The invention relates to stabilized dispersions containing nanoparticles of use for the administration of medicaments. The dispersions comprise excipient nanoparticles, a dispersed phase comprising medicament and a continuous phase comprising propellant.

Description of the Invention

SUMMARY

In one aspect, the invention provides a stable pharmaceutical dispersion which comprises a dispersed solid phase comprising a medicament and a continuous liquid phase comprising propellant and excipient nanoparticles.

In another aspect, the invention provides a method of treating a mammal through its respiratory tract comprising the step of administering an effective amount of a pharmaceutical dispersion according to the invention to the respiratory tract of said mammal.

In another aspect, the invention provides a metered dose inhaler which comprises an aerosol container having a metering valve, and a stable pharmaceutical dispersion of the invention disposed in the container.

In another aspect, the invention provides a method of making an aerosol dispersion comprising the steps of providing an aerosol container, and charging to said container a pharmaceutical dispersion of the invention.

In another aspect, the invention provides a method of stabilizing a pharmaceutical dispersion comprising the step of adding an effective amount of excipient nanoparticles to a dispersion which comprises a dispersed solid phase comprising a medicament and a continuous liquid phase comprising propellant.

In another aspect, the invention provides a stable pharmaceutical dispersion which consists essentially of a dispersed solid phase comprising a medicament and a continuous liquid phase comprising propellant and excipient nanoparticles.

DETAILED DESCRIPTION

The dispersions of the invention are stable dispersions that provide reproducible dosing of a medicament, in the form of an aerosol, over a useful time period without substantial agitation of the dispersion or which are easily redispersed with minimal energy input. The dispersions comprising medicament and propellant are rendered stable by incorporation of an effective amount of excipient nanoparticles into the dispersion. An "effective amount" of excipient nanoparticles is an amount that minimizes the aggregation of the medicament particles and forms stable dispersions that remain dispersed over a useful time period without substantial agitation of the dispersion or which are easily redispersed with minimal energy input. Without wishing to be bound by any theory, the nanoparticles are believed to sterically inhibit the aggregation of the dispersed phase and not through particle charge. The excipient nanoparticles used in the dispersions of the invention appear to be soluble in the continuous phase of the dispersion and do not precipitate, flocculate, etc., in the dispersions of the invention. In addition, the excipient nanoparticles do not substantially associate with the surface of the medicament particles and may be effective suspension aids at low concentrations as compared with conventional suspension aids. The stable dispersions of the invention may contain less than 0.001 weight percent of surfactant, surface-active agents, traditional emulsifiers, detergents, and/or protective colloids.

As used herein, "dispersion" means a solid distributed throughout a liquid continuous phase which does not separate over a useful time period.

As used herein, "separate" means that the solid particles in a liquid dispersion gradually settle or cream, forming distinct layers with very different concentrations of the solid particles and continuous liquid phase.

As used herein, "dispersion stability" is a description of the tendency of a dispersion to separate. For a dispersion with good dispersion stability, the particles remain approximately homogeneously distributed within the continuous phase. For a dispersion with poor dispersion stability, the particles do not remain approximately homogeneously distributed within the continuous phase and may separate.

As used herein, an "excipient" refers broadly to any inert additive other than the primary active medicament moiety used to improve some aspect of the aerosol dispersion formulation.

As used herein, "aerosol dispersion" means a medicinal dispersion which includes a medicament and propellants capable of delivering the medicament to the patient when under pressure.

As used herein, "nanoparticles" means organic or inorganic particles or molecules and combinations thereof that appear to be soluble in the continuous phase wherein each particle has nanoscale dimensions in the continuous phase and that occupies or provides a zone of steric exclusion of less than 100 nanometers, within the continuous phase.

