MXPA97007863A - Inhaler of dose measured for albute - Google Patents

Abstract

A metered dose inhaler having part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more fluorocarbon-free polymers, to deliver a formulation of the drug for inhalation comprising albuterol or a salt thereof. same physiologically acceptable, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents and one or more excipient

Description

INHALER OF DOSE MEASURED FOR ALBUTEROL FIELD AND BACKGROUND OF THE INVENTION Frequently drugs are administered for the treatment of respiratory and nasal disorders, in aerosol formulations or sprayed through the mouth or nose. A widely used method for distribution such as aerosol drug formulations involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispersed by activation of a dosage or dose regulation valve fixed to the container or container. A metering valve can be designed to consistently release a predetermined, fixed mass of the drug formulation during each activation. When the suspension is forced from the container or container through the dose regulating valve by the high vapor pressure of the propellant, the propellant rapidly vaporizes leaving a rapidly moving cloud or turbidity of EF: 25832 several fine particles of the drug formulation. This cloud of particles is directed towards the nose or mouth of the patient by a channeled transmission device such as a cylinder or cone with an open end. Commonly with the activation of the aerosol dose regulating valve, the patient inhales the drug particles into the lungs or the nasal cavity. Drug delivery systems in this way are known as "metered dose or regulated inhalers" (IsDM). See Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, FL (1990) for a general background of this form of therapy. Patients often rely on medication supplied by IsDM for the rapid treatment of respiratory disorders which are debilitating and in some cases even life threatening. Therefore, it is essential that the prescribed dose of aerosol medication delivered to the patient consistently meets the specifications claimed by the manufacturer and meets the requirements of the FDA and other regulatory authorities. That is, all doses in the cylindrical container or container must be the same within closed or limited tolerances.

Some aerosol drugs tend to adhere to the internal surfaces, i.e. walls of the cylindrical container or containers, valves, and caps, of the IDM. This can lead the patient to obtain significantly less than the prescribed amount of drug in each activation of the IDM. The problem is particularly acute with hydrofluoroalkane (also known as "fluorocarbon" simply) propellant systems, for example, P134a and P227, under development in recent years to replace chlorofluorocarbons such as Pll, P114 and P12. It has been found that surface coating The interior of the IsDM cylindrical container or container with a fluorocarbon polymer significantly reduces or essentially eliminates the problem of adhesion or deposition of albuterol in the walls of the cylindrical container or container and thus ensures consistent delivery of aerosolized medication from of the IDM.

BRIEF DESCRIPTION OF THE INVENTION A metered dose or regulated inhaler having part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more polymers without fluorocarbon, to deliver a drug formulation for inhalation comprising albuterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.

