Patent Application
20130167838
This invention relates to a nasal formulation and particularly to a nasal formulation containing azelastine and beclomethasone dipropionate.
Azelastine is a known histamine-H1-receptor antagonist and is classified as a potent long-acting anti-allergy compound. It has the following chemical structure:
Azelastine is administered nasally and is indicated for the treatment of both seasonal allergic rhinitis (e.g. hay fever) and perennial allergic rhinitis. The commercial product on the market containing azelastine is Rhinolast® Nasal Spray. This formulation contains azelastine hydrochloride, citric acid and water. The formulation is administered from a pump dispenser.
Beclomethasone dipropionate (BDP) is a known glucocorticosteroid and has the following chemical structure:
BDP may also be administered nasally and, when administered in this manner, is indicated for the prevention and treatment of allergic rhinitis, including hay fever. The commercial product on the market containing BDP is Beconase® Hayfever Nasal Spray. This formulation contains Avicel RC 591 (microcrystalline cellulose and carboxymethylcellulose sodium), anhydrous dextrose, benzalkonium chloride (added as benzalkonium chloride solution), phenylethyl alcohol, polysorbate 80 and purified water. The formulation is administered via a metering, atomising pump and nasal applicator.
WO 2005/027839 discloses the combination of an antihistamine, e.g. azelastine, and a steroid, e.g. BDP. It is beneficial to administer azelastine and BDP in combination in order to increase patient convenience and hence compliance with the treatment. However, WO 2005/027839 is not specifically directed to the combination of azelastine and BDP and provides no general guidance on formulations nor any consideration of formulating this specific combination. Moreover, routes of administration for the various embodiments include topical, transdermal, nasal and systemic administration (e.g. intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration) and there is no particular guidance on nasal formulations.
There remains, therefore, a need for suitable formulations for administering this combination product.
Accordingly, the present invention provides a solution formulation for nasal administration comprising azelastine, beclomethasone dipropionate, a co-solvent, an acid and an HFA propellant.
The present invention will now be described with reference to the accompanying drawings, in which:
Nasal spray devices include unit-dose (single use) devices having syringe-like mechanisms and metered-dose devices intended for multiple usage cycles. Unit dose devices are appropriate for delivering certain medicaments such as vaccines, whereas metered-dose devices are more suited to long-term dosage regimes, for example for the treatment of rhinitis. The commercially available metered-dose devices discussed hereinabove comprise a vial containing an aqueous suspension of the medicament. The vial is provided with a manually operated pump adapted to atomise metered doses of the medicament formulation for delivery to the nasal cavity. Further examples of this type of nasal spray device include Flixonase® (fluticasone propionate, GSK), Nasacort AQ® (triamcinolone acetoinide, Sanofi-Aventis) and Nasonex® (momethasone furoate monohydrate, Schering-Plough).
Although nasal spray devices having manually operated pumps have achieved some success in the marketplace, they have a number of drawbacks. For example, manually operated pumps have a relatively large actuation force which may, for some users, such as the very young and the elderly, be difficult to achieve on a repeatable basis. Variations in the applied actuation force can lead to some users receiving medicament doses with less than optimal spray characteristics. Moreover, aqueous-based nasal sprays tend to suffer from post-nasal drip which is a particular problem for azelastine as it has a strong and unpleasant taste.
To address the problems associated with these known metered-dose nasal spray devices, the present inventors have replaced the manually operated pump with a pressurised aerosol canister. A typical aerosol canister comprises a cylindrical vial containing the medicament. The medicament is typically an active ingredient together with a suitable propellant. The medicament may be in the form of a solution or a suspension in the propellant and excipients may be added to facilitate dissolution of the active ingredient (e.g. co-solvents) or to stabilise the suspension (e.g. surfactants). The vial is provided with a metering valve having an axially extending valve stem. Displacement of the valve stem relative to the vial causes the dispensation of a metered dose of the medicament formulation as an aerosol. Compared to manually operated pumps, pressurised aerosol canisters require low actuation forces, provide consistent aerosol characteristics, and do not suffer from the problem of post-nasal drip.
