administered in a volume of 137 ⁇ per puff.
  • 1-2 sprays are administered once or twice a day for a total of 2-8 sprays a day, more preferably one for each nostril, 1 spray in the morning and 1 spray in the evening for a total of 4 sprays per day.
  • compositions are given by way of example, without the invention being restricted thereby:

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a nasal formulation comprising as its active ingredient an intranasal corticosteroid, and also to a method for prophylaxis or treatment of seasonal or perennial allergic and non-allergic rhinitis and rhinoconjunctivitis.

Description

NASALE PHARMAZEUTISCHE FORMULIERUNG ENTHALTEND FLUTICASON  NASAL PHARMACEUTICAL FORMULATION CONTAINING FLUTICASON
Die vorliegende Erfindung betrifft eine nasale Formulierung enthaltend als Wirkstoff ein intranasales Kortikosteroid. In einer bevorzugten Ausführung betrifft die Erfindung eine nasale Formulierung enthaltend Fluticason oder dessen pharmazeutisch einsetzbaren Ester oder Salze. In einer besonders bevorzugten Ausführungsform betrifft die Erfindung eine nasale Formulierung enthaltend Fluticasonpropionat. The present invention relates to a nasal formulation containing as active ingredient an intranasal corticosteroid. In a preferred embodiment, the invention relates to a nasal formulation comprising fluticasone or its pharmaceutically usable esters or salts. In a particularly preferred embodiment, the invention relates to a nasal formulation containing fluticasone propionate.
Die vorliegende Erfindung betrifft weiterhin eine Methode zur Prophylaxe oder The present invention further relates to a method for prophylaxis or
Behandlung der saisonalen oder perennialen allergischen und nicht allergischen Rhinitis und Rhinokonjunktivitis sowie zur Behandlung von nasalen Polypen, zur Polyp- Rezidivprohylaxe nach einer operativen Entfernung nasaler Polypen, als adjuvante Therapie bei akuter und chronischer Sinusitis, bei Schlafapnoe, Schnarchen oder entzündungsbedingten obstruktiven Schlafstörungen mit einer nasalen Formulierung enthaltend als Wirkstoff ein intranasales Kortikosteroid, bevorzugt Fluticason oder dessen pharmazeutisch einsetzbaren Ester oder Salze. In einer besonders bevorzugten Ausführungsform betrifft die Erfindung eine Methode zur Prophylaxe oder Behandlung der saisonalen oder perennialen allergischen Rhinitis und Rhinokonjunktivitis mit einer nasalen Formulierung enthaltend Fluticasonpropionat. Treatment of seasonal or perennial allergic and non-allergic rhinitis and rhinoconjunctivitis and for the treatment of nasal polyps, for polyp relapse prophylaxis after surgical removal of nasal polyps, as adjunctive therapy in acute and chronic sinusitis, in sleep apnea, snoring or inflammatory obstructive sleep disorders with nasal Formulation containing as active ingredient an intranasal corticosteroid, preferably fluticasone or its pharmaceutically usable ester or salts. In a particularly preferred embodiment, the invention relates to a method for the prophylaxis or treatment of seasonal or perennial allergic rhinitis and rhinoconjunctivitis with a nasal formulation containing fluticasone propionate.
Die vorliegende Erfindung betrifft weiterhin ein Verfahren zur Herstellung einer nasalen Formulierung enthaltend als Wirkstoff ein intranasales Kortikosteroid, bevorzug Fluticason oder dessen pharmazeutisch einsetzbaren Ester oder Salze. In einer bevorzugten Ausführungsform betrifft die Erfindung ein Verfahren zur The present invention furthermore relates to a process for the preparation of a nasal formulation containing as active ingredient an intranasal corticosteroid, preferably fluticasone or its pharmaceutically usable esters or salts. In a preferred embodiment, the invention relates to a method for
Herstellung einer nasalen Formulierung enthaltend Fluticasonpropionat Preparation of a nasal formulation containing fluticasone propionate
