MXPA97007878A - Inhaler of measured dose for dipropionate of beclometasone - Google Patents

Abstract

The present invention relates to a metered dose inhaler, having all internal surfaces, or parts thereof, coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for delivery of a drug formulation for inhalation, comprising beclomethasone dipropionate or a physiologically acceptable solvate thereof, and a propellant or impeller based on fluorocarbon, optionally in combination with one or more other pharmacologically active agents, or one or more excipients

Description

INHALER OF MEASURED DOSE, FOR DIPROPIONATE OF BECLOMETASONE BACKGROUND OF THE INVENTION Drugs for the treatment of respiratory and nasal disorders are often administered in aerosolized formations, through the mouth or nose. A method widely used to deliver such aerosol formulations of the drug involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as propellant or propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to keep the propellant liquid. The suspension is dispersed by activating a dose regulating valve, attached to the container. A regulating valve can be designed to consistently release a fixed, predetermined mass of the drug formulation, at each activation. As the suspension is forced from the container, through the valve REF: 25888 regulator of the dose, by means of the high steam pressure of the propellant, the propellant vaporizes quickly leaving a cloud, which moves quickly, of very fine particles of the drug formulation. This cloud of particles is directed towards the nose or mouth of the patient through a channel device, such as a cylinder or open-ended cone. Concurrently with the activation of the dose regulating valve, the aerosol, the patient inhales the drug particles into the lungs or into the nasal cavity. Systems for the delivery of drugs in this form are known as "metered dose inhalers" (MDI, for its acronym in English). See Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, FL (1990) for the general background analysis of this form of therapy. Patients often depend on the medication provided by MDI for the rapid treatment of respiratory disorders that weaken them and in some cases put their lives at risk. Therefore, it is essential that the prescribed dose of the aerosol medication, supplied to the patient, consistently meet the specifications required by the manufacturer and comply with the requirements of the FDA and other regulatory authorities. That is, each dose of the can must be the same within narrow tolerances. Some aerosol drugs tend to adhere to the internal surfaces, that is, the walls of the can, valves, and caps, of the MDI. This can lead to the patient perceiving significantly less than the prescribed amount of the drug, at each activation of the MDI. The problem is particularly acute with propeller systems based on hydrofluoroalkanes (also known simply as "fluorocarbons", for example, P134a and p227, under development in recent years, to replace chlorofluorocarbons such as Pll, P114, and P12). The inventors of the present have found that by coating the internal surfaces of the MDI can with a fluorocarbon polymer, it significantly reduces or essentially eliminates the problem of the adhesion or deposition of the drug on the walls of the can and thus ensures the consistent supply of the medication in the form of aerosol, from the MDI.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a metered dose inhaler, having all or part of its internal surfaces, coated with one or more fluorocarbon polymers, optionally in combination with one or more polymers that are not fluorocarbons, to supply a drug formulation for inhalation, comprising beclomethasone dipropionate or a physiologically acceptable solvate thereof, and a fluorocarbon-based 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 WMD? "Means a unit comprising a can, a lid secured by folding and tightening, covering the can nipple, and a dose regulating valve located on the lid, while the term "MDI system" also includes a suitable channel device. The terms "MDI can" means the container without the lid and without the valve. The term "drug regulating valve" or "MDI valve" refers to a valve and its associated mechanisms, which deliver a predetermined amount of drug formulation, of an MDI, at each activation. The channel device comprises, for example, an actuator for the valve and a cylindrical or cone-shaped passage, through which the medicament can be delivered from the MDI via the valve of the MDI, towards the nose or mouth of the patient. , for example an actuator in the shape of a mouth piece. The relationship of the parts of a typical MDI is illustrated in U.S. Patent No. 5,261,538 incorporated herein by reference. US Patent No. 3, 312, 590, incorporated herein by reference, discloses an anti-inflammatory steroidal compound, known by the chemical name 9-chloro-l ID, 17, 21-trihydroxy-16-methyl-prepregna-1, -3,20-dione 17.21-dipropionate and the generic name of "beclomethasone dipropionate". Beclomethasone dipropionate in the form of aerosol, has been accepted by the medical community, as useful in the treatment of asthma and is sold under the trademarks "Beclovent", "Becstide", and "Beconase". The term "drug formulation" means beclomethasone dipropionate (or a physiologically acceptable solvate thereof) optionally in combination with one or more pharmacologically active agents such as other 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 do not have pharmacological activity or that do have it is small (by the amounts used) but that improve the formulation of the drug or the efficiency of the MDI system. For example, excipients include but are not limited to surfactants, preservatives, flavors, antioxidants, antiaggregation agents, and cosolvents, such as for example ethanol and diethyl ether. 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 desirably in the range of 0.0001% to 50%, weight / weight ratio, with respect to the drug, in particular, from 0.005 to 5% in relation weight / weight. A particularly useful surfactant is l, 2-di [7- (F-hexyl) exanoyl] -glycero-3-phospho-N, N, N-trimethylethanolamine also known as 3,5,9-trioxa-4 -phosfadocosan-l-aminium, 17,17,18,18,19,19,20,20,21,21,22,22-tridecacluoro-7- [(8,8,9,9,10,10,11 , 11,12,12,13,13,13-tridecafluoro-l-oxotri-ecil) oxy] -4-hydroxy-N, N, N-trimethyl-10-oxo-, internal salt ,. 