However, a significant problem in providing a combined formulation of azelastine and BDP is that BDP is an ester and hence is unstable in the presence of acid or base (esters are well known to hydrolyse to the free acid in the presence of acid or base) and azelastine is a basic molecule. Azelastine has been marketed as the hydrochloride salt, but the problem is that the hydrochloride salt is not soluble in an HFA/ethanol formulation.
One option taken in the area of inhalable medicaments has been to formulate the BDP as a suspension. Ventide® is a suspension formulation of BDP and salbutamol sulfate. The salbutamol has to be present as the sulfate salt because salbutamol is basic and would destabilise the BDP. To address this problem, the product contains an insoluble salbutamol salt rather than the soluble free base. That is, the formulator decided to use a suspension to solve the problem of chemical instability. However, suspension formulations are less physically stable than solutions and have a tendency to agglomerate and also to block the narrow orifice in the stem block of the device.
It has now been found that a combination product containing these active ingredients can be prepared by providing a precisely defined ratio of azelastine to acid such that the azelastine is both soluble in HFA/ethanol and does not chemically degrade the BDP, allowing the product to be formulated as a solution. This allows the combination of azelastine and BDP advantageously to be formulated as an HFA solution formulation.
A therapeutically effective amount of the active ingredient needs to be delivered. The azelastine is preferably present in an amount to provide a dosage per actuation of 0.1-1 mg, more preferably 0.3-0.8 mg. The formulation will typically contain 0.20-1.00% of azelastine, calculated as the free base and based on the total weight of the formulation. The BDP is preferably present in an amount to provide a dosage per actuation of 10-200 μg, more preferably 30-100 μg. The formulation will typically contain 0.02-0.60% of BDP based on the total weight of the formulation. The formulation contains azelastine which is present in the form of both azelastine free base and an azelastine salt. This form of azelastine is prepared by combining azelastine free base with an acid. The acid is preferably hydrochloric acid, and hence the salt is preferably the hydrochloride salt. The molar ratio of azelastine free base to hydrochloric acid is preferably 6:1 to 15:1, more preferably 9:1 to 12:1. This provides further improvements to stability. In an alternative, but less preferred, embodiment the molar ratio of azelastine free base to hydrochloric acid is 9:1 to 10:9, or 2.5:1 to 4:1. A molar ratio is quoted rather than a pH value because an HFA solution provides a non-aqueous environment which renders a measure of pH inappropriate.
Typically, concentrated hydrochloric acid is used, for example 12N hydrochloric acid. An example of a suitable formulation using 12 N hydrochloric acid is as follows:
The amounts of hydrochloric acid added to the formulation range form 0.007-0.018% w/w, which corresponds to a ratio of 15:1 to 6:1. The amount of acid may be varied within this range to provide other ratios. The effect is that the azelastine is present in the form of both azelastine free base and an azelastine salt, with hydrochloric acid, the hydrochloride salt.
The water present in the formulation may accelerate the degradation and hence it is preferred to have low levels of water. Preferably water is present at 0.01-0.20 wt %, more preferably 0.02-0.05 wt %, based on the total weight of the formulation.
The propellant of the pharmaceutical solution of the present invention is a hydrofluoroalkane (HFA) propellant, more preferably an HFA propellant selected from P134a (1,1,1,2-tetrafluoroethane), P227 (1,1,1,2,3,3,3-heptafluoropropane) or mixtures thereof. Other hydrofluorocarbons, hydrocarbons or aliphatic gases (e.g. butane or dimethylether) may be added to modify the propellant characteristics as required. However, it is preferred that P134a and/or P227 are the sole propellants present and most preferably P134a is the sole propellant present. The propellant preferably constitutes 80% to 99% w/w, more preferably 90 to 98% w/w, based on the total weight of the solution.
