NZ616149B2 - Nasal Pharmaceutical Formulation Comprising Fluticasone - Google Patents

Abstract

Provided is a nasal pharmaceutical formulation comprising fluticasone. In a preferred embodiment the formulation comprises fluticasone propionate, microcrystalline cellulose, sodium carboxymethylcellulose, disodium edetate, polysorbate 80, glycerol and one or more of benzalkonium chloride or phenylethyl alcohol, wherein the formulation is adapted to be applied as droplets and half of the droplets in the administered dose unit are between 75um and 95 um in size. The formulation may be useful for the prophylaxis or treatment of seasonal or perennial allergic and non-allergic rhinitis, and rhinoconjunctivitis. thyl alcohol, wherein the formulation is adapted to be applied as droplets and half of the droplets in the administered dose unit are between 75um and 95 um in size. The formulation may be useful for the prophylaxis or treatment of seasonal or perennial allergic and non-allergic rhinitis, and rhinoconjunctivitis.

Description

— l — Nasal pharmaceutical formulation comprising fluticasone The :present invention relates to a :nasal formulation sing an intranasal osteroid as active ingredient. In a preferred embodiment, the invention relates to a nasal formulation sing fluticasone or pharmaceutically acceptable esters or salts thereof. ha a particularly preferred embodiment, the invention relates to a nasal ation comprising fluticasone propionate.

The present invention further relates to a method for the laxis or treatment of seasonal or perennial allergic and non—allergic rhinitis and rhinoconjunctivitis and also for the treatment of nasal polyps, for prophylaxis of polyp recurrence following surgical removal of nasal polyps, as adjuvant therapy for acute and chronic sinusitis, for sleep apnea, snoring or inflammation—related obstructive sleep ers, with a nasal formulation comprising an intranasal corticosteroid as active ingredient, preferably" fluticasone or pharmaceutically' acceptable esters or salts thereof. SUI a particularly preferred embodiment, the invention relates to a method for the prophylaxis or treatment of seasonal or ial ic rhinitis and rhinoconjunctivitis with a nasal formulation comprising fluticasone propionate.

The present invention further relates to a method for preparing a nasal formulation sing an intranasal corticosteroid as active ingredient, preferably fluticasone or pharmaceutically acceptable esters or salts thereof. In a preferred embodiment, the invention relates to a method for preparing a nasal formulation sing fluticasone propionate.

Allergic rhinitis is a global health problem with increasing prevalence. Currently about 500 million people worldwide are affected by it. Symptoms of allergic rhinitis affect social life, sleep, the ability to learn and work and therefore cause erable stress uet et al., Allergy. 2008 Apr; 63 Suppl 86:8—160).

For patients with er symptoms, particularly nasal congestion, intranasal corticosteroids are the treatment of choice (LaForce J .Allergy Clin Immunol 1999; 103; pp. 388-94; Brozek et al., J Allergy Clin Immunol 2010; 126: , Wallace J Allergy Clin Immunol. 2008 Aug; 122 (2 Suppl): pp. 1—84).

Fluticasone is an active ingredient from the corticosteroid class and is used for the treatment of seasonal or' perennial allergic rhinitis. Formulations on the market for nasal application are, for example, Flutide, Flonase or Fluticasone Propionate Nasal Spray 2O 50 pg (Roxane Laboratories). In the suspensions, the active ient fluticasone is present as a microfine dispersion in the liquid. ch shows, however, that more than 60% of patients with allergic rhinitis are not satisfied with their current treatment, ularly due to lack of efficacy (Bousquet, J' Allergy" Clin. Immunol. 2009 Sep; 124(3): 428—33). Thus, there exists a need for improved medicaments for the treatment of allergic is.

The object of the present invention is to jprovide a corticosteroid—containing medicament for the treatment of allergic rhinitis with improved efficacy, or to at least e the public with. a useful choice. The _ 3 - object is achieved by means of a nasal ation of fluticasone, particularly fluticasone propionate, sing microcrystalline cellulose + Na carboxymethylcellulose (Avicel CL 611), disodium edetate, polysorbate 80, ine, benzalkonium de and. phenylethyl alcohol as auxiliaries. The nominal dose of fluticasone propionate is 50 pg.

