WO2002015883A1

WO2002015883A1 - A method of stabilizing a dry powder pharmaceutical formulation

Info

Publication number: WO2002015883A1
Application number: PCT/US2001/025837
Authority: WO
Inventors: Akwete L. Adjei; Anthony J. Cutie
Original assignee: Aeropharm Technology Incorporated
Priority date: 2000-08-21
Filing date: 2001-08-17
Publication date: 2002-02-28
Also published as: AU2001283438A1

Abstract

A method of stabilizing a dry powder formulation is disclosed. The method comprises calculating the moisture content as a function of time required for normal or accelerated storage of the formulation. This calculation is carried out using a mathematical equation to predict a calculated value for added water required for achieving the possible maximum water content of a formulation. The moisture content of the formulation is then adjusted from its initial value to the calculated maximum value using the calculated maximum moisture content for the product at the respective storage temperature and humidity conditions.

Description

A METHOD OF STABILIZING A DRY POWDER PHARMACEUTICAL

FORMULATION

This application makes reference to U.S. application Serial No. 09/158,369 filed on September 22, 1998, and 60/177,983 filed on January 25, 2000, which are incorporated hereinto by reference in their entirety.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to a method of stabilizing a dry powder pharmaceutical formulation, and more particularly, to such method which comprises adjusting the moisture content of the formulation to a mathematically calculated value. Description of the Related Art

Pharmaceutical (medicament) powders often must absorb water from the ambient as a result of diffusion across primary packaging systems used for storage of medicaments. The amount of ingressed water may only be controlled with a desiccant but this inadequately preserves the equilibrium amount of moisture that must be absorbed by the powder over time. Furthermore, because electrostatic charges usually associated with pharmaceutical powders enhance aggregation, explosion propensity, and other physical instability problems, a method to modulate these powder characteristics is needed.

SUMMARY OF THE INVENTION This invention relates to a method of stabilizing a dry powder medicinal formulation or composition, and more particularly to a method of adjusting the moisture content of such composition to a mathematically calculated value.

DESCRIPTION OF THE FIGURE The FIGURE is a graphical representation of the moisture level in ppm versus time in months for a typical dry powder corticosteroid formulation. DETAILED DESCRIPTION OF THE INVENTION

A suitable medicament is selected. A suitable medicament is one which can exist in a dry powder dosage form, e.g. a dry powder aerosol dosage form. Therapeutic categories of drugs or medicaments include cardiovascular drugs, antiallegics, analgesics, antihistamines, antitussives, antifungals, antivirals, antibiotics, pain medicaments, anti-inflammatories and steroids.

Other medicaments delivered via the airways for treating localized lung disease as well as drugs that may be delivered in aerosolized form for uptake into the systemic circulation of the patient being treated, e.g. a human being or another animal, include asthma drugs like β₂-agonists, catecholamines, cyclic corticosteroid drugs, antihistamines, anticholinergics and other bronchodilators; systemically acting drugs like pain management compounds, such as morphine and fentanyl; proteins and peptides, such as insulin and leuprolide; and anti-migraine drugs like ergotamine.

Particularly suitable medicaments or drugs include albuterol (also known as salbutamol), atropine, budesonide, cromolyn, epinephrine, ephedrine, fentanyl, flunisolide, formoterol, ipratropium bromide, isoproterenol, pirbuterol, prednisolone, mometasone, triamcinolone acetonide, salmeterol, amiloride, fluticasone esters, such as phosphate, monohydrate and furoate, (-)4-amino-3,5- dichloro-α-[[[6(2-pyridinyl)ethoxy] hexyl] amino] methyljbenzene-methanol. Also included are the suitable acid addition salts of the foregoing drugs, their hydrates and their other solvates. In this regard, suitable acid addition salts include the salts obtained from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids as well as organic acids such as tartaric, citric, acetic, succinic, maleic, fumaric and oxalic acids. Suitable pharmaceutically acceptable solvates include solvates with ethylactate, alkanes, ethers, alcohols and water.