The co-solvent is present in order to solubilise the active ingredients. The co-solvent is preferably a C2-6 aliphatic alcohol, such as ethanol or isopropyl alcohol, and preferably ethanol. The co-solvent is present in an amount sufficient to dissolve the medicaments present in the formulation and to maintain the medicaments dissolved over the time period and conditions experienced by commercial aerosol products. Preferably the solvent is present in an amount to prevent precipitation of the active ingredient even at temperatures down to −20° C. The co-solvent is typically present at 1-20% w/w, more preferably 6-15% w/w and most preferably 7-10% w/w, based on the total weight of the solution. A particularly preferred embodiment uses ethanol in a range of 1-20% w/w, more preferably 6-15% w/w and most preferably 7-10% w/w, based on the total weight of the solution.
In a specific embodiment of the present invention, the pharmaceutical solution comprises azelastine, beclomethasone dipropionate, ethanol, hydrochloric acid and a propellant selected from 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) and a mixture thereof.
In a preferred embodiment, the formulation of the present invention comprises azelastine, beclomethasone dipropionate, ethanol, hydrochloric acid and a propellant selected from 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) and a mixture thereof, wherein the molar ratio of azelastine free base to hydrochloric acid is 6:1 to 15:1.
A preferred solution formulation according to the present invention comprises 0.20-1.00% of azelastine, calculated as the free base, 0.02-0.6% w/w beclomethasone dipropionate, 1% to 20% w/w ethanol, hydrochloric acid and 80 to 99% w/w of propellant, wherein the percentages by weight are based on the total weight of the solution aerosol and the molar ratio of azelastine free base to hydrochloric acid is 6:1 to 15:1. A particularly preferred solution consists essentially of these components and more preferably the solution consists of these components.
The pharmaceutical solution of the present invention is preferably substantially free of surfactant. Surfactants are often added to suspensions to stabilise the suspension. However, since the formulation of the present invention is a solution, a surfactant is not required. Nevertheless, small quantities can be tolerated without adversely affecting the formulation. Preferably the formulation contains no more than 0.0005% w/w of a surfactant based on the total weight of the solution. Preferred formulations contain no surfactant. The presence of a significant amount of a surfactant is believed to be undesirable for solution formulations of beclomethasone dipropionate because surfactants such as oleic acid and lecithin are believed to promote chemical degradation of the active ingredient when the latter is dissolved in the mixture of the propellant and ethanol.
The formulation of the present invention is intended to be used for the prophylaxis and/or treatment of seasonal allergic rhinitis (including hay fever) and perennial rhinitis.
The pharmaceutical solution of the present invention may be prepared by dissolving the desired amount of active ingredients/acid in the desired amount of co-solvent accompanied by stirring or sonication. The aerosol canister may then be filled using conventional cold-fill or pressure-fill methods.
The present invention also provides a nasal spray device for the delivery of a pharmaceutical solution to the nasal cavity in metered doses, wherein the pharmaceutical solution is the formulation described herein. Preferably, the device comprises a pressurised aerosol canister including a vial containing the pharmaceutical solution, the aerosol canister further including a metering valve having a valve stem; and an actuator for the aerosol canister, the actuator including a stem block having a receptacle into which the valve stem of metering valve of the aerosol canister is received and axially located and being displaceable relative to the vial of the aerosol canister to actuate the metering valve of the aerosol canister, a sump extending below the receptacle, the stem block further defining a discharge orifice for the pharmaceutical solution and a transfer channel through which a dispensed dose of the pharmaceutical solution is able to pass from the sump to the discharge orifice, wherein the actuator further comprises a delivery outlet for the aerosol plume, the discharge orifice being arranged to direct the aerosol plume through the delivery outlet.
The device comprises a pressurised aerosol canister. Such canisters are known in the art and are commercially available. The aerosol canister is typically composed of aluminium or an aluminium alloy. The internal surfaces of the aerosol canister may be coated with a fluorocarbon polymer, such as PTFE or FEP, optionally together with non-fluorinated polymer to promote adhesion, such as PES. The canister includes a vial containing a pharmaceutical solution comprising an active ingredient and a propellant. The aerosol canister further includes a metering valve having a valve stem axially displaceable relative to the vial to cause the dispensation of a metered dose of the pharmaceutical solution through the valve stem. The device also comprises an actuator for the aerosol canister including a stem block having a receptacle into which the valve stem of the aerosol canister is received and axially located, and being displaceable relative to the vial of the aerosol canister to actuate the metering valve of the aerosol canister. The stem block further defines a discharge nozzle for the pharmaceutical solution and a channel through which a dispensed dose of the pharmaceutical solution is able to pass from the valve stem to the discharge orifice. The actuator further comprises a delivery outlet, such as a nose piece, for the aerosol plume, the discharge orifice being arranged to direct the aerosol plume through the delivery outlet.