DETAILED DESCRIPTION OF THE INVENTION The term "metered dose inhaler" or IDM "means a unit comprising a cylindrical container or container., a folded or capped lid covering the mouth of the cylindrical container or container, and a drug metering valve located in the cylindrical container or container, while the term "IDM system" also includes a suitable channeling device. The term "IDM cylindrical container or container" means the container or container without the cap and valve. The term "drug metering valve" or "IDM valve" refers to a valve and its associated mechanisms which provide a predetermined amount of drug formulation from an IDM during each activation. The channeling or channeling device may comprise, for example, a drive device for the valve and a cone-shaped cylinder or passage through which the medicament can be supplied from the full IDM cylindrical container or container via the valve. IDM to the nose or mouth of a patient, for example, a mouthpiece or mouthpiece actuator. The relationship of the parts of a typical IDM is illustrated in US Patent 5,261,538 incorporated herein by reference. The term "fluorocarbon polymers" means a polymer in which one or more of the hydrogen atoms of the hydrocarbon chain have been replaced by fluorine atoms. Thus, "fluorocarbon polymers" include perfluorocarbon, hydrofluorocarbon, chlorofluorocarbon, hydrochlorofluorocarbon polymers or other derivatives thereof substituted with halogen. The "fluorocarbon polymers" can be homopolymers or branched copolymers. U.S. Patent No. 3,644,363, incorporated herein by reference, teaches a group of bronchodilator compounds that are particularly useful in the treatment of asthma and other respiratory diseases. The preferred compound taught herein is a1-tert-butylaminomethyl-4-hydroxy-m-xylene-a1, a3-diol also known in the United States by its generic name "albuterol" and, in other cities more as "salbutamol". Albuterol as the free base and as acid addition salts (particularly as the sulfate salt), especially in the aerosol form, has been widely accepted by the medical community in the treatment of asthma and is sold under trademarks such as "Ventolin" and "Proventil". The term "drug formulation" means albuterol or a physiologically acceptable salt thereof (particularly the sulfate salt) optionally in combination with one or more pharmacologically active agents such as anti-inflammatory agents, analgesic agents or other respiratory drugs and optionally containing one or more excipients. The term "excipients" as used herein means chemical agents that have little activity or do not have pharmacological activity (for the amounts used) but which improves the drug formulation or the functioning of the MDI system. For example, excipients include but are not limited to surfactants, preservatives, flavors, antioxidants, antiaggregation agents, and cosolvents, for example, ethanol and diethyl ether. The albuterol or salt thereof can be used in the form of its R-isomer. Suitable surfactants are generally known in the art, for example, those surfactants described in European Patent Application No. 0327777. The amount of surfactant employed is desirable in the range of 0.0001% to 50% in relation or proportion of weight to weight in relation to the drug, in particular, 0.05 to 5% in relation of weight to weight. A particularly useful surfactant is 1,2-di [7- (F-hexyl) hexanoyl] -glycero-3-phospho-N, N, N-trimethylethanolamine known as 3, 5, 9-trioxa-4-phospadocosan-1. -amino, 17, 17, 18, 18, 19,19,20,20,21,21,22,22,22-tridecafluoro-7- [(8, 8, 9, 9, 10, 10, 11, 11 , 12, 12, 13, 13, 13-tridecafluoro-1-oxotridecyl) oxy] -4-hydroxy-N, N, N-trimethyl-10-oxo-, internal salt, 4-oxide. A polar cosolvent such as C 2-6 aliphatic alcohols and polyols for example, ethanol, isopropanol and propylene glycol, preferably ethanol, can be included in the formulation of the drug in the desired amount, either as the excipient alone or in addition to other excipients such as surfactants. Suitably, the drug formulation may contain 0.01 to 5% w / w based on the propellant of a polar cosolvent, for example, ethanol, preferably 0.1 to 5% w / w, for example, in about 0.1 to 1% w / w form p. It will be appreciated by those skilled in the art that the drug formulation for use in the invention may, if desired, contain albuterol or a salt thereof (eg, sulfate) in combination with one or more pharmacologically active agents. Such drugs can be selected from any suitable drug useful in inhalation therapy. The appropriate medicaments can thus be selected from, for example, analgesics, for example, codeine, dihydromorphine, ergotamine, fentanyl or morphine.; preparations for angina, for example, diltiazem; antiallergics, for example, cromoglycate, cetotifen or nedocromil; antiinfectants for example, cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines and pentamidine; antihistamines, for example, metapyrylene; anti-inflammatories, for example beclomethasone (for example dipropionate), flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, eg salbutamol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-) -4 -amino-3, 5-dichloro-a- [[[6- [2- (2-pyridinyl) ethoxy] -hexyl] amino] methyl] benzenemethanol; diuretics, for example, amiloride; anticholinergics, for example, ipratropium, atropine or oxitropium; hormones, for example, cortisone, hydrocortisone or prednisolone; xanthines, for example, inophylline, choline theophyllinate, usin theophyllinate or theophylline; and therapeutic proteins and peptides, for example insulin or glucagon. It will be clear to one skilled in the art that, where appropriate, the medicaments can be used in the form of salts (for example as alkali metal or amine salts or as acid addition salts) or as esters (e.g. , lower alkyl esters) or as solvates (for example hydrates) to optimize the activity and / or stability of the medicament and / or to minimize the solubility of the medicament in the propellant. Drug formulations contain albuterol particularly preferred or physiologically acceptable salt thereof in combination with an antiinflammatory spheroid as fluticasone propionate or beclomethasone dipropionate or physiologically acceptable solvates thereof. A particularly preferred drug combination is albuterol sulfate and beclomethasone dipropionate. "Propellants" used herein means pharmacologically inert liquids with boiling points from about room temperature (25 ° C) to about -25 ° C which alone or in combination exert a high vapor pressure at room temperature. During the activation of the IDM system, the high vapor pressure of the propellant in the IDM forces a measured or dosed amount of drug formulation out through the dosing valve then the propellant vaporizes very quickly by dispersing the drug particles. The propellants used in the present invention are fluorocarbons of low boiling temperature; in particular, 1,1,1,2 tetrafluoroethane also known as "propellant 134a" or "P 134a" and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane also known as "propellant 227" or "P 227". Preferably, however, the IDM cylindrical containers or containers employed in the present invention are made of aluminum or an alloy thereof.