4-oxide. A polar cosolvent such as the aliphatic alcohols and polyols of 2 to 6 carbon atoms, such as ethanol, isopropanol and propylene glycol, and preferably ethanol, can be included in the drug formulation, in the desired amount, either as the single excipient or in addition to other excipients such as surfactants. Conveniently, the drug formulation can contain from 0.001 to 5% w / w based on the propellant of a polar cosolvent such as for example ethanol, preferably from 0.1 to 5% w / w, for example from 0.1 to 1% w / w p. Those skilled in the art will appreciate that the formulation for use in the invention may contain, if desired, beclomethasone dipropionate (or a physiologically acceptable solvate thereof) in combination with one or more other pharmacologically active agents. These medications can be selected from any suitable drug, useful for inhalation therapy. The appropriate medicaments can thus be selected, for example, from analgesics, such as, for example, codeine, dihydro orphine, ergotamine, fentanyl or morphine.; anginal preparations, such as for example diltiazem; antiallergics, such as for example cro oglycate, ketotifen or nedocromil; antiinfectives, such as for example cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines and pentamidine; antihistanes, such as, for example, metapyrylene; anti-inflammatories, such as for example fluticasone (for example, propionate), flunisolide, budesonide, tripedane or tria cinolone acetonide; antitussives, such as for example noscapine; bronchodilators, such as for example salbutamol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaprot-erenol, phenylephrine, phenylpropanol-amine, pirbuterol, reproterol, rimiterol, terbutaline, isoetarin, tulobuterol, orciprenaline, or (* -) - 4-amino-3,5-dichloro-a- [[[6- [2- (2-pyridinyl) ethoxy] hexyl] amino] methyl] encenmetanol; diuretics, such as for example amiloride; anticholinergics, such as, for example, ipratropium, atropine or oxytropium; hormones, such as for example cortisone, hydrocort isone or prednisolone; xanthines, such as, for example, aminophylline, choline theophyllinate, theophyllinate, theophylline or theophylline; and therapeutic proteins and peptides, such as for example insulin or glucagon. For a person skilled in the art, it will be clear that, where appropriate, the medicaments can be used in the form of salts (for example, the amine or alkali metal salts, or as acid addition salts) or as esters (eg, lower alkyl esters) or as solvates (eg, hydrates) to optimize the activity and / or stability of the medicament and / or minimize the solubility of the medicament in the propellant. Particularly, preferred drug formulations contain beclomethasone dipropionate (or a physiologically acceptable solvate thereof) in combination with a bronchodilator such as salbutamol (e.g., as the free base of the sulfate salt) or salmeterol (e.g. , like xinafoato salt). The term "propellants", used herein, means pharmacologically inert liquids, with boiling points from about room temperature (25 C) to about -25 ° C, which in single or in combination exert a high vapor pressure at room temperature. By activating the MDI system, the high vapor pressure of the propellant found in the MDI forces a measured amount of drug formulation outward through the regulating valve, and then the propellant vaporizes very rapidly scattering the particles of the drug. The propellants used in the present invention are low boiling fluorocarbons; in particular 1, 1, 1, 2-tetrafluoroethane also known as "propellant 134a" or "P134a" and 1, 1, 2, 3, 3, 3-heptafluoropropane also known as "propellant 227" or "P 227". Drug formulations, for use in the invention, may be free or substantially free of excipients, such as for example surfactants and co-solvents, etc. These drug formulations are advantageous, since they can substantially be free of taste and odor, be less irritating and less toxic than formulations containing excipients. Thus, a preferred drug formulation consists essentially of beclomethasone dipropionate (or a physiologically acceptable solvate thereof), optionally in combination with one or more other pharmacologically active agents, particularly salbutamol (or a physiologically acceptable salt thereof). , and a fluorocarbon propellant. Preferred propellants are 1, 1, 1, 2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof, and especially 1,1,1,2 -tetrafluoroethane. More often, the MDI can and lid are made of aluminum or an aluminum alloy, although other metals not affected by the drug formulation can be used., such as stainless steel, a copper alloy, or tin plate. An MDI can can also be made of glass or plastic. However, preferably, the MDI cans used in the present invention are made of aluminum or an alloy thereof. Advantageously, MDI cans, reinforced aluminum or aluminum alloy can be used. These reinforced MDI cans are able to withstand coating and curing conditions, particularly full of stresses or fatigue, such as, for example, particularly high temperatures, which may be required for certain fluorocarbon polymers. The reinforced MDI cans, which have a reduced tendency to malign under high temperatures, include the MDI cans, which contain side walls and a base of increased thickness, and the MDI cans containing a substantially ellipsoidal base (which increases the angle between the side walls and the base of the can), instead of the hemispherical base of the standard MDI cans. MDI cans, which have an ellipsoidal base, offer the additional advantage of facilitating the coating process. The dose regulating valve consists of parts usually made of stainless steel, a propellant-resistant and pharmacologically inert polymer, such as acetal, polyamide (for example Nailon ™), polycarbonate, polyester, fluorocarbon polymer (e.g., Teflon ™ ) or a combination of these materials. Additionally, "O" seals and rings of various materials (e.g., nitrile rubbers, polyurethane, acetyl resin, fluorocarbon polymers), or other elastomeric materials are employed in or around the valve. Fluorocarbon polymers for use in the invention include fluorocarbon polymers that are made of multiple of one or more of the following monomer units: tetrafluoroethylene (PTFE), fluorinated ethylene-propylene (FEP), per-fluoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (ETFE) ), vinylidene fluoride (PVDF), and chlorinated ethylenetetrafluoroethylene. Fluorinated polymers having a relatively high ratio of fluorine to carbon are preferred, such as perfluorocarbon polymers, for example PTFE, PFA, and FEP. The fluorinated polymer can be mixed with non-fluorinated polymers such as polyamides, polyimides, polyethersulfones, polyphenylene sulfides and thermosetting resins based on aminefor aldehyde. These added polymers improve the adhesion of the polymer coating on the walls of the can. Preferred polymer blends are PTFE / FEP / idala ida, PTFE / polyether sulfone (PES) and FEP-benzoguanamine. Particularly preferred coatings are PFA, FEP, pure, and mixtures of PTFE and polyethersulfone (PES).

