Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics

Definitions

• This invention relates to stable pharmaceutical drug products such as stable metered dose inhalers that include an active pharmaceutical agent.
• Stability issues may include degradation of an active pharmaceutical agent (APA) or changes in the delivery of the pharmaceutical composition, such as a change in the particle sizes of an APA emitted from the inhaler. Changes to the particle size distribution of an APA can be particularly problematic since it can alter the effectiveness of the drug product. For instance, an increase in particle size of the drug product may alter the area where the drug product is delivered to a lung. As a result, the effectiveness of the drug product might be diminished.
• APA active pharmaceutical agent
• a pharmaceutical drug product which include storing a container at a temperature greater than ambient conditions for at least about seven days and conducting release testing on the container after storing.
• Products manufactured by this method have a more consistent fine particle size distribution (FSD) and fine particle fraction (FPF) at ambient conditions and at accelerated stability conditions over the life of the drug product.
• FSD fine particle size distribution
• FPF fine particle fraction
• such products may more reliably and regularly pass testing requirements as required for an approved drug product by regulatory authorities such as the United States Food and Drug Administration (USFDA).
• USFDA United States Food and Drug Administration
• drug products will avoid safety and efficacy concerns with products that may experience a change in FSD or FPF.
• the container may include a suspension or solution having at least one active pharmaceutical agent, optionally a propellant and optionally excipients.
• the APA is at least partially soluble in ethanol.
• a method of manufacturing a pharmaceutical drug product including preparing a container including a suspension or solution including at least one active pharmaceutical agent; and storing the container.
• Storing the container may be at a temperature greater than ambient conditions for at least about seven days.
• storing the container can be at a temperature greater than ambient conditions for a period of about 3 days followed by storing the container for about 3 days at ambient conditions and repeating such storing as desired until the at least one APA has a fine particle size distribution and/or a fine particle fraction that remains substantially the same over a period of time, such as sometime between about 2 months and about 2 years when stored at ambient conditions.
• the container may also include a propellant such as 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a combination thereof and optionally excipients.
• This method may further include conducting release testing on the container after storing.
• the at least one active pharmaceutical agent includes mometasone furoate and formoterol fumarate.
• Useful optional excipients include co-solvents, surfactants and combinations thereof.
• ethanol is included as an excipient.
• a drug product which includes a container, such as a metered dose inhaler container or a spray inhaler, such as a nasal spray container.
• the container includes a pharmaceutical formulation.
• the formulation may include a propellant and optionally one or more excipients as well as at least one active pharmaceutical agent.
• the APA has a fine particle size distribution that stays substantially the same over a period of time such as for about 6 months from the date of manufacture when stored at ambient conditions.
• a drug product having a MDI container which includes ethanol and a propellant, such as 1,1,1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane.
• Other embodiments provide for a nasal spray inhaler container which includes one or more excipients.
• the at least one APA includes a corticosteroid.
• Useful excipients include ethanol.
• Ethanol is a useful excipient since it may act as a co-solvent for APAs that are in need of co-solvent. Ethanol may assist in wetting the APA and reduce surface tension to help dissolve an APA and enable the preparation of a suspension when placed in the presence of a propellant such as 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoropropane.
• the at least one APA is at least partially soluble in ethanol.
• At least partially soluble in ethanol includes APAs that are very soluble in ethanol as well as APAs that are partially soluble in ethanol.
• a drug product that includes ethanol may be considered to be more robust in that it may stay as a better suspension for a longer period of time after shaking.
• Ambient conditions typically refer to a temperature range between about 20 0 C and 25°C. Substantially the same refers to when the fine particle size distribution does not change more than about 20%, preferably not more than about 15%, more preferably not more than 10% and even more preferably not more than about 5%.
• a drug product which includes a metered dose inhaler container that includes at least one active pharmaceutical agent, ethanol, a propellant.
• the at least one active pharmaceutical agent may have a fine particle fraction that stays substantially the same over a period of time for at least about 3 months from the date of manufacture when stored at ambient conditions.
• the at least one active pharmaceutical agent may include mometasone fiiroate and optionally formoterol fumarate.