Also included are derivatives of the medicaments. These derivatives include, besides the salts, ester, solvate and hydrate forms as well as their geometric and optical isomers, including their chiral forms.

A preferred embodiment of this invention are dry powder aerosol formulations of cardiovascular drugs, antiallergenics, analgesics, bronchodilators, antihistamines, antitussives, antifungal, antiviral, antibiotics, pain medicaments, anti-inflammatories, peptides, proteins and steroids and of the use of these aerosol formulations to treat the disease states associated with these medicaments. These medicaments and their use to treat a particular disease state are well known to a practitioner of the art.

Especially preferred, are formulations which comprise medicaments, such as β2-adrenergic agonists, corticosteroids, anticholinergics and leucotriene modulators. Especially preferred are B2-adrenergic agonists, such as albuterol and formoterol and corticosteroids, such as mometasone, hydrocortisone, fludrocortisone, dexamethasone, prednisone, cortisone, aldosterone hemi-acetal, betamethasone, beclomethasone dipropionate, triamcinolone acetonide, budesonide dipropionate, fluticasone propionate and flunisolide, anticholinergics, such as ipratropium bromide, histamine antagonists (mast cell modulators), such as cromolyn and non-steroidal antiinflamatory agents, such as acetaminophen or ibuprofen.

The leucotrienes contemplated in this invention are those which are implicated as mediators of allergic and inflammatory responses associated with bronchial asthma and rheumatoid arthritis. These medicaments are known in the art to constrict dramatically the pulmonary airways and small blood vessels. Thus, inhibitors or antagonists of leucotrienes are effective mediators of the allergic responses typified by asthma and maybe used to treat bronchial asthma and other disease states associated with inflammation of the airways. The leucotriene modulators contemplated in this application include, but are not limited to the following:

1. Inhibitors or antagonists of lecotriene, including the PAF receptor antagonists and 5-lipoxynase inhibitors, for example 2,5-diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 2,4-diaryl tetrahydrofurans, 2,4- diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes, 2,4-diaryl pyrrolidines, and 2,5-diaryl pyrrolidines, triazolo(4,3-A)(l,4)benzodiazepines and thieno (3,2- F)(l,2,4)triazolo(4,3-A)(l,4)diazepine compounds, 6- phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepines (see,

U.S. Patent Nos. 5,856,323; 5,358,938; 4,959,361; and 3,987,052), including, both optically pure and racemates (U.S. Patent No. 5,629,337). An example of this group of compounds is Zileuton® (Abbott Laboratories) and Acolate® (Merck).

2. Chromone-2-carboxylic acid derivatives as antagonists of SRS-A (slow reacting substance of anaphylaxis (see,

Samuelsson et al., Department of Chemistry, Karolinska Institutet, Stockholm, Sweden, TIPS, 227, May, 1980; J. Med. Che . 20 371 (1977)), such as 7-[3-(4-acetyl-3- hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo- 8-propyl-4H-l-benzopyran-2-carboxylate (FPL 55712), which is a specific antagonist of SRS-A as well as a standard for evaluating other inhibitors;

3. Aryloxyalkyloxy-and aralkyloxy-4-hydroxy-3 - nitrocoumarins as antagonists of SRS-A and inhibitors of histamine release, (see. e.g. Buckle et al., J. Med. Chem. 22 158 (1979); U.S. Patent No. 4,296,237; European Patent No. 0036663; U.S. Patent No. 4,296,120; and U.S. Patent No. 4,296,129), as well as other compounds which act as inhibitors of SRS-A including oxiranbutyric acid esters, 3-hydroxy-4- substituted-3-pyrroline-2,5-diones or carboxy-oxo- pyrrolidino)phenyl alkenamides and esters or (carboxyacylamino)phenyl alkenamides and esters, or the substituted derivatives of these before mentioned compounds, including, but not limited, to alkyl, hydroxy amino, dialkylamino, hydroxymethyl, aminomethyl, alkylaminomethyl or alkanoylaminomethyl of 1 to 12 carbon atoms; -CN, -CONH₂ or -CO₂M in which M is hydrogen, aryl, phenyl, or naphthyl, cyclohexyl, cyclopentyl, or fluoromethoxy; or 4. Antagonists and inhibitors of leukotriene including N-o- tolylsulfonylbenzamide compounds.