The fluorocarbon polymers are sold under the trademarks such as Teflon ™, Tefzel ™, Halar ™, Hostaflon ™, Polyflon ™ and Neoflon ™. Polymer grades include the DuPont 856-200 FEP, DuPont 857-200 PFA, DuPont 3200-100 PTFE-PES, DuPont 856P23485 PTFE-FEP-polyamideimide, FEP powder, DuPont 532 and PFA Hoechst 6900n. The thickness of the coating is in the range from about 1 μm to about 1 mm. Conveniently the thickness of the coating is in the range from about 1 μm to about 100 μm, for example from 1 μm to 25 μm. The coatings can be applied in the form of one or more coating layers. Preferably the fluorocarbon polymers, for use in the invention, are coated on the MDI cans made of metal, especially MDI cans made of aluminum or an alloy of the site. The particle size of the particular drug (eg, micronized) should be such as to allow the inhalation of substantially all of the drug in the lungs, in the administration of the aerosol formulation and therefore be less than 100 microns, desirably less than microns, and, in particular, in the range of 1-10 microns, for example 1-5 microns. The final aerosol formulation desirably contains from 0.005 to 10% by weight / weight, in particular from 0.005 to 5% by weight / weight, especially from 0.01 to 10% by weight / weight, of the drug, in relation to to the total weight of the formulation. A further aspect of the invention is a metered dose inhaler having all or a portion of its internal metal surfaces, coated with one or more fluorocarbon polymers, optionally in combination with one or more fluorocarbon polymers, for the delivery of a formulation of the drug, for inhalation, comprising beclomethasone dipropionate and a fluorocarbon propellant, optionally in combination with one or more pharmacologically active agents and one or more excipients. A particular formulation for use in the metered dose inhaler of the present invention comprises: (a) beclomethasone dipropionate onohydrate, wherein the particle size of substantially all of the monohydrate is less than 20 microns; (b) at least 0.015% by weight of the water formulation, in addition to the water of crystallization associated with the monohydrate; and (c) a fluorocarbon-based propellant. Those aerosol formulations desirably contain at least 0.015% (eg, 0.015 to 0.1%) by weight of the formulation, of water (excluding the water of crystallization associated with the beclomethasone dipropionate monohydrate), preferably at least 0.02%, for example 0.025% by weight or more of water added. Preferred formulations, according to the invention, contain at least 0.026%, for example from 0.026 to 0.08% by weight of water, in addition to the water of crystallization associated with beclomethasone dipropionate monohydrate. Optionally, a cosolvent such as ethanol may be included in the formulation, in the desired amount. Conveniently, the formulation may contain from 0.05 to 3.0% w / w based on the propellant of a polar cosolvent such as ethanol. Preferably the fluorocarbon-based propellant is 1,1,1,2-tetrafluoroethane, 1, 1, 2, 3, 3, 3-heptafluoro-n-propane or mixtures thereof, and especially 1, 1, 1, 2-tetrafluoroethane. Additional drug formulations, for use in the invention, are free or substantially free of surfactants. Thus, a further formulation comprises or consists essentially of beclomethasone dipropionate or a physiologically acceptable solvate thereof, optionally in combination with one or more pharmacologically active agents, a fluorocarbon-based propellant and from 0.01 to 0.05% w / w, in base to the propellant, of a polar cosolvent such as ethanol, formulation that is free of surfactant. Preferably the propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluo or-n-propane, although mixtures thereof can also be used. A particular aspect of the present invention is an MDI having part of, or essentially all internal surfaces, for example metal surfaces, coated with PFA or FEP, or mixed fluoropolymer resin systems, such as PTFE-PES with or without a suitable coating of polyamideimide or polyethersulfone, to disperse a drug formulation as described hereinabove. Preferably the MDI can is made of aluminum or an alloy thereof. The MDI can can be coated by means known in the metal coating art. For example, a metal, such as aluminum or stainless steel, can be precoated as a rolled material and cured before being stamped or stretched to take the shape