• Ambient conditions are considered to include temperatures between about 20 0 C and 25°C. Desirably, the fine particle fraction does not change more than about 20% or more than about 15%, or more than about 10% or more than about 5%.
• Useful excipients include co-solvents, surfactants, carriers and combinations of two or more thereof. More specifically, useful excipients include lactose, lecithin, oleic acid and combinations of two or more thereof.
• Various embodiments of the present invention provide for a method of stabilizing a drug product by storing a drug product for a period of time.
• the drug product may include a metered dose inhaler container which includes a suspension or solution including at least one active pharmaceutical agent for a period of time of at least about seven days at a temperature above ambient conditions.
• Useful storing periods include from about at least 2 weeks to about at least 10 weeks at 40°C/ambient RH. More particularly, useful stabilization periods of time include at lease about 2, 3, 4, 5, 6, 7, 8, 9 or about 10 weeks. One particularly useful stability period of time is at least about 6 weeks. Suitable storing or stabilizing times further include a time period of about 2, 3, 4,
• Additional useful storing times include a time period of at least about 2 weeks, of at least about 3 weeks, of at least about 4 weeks, about 5 weeks of at least about 6 weeks.
• the storing step may occur before release testing is performed on the metered dose inhaler.
• Useful storing temperatures include temperatures above ambient conditions. Specifically useful temperatures include temperatures between about 30° C and about 60° C, between about 35°C and about 45 0 C 5 about 30 0 C, about 35°C or about 40 0 C. In one embodiment the storing conditions are at a temperature about 40 0 C for a period for at least 2 weeks. In another embodiment the storing conditions are a temperature of about 40 0 C for about 4, about 5 or about
• storing may be conducted with a cycling procedure where the product may be stored at a temperature greater than ambient temperature for several days such as about 3 days and then at ambient conditions for several days such as 3 days and repeated as desired until the fine particle size distribution stays substantially the same over a period time such as about 6 months at ambient conditions.
• Useful temperatures greater than the ambient temperature include from about 30°C to about 60 0 C, from about 30 0 C to about 50 0 C, from about 35°C to about 45°C and at about 40 0 C.
• Useful active pharmaceutical agents include anticholinergics, corticosteroids, long acting beta agonists, phosphodiesterase IV inhibitors and combinations thereof. Such APAs may be useful in the prevention or treatment of a respiratory, inflammatory or obstructive airway disease.
• useful active pharmaceutical agents include mometasone furoate, formoterol fumarate and combinations thereof.
• Useful corticosteroids include mometasone furoate; beclomethasone dipropionate; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; (22R)-6.alpha.,9.alpha.-difluoro- 1 1.beta.,21-dihydroxy-16.alpha.,17.al ⁇ ha. -propylmethylenedioxy-4-pregnen-3,20-dione, tipredane, or a pharmaceutically acceptable salt, isomer or hydrate thereof.
• Useful corticosteroids that are partially soluble in ethanol include beclomethasone dipropionate; flunisolide; triamcinolone; mometasone furoate.
• Figure 1 shows the mometasone furoate fine particle distribution for the formoterol fumarate 5 meg / mometasone furoate 200 meg MDI through 45 weeks storage (individual ACI data).
• Figure 3 shows formoterol fumarate fine particle dose stabilization data for a full scale manufactured batch, formoterol fumarate 5 mcg/mometasone furoate 200 meg MDI, following storage at 40°C/75% RH and 40°C/arnbient RH.
• Figure 4 shows mometasone furoate fine particle dose stabilization data for a full scale manufactured batch, formoterol fumarate 5 mcg/mometasone furoate 200 meg MDI, following storage at 40°C/75% RH and 40°C/ambient RH.
• Figure 5 shows mometasone furoate fine particle dose stabilization data for formoterol fumarate 5 mcg/mometasone furoate 200 meg MDI, following storage at 40°C/ambient RH.
• Figure 6 shows formoterol fumarate fine particle dose stabilization data for formoterol fumarate 5 mcg/mometasone furoate 200 meg MDI, following storage at 40°C/ambient RH.
• drug products having an MDI container that includes some amount of ethanol and a propellant, such as 1,1,1,2-tetrafluoroethane, 1,1,1, 2,3,3, 3-heptafluoropropane, or a combination thereof and at least one APA that is partially soluble in ethanol may be more susceptible to a change of fine particle size distribution over a period of time.