Formulations of the drug for use in the invention may be free or substantially free of formulation excipients eg, surfactants and co-solvents etc. Such formulations of the drug are advantageous since they may be substantially free of taste and odor, less irritating and less toxic than the formulations containing the excipient. Thus, a preferred drug formulation consists essentially of albuterol or a physiologically acceptable salt thereof, optionally in combination with one or more pharmacologically active agents, particularly salmeterol (for example in the form of the xinafoate salt), and a fluorocarbon propellant. . Preferred propellants are 1, 1, 1, 2-tetrafluoroethane, 1,1,1,1,3,3,3-heptafluoro-n-propane or mixtures thereof, and especially 1,1,1,2-tetrafluoroethane . Additional drug formulations for use in the invention may be free or substantially free of surfactant. Thus, a further preferred drug formulation comprises or consists essentially of albuterol (or a physiologically acceptable salt thereof), optionally in combination with one or more pharmacologically active agents, a fluorocarbon propellant and 0.01 to 5% w / w based on the propellant of a polar cosolvent, this formulation is substantially free of surfactant. Preferred propellants are 1, 1, 1, 2-tetrafluoroethane, 1,1,1,1,3,3,3-heptafluoro-n-propane or mixtures thereof, and especially 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane. More often the cylindrical container or container of the IDM and the lid are made of aluminum or an aluminum alloy, although other metals not affected by the formulation of the drug, such as stainless steel, a copper alloy, or silver and tin, They can be used. An IDM container or container can also be made of glass or plastic. Preferably, however, the IDM containers or containers used in the present invention are made of aluminum or an alloy thereof. Advantageously, IDM containers of aluminum or aluminum alloy of increased concentration can be used. These reinforced IDM containers or containers are capable of particularly resisting full voltage curing and coating conditions, for example, particularly at elevated temperatures, which may be required for certain fluorocarbon polymers. The reinforced IDM containers or containers which have a reduced tendency to malformation under elevated temperatures include IDM containers or containers comprising side walls and a base of increased thickness and IDM containers or containers comprising a substantially ellipsoidal base (which increases the angle between the side walls and the base of the cylindrical container or container), faster than the hemispherical base of standard IDM containers or containers. IDM cylindrical containers or containers having an ellipsoidal base offer the additional advantage of facilitating the coating process. Fluorocarbon polymers for use in the invention include fluorocarbon polymers which are made of multiples of one or more of the following monomer units: tetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA), ethylene terafluoroethylene ( ETFE), vinylidene fluoride (PVDF), and chlorinated ethylene tetrafluoroethylene. Fluorinated polymers which have a relatively high fluorine to carbon ratio, such as perfluorocarbon polymers, for example, PTFE, PFA and FEP, are preferred.