of the can. This method is quite suitable for production in high volumes, for two reasons. First, the technique for coating roll material is well developed and many manufacturers can sell roll material for the metal coating, in high standards of uniformity and in a wide range of thicknesses. Second, the previously coated material can be stamped or stretched at high speeds and with high precision, essentially by the same methods used to stretch or stamp the uncoated material. Other techniques for obtaining coated cans are by electrostatic coating with dry powder, or by spraying preformed MDI cans, with formulations of the fluoropolymer / polymer based coating mixture, and curing. The preformed MDI cans can also be immersed in the fluorocarbon polymer / polymer based coating formulation and cured, thus being coated on the inside and the outside. The fluorocarbon / polymer polymer mixture formulation can also be poured into the MDI cans, subsequently draining and leaving the inside with the polymeric coating. Conveniently, for ease of manufacture, preformed MDI cans are spray coated with the fluoropolymer / polymer blend. The fluorocarbon / polymer polymer mixture can also be formed in situ in the walls of the can, using plasma polymerization, of the fluorocarbon monomers. The fluorocarbon polymer film can be blown into the MDI cans to form bags. As the film material, a variety of fluorocarbon polymers such as ETFE, FEP, and PTFE are available. The appropriate curing temperature is dependent on the fluorocarbon polymer / polymer blend selected for the coating and the coating method employed. However, for coating with roll material and spray coating, temperatures exceeding the melting point of the polymer are typically required, for example, about 50 ° C above the melting point, for a time of about 20 minutes. minutes, such as about 5 to 10 minutes, for example about 8 minutes or as required. For fluorocarbon / polymer polymer blends, mentioned above, curing temperatures which are in the range of about 300 ° C to about 400 ° C, for example about 350 ° C to 380 ° C, are suitable. For plasma polymerization, temperatures typically in the range of about 20 ° C to about 100 ° C may be used. The fluorocarbon polymer can also be formed in situ in the walls of the can, using plasma polymerization, of the fluorocarbon monomers. The fluorocarbon monomer film can be blown into the MDI cans, to form bags. A variety of fluorocarbon polymers, such as ETFE, FEP, and PTFE, are available as a film material. The MDIs described herein can be prepared by methods of the art (see, for example, Byron, supra, and U.S. Patent No. 5,345,980) by replacing conventional cans with those covered with a fluorinated polymer. That is, the beclomethasone dipropionate and other components of the formulation are introduced into an aerosol can coated with a fluorinated polymer. The can is adjusted with a cap assembly which is secured in place, by folding and tightening. The suspension of the drug in the fluorocarbon propellant, in liquid form, can be introduced through the regulating valve, as described in US Pat. No. 5,345,980 which is incorporated herein by reference. MDIs with MDI-coated interiors, described herein, can be used in medical practice, in a similar manner as MDI's now in clinical use. However, the MDIs described herein are particularly useful for containing and supplying drug formulations, inhaled, with hydrofluoroalkane fluorocarbon propellants, such as 134a with little excipient or essentially no excipient, and which tend to deposit or occlude the walls and internal parts of the MDI system. In certain cases it is advantageous to provide a drug for inhalation essentially without excipient, for example, wherein the patient may be allergic to an excipient or wherein the drug reacts with an excipient. The MDIs containing the formulations described above, the MDI systems and the use of those MDI systems for the treatment of respiratory disorders, for example asthma, comprise additional aspects of the present invention. Those skilled in the art will appreciate that modifications to the invention described herein can be made easily without departing from the spirit of the invention. Protection is sought for the entire matter of interest described herein, including any of the modifications. The following non-limiting Examples serve to illustrate the invention.