All of the aforementional prior literature is expressly incorporated by reference. These medicaments are known in the art to treat inflammatory diseases and include medicaments that block the release, production, secretion, or any other biochemical action arachidonic acid, prostaglandins and thromboxanes, or other leukotrienes that participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the immediate hypersensitivity reaction.

Especially preferred medicaments include groups comprising [1- formyl-5 -(cyclopentyloxycarbonyl)amino- 1 H-indol-3 -ylmethyl] -3 -methoxy-N-o- tolylsulfonylbenzamide, [l-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino- 1 H-indol-3 -ylmethyl] -3 -methoxy-N-o-tolylsulfonylbenzamide, [ 1 -((2- carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-lH-indol-3-ylmethyl]- 3-methoxy-N-o-tolylsulfonylbenzamide, [l-((2-tetrazolylethyl)carbamoyl)-5- (cyclopentyloxycarbonyl)amino-lH-indol-3-ylmethyl]-3-methoxy-N-o- tolylsulfonylbenzamide, [1 -(methylphenylcarbamoyl)-5- (cyclopentyloxycarbonyl)amino-lH-indol-3-ylmethyl]-3-methoxy-N-o- tolylsulfonylbenzamide, [1 -(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino- 1 H-indol-3 -ylmethyl] -3 -methoxy-N-o-tolylsulfonylbenzamide; [1 -carbamoyl-5 - (cyclopentyloxycarbonyl)amino-lH-indol-3-ylmethyl]-3-methoxy-N-o- tolylsulfonylbenzamide, and [l-(pyrrolidine-carbonyl)-5- (cyclopentyloxycarbonyl)amino-lH-indol-3-ylmethyl]-3-methoxy-N-o- tolylsulfonylbenzamide. Also, pharmaceutically acceptable salts of these agents, including addition salts derived from organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid and the like. In addition, the compounds in their free carboxylic acid form may be converted by standard techniques well-known to the practioner to their corresponding alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium or primary, secondary and tertiary alkylamine salts, the latter containing from 1 to 6 carbon atoms in their alkyl moieties or a pharmaceutically acceptable salt thereof. These components are known in the literature and are described, for example in Brown et al., J. Med. Chem., vol. 35(13), pp. 2419 to 2439 (1992) Jacobs et al., J. Med. Chem., vol. 37(9), pp. 1282 to 1297 (1994); AU 646 587 Australia 3/1993; McFadden, E.R., Jr., Am Rev. Resp. Dis., vol. 147 pp. 1306-1310 (1993); Greenberger, P.A., Chest, vol. 101 pp. 418S-421 S (1992); Lipworth, B.J.

Pharmacol. Ther., vol. 58 pp. 173-209 (1993); Busse, W. W., Chest, vol. 104 pp. 1565-1571 (1993); Anonymous, Executive Summary: Guidelines for the Diagnosis and Management of Asthma, Public Health Service, Publication 91-3042A, NIH, Bethesda, MD., pp. 1-44 (1991); Israel, E., and Drazen, J.M., N. Engl. J. Med., vol., 331 pp. 737-739 (1994); or Barnes, P.J., N. Engl. Med., vol. 332 pp. 868-875 (1995). All these prior publications are expressly incorporated by reference.

For purposes of those formulations, which are intended for inhalation into the lungs, the medicament or drug is preferably micronized whereby a therapeutically effective amount or fraction (e.g., ninety percent or more) of the drug is particulate. Typically, the particles have a diameter of less than about 10 microns, and preferably less than about 5 microns, in order that the particles can be inhaled into the respiratory tract and/or lungs.