In one aspect of the present invention, there is provided a nasal pharmaceutical ation adapted to be applied as droplets comprising fluticasone nate, microcrystalline cellulose and Na carboxy— methylcellulose (Avicel CL 611) as a suspension agent, disodium edetate as a chelating agent, polysorbate 80 as a wetting agent, glycerol as an osmotically active substance, and at least one preservative selected from the group comprising konium chloride and phenylethyl l, wherein the droplet size is between 75 um and 95 pm, in half of the droplets in an administered dose unit and wherein the formulation is formulated for administration by means of a spray pump.

A critical parameter for the ency of locally applied. and locally‘ acting substances is the nominal dose of active ingredient administered. It is generally assumed that drugs with the same nominal dose of the same active ingredient show comparable effects (LeSouef, Allergy 1999, 54, pp. 93—96). 3O The formulation according to the invention has the advantage, compared to the prior art, that the corticoid fluticasone has a better local availability [followed by page 3a] -3a... in the nose despite the same nominal dose (Derendorf et al., 2012 Br J Clin Pharmacol accepted) and can have a stronger effect there.

Table 1 shows a comparison between the inventive ation according t1) example 1. and a. formulation from the prior art casone Propionate Nasal Spray 50 Mg (Roxane Laboratories)) using the same nominal dose. The results are reported as the ence from baseline unless indicated otherwise (rTNSS: reflective Total Nasal Symptom Score; iTNSS: instantaneous Total Nasal Symptom Score; TOSS: Total Ocular Symptom Score). [followed by page 4] Parameter Inventive Comparison formulation (Fluticasone 50 pg from rTNSS —5.l —3.8 iTNSS -4.60 —3.46 rTOSS —2.71 —2.17 Nasal tion —1.10 -O.86 Nasal itching —l.lO —o.91 Ocular itching —O.96 —o.7o Watery eyes ~O.96 —0.82 rTNSS (baseline —5.42 —4.76 —__—_+ >18.9) __—L____ rTNSS (blocker) ~4.95 —3.92 Nasal congestion —l.26 -O.9O (blocker) Table 1 Compared to before treatment, the nasal and ocular symptom scores and also the individual complaints decrease more distinctly than with conventional fluticasone nasal spray at the same nominal dose. While tional fluticasone alters the overall score of the four relevant nasal symptoms (nasal congestion, sneezing, runny nose, nasal itching) on average by only 3.8 points on a scale of O to 24 during 14—day therapy (Hampel et al., Ann Allergy Asthma Immunol. 2010; 105: pp. 168—73), the new formulation. performs distinctly better at 5.1 points (Carr et al. J .Allergy Clin Immunol 129(5) 2012 pp. 1282—1289). — 5 - efficacy depends on As mentioned above, the superior the active better local availability of ingredient systemic which is reflected in the better available fluticasone bioavailability. The systemically mainly absorbed through the nasal must have been 1%. The mucosa, since oral tion. is only‘ about 6-sequence, 3— In one of two randomized, 3—period, treatment crossover studies, 19 healthy volunteers were 200 ug of each once intranasally administered fluticasone (nominally 50 in each nostril) ug, 2 sprays tional standard (Fluticasone Propionate Nasal (Roxane Laboratories)) and in the inventive Spray 50 ug 1. Serum formulation (new) ing to e fluticasone was measured over 24 hours. The mean fluticasone levels in [pg/ml] are plotted against time of in the in Figure l and show the degree improvement availability.

Further embodiments of the invention comprise, in place pharmaceutically acceptable ester of asone or a from or salt thereof, one or more active ingredients of intranasal corticosteroids consisting of the group budesonide, beclomethasone, mometasone, inolone, thasone, ciclesonide or pharmaceutically acceptable salts or esters thereof. one or more The formulation optionally comprises auxiliaries from the group of suspension agents/thickeners, such as carboxymethylcellulose, hydroxymethylcellulose, cellulose, gelatine, polyvinylpyrrolidone, polyethylene glycol, polyvinyl WO 63501 — 6 ~ alcohol, preferably microcrystalline cellulose + Na carboxymethylcellulose (Avicel CL 611), chelating agents, preferably disodium edetate, wetting agents such as polyoxyethylene derivatives of fatty acids or polyoxyethylene derivatives of partial fatty acid esters of sorbitol anhydrides, preferably" polysorbate 80, osmotically active substances such as sucrose, glucose, sorbitol, propylene glycol, NaCl, preferably glycerol, and. also preservatives such. as thiomersal, benzyl alcohol, alkonium and. konium salts, chlorhexidine ate, preferably benzalkonium chloride and phenylethyl alcohol.