EXAMPLES Example 1 Coated by spray (Livingstone Coatings, Charlotte, NC), standard or normal, 12.5 mL MDI cans (Presspart Inc., Cary NC) with sizing (DuPont 851-204) and cured according to the vendor's standard procedure, then they are coated by spraying in additional form, either with FEP or PFA (DuPont 856-200 and 857-200, respectively) and cured according to the vendor's standard procedure. The thickness of the coating is from about 10 μm to 50 μm. The air is then purged to these cans (see PCT application number W094 / 22722 (PCT / EP94 / 00921)), the valves are secured in place, by folding and tightening, and a suspension is introduced through the valve. of about 24 mg of beclomethasone dipropionate and about 18 g of P134a.

Example 2 Coated by spraying (DuPont, Wilmington, DE), aluminum sheet, standard or normal, 0.46 mm thick (United Aluminum), with FEP (DuPont 856-200) and cured. This sheet is then transformed into cans, by deep drawing (Presspart Inc., Cary NC). The thickness of the coating is from about 10 μm to 50 μm. These cans are then purged of air, the valves are secured in place, by folding and tightening, and a suspension of approximately 60 mg of beclomethasone dipropionate in approximately 18 g of P134A is introduced through the valve.

Example 3 12.5 mL standard or standard MDI cans (Presspart Inc., Cary, NC) with PTFE-PES blend (DuPont) are coated as a single spray and cured according to the vendor's standard procedure. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged from these cans, the valves are secured in place, by folding and tightening, and a suspension of approximately 68 mg of beclomethasone dipropionate monohydrate in approximately 6.1 mg of water is introduced through the valve and approximately 18 g of P134a.

Example 4 Standard or standard MDI cans of 12.5 mL (Presspart Inc., Cary, NC) are coated by spraying with PTFE-FEP-polyamideimide (DuPont) mixture and cured according to the seller's standard procedure. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged from these cans, the valves are secured in place, by folding and tightening, and a suspension of approximately 68 mg of beclomethasone dipropionate monohydrate in approximately 6.1 mg of water is introduced through the valve and approximately 18.2 g of P134a.

Example 5 Spray-coated, standard or normal, 12.5 mL MDI cans (Presspart Inc., Cary, NC) with FEP powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged from these cans, the valves are secured in place, by folding and tightening, and a suspension of approximately 68 mg of beclomethasone dipropionate monohydrate in approximately 6.1 mg of water is introduced through the valve and approximately 18.2 g of P134a.