The fluorinated polymer can be mixed with non-fluorinated polymers such as polyamides, polyimides, polyethersulfones, polyphenylene sulfides, and thermosetting aminoformaldehyde resins. These added polymers improve the adhesion of the polymeric coating to the walls of the container or container. Preferred polymer blends are PTFE / FEP / polyamideimide, PTFE / polyether sulfone (PES) and FEP-benzoguanamine. Preferably, the fluorocarbon polymers for use in the invention are coated on IDM cylindrical containers or containers made of metal, especially IDM cylindrical containers or containers made of aluminum or an alloy thereof. Particularly preferred coatings are pure PFA and mixtures of PTFE and polyethersulfone (PES). Fluorocarbon polymers are sold under the trademarks Teflon®, Tefzel®, Halar® and Hostaflon®, Polyflon® and Neoflon®. Polymer classes include DuPont 856-200 FEP, DuPont 857-200 PFA, DuPont 3200-100 PTFE-PES, DuPont 856P23485 PTFE-FEP-polyamideimide, DuPont 532 FEP powder, and Hoechst 6900n PFA. The thickness of the coating is in the range of approximately lμm to approximately lmm. Conveniently the thickness of the coating is in the range of about 1 μm to about 100 μm, for example, from 1 μm to 25 μm. The coatings can be applied in one or more coatings. The particle size of the particular drug (e.g., micronized) should be such as to allow the inhalation of substantially all of the drug in the lungs during administration of the aerosol formulation and will therefore be less than 100 microns, desirably less than 20 microns. , and, in particular, in the range of 1-10 microns, for example, 1-5 microns. The final aerosol formulation desirably contains 0.005-10% in weight ratio to weight ratio, in particular 0.005-5% relative to or weight to weight ratio, especially 0.01-1.0% by weight to weight ratio, drug in relation to the total weight of the formulation. A further aspect of the present invention is a metered dose or regulated inhaler having part or all of its internal metallic surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more polymers without fluorocarbon, to distribute a formulation of drug for inhalation comprising albuterol or a salt thereof and a fluorocarbon propellant optionally in combination with one or more other pharmacologically active agents and one or more excipients. A particular aspect of the present invention is an IDM that essentially has all its internal metal surfaces coated with PFA or FEP, or resin systems of mixed fluoropolymers such as PTFE-PES with or without a primary coating of a polyamideimide or polyethersulfone to distribute a drug formulation defined herein above. Preferred drug formulations for use in this MDI consist essentially of albuterol (or a physiologically acceptable salt thereof, eg, sulfate), optionally in combination with one or more pharmacologically active agents, particularly beclomethasone dipropionate (or a solvate of the and a fluorocarbon propellant, particularly 1,1,1,2-tetrafluoroethane, 1, 1, 1, 2, 3, 3, 3-heptafluoropropane or mixtures thereof, and especially 1,1,1,2-tetrafluoroethane. Preferably the IDM container or container is made of aluminum or an alloy thereof. The cylindrical container or container of the IDM can be coated by means known in the art of metal coating. For example, a metal, such as aluminum or stainless steel, may be pre-coated as a spiral or cylindrical material and cured before being punched or tempered in the form of a cylindrical container or container. This method is very suitable for high volume production for two reasons. First, the technique of coating well-developed circular material and various manufacturers can custom-make circular coated metal materials to high standards of uniformity and in a wide range of thicknesses. Second, the pre-coated material can be die cut or tempered at high speeds and precision by essentially the same methods used to repair or punch uncoated materials. Other techniques for obtaining coated cylindrical containers or containers is by coating with electrostatic dry powder or by spraying into preformed IDM cylindrical containers or containers with coating formulations of the fluoropolymer / polymer mixture and then curing. The cylindrical containers or containers of the preformed IDM can also be submerged in the formulation for coating of the fluorocarbon / polymer polymer mixture and cured, thus they become coated on the inside and outside. The formulation of the fluorocarbon polymer / polymer mixture can also be poured into the containers or containers of the IDM then drained to leave the interiors with the polymer coating. Conveniently, to facilitate manufacturing, the preformed IDM cylindrical containers or containers are spray coated or sprayed with the fluoropolymer / polymer blend. The fluorocarbon / polymer polymer mixture can also be formed in situ in the walls of the container or container using plasma polymerization of fluorocarbon monomers. The fluorocarbon polymer film can be blown into the containers or containers of the IDM to form bags. A variety of fluorocarbon polymers such as ETFE, FEP, and PTFE are available as film material. The appropriate curing temperature is dependent on the polymer / fluorocarbon polymer blend chosen for the coating and the coating method employed. However, for spiral coating and spraying or spraying, temperatures in excess of the melting point of the polymer are typically required, for example, about 50 ° C above the melting point for up to about 20 minutes such as about 5 a 10 minutes, for example, approximately 8 minutes or as required. For the above-mentioned preferred curing and curing of the particularly preferred fluorocarbon polymer / polymer blends, temperatures in the range of about 300 ° C to about 400 ° C, for example about 350 ° C to 380 ° are suitable. C. For plasma polymerization typically temperatures in the range of about 20 ° C to about 100 ° C can be employed. The IsDMs taught herein can be prepared by methods of the art (for example, see Byron, mentioned above and U.S. Patent 5,345,980) which replace conventional containers or containers with those coated with a fluorinated polymer / polymer mixture. That is, albuterol or a salt thereof and other components of the formulation are filled or loaded into a cylindrical aerosol can or container coated with a fluoropolymer / polymer blend. The container or container is fixed with a cap assembly which is secured in place. The suspension of the drug in the fluorocarbon propellant in the liquid form can be introduced through the metering valve as taught in U.S. Pat., 345,980 incorporated herein by reference. The IsDM with interiors coated with the fluorocarbon / polymer polymer blend taught herein can be used in medical practice in a similar manner as IsDM currently uncoated, in clinical use. However, the IsDMs taught herein are particularly useful for containing and distributing formulations of the inhaled drug with hydrofluoroalkane fluorocarbon propellants such as 134a with little, or essentially no excipient and which tends to deposit or adhere to the inner walls and parts of the body. IDM system. In certain cases it is advantageous to distribute a drug for inhalation essentially without excipient, for example, wherein the patient may be allergic to an excipient or to the reactions of the drug with an excipient. The IsDMs containing the formulations described above, the IDM systems and the use of such IDM systems for the treatment of respiratory disorders, eg, asthma, comprise additional aspects of the present invention. It will be apparent to those skilled in the art that the modifications to the invention described herein can easily be made without departing from the spirit of the invention. Protection is sought for the entire subject described here including any modifications. The following non-limiting examples serve to illustrate the invention.