Allergische Rhinitis ist ein globales Gesundheitsproblem mit steigender Verbreitung. Zur Zeit sind ca. 500 Millionen Menschen weltweit davon betroffen. Symptome der allergischen Rhinitis beeinflussen das Sozialleben, den Schlaf, die Lern- und Allergic rhinitis is a global health problem with increasing prevalence. At present, about 500 million people worldwide are affected. Symptoms of allergic rhinitis affect social life, sleep, and learning
Arbeitsfähigkeit und werden damit zu einer substanziellen Belastung (Bousquet et al., Allergy. 2008 Apr;63 Suppl 86:8-160). Ability to work and thus become a substantial burden (Bousquet et al., Allergy, 2008 Apr; 63 Suppl 86: 8-160).
Für Patienten mit stärkeren Symptomen, insbesondere verstopfter Nase, sind intranasale Kortikosteroide die Behandlung der Wahl (LaForce J Allergy Clin Immunol 1999; 103: S388-S94; Brozek et al., J Allergy Clin Immunol 2010;126:466-76, Wallace J Allergy Clin Immunol. 2008 Aug; 122(2 Suppl):S1-84). For patients with more severe symptoms, especially nasal congestion, intranasal corticosteroids are the treatment of choice (LaForce J Allergy Clin Immunol 1999; 103: S388-S94; Brozek et al., J Allergy Clin Immunol 2010; 126: 466-76, Wallace J Allergy Clin Immunol. 2008 Aug; 122 (2 Suppl): S1-84).
Fluticason ist ein Wirkstoff aus der Klasse der Kortikosteroide und wird zur Fluticasone is an active ingredient in the class of corticosteroids and is becoming
Behandlung der saisonalen oder perennialen allergischen Rhinitis eingesetzt. Treatment of seasonal or perennial allergic rhinitis used.
Formulierungen zur nasalen Applikation auf dem Markt sind beispielsweise Flutide, Flonase oder Fluticasone Propionate Nasal Spray 50 pg (Roxane Laboratories). In den Suspensionen liegt der Wirkstoff Fluticason mikrofein dispergiert in der Flüssigkeit vor. Formulations for nasal application in the market are, for example, Flutide, Flonase or Fluticasone Propionate Nasal Spray 50 pg (Roxane Laboratories). In the suspensions, the active ingredient fluticasone is microfine dispersed in the liquid.
Analysen zeigen jedoch, dass über 60% der Patienten mit allergischer Rhinitis nicht mit ihrer derzeitigen Behandlung zufrieden sind, insbesondere aufgrund mangelnder Wirksamkeit (Bousquet, J Allergy Clin Immunol. 2009 Sep; 124(3):428-33). Deshalb besteht Bedarf nach verbesserten Arzneimitteln zur Behandlung der allergischen Rhinitis. However, analyzes show that over 60% of patients with allergic rhinitis are not satisfied with their current treatment, especially due to lack of efficacy (Bousquet, J Allergy Clin Immunol 2009 Sep; 124 (3): 428-33). Therefore, there is a need for improved drugs for the treatment of allergic rhinitis.
Aufgabe der vorliegenden Erfindung ist die Bereitstellung eines Kortikosteroid haltigen Arzneimittels zur Behandlung der allergischen Rhinitis mit verbesserter Wirksamkeit. Die Aufgabe wird gelöst durch eine nasale Formulierung von Fluticason, insbesondere Fluticasonpropionat, enthaltend als Hilfsstoffe Mikrokristalline Cellulose + The object of the present invention is to provide a corticosteroid-containing drug for the treatment of allergic rhinitis with improved efficacy. The object is achieved by a nasal formulation of fluticasone, in particular fluticasone propionate, containing as excipients microcrystalline cellulose +
NaCarboxymethylcellulose (Avicel CL 61 1), Dinatrium Edetat, Polysorbat 80, Glycerol, Benzalkoniumchlorid, Phenylethylalkohol. Die nominale Dosis von Fluticasonpropionat beträgt 50 pg. Na carboxymethylcellulose (Avicel CL 61 1), disodium edetate, polysorbate 80, glycerol, benzalkonium chloride, phenylethyl alcohol. The nominal dose of fluticasone propionate is 50 pg.