• APAs that are partially soluble in ethanol may be at a higher risk of Ostwald Ripening.
• a drug product having a MDI container which includes ethanol and a propellant, such as 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoropropane, or a combination thereof and at least one APA that has some solubility in ethanol.
• a propellant such as 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoropropane, or a combination thereof
• APAs that are partially soluble in ethanol include, but are not limited, to triamcinolone, flunisolide, beclomethasone and mometasone furoate.
• various aspects of the present invention provide for a method of manufacturing a pharmaceutical drug product including preparing a container including a suspension or solution including at least one active pharmaceutical agent, a propellant selected from the group consisting of 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a combination thereof and optionally excipients; storing said container in at a temperature greater than ambient conditions for at least about seven days.
• a propellant selected from the group consisting of 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a combination thereof and optionally excipients
• Useful storing or stabilizing periods include from about at least 2 weeks to about at least 10 weeks at 40°C/ambient RH. More particularly, useful stabilization periods of time include at lease about 2, 3, 4, 5 7 6, 7, 8, 9 or about 10 weeks. One particularly useful stability period of time is at least about 6 weeks. Suitable storing or stabilizing times further include a time period of about 2, 3, 4, 5 or 6 weeks. Additional useful storing times include a time period of at least about 2 weeks, of at least about 3 weeks, of at least about 4 weeks, about 5 weeks of at least about 6 weeks. The storing step may occur before release testing is performed on the metered dose inhaler.
• Useful storing temperatures include temperatures above ambient conditions. Specifically useful temperatures include temperatures between about 30° C and about 60° C, between about 35°C and about 45°C, about 30 0 C, about 35°C or about 40 0 C. In one embodiment the storing conditions are at a temperature about 40 0 C for a period for at least 2 weeks. In another embodiment the storing conditions are a temperature of about 40 0 C for about 4, about 5 or about 6 weeks.
• storing may be conducted with a cycling procedure where the product may be stored at a temperature greater than ambient temperature for several days such as about 3 days and then at ambient conditions for several days such as 3 days and repeated as desired until the fine particle size distribution stays substantially the same over a period time such as about 6 months at ambient conditions.
• Useful temperatures greater than the ambient temperature include from about 30 0 C to about 60 0 C, from about 30 0 C to about 50 0 C, from about 35°C to about 45°C and at about 40 0 C.
• Useful active pharmaceutical agents include anticholinergics, corticosteroids, long acting beta agonists, phosphodiesterase IV inhibitors and combinations thereof. Such APAs may be useful in the prevention or treatment of a respiratory, inflammatory or obstructive airway disease.
• useful active pharmaceutical agents include mometasone furoate, formoterol fumarate and combinations thereof.
• Useful corticosteroids include mometasone furoate; beclomethasone dipropionate; budesonide; fluticasone; dexamethasone; flunisolide; triamcinolone; (22R)-6.alpha.,9.alpha.-difluoro- 11.beta.,21-dihydroxy-16.alpha.,17.alpha. -propylmethylenedioxy-4-pregnen-3,20-dione, tipredane, or a pharmaceutically acceptable salt, isomer or hydrate thereof.
• Useful corticosteroids that are partially soluble in ethanol include beclomethasone dipropionate; flunisolide; triamcinolone; mometasone furoate.
• Useful anticholinergics include (R)-3-[2-hydroxy-2,2-(dithien-2-yl)acetoxy]-l-l[2- (phenyl)ethyl]-l-azoniabicyclo[2.2.2] octane, glycopyrrolate, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, methscopolamine, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide, GSK202405, or a pharmaceutically acceptable salt, isomer or hydrate of any of the above, or a combination of two or more of the above Anticholinergics that are known to be partially soluble in ethanol include but is not limited
• Useful long acting beta agonists include carmoterol, indacaterol, TA-2005, albuterol, terbutaline, salmeterol, bitolterol, formoterol, fenoterol, metaprotenerol, GSKl 59802, GSK642444, GSKl 59797, GSK597901, GSK678077, or a pharmaceutically acceptable salt, isomer or hydrate of any of the above.
