United States Patent:  6,039,932

Assignee:  3M Innovative Properties Company (St. Paul, MN)

Filed:  September 25, 1997

A pharmaceutical aerosol formulation, suitable for administration by oral or nasal inhalation, containing a suspension of particulate budesonide, hydrofluoroalkane propellant and, optionally, additional hydrofluoroalkane propellants, surfactant selected from oleic acid, sorbitan oleates and lecithin, and adjuvant have a Kauri-butanol value of at least 10.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a pharmaceutical aerosol formulation suitable for administration to a patient by oral or nasal inhalation consisting of a suspension of particulate budesonide, a hydrofluoroalkane propellant and optionally one or more of:

(i) one or more additional hydrofluoroalkane propellants

(ii) surfactant selected from oleic acid, sorbitan oleates and lecithin, and

(iii) adjuvant having a Kauri-butanol value of at least 10.

It has been found that it is possible to achieve stable suspensions of particulate budesonide by employing up to 3% of an adjuvant having a Kauri-butanol value greater than 10, e.g., ethanol. In such formulations, the level of adjuvant is selected to decrease the propensity for rapid formation of coarse flocs and for deposition of drug on manufacturing equipment and on the internal surfaces of the container closure system of the inhaler. However, the levels are not so high as to cause significant solubilization of drug, leading to problems of chemical degradation and particle size increase on storage.

According to a further aspect of the present invention there is provided a pharmaceutical aerosol formulation suitable for administration to a patient by oral or nasal inhalation consisting essentially of a suspension of budesonide particles in a mixture of hydrofluoroalkane propellants and optionally one or more excipients selected from:

(i) an adjuvant having a Kauri-butanol value of at least 10,

(ii) the combination of an adjuvant (i) and a surfactant selected from oleic acid, sorbitan oleates and lecithin, and

such that the liquid mixture has a density at 20^oC. substantially equal to the density of budesonide.

It has been found that it is possible to achieve stable suspensions of particulate budesonide by employing a mixture of HFA propellants by matching the density of the propellant mixture to be substantially identical to the density of budesonide. Such formulations are referred to herein as "density matched". The particles preferably have an average size in the range 1 to 10 .mu.m.

In addition to its use for the control of asthma, budesonide is particularly suited for nasal delivery in the treatment cf allergic rhinitis. Formulations for this application preferably do not contain high levels of ethanol in order to avoid irritation of the nasal mucosa. Levels of about 1% by weight ethanol have been found not to produce irritation.

Formulations of the invention exhibit substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, are substantially and readily redispersible, and upon redispersion do not flocculate so quickly as to prevent reproducible dosing of the drug.

It has been found that budesonide particles will sink when suspended in 100% HFA 134a but float when suspended in 100% HFA 227.

It has been found that it is possible to match the density of budesonide using a propellant mixture of HFA's, particularly a mixture of HFA 134a and HFA 227. Suitable propellant mixtures comprise from 15 to 35%, HFA 227 and correspondingly 65 to 85% by weight HFA 134a.

Although density matched mixtures of HFA propellants provide improved formulations of suspended budesonide compared with the use of single propellants, such mixtures do not necessarily prevent the formation of large flocs or prevent drug deposition on the walls of the container or equipment used in preparing the formulation. It has been found that the presence of an adjuvant having a Kauri-butanol value of at least 10 may improve the properties of both density matched and other formulations of suspended budesonide. The preferred adjuvant is ethanol, but other adjuvants such as isopropyl alcohol and polyethylene glycol may be used. The adjuvant is preferably present in a proportion which does not lead to excessive crystal growth or produce irritation wheei inhaled, particularly when inhaled intranasally.

In addition, small amounts of surfactant, preferably from 0.0005 to 0.01% may provide improved properties, e.g., preventing particles adhering to surfaces and providing lubrication for valve components in contact with the formulation. The surfactant is selected from oleic acid, lecithin and sorbitan oleates, e.g., sorbitan monooleate, sorbitan sesquioleate and scrbitan trioleate. The preferred surfactant is oleic acid.

The budesonide is generally present to provide a dose of from 1 to 8 mg/ml of formulation. Exemplary doses are 1, 2, 4, and 8 mg/ml. Such doses are achieved using a concentration of budesonide of :from about 0.075 to 0.66% by weight of the formulation depending upon the precise formulation.

Preferred formulations in accordance with the invention consist of:

particulate budesonide

oleic acid

ethanol

HFA 134a

HFA 227

It is conventional practice when preparing aerosol formulations to mix the drug with the highest boiling point material and thereafter mix with the propellant. However, when making the formulation; of the present invention it is important to ensure the budesonide does not come into contact with high concentrations, e.g., above 5% w/w, of ethanol since the drug would dissolve leading to instability and crystal growth problems in the final formulation. Preferably the maximum concentration of ethanol during formulation is less than 1%.

When preparing formulations of the invention with a content of up to 1% w/w ethanol, the concentration of ethanol at any stage in the presence of budesonide must be maintained no higher than this level. A procedure for preparing a budesonide suspension formulation by cold-filling is as follows:

a) Add all of the formulation quantity of HFA 134a and half of the formulation quantity of HFA 227 to a batching vessel.

b) Prepare a first concentrate containing any surfactant and at least 85% of the formulation quantity of ethanol. Add this to the batching vessel.

c) Prepare a second concentrate containing the other half of the formulation quantity of HFA 227 and the remainder of the ethanol (i.e., no more than 1% w/w of the second concentrate), and add the micronized drug while mixing under high shear. Add the second concentrate to the batching vessel.

Claim 1 of 15 Claims

1. A pharmaceutical aerosol formulation suitable for administration to a patient by oral or nasal inhalation consisting of a suspension of particulate budesonide, a hydrofluoroalkane propellant and optionally one or more of:

(i) one or more additional hydrofluoroalkane propellants

(ii) surfactant selected from oleic acid, sorbitan oleates and lecithin, and

(iii) adjuvant having a Kauri-butanol value of at least 10.

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