The particulate medicament or drug is present in the formulations in a therapeutically effective amount, that is, an amount such that the drug can be administered as an aerosol, such as topically, or via inhalation, oral inhalation or nasal inhalation, and cause its desired therapeutic effect, typically preferred with one dose, or through several doses. The particulate drug is administered as an aerosol from a conventional reservoir or non-reservoir dry powder device, or from a pressurized metered dose inhaler device, e.g., a metered dose valve. The term "amount" as used herein refers to quantity or to concentration as appropriate to the context. The amount of a drug that constitutes a therapeutically effective amount varies according to factors such as the potency of the particular drug, the route of administration of the formulation, and the mechanical system used to administer the formulation. A therapeutically effective amount of a particular drug can be selected by those of ordinary skill in the art with due consideration of such factors. Generally a therapeutically effective amount will be from about 0.001 parts by weight to about 2 parts by weight based on 100 parts by weight of the dry powder vehicle or propellant system for the pressurized metered dose inhaler utilized.

For a dry powder aerosol application, the powdered medicament is formulated by mixing, blending, or triturating the medicament with an appropriate amount of added water and an aliquot of diluent used, if any, to prepare the formulation. Alternatively, the added water may be added as steam, mist, or vapor to the dry powder formulation during packaging. However, other procedures known to those in this field of formulation science may be used to manufacture such added water dry powder products. For pressurized metered dose inhaler formulations, a suitable propellant is selected. A suitable propellant is any fluorocarbon, e.g. a 1-4 hydrogen containing flurocarbon, such as CHF₂CHF₂, CF₃CH₂F, CH F₂CH₃ and CF₃CHFCF₃₎), a perfluorocarbon, e.g. a 1-4 carbon perfluorocarbon, (such as CF₃CF₃, CF₃CF₂CF₃); or any mixture of the foregoing, having a sufficient vapor pressure to render them effective as propellants. Some typical suitable propellants include conventional chlorofluorocarbon (CFC) propellants such as mixtures of propellants 11, 12 and 114. Non-CFC propellants such as 1,1,1,2-tetrafluoroethane (Propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixtures thereof are preferred. The propellant is preferably present in an amount sufficient to propel a plurality of the selected doses of drug formulation from an aerosol canister This invention discloses a mathematical model that calculates equilibrium moisture of any pharmaceutical or medicament powder formulation so that upon either addition of or removal of water ("adjustment") to the formulation any further moisture ingress during normal storage is averted. Typically, after the calculation is conducted, water must be added to the formulation to achieve the calculated value. Very rarely does water need to be removed, e.g. by evaporation techniques.

It has been found that when the dry powder medicament formulation has been adjusted, e.g. water is added, beyond what is normally associated with the medicament formulation, such as nascent water and a hydrated form of the medicament, the physical properties of such powder formulation is significantly improved. These improvements include, besides enhanced stability, enhanced flowability, thereby optimizing handling and leading to greater uniformity in processing equipment.

By "nascent water" is meant water which is always present and which develops during processing and/or storage of the dry powder medicament formulation.

Water in solid pharmaceutical compositions is normally problematic as it is implicated in aggregation, sol-phase degradation of water-labile drugs, caking and surface adsorption to processing and primary packaging materials. Hence, most pharmaceutical solid products, like sachets, dry powder aerosols (DPIs), lyophilized powders, etc. are often packaged with water sorbent materials and desiccants. Yet, even in the presence of such materials, water ingress into pharmaceutical preparations remains a problem. It has been found that the above-discussed adjustment of the water content to the formulation, e.g. the addition of amounts of water, prevents further ingress of water into the pharmaceutical preparation upon storage. The degree of moisture sorption into a typical pharmaceutical composition has been modeled mathematically whereby one can obtain the equilibrium water content of any pharmaceutical preparation using compliance to gas law theory. The mathematical model is described below for a typical dry powder medicinal formulation or composition. The method of the invention comprises calculating the theoretical equilibrium moisture content in units of ppm, micrograms per gram, milligrams per kilogram, etc., as a function of the dry powder medicament formulation, or liquid aerosol composition in the case of pressurized metered dose inhaler formulations, according to the mathematical equation,