Example 6 Coated by spraying, aluminum sheet, standard or normal, 0.46 mm thick, with FEP-Benzoguana ina and cured. This sheet is then transformed into cans, by deep drawing. These cans are then purged of the air, the valves are secured in place, by folding and tightening, and a suspension of approximately 68 mg of beclomethasone dipropionate in approximately 6.1 mg of water is introduced through the valve. approximately 18.2 g of P134A.

Example 7 Standard or standard MDI cans of 12.5 mL (Presspart Inc., Cary, NC) are coated by spraying with an aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and a suspension of approximately 68 mg of beclomethasone dipropionate monohydrate, micronized, is introduced through the valve at approximately 6.1 mg. of water and approximately 18.2 g of P134a.

Example 8 Standard or normal MDI cans of 12.5 mL (Presspart Inc., Cary NC) with PTFE-PES (DuPont) blend are coated as a spray, as a single coating, and cured according to the seller's standard procedure. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and about 68 mg of micronized beclomethasone dipropionate monohydrate is introduced through the valve into approximately 182 mg of ethanol and approximately 18.2 g of P134a.

Example 9 Standard or standard MDI cans of 12.5 L (Presspart Inc., Cary NC) are coated by spraying with PTFE-FEP-polyamideimide (DuPont) mixture, and cured according to the seller's standard procedure. The thickness of the coating is between approximately 1 μm and approximately 20 μ. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and about 68 mg of micronized beclomethasone dipropionate monohydrate is introduced through the valve into approximately 182 mg of ethanol and about 18.2 g of P134a.

Example 10 Standard or standard MDI cans of 12.5 mL (Presspart Inc., Cary NC) are coated by spraying with FEP powder (DuPont FEP 532), using an electrostatic gun. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged from these cans, the valves are secured in place, by folding and tightening, and about 68 mg of micronized beclomethasone ditrionate monohydrate is introduced through the valve into approximately 182 mg of ethanol and approximately 18.2 g of P134a.

Example 11 Coated by spraying, aluminum sheet, standard or normal, 0.46 mm thick, with FEP-Benzoguanamina and cured. This sheet is then transformed into cans, by deep drawing. These cans are then purged of the air, the valves are secured in place, by folding and tightening, and a suspension of approximately 68 mg of micronized beclomethasone dipropionate monohydrate is introduced through the valve, at about 180.degree. mg of ethanol and approximately 18.2 g of P134A, Example 12 Standard or standard MDI cans of 12.5 mL (Presspart Inc., Cary NC) are coated by spraying with an aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged from these cans, the valves are secured in place, by folding and tightening, and through the valve, approximately 68 mg of beclomethasone dipropionate monohydrate, micronized, is introduced into approximately 182 mg of ethanol and approximately 18.2 g of P134a.

Example 13 Standard or standard MDI cans of 12.5 L (Presspart Inc., Cary NC) with PTFE-PES blend (DuPont) are coated by spraying as a single coating and cured according to the vendor's standard procedure. The thickness of the coating is between approximately 1 μm and approximately 20 μ. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and through the valve, approximately 13.6 mg of beclomethasone dipropionate, micronized, is introduced into approximately 107 mg of ethanol and approximately 21.4 g of P227.

Example 14 12.5 mL standard or standard MDI cans (Presspart Inc., Cary NC) are coated by spraying with PTFE-FEP-polyamideimide (DuPont) mixture, and cured according to the seller's standard procedure. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and through the valve, approximately 13.6 mg of beclomethasone dipropionate, micronized, is introduced into approximately 107 mg of ethanol and approximately 21.4 g of P227.

Example 15 Spray-coated, standard or normal, 12.5 mL MDI cans (Presspart Inc., Cary NC) with FEP powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately 1 μm and approximately 20 μ. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and through the valve, approximately 13.6 mg of beclomethasone dipropionate, micronized, is introduced into approximately 107 mg of ethanol and approximately 21.4 g of P227.

Example 16 Coated by spraying, aluminum sheet, standard or normal, 0.46 mm thick, with FEP-Benzoguanamina and cured. This sheet is then transformed into cans, by deep drawing. To these cans the air is then purged, the valves are secured in place, by folding and tightening, and about 13.6 mg of beclomethasone dipropionate, micronized, is introduced through the valve into approximately 107 mg of ethanol and approximately 21.4 g of P227.