Stabilized dispersions of the invention include surface-modified inorganic nanoparticles, surface-modified organic nanoparticles, and/or steric organic molecules having unmodified surfaces (nanoparticles). "Steric organic molecules" means single molecules (for example, polymers) that have an exclusion volume describable in nanometer diameter dimensions and comprised of covalently-bound organic units. "Steric organic molecules" do not include linear polymers that are soluble in the continuous phase. In one embodiment, they are substantially composed of the same moieties on the surface as are present in the inner portion or core of the nanoparticle. The nanoparticles are desirably individual, unassociated (i.e., non-aggregated) nanoparticles dispersed throughout the continuous phase and desirably do not irreversibly associate with each other and do not associate with the dispersed medicament. The term "associate with" or "associating with" includes, for example, covalent bonding, hydrogen bonding, electrostatic attraction, London forces, and hydrophobic interactions.

The nanoparticles are selected such that the composition formed therewith is free from a degree of particle agglomeration or aggregation that would interfere with the desired properties of the composition. The surface-modified organic or inorganic nanoparticles have surface groups that modify the "solubility" or "wettability" characteristics of the nanoparticles. The surface groups are selected to render the particle compatible with the continuous phase including, components of the continuous phase. The un-modified nanoparticles are compatible with the continuous phase without further surface modification.

One method of assessing the compatibility of the nanoparticles with the continuous phase includes determining whether the resulting composition forms a stable dispersion. Incompatible nanoparticles will not improve the quality of the suspension at expected effective concentrations. For transparent continuous phases, one useful method of assessing the compatibility of the nanoparticles with the transparent continuous phase includes the step of combining the nanoparticles and the continuous phase and observing whether the nanoparticles appear to dissolve in the continuous phase such that the resulting dispersion is transparent or translucent.

For surface-modified nanoparticles, the nature of the inorganic or organic particle component of the surface-modified nanoparticle will prevent the surface-modified particle from actually dissolving in the continuous phase, i.e., the surface-modified nanoparticles will be dispersed in the continuous phase. However, the compatibility of the surface groups with the continuous phase will give the surface-modified nanoparticles the appearance of dissolving in the continuous phase. As the size of the surface-modified nanoparticles increases, the haziness of the continuous phase generally increases. Preferred surface-modified nanoparticles are selected such that they do not settle out of the continuous phase. The further step in assessing the compatibility of the continuous phase and the surface-modified or unmodified nanoparticles includes determining whether, upon subsequent introduction of medicament particles to be dispersed in the continuous phase, the composition forms a stable dispersion.

Suitable surface groups can also be selected based upon the solubility parameter of the surface group and the continuous phase. Desirably the surface group, or the agent from which the surface group is derived, has a solubility parameter similar to the solubility parameter of the continuous phase. When the continuous phase is hydrophobic, for example, one skilled in the art can select from among various hydrophobic surface groups to achieve a surface-modified particle that is compatible with the hydrophobic continuous phase. Similarly, when the continuous phase is hydrophilic, one skilled in the art can select from hydrophilic surface groups, and, when the continuous phase is a hydrofluorocarbon, one skilled in the art can select from among various compatible surface groups. The nanoparticle can also include at least two different surface groups that combine to provide a nanoparticle having a solubility parameter that is similar to the solubility parameter of the continuous phase. The surface-modified nanoparticles are not amphiphilic.

The surface groups may be selected to provide a statistically averaged, randomly surface-modified particle.

If required, the surface groups are present on the surface of the nanoparticle in an amount sufficient to provide surface-modified nanoparticles that are capable of being subsequently dispersed in the continuous phase without aggregation. The surface groups desirably are present in an amount sufficient to form a monolayer, desirably a continuous monolayer, on the surface of the nanoparticle.

Surface modifying groups may be derived from surface modifying agents. Schematically, surface modifying agents can be represented by the formula A-B, where the A group is capable of attaching to the surface of the particle and the B group is a compatibilizing group (non-reactive with the continuous phase) or a linking group to a compatibilizing group. Compatibilizing groups can be selected to render the particle relatively more polar, relatively less polar, or relatively non-polar.

Suitable classes of surface-modifying agents include, e.g., silanes, organic acids, organic bases, alcohols, and combinations thereof.