With reference to
The aerosol canister 3 is constructed to a standard design and specification and comprises a substantially cylindrical vial body 4 which contains the pharmaceutical solution. The aerosol canister 3 is charged with a pharmaceutical solution as described hereinabove. The vial body 4 is provided with a ferrule 5 which is crimped over a lip of the body to seal hermetically the pharmaceutical solution under pressure.
The ferrule 5 of the aerosol canister 3 is provided with a metering valve 6 designed to deliver a metered amount of the pharmaceutical solution to the user for each actuation of the valve 6. The metering valve 6 is of a known type available from manufacturers such as Consort Medical plc and 3M Drug Delivery Systems. See WO 99/47195 for further details of the metering valve suitable for use in the device of the present invention. The valve 6 generally comprises a metering chamber (not visible in
With further reference to
Although similar in the above-described respects, the nasal spray device 1 according to the present invention differs from conventional pMDIs in that the actuator body 10 defines a delivery outlet in the form of a nose piece 12 (rather than a mouth piece) for delivering the atomised pharmaceutical solution to the nasal cavity. The delivery outlet may be a tubular nose piece adapted for insertion into the nostril, and a circular end of the nose piece may have an inner diameter of 5 to 7.5 mm, preferably about 7.2 mm. The delivery outlet, the delivery orifice and the transfer channel may be aligned with each other, that is to say they may have substantially identical axes. The axis of the delivery outlet may be substantially perpendicular, or at an angle of up to 20° to the perpendicular, to the aerosol canister and the receptacle of the stem block. Preferably an axis of the nose piece 12 defines an angle of about 80° with the sleeve-like portion of the actuator body 10. The nose piece 12 directly faces the stem block 11 so that an aerosol plume produced at the valve stem can be delivered through the nose piece 12 into the nasal cavity.
The stem block 11 is moulded with a discharge orifice 17 facing the delivery outlet, and the discharge orifice 17 is fluidly connected to the receptacle of the stem block 11 so that the pharmaceutical solution is able to pass from the aerosol canister out through the nose piece 12, and into the nasal cavity of a user. In
A formulation in accordance with the present invention was prepared as follows:
The molar ratio of azelastine to hydrochloric acid in this formulation was 14:1.
A preferred formulation has a molar ratio of azelastine to hydrochloric acid of 9:1:
Further formulations were prepared containing the active ingredient(s) and ethanol with and without hydrochloric acid in order to test the stability of the active ingredients. The formulations were:
Formulation (i): azelastine+BDP, with acid
Formulation (ii): BDP without acid
Formulation (iii): BDP with acid
Formulation (iv): azelastine+BDP, without acid
The precise ethanol formulations were as follows:
The formulations were stored at 60° C. for 21 days and the amounts of the active ingredients measured at intervals during the test period. The amounts of the active ingredients were measured using HPLC with external standards of azelastine free base and BDP. The results are shown graphically in
Further formulations were prepared containing the active ingredient(s) and ethanol as follows:
The formulations were stored at 60° C. for two weeks. The amounts of the active ingredients and impurity levels were determined at 4, 7 and 14 days. All formulations showed favourable stability, although the best results were obtained with the 12:1 formulation.
Further formulations were prepared containing the active ingredient(s) and ethanol, with high and low water contents. The formulations were as follows:
The formulations were stored at 40 or 60° C. for two weeks. The amounts of the active ingredients and impurity levels were determined at 4, 7 and 14 days. All formulations showed favourable stability, although the best results were obtained with the low-water formulations, indicating that less water in the formulation is preferable.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1121812.0 | Dec 2011 | GB | national |
This application claims priority of U.S. Provisional Patent Application No. 61/567,893, filed Dec. 7, 2011, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 61567893 | Dec 2011 | US |