EXAMPLES Example 1 Cylindrical containers or recipients of the standard 12.5 ml IDM (Presspart Inc., Cary, NC) were spray-coated (Livingstone Coatings, Charlotte, NC) with primer (DuPont 851-204) and cured for the vendor's standard procedure or supplier, then they were coated by additional spraying with either FEP or PFA (DuPont 856-200 and 857-200, respectively) and cured in accordance with the standard procedure of the vendor or supplier. The coating thickness is approximately 10 μm a 50μm These containers or containers are then purged of air (see PCT application number W094 / 22722).

(PCT / EP94 / 00921)), the valves are folded or folded in place, and a suspension of approximately 29 mg of albuterol sulfate in approximately 18.2 gm P134a is filled or charged through the valve.

Example 2 A standard aluminum sheet 0.46 mm thick (United Aluminum) was spray coated (DuPont, Wilmington, DE) with FEP (DuPont 856-200) and cured. The thickness of the coating is approximately 10 μm to 50 μm. This sheet was then crammed into cylindrical containers or containers (Presspart Inc., Cary, NC). These containers or containers were then purged with air, the valves were bent or pecked in place, and a suspension of approximately 12 mg of albuterol sulfate in approximately 7.5 gm of P134A was filled or charged through the valve.

Example 3 Standard IDM containers or containers 12. 5 ml (Presspart Inc., Cary, NC) were spray-coated with the PTFE-PES (DuPont) mixture as a single coating and cured in accordance with the standard procedure of the vendor or supplier. The thickness of the coating is between approximately lμm and approximately 20μm. These containers or containers were then purged of air, the valves were folded or folded into place, and a suspension of approximately 31.8 mg or approximately 15.4 mg of micronized albuterol sulfate in approximately 19.8go approximately 9.6g respectively of P134a was filled or load through the valve.

Example 4 Standard 12.5 ml IDM containers or containers (Presspart Inc., Cary, NC) were spray-coated with the PTFE-FEP-polyamideimide (DuPont) mixture and cured in accordance with the standard procedure of the vendor or supplier. The thickness of the coating is between approximately lμm and approximately 20μm. These containers or containers were then purged of air, the valves were folded or folded into place, and a suspension of approximately 31.8 mg or approximately 15.4 mg of micronized albuterol sulfate in approximately 19.8go approximately 9.6g respectively of P134a was charged. or stuffed through the valve.