Examples of useful silanes include organosilanes including, e.g., alkylchlorosilanes, alkoxysilanes, e.g., methyltrimethoxysilane, methyltriethoxysilane, ethyltrimethoxysilane, ethyltriethoxysilane, n-propyltrimethoxysilane, n-propyltriethoxysilane, i-propyltrimethoxysilane, i-propyltriethoxysilane, butyltrimethoxysilane, butyltriethoxysilane, hexyltrimethoxysilane, octyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane, n-octyltriethoxysilane, phenyltriethoxysilane, polytriethoxysilane, vinyltrimethoxysilane, vinyldimethylethoxysilane, vinylmethyldiacetoxysilane, vinylmethyldiethoxysilane, vinyltriacetoxysilane, vinyltriethoxysilane, vinyltriisopropoxysilane, vinyltrimethoxysilane, vinyltriphenoxysilane, vinyltri(t-butoxy)silane, vinyltris(isobutoxy)silane, vinyltris(isopropenoxy)silane and vinyltris(2-methoxyethoxy)silane; trialkoxyarylsilanes; isooctyltrimethoxy-silane; N-(3-triethoxysilylpropyl) methoxyethoxyethoxy ethyl carbamate; N-(3-triethoxysilylpropyl) methoxyethoxyethoxyethyl carbamate; silane functional (meth)acrylates including, e.g., 3-(methacryloyloxy)propyltrimethoxysilane, 3-acryloyloxypropyltrimethoxysilane, 3-(methacryloyloxy)propyltriethoxysilane, 3-(methacryloyloxy)propylmethyldimethoxysilane, 3-(acryloyloxypropyl)methyldimethoxysilane, 3-(methacryloyloxy)propyldimethylethoxysilane, 3-(methacryloyloxy)methyltriethoxysilane, 3-(methacryloyloxy)methyltrimethoxysilane, 3-(methacryloyloxy)propyldimethylethoxysilane, 3-(methacryloyloxy)propenyltrimethoxysilane, and 3-(methacryloyloxy)propyltrimethoxysilane; polydialkylsiloxanes including, e.g., polydimethylsiloxane, arylsilanes including, e.g., substituted and unsubstituted arylsilanes, alkylsilanes including, e.g., substituted and unsubstituted alkyl silanes including, e.g., methoxy and hydroxy substituted alkyl silanes, and combinations thereof.

Methods of surface-modifying silica using silane functional (meth)acrylates are described, e.g., in U.S. Pat. Nos. 4,491,508 and 4,455,205 (Olsen et al.); U.S. Pat. Nos. 4,478,876 and 4,486,504 (Chung); and U.S. Pat. No. 5,258,225 (Katsamberis), and incorporated herein.

Useful organic acid surface-modifying agents include, e.g., oxyacids of carbon (e.g., carboxylic acid), sulfur and phosphorus, and combinations thereof.

Representative examples of polar surface-modifying agents having carboxylic acid functionality include CH.sub.3O(CH.sub.2CH.sub.2O).sub.2CH.sub.2COOH (hereafter MEEAA) and 2-(2-methoxyethoxy)acetic acid having the chemical structure CH.sub.3OCH.sub.2CH.sub.2OCH.sub.2COOH (hereafter MEAA), acid functionalized polyethylene glycols (PEGS) such as mono(polyethylene glycol) succinate and polyethylene glycols mono substituted with acetic, propionic, or butanoic acids. Such polymers or their derivatives may be prepared as described in U.S. Pat. No. 5,672,662 or purchased commercially.

Representative examples of non-polar surface-modifying agents having carboxylic acid functionality include octanoic acid, dodecanoic acid and oleic acid.

Examples of suitable phosphorus containing acids include phosphonic acids including, e.g., octylphosphonic acid, laurylphosphonic acid, decylphosphonic acid, dodecylphosphonic acid, octadecylphosphonic acid, and phosphate or phosphonic substituted polyethylene glycols.