Ein entscheidender Parameter für die Effizienz lokal applizierter und lokal wirkender Substanzen ist die nominale Dosis des Wirkstoffs, die verabreicht wird. Generell wird davon ausgegangen, dass Arzneimittel mit der gleichen nominalen Dosis desselben Wirkstoffs vergleichbare Wirkung zeigen. (Le Souef, Allergy 1999, 54, S93-96) A key parameter for the efficiency of locally applied and locally acting substances is the nominal dose of the drug being administered. In general, it is assumed that medicinal products with the same nominal dose of the same active substance show comparable effects. (Le Souef, Allergy 1999, 54, S93-96)
Die erfindungsgemäße Formulierung hat gegenüber dem Stand der Technik den Vorteil, dass das Kortikoid Futicason trotz gleicher nominaler Dosis besser lokal in der Nase verfügbar wird (Derendorf, et al, 2012 Br J Clin Pharmacol accepted) und dort eine stärkere Wirkung entfalten kann: Tabelle 1 zeigt den Vergleich zwischen der erfindungsgemäßen Formulierung gemäß Beispiel 1 und einer Formulierung aus dem Stand der Technik (Fluticasone Propionate Nasal Spray 50 Mg (Roxane Laboratories))mit gleicher nominaler Dosis. Dabei werden die Ergebnisse als Differenz zur Baseline angegeben, wenn nicht anders Compared to the prior art, the formulation according to the invention has the advantage that the corticoid futicasone is better available locally in the nose despite the same nominal dose (Derendorf, et al., 2012 Br J Clin Pharmacol accepted) and can exert a stronger effect there: Table 1 shows the comparison between the formulation according to the invention according to Example 1 and a formulation of the prior art (Fluticasone Propionate Nasal Spray 50 mg (Roxane Laboratories)) with the same nominal dose. The results are given as the baseline difference, if not otherwise
gekennzeichnet (rTNSS: reflective Total Nasal Symptom Score; iTNSS: instantaneous Total Nasal Symptom Score; TOSS: Total Ocular Symptom Score) : Total Total Nasal Symptom Score (iTNSS: Instantaneous Total Nasal Symptom Score; TOSS: Total Ocular Symptom Score)
Tabelle 1 Table 1
Im Vergleich zu vor der Behandlung gehen der nasale und okulare Symptom-Score sowie auch die einzelnen Beschwerden deutlicher zurück als unter herkömmlichen Fluticason Nasensprays in gleicher nominaler Dosierung. Während herkömmliches Fluticason den Summenscore aus den vier relevanten nasalen Symptomen (Nasale Verstopfung, Niesen, laufende Nase, Nasenjucken) auf einer Skala von 0 bis 24 unter 14-tägiger Therapie im Mittel lediglich um 3.8 Punkte verändert (Hampel et al Ann Allergy Asthma Immunol. 2010; 105:S168-73), gelingt dies unter der neuen Formulierung mit 5.1 Punkten deutlich besser (Carr et al. J Allergy Clin Immunol 129(5) 2012 S1282-1289). Compared to before treatment, the nasal and ocular symptom score as well as the individual complaints are more pronounced than with conventional fluticasone nasal sprays in the same nominal dosage. Whereas conventional fluticasone changed the sum score of the four relevant nasal symptoms (nasal congestion, sneezing, runny nose, nasal itching) only by 3.8 points on a scale of 0 to 24 under 14-day therapy (Hampel et al Ann Allergy Asthma Immunol. 2010; 105: S168-73), this succeeds under the new Formulation with 5.1 points significantly better (Carr et al J Allergy Clin Immunol 129 (5) 2012 S1282-1289).
Wie oben erwähnt, beruht die bessere Wirksamkeit auf der besseren lokalen As mentioned above, the better effectiveness is based on the better local
Verfügbarkeit des Wirkstoffs, die sich in der besseren systemischen Bioverfügbarkeit reflektiert. Das systemisch verfügbare Fluticason muss im Wesentlichen über die Nasenschleimhaut resorbiert worden sein, da die orale Resorption bei nur etwa 1 % liegt. Die bessere Bioverfügbarkeit wurde in der Studie von Derendorf, et al, 2012 gezeigt. Availability of the drug, which is reflected in the better systemic bioavailability. The systemically available fluticasone must have been absorbed essentially via the nasal mucosa, since the oral absorption is only about 1%. The better bioavailability was shown in the study by Derendorf, et al, 2012.
