Aqueous nasal formulation

Details Aqueous nasal formulation Aqueous nasal formulation

2002-05-16

2004-08-24

Page, Thurman K. (Department: 1616)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C424S046000, C424S434000, C424S493000, C514S853000

Reexamination Certificate

active

06780398

ABSTRACT:

The present invention relates to an aqueous nasal formulation for use in the treatment of respiratory disorders.
Aerosol formulations are commonly used as effective anti-inflammatory treatments, but have implications with environmental safety. The most commonly used propellants in such formulations were previously chlorofluorocarbon containing (or CFC) propellants, however, these are currently being phased out, following the 1987 Montreal Protocol Agreement.
Since then, safer hydrogen containing fluorocarbons have been used as propellants in aerosol formulations, but these are relatively expensive and the environmental impact of these new propellants has also been questioned.
Thus, there is a need for safe anti-inflammatory treatments such as aqueous nasal formulations. The corticosteroid beclomethasone dipropionate (9&agr;-chloro-16&bgr;-methyl-1,4-pregnadiene-11&agr;, 17&agr;, 21-triol-3, 20-dione-17,&agr;21-dipropionate) is well known as a topical anti-inflammatory steroid and is found in aqueous nasal formulations.
Prior aqueous nasal formulations containing beclomethasone dipropionate, used in treating such indications as allergic rhinitis (such as Beconase™AQ) have utilised beclomethasone dipropionate monohydrate in addition to the following constituents:
Anhydrous dextrose;
Avicel RC591 (Microcrystalline cellulose and carboxymethylcellulose sodium);
Phenylethyl alcohol;
Benzalkonium chloride;
Polyoxyethylene (20) sorbitan monooleate; and purified water
Beclomethasone dipropionate monohydrate is not currently licensed in all territories of the world (notably not in Japan) and as a consequence, nasal formulations containing such a medicament cannot be marketed in such territories without substantial research effort and expense. However, there is an alternative anhydrous form of beclomethasone dipropionate, previously used in a nasal formulation (eg. Aldecin™ AQ) which contains the following constituents:
Micronised beclomethasone dipropionate anhydrate;
Avicel RC591 (Microcrystalline cellulose and carboxymethylcellulose sodium);
Glycerol;
Propylene glycol:
Polyoxyethylene (20) sorbitan monooleate; and purified water.
However, in the absence of a sealed pressurised container, as with the propellant based delivery systems, these formulations may be prone to contamination. As a consequence, potentially harmful bacteria may contaminate the formulation and then be inhaled directly into the nasal cavity. Additionally, these formulations have also been known to cause irritancy, which is especially undesirable in respect of paediatric treatment.
Thus, according to the present invention we provide a pharmaceutical formulation which comprises an aqueous solution of carboxy methylcellulose sodium, glycerol, propylene glycol and polyoxyethylene (20) sorbitan monooleate, containing suspended therein particulate microcrystalline cellulose and beclomethasone dipropionate anhydrate characterised in that said aqueous suspension further comprises:
Dextrose;
Phenylethyl alcohol;
Benzalkonium chloride;
Disodium hydrogen orthophosphate; and
Citric acid
The presence of dextrose, disodium hydrogen orthophosphate and citric acid is intended to overcome the irritancy problems associated with current anhydrous beclomethasone dipropionate formulations. This improvement is believed to be mediated through the dextrose acting as an isotonicity adjusting agent. Furthermore, the beclomethasone dipropionate anhydrate may be stabilised by appropriate selection of pH using disodium hydrogen orthophosphate and citric acid to act as a buffer.
In addition, phenylethylalcohol and benzalkonium chloride are present within the formulation to act as preservatives.
Dextrose is preferably used as dextrose anhydrous. Disodium hydrogen orthophosphate is preferably used as disodium hydrogen orthophosphate anhydrous. Citric acid is preferably used as citric acid monohydrate. Microcrystalline cellulose and carboxy methylcellulose sodium is preferably used as the branded product Avicel RC591 (which typically contains 87-91% microcrystalline cellulose and 9-13% carboxy methylcellulose sodium).
Particulate beclomethasone dipropionate anhydrate will suitably be micronised and have a mean particle size less than 20&mgr;m, preferably less than 10&mgr;m, especially 1-5&mgr;m. Particulate microcrystalline cellulose will preferably have a particle size in the range 1 to 100&mgr;m.
A pharmaceutically acceptable amount of micronised beclomethasone dipropionate anhydrate is present within the formulation, which is preferably between 0.025-0.25% (w/w), especially 0.1% (w/w). The branded product Avicel RC591 and propylene glycol are suspending agents and are desirably added in a suitable amount to achieve this function, preferably between 1-5% and 0.1-20% (w/w) respectively, especially 1.5% and 1.0% (w/w) respectively.
We believe that Avicel RC591 acts as a suspending agent by imparting thixotropic properties to the formulation, wherein the formulation may become a stable suspension upon being stirred, shaken or otherwise disturbed. We similarly believe that propylene glycol aids stabilization of the formulation by reducing the bubbles which arise due to the presence of Avicel RC591 and benzalkonium chloride in the formulation.
Glycerol is added in a suitable amount to achieve its desired function as an excipient which reduces the solubility of beclomethasone dipropionate anhydrate in formulation; preferably the amount of glycerol will be such as to make the beclomethasone dipropionate anhydrate essentially insoluble in the formulation. An amount of glycerol which is preferably between 0.1-6% (w/w), especially 4.0% (w/w) will be suitable. The wetting agent, polyoxyethylene (20) sorbitan monooleate (typically supplied as the branded product Polysorbate 80) is desirably added in a sufficient quantity to achieve this function, preferably between 0.001-0.01% (w/w), especially 0.007% (w/w). The components disodium hydrogen orthophosphate anhydrous and citric acid monohydrate, which act as buffers, are desirably added in a suitable amount to achieve a final pH, following adjustment if necessary, of between 5 and 6, especially 5.5. Suitable concentrations of each component are 0.01-0.4% and 0.01-0.2% (w/w) respectively, especially 0.31% and 0.2% (w/w) respectively. Dextrose anhydrous is an isotonicity adjusting agent and is added in a suitable amount to achieve isotonicity with fluids of the nasal cavity. Suitable concentrations are between 0.1 and 5% (w/w), especially 5.0% w/w. Phenylethyl alcohol and benzalkonium chloride are preservatives which are preferably added in concentrations between 0.001-1% (v/w) and 0.001-1% (w/w) respectively, especially 0.275% (v/w) and 0.02% (w/w), respectively.
Besides its very good antiallergic properties and the above mentioned reduction in irritancy, the benefits of the invention may include the following:
Surprisingly, we have found that phenylethylalcohol has preservative properties by killing
Pseudomonas cepacia
(now known as
Burkhoderia cepacia
) by a synergistic effect with benzalkonium chloride.
Ps. cepacia
is a bacterium which is capable of opportunistic infections such as blood poisoning and due to the bacterium being largely resistant to antibiotics, clinical treatment is complex. Results demonstrating this effect are shown in FIG.
7
.
A formulation of the present invention may be prepared by the manufacturing process according to the flow diagram shown in FIG.
1
.
A typical container suitable for a formulation of the present invention may be of the type exemplified in
FIGS. 2 and 3
. As a further aspect of the present invention we provide a container comprising a pharmaceutical formulation according to the present invention suitable for delivering it in the form of a nasal spray.
A suitable dosing regime for the formulation of the present invention would be for the patient to inhale deeply subsequent to the nasal cavity being cleared. During inhalation the formulation would be applied to one nostril while the other is manually compressed. This procedure would then be repeated for the ot

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