M(f) = Moo - (M_∞ - Mo) exp - -Tγ t (1)

where Moo is the equilibrium moisture level for a specific temperature and humidity in units of ppm, micrograms per gram, milligrams per kilogram, etc., M₀ is the initial moisture level or content of the dry powder formulation in units of ppm, micrograms per gram, milligrams per kilogram, etc., F is the ration of (F_p/F_w), where F_p is the fractional composition of propellant or dilluent, if any, of the dry powder formulation and F_w is the fractional composition of water in the liquid or dry powder formulation in mole fraction units. Pw is the permeation coefficient of water in units of mass per time; γ is the activity coefficient of water in the condensed phase in its dimensionless units; and t is the time in units of months or years as required for the particular medicament product. After obtaining the calculated moisture content using equation (1), the moisture content of the selected dry powder medicament formulation is adjusted, e.g. water is added, to reach the calculated value of moisture content [M(oo)].

Equation (1) is obtained using the following calculations. The pseudo-steady state rate (in grams per sec) of moisture transfer across a thin membrane can be described by the following mass balance:

where: D = diffusion coefficient (cm² sec^"1)

A = surface area through which mass transfer occurs (cm²) Η = partition coefficient δ = membrane thickness (cm)

ΔC = difference in diffusant concentration on each side of the membrane

(mol cm^" ) dt = differential time m_w = mass of water diffused into the formulation.

The concentration of water on each side of the membrane in terms of partial pressure (Pw) is,

CvX η^ (3),

where Pw = is partial pressure of water on each side of the primary package

R = is the universal gas constant

T = is temperature in absolute units

The proportionality constant, P_w, is parametrically dependent on the type of material in the particular membrane or gasket or closure system used to package the dry powder or pressurized metered dose inhaler formulation. Pw is also dependent on thickness, metrics, configuration, and temperature of the particular package or container used for the product. The permeation coefficient of water, P_w, has the units of mass per time. The term C_w may also be expressed in terms of water activity as follows:

P o

where a_w = the activity coefficient of water

P°_w = partial pressure of water at the ground state

Applying equations (1) and (3) to both sides of equation (4) yields:

dM 18.0W_wH_wAp_w° ₍ r

(X - a¹¹¹) (5), dt δRT

where a¹ = activity of water outside of the primary package

a¹¹¹ = activity of water inside the formulation

where dM/dt = differential mass of water per unit time

where Δα = α^out - a^m and the ratio of the mass (m) of water (w) to the sample formulation (f) is

M = — (6), ntf

where m_w = mass ratio of water

πi_f = mass ratio of the rest of the formulation

The normalized version of equation (5) is:

where the permeability coefficient is

_{p =} ISMD_WH_WA_PW° δRT '^'

Equation (7) describes the proportionality between the total moisture transferred per unit time into the dry powder or pressurized metered dose aerosol package, dM/dt, and the difference in the activity of water outside and inside the canister or metered dose inhaler employed.

Generally, during Karl Fischer titration, the moisture content measured is that of the condensed phase in the metered dose inhaler contemplated by this invention. The activity of water in the condensed phase can be written as:

α = γ x (9),

where x is the mole fraction and γ is the activity coefficient of water in the condensed phase. The mole fraction is defined as:

_{x =} —w ₌ nw (10), nf n_w + rip + n_s

where n is the number of moles and the subscripts p and s refer to the respective product compositions, example propellant of diluent and surfactant. The mole fraction of water in the condensed phase reduces to:

x = MT (11),

by noting that nf « n, if the moles of water and surfactant are negligible compared to propellant (n_w + n_s « n_p). Also, the constant T has been used to replace the ratio of formula weights (F_p / F_w) where F_p. = formula weight of propellant or diluent used in either the pressurized metered dose inhaler or the dry powder formulation, and F_w = Formula weight of water. Finally, using the above expressions for the activity and mole fraction of water, equation (9) becomes:

^ ₌ _^_{r γ M} = ^a^0Ut (12) dt mf mf The various parameters expressed in the above mathematical formulae are well known to those of ordinary skill in the art and are easily measurable.