In einer der beiden randomisierten, 3-Perioden, 6-Sequenzen, 3-Behandlungen Cross- over Studie wurde 19 gesunden Probanden jeweils einmalig 200 [ig Fluticason intranasal (nominal 50 Mg, 2 Sprays in jedes Nasenloch) verabreicht, als In one of the two randomized, 3-period, 6-sequence, 3-treatment crossover studies, 19 healthy volunteers were each given a single dose of fluticasone intranasal (nominally 50 mg, 2 sprays in each nostril)
herkömmlicher Standard (Fluticasone Propionate Nasal Spray 50 g (Roxane conventional standard (Fluticasone Propionate Nasal Spray 50 g (Roxane
Laboratories)) und in der erfindungsgemäßen Formulierung (New) gemäß Beispiel 1. Serum Fluticason wurde über 24 Stunden gemessen. Die durchschnittlichen Laboratories)) and in the inventive formulation (New) according to Example 1. Serum fluticasone was measured over 24 hours. The average
Fluticasonwerte in [pg/ml] sind in Figur 1 über die Zeit aufgetragen und zeigen das Ausmaß der Verbesserung in der Verfügbarkeit: Fluticasone values in [pg / ml] are plotted over time in Figure 1 and show the extent of improvement in availability:
Weitere Ausführungsformen der Erfindung enthalten an Stelle von Fluticason oder einem seiner pharmazeutisch einsetzbaren Ester oder Salze eines oder mehrere Wirkstoffe aus der Gruppe der intranasalen Kortikosteroiden Budesonide, Further embodiments of the invention comprise, instead of fluticasone or one of its pharmaceutically usable esters or salts, one or more active substances from the group of intranasal corticosteroids, budesonides,
Beclomethason, Mometason, Triamcinolon, Dexamethason, Ciclesonid oder ihren pharmazeutisch einsetzbaren Salzen oder Estern. Beclomethasone, mometasone, triamcinolone, dexamethasone, ciclesonide or their pharmaceutically acceptable salts or esters.
Die Formulierung enthält gegebenenfalls einen oder mehrere Hilfsstoffe aus der Gruppe der Suspensionsvermittler/Verdickungsmitteln, wie Carboxymethylcellulose, Hydroxymethylcellulose, Methylcellulose, Gelatine, Polyvinylpyrrolidon, The formulation optionally contains one or more excipients from the group of suspending agents / thickeners, such as carboxymethylcellulose, hydroxymethylcellulose, methylcellulose, gelatin, polyvinylpyrrolidone,
Polyethylenglycol, Polyvinylalkohol, bevorzugt Mikrokristalline Cellulose + Polyethylene glycol, polyvinyl alcohol, preferably microcrystalline cellulose +
NaCarboxymethylcellulose (Avicel CL 61 1), Chelatbildner, bevorzugt Dinatriumedetat, Benetzungsmittel, wie Polyoxyethylenderivate von Fettsäuren oder Na carboxymethylcellulose (Avicel CL 61 1), chelating agents, preferably disodium edetate, wetting agents, such as polyoxyethylene derivatives of fatty acids or
Polyoxyethylenderivate von Fettsäureteilestern von Sorbitolanhydriden, bevorzugt Polysorbat 80, osmotisch aktiven Substanzen, wie Saccharose, Glukose, Sorbitol, Propylenglykol, NaCI bevorzugt Glycerol sowie Konservierungsstoffe, wie Thiomersal, Benzylalkohol, Alkonium-und Benzalkoniumsalze, Chlorhexidinglukonat, bevorzugt Benzalkoniumchlorid und Phenylethylalkohol. Polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydrides, preferably polysorbate 80, osmotically active substances, such as sucrose, glucose, sorbitol, Propylene glycol, NaCl preferably glycerol and preservatives, such as thiomersal, benzyl alcohol, alkonium and benzalkonium salts, Chlorhexidinglukonat, preferably benzalkonium chloride and phenylethyl alcohol.
Die Herstellung der erfindungsgemäßen Formulierung erfolgt beispielsweise, indem gereinigtes Wasser auf 30 - 40°C temperiert wird. Nacheinander werden The preparation of the formulation according to the invention is carried out, for example, by tempering purified water to 30-40.degree. Become one after another
Dinatriumedetat und Glycerin zugegeben und jeweils ca. 5 min. gemischt.  Disodium edetate and glycerol added and each about 5 min. mixed.
Mikrokristalline Cellulose und NaCarboxymethylcellulose werden durch ein  Microcrystalline cellulose and Na carboxymethyl cellulose are passed through