• Useful phosphodiesterase IV inhibitors cilomilast, roflumilast, tetomilast, 1-[[5-(1(S)- aminoethyl)-2-[8-methoxy-2-(trifluoromethyl)-5-quinolinyl]-4-oxazolyl]carbonyl]-4(R)- [(cyclopropylcarbonyl)amino]-L-proline.
• Mometasone furoate the active component of NASONEX® is an anti-inflammatory corticosteroid having the chemical name, 9,21-Dichloro-ll(beta). 17-dihydroxy-16(alpha)- methylpregna-l,4-diene-3,20-dionel7-(2 Furoate). This component may be present in an amount of about 25 to about 500 micrograms per actuation of the MDI. This product is available from Schering-Plough Corporation, Kenilworth, NJ.
• Formoterol fumarate is a selective beta 2 -adrenergic bronchodilator. Its chemical name is ( ⁇ )-2- hydroxy-5-[( 1 RS)-I -hydroxy-2-[ [( 1 RS)-2-(4-methoxyphenyl)- 1 -methylethyl]-am ino] ethyl] formanilide Fumarate dihydrate. This component may be present in an amount of about 3 to about 50 micrograms per actuation. This product is available commercially from Novartis Corporation, East Hanover, NJ. and Schering-Plough Corporation, Kenilworth, NJ. under the trademark FORADIL®.
• Propellant-based pharmaceutical aerosol formulations in the art typically use a mixture of liquid chlorofluorocarbons as the propellant, although many others use a single propellant.
• the propellant serves as a vehicle for both the active agents and excipients.
• Fluorotrichloromethane, dichlorodifluoromethane and dichlorotetrafluoroethane are the most commonly used propellants in aerosol formulations for administration by inhalation.
• Such chlorofluorocarbons (CFCs) have been implicated in the destruction of the ozone layer and their production is being phased out.
• Non-CFC propellants are said to be less harmful to the ozone than many chlorofluorocarbon propellants.
• Non-CFC propellants systems must meet several criteria for pressurized metered dose inhalers. They must be non-toxic, stable and non- reactive with the medicament and the other major components in the valve/actuator.
• One propellant that has been found to be suitable is CF 3 CHFCF 3 , also known as HFA 227, HFC 227 or 1,1,1,2,3,3,3 heptafluoropropane.
• Another such propellant for use in metered dose inhalers is CF 3 CH 2 F, also known as 1,1,1,2-tetrafluoroethane or HFA 134a.
• Useful formulations typically may include HFA 227 or HFA 134a, or a combination thereof, in combination with mometasone furoate and optionally, formoterol fumarate, a liquid excipient, and a surfactant.
• the excipient facilitates the compatibility of the medicament with the propellant and also lowers the discharge pressure to an acceptable range, i.e., about 2.76-5.52x10 5 newton/meter 2 absolute (40 to 80 psi), preferably 3.45-4.83x10 5 newton/meter 2 absolute (50 to 70 psi).
• excipient chosen must be non-reactive with the medicaments, relatively non-toxic, and should have a vapor pressure below about 3.45x10 5 newton/meter 2 absolute (50 psi).
• Suitable excipients include but are not limited to co-solvents, surfactants, carriers and combinations thereof. More specifically, useful excipients include ethanol, oleic acid and combinations thereof.
• a surfactant may optionally be added.
• Surfactants may be any suitable, non-toxic compound that is non-reactive with the medicament and that substantially reduces the surface tension between the medicament, the excipient and the propellant and/or acts as a valve lubricant.
• Useful surfactants include oleic acid available under the tradenames MEDNIQUE 6322 and EMERSOL 6321 (from Cognis Corp., Cincinnati, Ohio); cetylpyridinium chloride (from Arrow Chemical, Inc. Westwood, N.J.); soya lecithin available under the tradename EPIKURON 200 (from Lucas Meyer Decatur, IU.