Since the activity of water in the environmental chamber, a^out, does not change, and the activity coefficient may be constant, the mass transfer equation can be recognized as a first order linear non-homogenous ordinary differential equation, namely equation (1).

The amount of water typically added acts as a stabilizer in the same manner as the "water addition" or "water of addition" of U.S. applications, Serial No. 09/209,228, filed December 10, 1998, which is incorporated hereinto by reference in their entirety.

The adjusted aerosol formulation comprises an amount of water which is effective to stabilize the formulation relative to an identical formulation containing only nascent formulation water, such that the drug does not settle, aggregate, cream or flocculate after agitation or during normal storage to prevent reproducible dosing of the drug. Reproducible dosing can be achieved if the formulation retains a substantially uniform drug concentration for about two or three seconds after agitation.

The amount of water present in the formulation is in excess of the concentration of the nascent formulation water. Such concentration of nascent formulation water typically ranges up to 300 parts by weight per one million parts by weight of the total weight of the dry powder aerosol formulation. Accordingly, the adjusted water value in excess of this nascent water concentration typically ranges from about 300 parts by weight to 2000 parts by weight per one million parts by weight of the total aerosol formulation weight. Most preferred is that the concentration of the water is from 500 parts by weight to 700 parts by weight per one million parts by weight of the total weight of the medicinal aerosol formulation.

It is to be emphasized that this is an amount which exceeds the amount of nascent or developed formulation water. It is also to be stressed that this amount of water can be added and initially combined with the other components of the formulation, e.g. medicament, such as triamcinolone acetonide, and propellant, e.g. 1,1,1,2-tetrahydrofluoroethane, or added to the resultant formulation after these other components have been processed, e.g. prior to or subsequent to storage.

It has surprisingly been found that the formulations are stable without the necessity of employing a cosolvent, such as ethanol, or surfactants. However, further components, such as conventional lubricants or surfactants, cosolvents, ethanol, etc., can also be present in an aerosol formulation in suitable amounts readily determined by those skilled in the art. In this regard, reference is made to U.S. Patent No. 5,225,183, which is incorporated by reference hereinto in its entirety. Generally the formulations of the invention can be prepared by combining (i) the drug in an amount sufficient to provide a plurality of therapeutically effective doses; (ii) the adjusted water (mf) in an amount effective to stabilize each of the formulations; (iii) the propellant in an amount sufficient to propel a plurality of doses from an aerosol canister; and (iv) any further optional components e.g. ethanol as a cosolvent; and dispersing the components. The components can be dispersed using a conventional mixer or homogenizer, by shaking, or by ultrasonic energy. Bulk formulations of dry powders may be repackaged into unit dose containers, such as blisters or pouches, and stored under normal conditions for medicaments. In the case of liquid products, the bulk formulations can be transferred to smaller individual aerosol containers or vials by using valve to valve transfer methods, pressure filling or by using conventional cold- fill methods. It is not required that a stabilizer used in a suspension aerosol formulation be soluble in the propellant. Those that are not sufficiently soluble can be coated onto the drug particles in an appropriate amount and the coated particles can then be incorporated in a formulation as described above.

Dry powder aerosol devices used on the market today, as well as those in development in various organizations can be selected and used for dry powder formulations described in this invention. Aerosol canisters equipped with conventional valves, preferably metered dose valves, can be used to deliver the liquid formulations of the invention. It has been found, however, that selection of appropriate valve assemblies for use with aerosol formulations is dependent upon the particular stabilizer and other adjuvants used (if any), on the propellant, and on the particular drug being used. Conventional neoprene and buna valve rubbers used in metered dose valves for delivering conventional CFC formulations often have less than optimal valve delivery characteristics and ease of operation when used with formulations containing HFC- 134a or HFC-227. Therefore certain formulations of the invention are preferably dispensed via a valve assembly wherein the diaphragm is made of a nitrile rubber such as DB-218 (American Gasket and Rubber, Schiller Park, 111.) or an EPDM rubber such as Vistalon™ (Exxon), Royalene™ (UniRoyal), bunaEP (Bayer). Also suitable are diaphragms fashioned by extrusion, injection molding or compression molding from a thermoplastic elastomeric material such as FLEXOMER™ GERS 1085 NT polyolefm (Union Carbide). Conventional aerosol canisters, coated or uncoated, anodized or unanodized, e.g., those of aluminum, glass, stainless steel, polyethylene terephthalate, and coated canisters or cans with epon, epoxy, etc., can be used to contain a formulation of the invention. The contents of the canister can be introduced into the canister by either the cold fill process or the pressure fill process. These processes as well as other processes, devices, etc are described in "Metered Dose Inhaler Technology," Tol. S. Purewal et al, Ed., Interpharm Press Inc., 1998, which is incorporated by reference hereinto in its entirety.