The preparation of the formulation according to the invention is carried out, for example, by heating purified water to 30 — 40°C. Disodium edetate and glycerol then sively added and both are mixed are min. Microcrystalline cellulose and Na for ca. 5 carboxymethylcellulose sieved through a 40 mesh then added with stirring and the mixture sieve and are is r stirred for ca. 30 min. with a separate vessel, polysorbate 80 is stirred purified water for ca. 5 min. Fluticasone propionate is added with further stirring and the e is r stirred for ca. 30 min. further mixed The two dispersions are combined and are min. Benzalkonium chloride solution 10% for ca. 10 (w/v) is added and the mixture is mixed by stirring for ca. 10 min. is mixed Phenylethyl alcohol is added and the mixture ng for 10 min. After addition of purified by ca. — 7 — for ca. 30 min. water, the suspension is homogenized and is passed through a 200 mesh sieve.

The administration. of the formulation is effected. by with commercially available pumps, such spray bottles as those front Aptar or MeadWestvaco Corporation.

VP3/l4OF CSZO—AG pump from Aptar is particularly preferred. the invention is d The formulation according to with 150 a droplet size of no more than um, preferably between 50 um and 100 um, particularly preferably between 75 um and 95 um, in half of the droplets in the administered dose unit. dose unit comprises between 10 and 200 One pg, preferably between 25 and 100 ug, particularly ably between. 40 and 60 ug of intranasal osteroid. One dose unit comprises, for example, 50 pg of asone propionate. corticosteroid The dose unit of the intranasal is administered in a volume between 50 and 250 pl, 100 and 150 pl. A dose unit of preferably' between for example, in asone propionate is administered, a volume of 137 pl per spray. once or twice 1—2 administered sprays per nostril are daily and therefore in total 2-8 sprays per day; ular preference is given to administering l spray nostril in the morning and l spray in the evening per and therefore in total 4 sprays per day. - 8 Examples: example The following compositions are listed by way of without restricting the invention.

Example 1: ient Amount [9/100 g] '— ’1 Fluticasone 0.0365 propionate MCC+NaCMC* * 2 . o o (Avicel CL 611) Disodium 0.01 edetate L————*—*————*—*—*r—*—~—————fi Polysorbate 80 0.005 L— i Glycerol 2.30 Benzalkonium 0.01 chloride t_ n Phenylethyl 0.25 alcohol Purified water to 100 L L e 2: Ingredient Fluticasone '——“—,'—’_‘_-_‘_—__~—‘-—-l proplonate L______l_________fi.__l_.__l__J MCC+NaCMC** 2.00 (Avicel CL 611) \ um 0.01 edetate ral§cerol I_§—.30 _1 Benzalkonium 0.01 chloride 4 1 Phenylethyl 0 .25 alcohol réurified water to 100 [_______________—.—————

Claims (1)

1. Claims A nasal pharmaceutical formulation adapted to be applied as droplets comprising asone propionate, microcrystalline cellulose and Na carboxy—methylcellulose (Avicel CL 611) as a suspension agent, disodium edetate as a chelating agent, polysorbate 80 as a wetting agent, glycerol as an cally active substance, and at least one preservative selected from the group 10 sing konium chloride and. phenylethyl alcohol, wherein the droplet size is between 75 pm and 95 pm, in half of the droplets in an administered dose unit and wherein the formulation is formulated, for administration. by means of a 15 spray pump. The use of a formulation as claimed in claim 1 in the cture of a medicament for prophylaxis or treatment of allergic seasonal or perennial 20 is or rhinoconjunctivitis. The formulation as claimed in claim 1, substantially" as herein. described. with. reference to the