• polyoxyethylene(20)sorbitan rnonolaurate available under the tradename TWEEN 20 (from ICI Specialty Chemicals, Wilmington, Del.); polyoxyethylene(20)sorbitan monostearate available under the tradename TWEEN 60 (from ICI); polyoxyethylene(20)sorbitan monooleate available under the tradename TWEEN 80 (from ICI); polyoxyethylene (10) stearyl ether available under the tradename BRIJ 76 (from ICI); polyoxyethyiene (2) oleyl ether available under the tradename BRIJ 92 (frown ICI); Polyoxyethylene-polyoxypropylene-ethylenediamine block copolymer available under the tradename TETRONIC 150 Rl (from BASF); polyoxypropylene-polyoxyethylene block copolymers available under the tradenames PLURONIC L-92, PLURONIC L-121 end PLURONIC F 68 (from BASF); castor oil ethoxylate available under the tradename ALKASU
• Suitable excipients include "medium chain fatty acids” which refers to chains of alkyl groups terminating in a ⁇ COOH group and having 6-12 carbon atoms, preferably 8-10 carbon atoms.
• the term “short chain fatty acids” refers to chains of alkyl groups terminating in a ⁇ COOH group and having 4-8 carbon atoms.
• the term “alcohol” includes C 1 -C 3 alcohols, such as methanol, ethanol and isopropanol.
• Suitable excipients include propylene glycol diesters of medium chain fatty acids available under the tradename MIGLYOL 840 (from HuIs America, Inc. Piscataway, NJ.); triglyceride esters of medium chain fatty adds available under the tradename MIGLYOL 812 (from HuIs); perfluorodimethylcyclobutane available under the tradename VERTREL 245 (from E. I. DuPont de Nemours and Co. Inc.
• MIGLYOL 840 from HuIs America, Inc. Piscataway, NJ.
• triglyceride esters of medium chain fatty adds available under the tradename MIGLYOL 812 (from HuIs)
• perfluorodimethylcyclobutane available under the tradename VERTREL 245 (from E. I. DuPont de Nemours and Co. Inc.
• Y. diethylene glycol monoethylether available under the tradename TRANSCUTOL (from Gattefosse); polyglycolized glyceride of medium chain fatty adds available under the tradename LABRAFAC HYDRO WL 1219 (from Gattefosse); alcohols, such as ethanol, methanol and isopropanol; eucalyptus oil available (from Pluses-Stauffer International); and combinations thereof.
• TRANSCUTOL from Gattefosse
• polyglycolized glyceride of medium chain fatty adds available under the tradename LABRAFAC HYDRO WL 1219 (from Gattefosse)
• alcohols such as ethanol, methanol and isopropanol
• eucalyptus oil available (from Pluses-Stauffer International); and combinations thereof.
• a certain minimum level of ethanol maybe used to provide consistent and predictable delivery of the drug from a metered dose dispenser. Suitable minimum levels include about 1 weight percent of the total formulation which results in a marginally acceptable drug delivery. Increased amounts of ethanol generally improve drug delivery characteristics. However, to help prevent drug crystal growth in the formulation, the concentration of ethanol maybe limited.
• the slurry of bulking agent may be advantageously prepared with an appropriate amount of ethanol.
• the slurry is subjected to high pressure homogenization prior to adding it to the remainder of the formulation.
• formoterol and mometasone are typically, initially dispersed with an appropriate amount of HFA 134a and/or HFA 227 and, if applicable or desired ethanol, i.e. such an amount of ethanol to aid dispersion but not so as to result in excessive partial solubilisation of either of the drugs, to prepare a cold concentrate.
• This dispersion typically after high shear mixing, is then added to a second appropriate amount of HFA 134a and/or HFA 227 in liquid form, chilled to below its boiling point or range.
• the bulking agent slurry may be added to the second appropriate amount of propellant before the drug dispersion is added.
• surfactant it is preferably dissolved at ambient temperature in an appropriate amount of ethanol, and it is either added to the drug containing dispersion or the bulking agent slurry.
• Products having an aerosol vial equipped with conventional dispensing valves can be used.
• Conventional dispensers and aerosol vials may be used to contain a suspension or solution.
• a glass aerosol vial or a metal, in particular aluminum, vial having an interior surface coated with a polymer, in particular a fluorocarbon polymer may be used.
• Internal surfaces, in particular such surfaces of components of the valve, or all of the internal surfaces of the dispenser may be coated with a polymer, in particular a fluorocarbon polymer.