Useful organic base surface-modifying agents include, e.g., alkylamines including, e.g., octylamine, decylamine, dodecylamine and octadecylamine, or amine functionalized polyethylene glycols.

Examples of other useful non-silane surface modifying agents include acrylic acid, methacrylic acid, beta-carboxyethyl acrylate, mono-2-(methacryloyloxyethyl)succinate, and combinations thereof. A useful surface modifying agent that imparts both polar character and reactivity to the nanoparticles is mono(methacryloyloxypolyethyleneglycol)succinate.

Examples of suitable surface-modifying alcohols include, e.g., aliphatic alcohols including, e.g., octadecyl, dodecyl, lauryl and furfuryl alcohol, alicyclic alcohols including, e.g., cyclohexanol, and aromatic alcohols including, e.g., phenol and benzyl alcohol, polyethylene glycols, monomethyl polyethylene glycols, and combinations thereof.

A variety of methods are available for modifying the surface of nanoparticles including, e.g., adding a surface modifying agent to nanoparticles (e.g., in the form of a powder or a colloidal dispersion) and allowing the surface modifying agent to react with the nanoparticles. One skilled in the art will recognize that multiple synthetic sequences to bring the nanoparticle together with the compatibilizing group are possible and are envisioned within the scope, e.g., the reactive group/linker may be reacted with the nanoparticle followed by reaction with the compatibilizing group. Alternatively, the reactive group/linker may be reacted with the compatibilizing group followed by reaction with the nanoparticle. Other useful surface modification processes are described in, e.g., U.S. Pat. Nos. 2,801,185 and 4,522,958, and incorporated herein.

The nanoparticles are primarily inorganic or organic or a combination thereof. Examples of suitable inorganic nanoparticles include silica and metal oxide nanoparticles including zirconia, titania, ceria, alumina, iron oxide, vanadia, antimony oxide, tin oxide, alumina/silica, calcium phosphate, calcium phosphate, e.g., hydroxy-apatite, and combinations thereof, and include combined materials such as a mixture of materials or layers of materials surrounding a central inorganic or organic core. Examples of suitable organic nanoparticles include buckminsterfullerenes (fullerenes), dendrimers, propellant-insoluble sugars such as lactose, trehalose, glucose or sucrose; aminoacids, and linear or branched or hyperbranched "star" polymers such as 4, 6, or 8 armed polyethylene oxide (available from Aldrich Chemical Company, Milwaukee, Wis., or Shearwater Corporation, Huntsville, Ala.) with a variety of end groups, and combinations thereof.

Specific examples of fullerenes include C.sub.60, C.sub.70, C.sub.82, and C.sub.84. Specific examples dendrimers include polyamidoamine (PAMAM) dendrimers of Generations 2 through 10 (G2-G10) (available from Aldrich Chemical Company).

As one skilled in the art will understand, the nanoparticles described above may be used as is or surface-modified and in any combination. Insoluble nanoparticles (such as inorganics, sugars such as trehalose or lactose, or certain dendrimers) should be appropriately surface modified to make them wettable in the continuous phase. The modification may also be used to control the volume of the zone of steric exclusion. Non-limiting methods for surface modification include adsorption, ionic, or covalent chemical reaction with the "surface", or encapsulating or coating the nanoparticle with a reactive moiety to create a shell that increases the "solubility" of the particle in the continuous phase. If adsorption is the primary method of modifying the surface of the nanoparticle, the adsorbed species should be selected by one skilled in the art so to avoid substantial desorption and subsequent modification of the surface of the medicament.

When nanoparticles are present in continuous phases containing HFAs, the nanoparticle surface may desirably be comprised of a plurality of ether, ester, or amide moieties. For continuous phases also containing cosolvents (e.g., ethanol) or dimethyl ether, propane, butane, or blends thereof, the nanoparticle surface may be more hydrophobic in nature. Desirable nanoparticle surfaces are comprised of known biocompatible materials such as polyethylene glycols, or polyesters derived from lactide or caprolactone.