Example 17 Standard or standard MDI cans of 12.5 mL (Presspart Inc., Cary NC) are coated by spraying with an aqueous dispersion of PFA (Hoechst PFA-6900n), and cured. The thickness of the coating is between about 1 μm and about 20 μm. The air is then purged to these cans, the valves are secured in place, by folding and tightening, and through the valve, approximately 13.6 mg of beclomethasone dipropionate, micronized, is introduced into approximately 107 mg of ethanol and approximately 21.4 g of P227.

Examples 18-22 Examples 3 through 7 are repeated, except that through the valve approximately 24 mg of salbutamol is introduced as the free base or equivalent weight of salt, for example sulfate, with approximately 12 mg of beclomethasone dipropionate monohydrate, in about 364 mg of ethanol and approximately 18.2 g of P134.

Examples 23-42 Examples 3 through 22 are repeated, except that modified 12.5 mL MDI cans having a substantially ellipsoidal base are used (Presspart Inc., Cary NC). It is found that the dose supply, of the MDI, analyzed under simulated conditions, is constant compared to MDI using uncoated cans, which exhibit a significant decrease in the dose delivered, through use. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, the content of the following is claimed as property:

Claims (21)

1. A metered dose inhaler, characterized in that it has all its internal surfaces or a part thereof, coated with one or more fluorocarbon polymers, optionally in combination with one or more polymers that are not fluorocarbons, for the delivery of a drug formulation The invention relates to inhalation, which contains beclomethasone dipropionate or a physiologically acceptable solvate thereof, and a fluorocarbon-based propellant or impeller, optionally in combination with one or more other 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 also comprises a surfactant.

4. An inhaler according to claim 2 or claim 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 weight of the propellant, of a polar cosolvent, formulation that is substantially free of surfactant.

6. An inhaler according to claim 4 or claim 5, characterized in that the polar cosolvent is ethanol.

7. An inhaler according to any of claims 2 to 6, characterized in that the drug formulation comprises beclomethasone dipropionate or a physiologically acceptable solvate thereof, in combination with salmeterol or salbutamol or a physiologically acceptable salt thereof.

An inhaler according to claim 2, characterized in that the drug formulation comprises (a) beclomethasone dipropionate monohydrate, and the particle size of substantially all of the monohydrate is less than 20 microns; (b) at least 0.15% by weight of the water formulation, in addition to the water of crystallization associated with the monohydrate; and (c) a propellant or impeller based on fluorocarbons.

9. An inhaler according to claim 8, characterized in that the formulation further comprises 0.05 to 3% w / w, based on the propellant, of a polar cosolvent.

10. An inhaler according to claim 9, characterized in that the polar cosolvent is ethanol.

11. An inhaler according to claim 2, characterized in that the drug formulation consists essentially of beclomethasone dipropionate or a physiologically acceptable solvate thereof, optionally in combination with one or more other pharmacologically active agents, a fluorocarbon propellant, and from 0.01 to 5% w / w, based on the propellant, of a polar cosolvent, and the formulation is substantially free of a surfactant.

12. An inhaler according to any of claims 2 to 11, 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.

13. An inhaler according to claim 12, characterized in that the fluorocarbon propellant is 1,1,1,2-tetrafluoroethane.

14. An inhaler according to any of claims 1 to 13, characterized in that it comprises a can made of metal, wherein all the metallic surfaces, internal, or part thereof, are coated.

15. An inhaler according to claim 14, characterized in that the metal is aluminum or an alloy thereof.

16. An inhaler according to any of claims 1 to 15, characterized in that the fluorocarbon polymer is a perfluorocarbon polymer.

17. An inhaler according to claim 16, characterized in that the fluorocarbon polymer is selected from PTFE, PFA, FEP and mixtures thereof.

18. An inhaler according to any of claims 1 to 17, characterized in that the fluorocarbon polymer is in combination with a polymer that is not a fluorocarbon, selected from a polyamideimide and a polyethersulphone.

19. An inhaler according to any of claims 1 to 18, characterized in that it comprises a substantially ellipsoidal base.

20. A metered dose inhaler system, characterized in that it comprises a metered dose inhaler, according to any of claims 1 to 19, equipped with a channel device, suitable for oral or nasal inhalation of the formulation of the drug.

21. The use of the metered dose inhaler system, according to claim 20, for the treatment of disorders or respiratory diseases.