Example 5 Standard 12.5 ml IDM containers or containers (Presspart Inc., Cary, NC) were spray coated with FEP powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately lμm and approximately 20μm. These cylindrical containers or containers were then purged of air, the valves were folded or folded into place, and a suspension of approximately 31.8 mg or approximately 15.4 mg of micronized albuterol sulfate at approximately 19.8go approximately 9.6g respectively of P134a was loaded or filled through the valve.

Example 6 A 0.46 mm thick, standard aluminum foil (United Aluminum) was spray-coated with FEP-Benzoguanamine and cured. Then this sheet was stuffed into cylindrical containers or containers. These cylindrical containers or containers were then purged of air, the valves were folded into place, and a suspension of approximately 31.8 mg or approximately 15.4 mg of micronized albuterol sulfate in approximately 19.8 g or approximately 9.6 g of P134a respectively. charged or filled through the valve.

Example 7 IDM cylindrical containers or containers of 12.5 ml, standard (Presspart Inc., Cary, NC) were spray coated with an aqueous dispersion of PFA (Hoechst PFA-6900m) and cured. The thickness of the coating is between approximately lμm and approximately 20μm. These cylindrical containers or containers are then purged of air, the valves are folded or folded in place, and a suspension of approximately 31.8 mg or approximately 15.4 mg of micronized albuterol sulfate in approximately 19.8go approximately 9.6g respectively. of P134a, was filled or charged through the valve.

Example 8 Standard 12.5 ml IDM cylindrical containers or containers (Presspart Inc., Gary, NC) were spray-coated with PTFE-PES (DuPont) mixture as a single coating and cured according to the standard procedure of the vendor or supplier. The thickness of the coating is between approximately lμm and approximately 20μm. These containers or containers are then purged of air, the valves are folded or swaged in place, and a suspension of approximately 28.9 mg of micronized albuterol sulfate in about 18g of P134a is filled or charged through the valve.

Example 9 IDM cylindrical containers or containers of 12.5 ml, standard, (Presspart Inc., Cary, NC) were spray coated with the PTFE-FEP-polyamideimide (DuPont) mixture and cured according to the standard procedure of the vendor or supplier . The thickness of the coating is between approximately lμm and approximately 20μm. These containers or containers are then purged of air, the valves are folded or softened in place, and a suspension of approximately 28.9 mg of micronized albuterol sulfate in approximately 18 g of P134a is loaded or filled through the valve.

Example 10 Standard 12.5 ml IDM cylindrical containers or containers (Presspart Inc., Cary, NC) were spray coated with FEP powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately lμm and approximately 20μm. These cans or cylindrical containers are then purged of air, the valves are folded or swaged in place, and a suspension of approximately 28.9 mg of micronized albuterol sulfate in approximately 18g of Pl34a is filled or charged through the valve.

Example 11 An aluminum sheet 0.46 mm thick, standard, (United Aluminum) is spray-coated or sprayed with FEP-Benzoguanamine and cured. This sheet is then stuffed into cylindrical containers or containers. Then these containers or containers were purged of air, the valves are folded or folded in place, and a suspension of approximately 28.9 mg of micronized albuterol sulfate in about 18g of P134a is filled or charged through the valve.

Example 12 IDM cylindrical containers or containers of 12.5 ml, standard, (Presspart Inc., Cary, NC) were spray coated with an aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of the coating is between approximately lμm and approximately 20μm. These cylindrical containers or containers are then purged of air, the valves are folded or cushioned in place, and a suspension of approximately 28.9 mg of micronized albuterol sulfate in approximately 18g of P134a is filled through the valve.

Examples 13 to 17 Examples 3 to 7 were repeated except that a suspension of 29 mg of micronized albuterol sulfate in approximately 21.4 g P227 is filled or charged through the valve.