PAMAM dendrimers are currently commercially available with primary amine, hydroxyl, carboxylate sodium salt, mixed amine/hydroxyl, and C.sub.12 surface functional groups. One skilled in the art will recognize these dendrimers can be used as is or modified to make the surface compatible with the continuous phase if required.

Useful zirconia nanoparticles include zirconia nanoparticles having a combination of oleic acid and acrylic acid adsorbed onto the surface of the particle.

Useful silica nanoparticles include silica nanoparticles surface-modified with silane surface modifying agents including, e.g., acryloyloxypropyl trimethoxysilane, 3-methacryloyloxypropyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane, n-octyltrimethoxysilane, isooctyltrimethoxysilane, and combinations thereof. Silica nanoparticles can be treated with a number of surface modifying agents including, e.g., alcohol, organosilane including, e.g., alkyltrichlorosilanes, trialkoxyarylsilanes, trialkoxy(alkyl)silanes, and combinations thereof and organotitanates and mixtures thereof.

Useful surface-modified iron oxide particles include iron oxide particles modified with long chain hydrocarbons or ethers (e.g., polyethylene glycols) derived with silyl or cyano. Useful surface-modifying groups for calcium phosphate include ionic linkages based on 1) acyl or alkyl acids such as carboxylates, phosphates or sulfates-optionally with greater than mono-valent metal cations, or 2) alkyl or amines and derivatives.

In continuous phases containing HFAs, useful surface modifiers include polyesters or esters with the above listed functionality, e.g., monofunctional PEGs having alcohol, acid, or amine functionality.

Useful surface-modifying groups for buckminsterfullerenes (fullerenes) and polyamidoamine (PAMAM) dendrimers include straight or branched alkyl groups and may range from at least C.sub.3 to not greater than C.sub.30, and may be any size or range in between C.sub.3 and C.sub.30.

The nanoparticles, whether surface-modified, or not, have an average particle diameter less than about 100 nm, in other embodiments, no greater than about 50, 40, 30, 20, 15, 10, or 5 nm, in other embodiments, from about 3 nm to about 50 nm, in other embodiments, from about 3 nm to about 20 nm, and in other embodiments, from about 5 nm to about 10 nm. If the nanoparticles are aggregated, the maximum cross sectional dimension of the aggregated particle is within any of these preferable ranges.

The nanoparticles may be in the form of a colloidal dispersion. Examples of useful commercially available unmodified silica include nano-sized colloidal silicas, available under the product designations NALCO 1040, 1050, 1060, 2326, 2327, and 2329 colloidal silica from Nalco Chemical Co., Naperville, Ill.

Useful metal oxide colloidal dispersions include colloidal zirconium oxide, suitable examples of which are described in U.S. Pat. No. 5,037,579, incorporated herein, and colloidal titanium oxide, useful examples of which are described in PCT Publication No. WO 00/06495, entitled, "Nanosize Metal Oxide Particles for Producing Transparent Metal Oxide Colloids and Ceramers," (Arney et al.), filed Jul. 30, 1998, incorporated herein.

The nanoparticles are employed in the dispersions of the invention in an effective amount to minimize aggregation of the medicament particles. Nanoparticles are generally present in an amount from 0.005 to 0.5 percent by weight and may be present in any amount or range between 0.001 and 0.5 percent by weight. In other embodiments, the dispersions of the invention contain less than 0.5, 0.4, 0.3, or 0.2 percent by weight. One skilled in the art will recognize that the effective amount required will depend upon the type of the propellant, the surface functionality and particle size of the nanoparticles, the medicament concentration and type, and the presence of other excipients. Combinations of different types of nanoparticles described herein may be used.