The formulations of this invention, liquid metered dose inhalers as well as dry powder formulations, can be delivered to the respiratory tract and/or lung by oral inhalation in order to effect bronchodilation or in order to treat a condition susceptible of treatment by inhalation, e.g., asthma, chronic obstructive pulmonary disease. These formulations can also be delivered by nasal inhalation in order to treat, e.g., allergic rhinitis, rhinitis, (local) or diabetes (systemic), or they can be delivered via topical (e.g., buccal) administration in order to treat, e.g., angina or local infection.

The formulations of this invention can also be delivered to the respiratory tract and/or lung for the treatment of systemic diseases away from the respiratory system, such as hormone replacement, pain, ailments of growth process in the body, conditions of the heart, and maladies of the reproductive system or pancreas or brain or the grastrointestinal tract. EXAMPLE

Referring to the FIGURE 1, results from a typical moisture sorption profile for a corticosteroid formulation is graphically displayed. Using 6 months real time stability and the data shown in the Table below, the predicted equilibrium moisture content and the corresponding equilibration concentration and time were 1700 ppm and 12 months at 25°C/60% relative humidity, respectively, using equation (1). The results demonstrate that the pharmaceutical composition of this typical corticosteroid formulation may be spiked apriori with enough mositure as to bring it to a total moisture content of 1700 ppm of added water to quench further moisture ingress. In the case of solid powder particles this added water would not be available for its own independent inter-molecular reactions; rather, the added water would sterically stabilize the corticosteroid medicament particles, subsequently reducing surface energetics and other characteristics that could promote physical instability of the product. TABLE

R = 0.9879 R² = 0.9760 Adjusted R² - 0.9663; Standard Error of Estimate = 116.36

Coefficient Std. Error t y∞ 1743.06 82.386 21.16 O.0001 yo 100.86 99.42 1.01 0.3569 b 0.2298 0.04 5.24 0.0034

Claims

We Claim:

1. A method of improving a dry powder formulation, which comprises adjusting the moisture content thereof to a mathematically determined value.

2. The method as defined in claim 1 wherein said value (M_∞ -

Mo) is obtained using the equation P,

M(f) = Moo - (M_∞ - M₀) exp- γ t , where Moo - Mo is the amount of ntf added water needed to stabilize the formulation;

where Moo is the equilibrium moisture level for a specific temperature and humidity; M₀ is the initial moisture level or moisture content of the formulation; Y is the ratio of (Fp/F_w), where F_p is formula weight of propellant or diluent used in either the pressurized metered dose inhaler or the dry powder formulation and F_w is formula weight of water used in either a pressurized metered dose inhaler or a dry powder formulation; Pw is the permeation coefficient of water; γ is the activity coefficient of water in the bulk phase ; and t is the time.

3. A method of stabilizing a dry powder aerosol formulation, which comprises

(a) calculating the moisture content in terms of a function of time of the dry powder aerosol formulation according to the following equation

M(f) = M_∞ - (Moo - M_o) exp ,

where M_∞ is the equilibrium moisture level for a specific temperature and humidity; M₀ is the initial moisture or content of the dry powder formulation; Y is the ratio (F_p/F_w); and

(b) adjusting the moisture content of the dry powder aerosol formulation to said calculated moisture content.