Examples 18 to 22 Examples 3 to 7 were repeated except that 24 mg or 15 mg of micronized albuterol sulfate in approximately 364 mg or 182 mg of ethanol respectively and approximately 18.2 g of P134a were filled or charged by the valve.

Examples 23 to 42 Examples 3 to 22 were repeated except that cylindrical containers or containers of the modified 12.5 ml IDM having a substantially ellipsoidal base (Presspart Inc. Cary NC) are used. Delivery of the dose from the IsDM tested under simulated use conditions is found to be constant, compared to the control IsDM filled in uncoated containers or containers which exhibit a significant decrease in dose delivered through use.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which refers to the manufacture of the objects to which it refers.

Having described the invention as above, the content of the following is claimed as property

Claims (22)

1. A metered dose inhaler characterized in that it has part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more polymers without fluorocarbon, to distribute a formulation of the inhalation drug comprising albuterol or a salt physiologically acceptable thereof, and a fluorocarbon propellant, optionally in combination with one or more pharmacologically active agents or one or more excipients.

2. An inhaler according to claim 1, characterized in that it contains the drug formulation.

3. An inhaler according to claim 2, characterized in that the drug formulation further comprises a surfactant.

4. An inhaler according to claim 2 or 3, characterized in that the drug formulation further comprises a polar cosolvent.

5. An inhaler according to claim 2, characterized in that the drug formulation comprises 0.01 to 5% w / w based on the propellant of a polar cosolvent, this formulation being substantially free of surfactant.

6. An inhaler according to any of claims 2 to 5, characterized in that the formulation of the drug comprises albuterol or a physiologically acceptable salt thereof in combination with an anti-inflammatory or an anti-allergic spheroid.

7. An inhaler according to claim 6, characterized in that the formulation of the drug comprises albuterol or a physiologically acceptable salt thereof in combination with beclomethasone dipropionate or a physiologically acceptable solvate thereof.

8. An inhaler according to claim 2, characterized in that the drug formulation consists essentially of albuterol or a physiologically acceptable salt thereof, optionally in combination with one or more pharmacologically active agents, and a fluorocarbon propellant.

9. An inhaler according to claim 8, characterized in that the drug formulation consists essentially of albuterol or a physiologically acceptable salt thereof in combination with an anti-inflammatory or an anti-allergic spheroid.

10. An inhaler according to claim 9, characterized in that the drug formulation consists essentially of albuterol or a physiologically acceptable salt thereof in combination with beclomethasone dipropionate or a physiologically acceptable solvate thereof.

11. An inhaler according to claim 2, characterized in that the drug formulation consists of albuterol or a physiologically acceptable salt thereof and a fluorocarbon propellant.

12. An inhaler according to any of claims 2 to 11, characterized in that the albuterol is in the form of the sulfate salt.

13. An inhaler according to any of claims 2 to 12, characterized in that the fluorocarbon propellant is 1, 1, 1, 2-tetrafluoroethane, or 1, 1, 2, 3, 3, 3-heptafluoro-n-propane or mixtures thereof.

14. An inhaler according to claim 13, characterized in that the fluorocarbon propellant is 1,1,1,2-tetrafluoroethane.

15. An inhaler according to any of claims 1 to 14, characterized in that it comprises a cylindrical container or container made of metal in which part or all of the internal metallic surfaces are coated.

16. An inhaler according to claim 15, characterized in that the metal is aluminum or an alloy thereof.

17. An inhaler according to any of claims 1 to 16, characterized in that the fluorocarbon polymer is a perfluorocarbon polymer.

18. An inhaler according to claim 17, characterized in that the fluorocarbon polymer is selected from PTFE, PFA, FEP and mixtures thereof.

19. An inhaler according to any of claims 1 to 18, characterized in that the fluorocarbon polymer is in combination with a fluorocarbon-free polymer selected from the polyamideimide and polyethersulfone.

20. An inhaler according to any of claims 1 to 19, characterized in that it comprises a substantially ellipsoidal base.

21. A metered dose inhaler system comprising a metered dose inhaler according to any of claims 1 to 20 affixed to the channeling device suitable for oral or nasal inhalation of the drug formulation.

22. The use of a metered dose inhaler system according to claim 21 for the treatment of respiratory disorders.