40 Maschensieb gesiebt und dann unter Rühren zugegeben und ca. 30 min weiter gerührt.  Sifted 40 mesh screen and then added with stirring and stirred for about 30 min further.
In einem separaten Gefäß wird Polysorbat 80 mit gereinigtem Wasser ca. 5 min. gerührt. Unter weiterem Rühren wird Fluticasonproionat zugegeben und weiter für ca. 30 min. gerührt. In a separate vessel Polysorbate 80 with purified water for about 5 min. touched. With further stirring, fluticasone propionate is added and continued for about 30 min. touched.
Beide Dispersionen werden zusammengeführt und für weitere ca.10 min. gemischt. Benzalkoniumchloridlösung 10% (w/v) wird zugegeben und unter ca. 10 minütigem Rühren gemischt. Both dispersions are brought together and for a further ca. 10 min. mixed. Benzalkonium chloride solution 10% (w / v) is added and mixed with stirring for about 10 minutes.
Phenylethylalkohol wird zugegeben und unter ca. 10 minütigem Rühren gemischt. Nach Zugabe von gereinigtem Wasser wird die Suspension für ca. 30 min. Phenylethyl alcohol is added and mixed with stirring for about 10 minutes. After addition of purified water, the suspension for about 30 min.
homogenisiert und durch ein 200 Maschensieb gegeben. homogenized and passed through a 200 mesh screen.
Die Verabreichung der Formulierung erfolgt über Sprühflaschen mit handelsüblichen Pumpen, wie sie beispielsweise von den Firmen Aptar oder MeadWestvaco The formulation is administered via spray bottles with commercially available pumps, such as those from the companies Aptar or MeadWestvaco
Corporation bekannt sind. Besonders bevorzugt wird die Pumpe VP3/140F CS20-AG von Aptar. Corporation are known. Particularly preferred is the pump VP3 / 140F CS20-AG from Aptar.
Die erfindungsgemäße Formulierung wird mit einer Tröpfchengröße von nicht mehr als 150 pm, bevorzugt zwischen 50 pm und 100 pm, besonders bevorzugt zwischen 75 pm und 95 pm bei der Hälfte der Tröpfchen in der verabreichten Dosiseinheit appliziert. Eine Dosiseinheit enthält zwischen 10 und 200 g, vorzugsweise zwischen 25 und 100 g, besonders bevorzugt zwischen 40 und 60 pg des intranasalen Kortikosteroids. Beispielsweise enthält eine Dosiseinheit 50 pg Fluticasonpropionat. The formulation according to the invention is applied with a droplet size of not more than 150 μm, preferably between 50 μm and 100 μm, more preferably between 75 μm and 95 μm, in half of the droplets in the administered dosage unit. A dosage unit contains between 10 and 200 g, preferably between 25 and 100 g, more preferably between 40 and 60 pg of the intranasal corticosteroid. For example, one unit dose contains 50 pg fluticasone propionate.
Die Dosiseinheit des intranasalen Kortikosteroids wird in einem Volumen zwischen 50 und 250 μΙ, bevorzugt zwischen 100 und 150 μΙ verabreicht. Beispielsweise wird eine Dosiseinheit Fluticasonpropionat in einem Volumen von 137 μΙ pro Sprühstoß verabreicht. The dosage unit of the intranasal corticosteroid is administered in a volume between 50 and 250 μΙ, preferably between 100 and 150 μΙ. For example, one unit dose of fluticasone propionate is administered in a volume of 137 μΙ per puff.
Pro Nasenloch werden 1-2 Sprühstöße einmal oder zweimal täglich verabreicht, damit insgesamt 2-8 Sprühstöße am Tag, besonders bevorzugt wird pro Nasenloch 1 Sprühstoß am Morgen und 1 Sprühstoß am Abend verabreicht, damit insgesamt 4 Sprühstöße am Tag. For each nostril, 1-2 sprays are administered once or twice a day for a total of 2-8 sprays a day, more preferably one for each nostril, 1 spray in the morning and 1 spray in the evening for a total of 4 sprays per day.
Beispiele: Examples:
Die folgenden Zusammensetzungen sind beispielhaft aufgeführt, ohne dass die Erfindung dadurch eingeschränkt werden soll:  The following compositions are given by way of example, without the invention being restricted thereby:
Beispiel 1 : Example 1 :
Beispiel 2: Example 2:

Claims

Ansprüche claims
1. Nasale pharmazeutische Formulierung enthaltend Fluticason oder eines seiner pharmazeutisch verwendbaren Ester oder Salze und gegebenenfalls einen oder mehrere Hilfsstoffe. 1. Nasal pharmaceutical formulation containing fluticasone or one of its pharmaceutically acceptable esters or salts and optionally one or more excipients.
2. Formulierung gemäß Anspruch 1, dadurch gekennzeichnet, dass 2. Formulation according to claim 1, characterized in that
Fluticasonpropionat eingesetzt wird.  Fluticasone propionate is used.
3. Formulierung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass ein oder mehrere Hilfsstoffe aus der Gruppe der Suspensionsvermittler, Chelatbildner, Benetzungsmittel, osmotisch aktiven Substanzen, Konservierungsstoffe enthalten sind. 3. Formulation according to claim 1 or 2, characterized in that one or more auxiliaries from the group of the suspension agents, chelating agents, wetting agents, osmotically active substances, preservatives are included.
4. Formulierung gemäß Anspruch 3, dadurch gekennzeichnet, dass als 4. Formulation according to claim 3, characterized in that as
Suspensionsvermittler Mikrokristalline Cellulose und Na Carboxymethylcellulose (Avicel CL 611) enthalten ist.  Suspension Mediator Microcrystalline cellulose and Na carboxymethylcellulose (Avicel CL 611) is included.
5. Formulierung gemäß Anspruch 3, dadurch gekennzeichnet, dass als 5. Formulation according to claim 3, characterized in that as
Chelatbildner Dinatriumedetat enthalten ist.  Chelating agent disodium edetate is included.
6. Formulierung gemäß Anspruch 3, dadurch gekennzeichnet, dass als 6. Formulation according to claim 3, characterized in that as
Benetzungsmittel Polysorbat 80 enthalten ist.  Wetting agent polysorbate 80 is included.
7. Formulierung gemäß Anspruch 3, dadurch gekennzeichnet, dass als osmotisch aktive Substanz Glycerol enthalten ist. 7. A formulation according to claim 3, characterized in that is contained as the osmotically active substance glycerol.
8. Formulierung gemäß Anspruch 3, dadurch gekennzeichnet, dass als Formulation according to claim 3, characterized in that as
Konservierungsstoffe mindestens einer aus der Gruppe enthaltend  Preservatives containing at least one of the group
Benzalkoniumchlorid und Phenylethylalkohol enthalten ist. Benzalkonium chloride and phenylethyl alcohol is included.
9. Formulierung gemäß einem der vorhergehenden Ansprüche, dadurch gekennzeichnet, dass sie über eine Sprühpumpe verabreicht wird. 9. Formulation according to one of the preceding claims, characterized in that it is administered via a spray pump.
10. Verwendung einer Formulierung gemäß einem der vorhergehenden Ansprüche zur Prophylaxe oder Behandlung der allergischen saisonalen oder perennialen Rhinitis oder Rhinokonjunktivitis . 10. Use of a formulation according to any one of the preceding claims for the prophylaxis or treatment of allergic seasonal or perennial rhinitis or rhinoconjunctivitis.
EP12745769.5A 2011-05-27 2012-05-24 Nasal pharmaceutical formulation Withdrawn EP2714005A1 (en)

Applications Claiming Priority (2)

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DE102011103347.9A DE102011103347B4 (en) 2011-05-27 2011-05-27 Nasal pharmaceutical formulation
PCT/EP2012/002222 WO2012163501A1 (en) 2011-05-27 2012-05-24 Nasal pharmaceutical formulation

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US (1) US20140194400A1 (en)
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JP (1) JP2014515360A (en)
CN (1) CN103561721A (en)
AU (1) AU2012265231B2 (en)
BR (1) BR112013030260A2 (en)
CA (1) CA2836025A1 (en)
DE (1) DE102011103347B4 (en)
EA (1) EA025203B1 (en)
GE (1) GEP201606577B (en)
IL (1) IL229497A0 (en)
MX (1) MX2013013879A (en)
WO (1) WO2012163501A1 (en)
ZA (1) ZA201308905B (en)

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CA2953207A1 (en) * 2014-06-25 2015-12-30 Optinose As Nasal administration

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GEP201606577B (en) 2016-11-25
US20140194400A1 (en) 2014-07-10
IL229497A0 (en) 2014-01-30
CA2836025A1 (en) 2012-12-06
EA025203B1 (en) 2016-11-30
AU2012265231B2 (en) 2016-09-08
DE102011103347A1 (en) 2012-11-29
NZ616149A (en) 2015-11-27
EA201391686A1 (en) 2014-03-31
DE102011103347B4 (en) 2014-10-30
ZA201308905B (en) 2015-03-25
MX2013013879A (en) 2014-01-23
BR112013030260A2 (en) 2016-12-06
WO2012163501A9 (en) 2013-03-07
JP2014515360A (en) 2014-06-30
WO2012163501A1 (en) 2012-12-06

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