This invention is applicable to any medicament to be prepared as an aerosol dispersion. Non-limiting examples of other suitable medicaments include antiallergics, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, diuretics, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid or a steroid, and combinations of these specific examples or medicaments which may be employed are: isoproterenol, phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, dihydromorphine, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, isoprenaline, fenoterol, oxitropium bromide, reproterol, budesonide, flunisolide, ciclesonide, formoterol, fluticasone propionate, salmeterol, procaterol, ipratropiurn, triamcinolone acetonide, tipredane, mometasone furoate, colchicine, pirbuterol, beclomethasone dipropionate, orciprenaline, fentanyl, diamorphine, and dilitiazem. Others are antibiotics, such as neomycin, cephalosporins, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline; adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone; antiallergy compounds such as cromolyn sodium, and nedocromil; protein and peptide molecules such as insulin, pentamidine, calcitonin, amiloride, interferon, LHRH analogues, IDNAase, heparin, etc. If applicable, the medicaments exemplified above may be used as either the free base or as one or more salts known to the art. Vaccines may also benefit from this approach.

The medicaments exemplified above may be used as either the free base or as one or more salts known to the art. The choice of free base or salt will be influenced by the physical stability of the medicament in the dispersion. The following salts of the medicaments mentioned above may be used: acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphatediphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide.

Cationic salts may also be used. Suitable cationic salts include the alkali metals, e.g., sodium and potassium, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, e.g., glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2isopropylaminoethanol.

For pharmaceutical purposes, the particle size of the medicament powder should desirably be no greater than 100 micrometers diameter, since larger particles may clog the valve or orifice of the container. In another embodiment, the particle size should be less than 25 micrometers in diameter. Desirably, the particle size of the finely-divided solid powder should for physiological reasons be less than about 25 micrometers and in another embodiment, less than about 10 micrometers in diameter. The particle size of the powder for inhalation therapy is desirably less than about 5 micrometers.

Medicinal dispersions according to the present invention contain a medicament dispersed in the dispersion in a therapeutically effective amount. "Therapeutically effective amount" means an amount sufficient to induce a therapeutic effect, such as bronchodilation or antiviral activity. The amount will vary according to factors known to those skilled in the art, such as pharmacological activity of the particular medicament, the condition being treated, the frequency of administration, the treatment site, and the presence of any other therapeutic agents being co-administered. The concentration of medicament depends upon the desired dosage, but is generally in the range of 0.01 to 15; 0.01 to 10; 0.01 to 5; 0.01 to 4; 0.01 to 3; or 0.01 to 2 percent by weight and may be present in any amount or range between 0.001 and 15 percent by weight.

Suitable propellants include, for example, a chlorofluorocarbon (CFC), such as trichlorofluoromethane (also referred to as propellant 11), dichlorodifluoromethane (also referred to as propellant 12), and 1,2-dichloro-1,1,2,2-tetrafluoroethane (also referred to as propellant 114), a hydrochlorofluorocarbon, a hydrofluorocarbon (HFC), such as 1,1,1,2-tetrafluoroethane (also referred to as propellant 134a, HFC-134a, or HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (also referred to as propellant 227, HFC-227, or HFA-227), carbon dioxide, dimethyl ether, butane, propane, or mixtures thereof. In other embodiments, the propellant includes a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or mixtures thereof. In other embodiments, a hydrofluorocarbon is used as the propellant. In other embodiments, HFC-227 and/or HFC-134a are used as the propellant.

Propellant is present in the dispersions of the invention in an amount of at least 70 percent by weight of the dispersion, normally from about 85 to 99.99 percent by weight.

Suitable adjuvants include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether, and surfactants such as fluorinated and non-fluorinated surfactants, carboxylic acids, and polyethoxylates. The adjuvant should be miscible with the propellant and any co-adjuvant in the amounts employed.
 

Claim 1 of 21 Claims

1. A stable pharmaceutical dispersion comprising: a dispersed solid phase comprising a medicament; and a continuous liquid phase comprising propellant and excipient nanoparticles having an average particle diameter of less than 100 nm, wherein said excipient nanoparticles are present in the dispersion in an amount from 0.001 to less than 0.5 percent by weight, wherein the dispersion does not flocculate when left undisturbed for more than 30 seconds after being shaken for 30 seconds, and wherein the excipient nanoparticles are surface-modified and do not comprise a medicament.

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