• Suitable fluorocarbon polymers include fluorocarbon polymers, which are made of multiples of one or more of the following monomeric units: tetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (ETFE), vinylidenefluoride (PVDF), and chlorinated ethylene tetrafluoroethylene.
• PTFE tetrafluoroethylene
• FEP fluorinated ethylene propylene
• PFA perfluoroalkoxyalkane
• ETFE ethylene tetrafluoroethylene
• PVDF vinylidenefluoride
• chlorinated ethylene tetrafluoroethylene chlorinated ethylene tetrafluoroethylene.
• Polymers which have a relatively high ratio of fluorine to carbon, such as perfiuorocarbon polymers e.g. PTFE, PFA, and FEP.
• the valve may be any suitable metering valve with an outlet made from;, for example, stainless steel, acetal, nylon or polybutylene terephthalate and with seals made from nitrile or EPDM elastomer.
• Useful methods for preparing a container include cold fill process and pressure fill process.
• a useful method of preparing includes introducing mometasone furoate anhydrous, a chlorflourocarbon free propellant selected from the group consisting of of 1,1, 1,2- tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a combination thereof and optionally excipients selected from the group consisting of co-solvents, surfactant and combinations thereof into a vessel that is held under pressure to form a suspension or solution; circulating the suspension or solution from the vessel through a line which includes a filling head; bringing the filling head into communication with the metered dose inhaler container through the valve of said metered dose inhaler container; introducing a quantity of such suspension or solution into the container from the filling head of the line through said valve of the metered dose inhaler container; withdrawing the filling head from the metered dose inhaler container; sealing the metered dose inhaler container.
• Samples in Tables 1 and 2 are prepared in accordance with the cold fill process.
• chilled propellant HFA 227 is added to a chilled batching vessel and stirred continuously.
• a concentrate vessel a mixture of ethanol and oleic acid is prepared and added to the batching vessel to form a placebo mix.
• some of the placebo mix is transferred from the batching vessel to a pre-chilled cold concentrate vessel.
• the active pharmaceutical agent(s) is added to the chilled content in the cold concentrate vessel and mixed.
• the concentrate is mixed in the cold concentrate vessel and then transferred back into the batching vessel.
• the resulting formulation is mixed continuously and maintained between about -50 0 C and about -60 0 C.
• the desired quantity of formulation is dispensed into suitable canisters such as FEP internally coated aluminum canisters, which are immediately sealed with metering valves.
• suitable canisters such as FEP internally coated aluminum canisters, which are immediately sealed with metering valves.
• the units are check-weighed and heat stressed.
• the units are stored for a minimum of one week, to allow for valve equilibration, 100% function tested for correct valve function and 100% check-weighed.
• the units are stabilized at 40°C/ambient relative humidity for a period of about 4 to about 6 weeks, and 100% check-weighed.
• Product stabilization profile is determined by analyzing the FPD on APAs by monitoring the aerodynamic particle size distribution (APSD) using the Anderson Cascade Impaction (ACI).
• the Andersen sampler (Apparatus 1, US Pharmacopoeia 24 monograph ⁇ 601>) was used as follows. A filter paper (Whatman 934-AH) was cut to fit the "F" stage, which was incorporated into the stack. The remainder of the stack was assembled, including the USP throat.
• Testing consists of priming shots, typically about 4 actuations, are fired through a standard actuator.
• the valve and valve stem interior are cleaned with water (30 ml) followed by ethanol (30 ml) and dried thoroughly.
• An unused sample actuator was used to dispense doses while the Andersen sampler was drawing air at 28.3 liter per minute. This was kept sealed into the port of the USP throat with a grommet until 5 seconds after actuation. 6 shots were fired, using the actuation protocol described for uniformity of content.
• the vacuum source was switched off 30 seconds after the final actuation. The unit was weighed.
• valve stem including the interior
• actuator including grommet
• throat including grommet
• Stage 0 and inlet cone plates 0-2, plates 3-5, plates 6-7 and the filter were separately rinsed with an appropriate solvent.
• the sample diluent was as used for uniformity of content. Each washing is analysed by High Pressure Liquid Chromatography to determine each drug content in micrograms.
• fine particle fraction is determined by the amount of APA analysed from plates 3 to 7 divided by total APA recovered by the rest of the impactor excluding the valve and the actuator from the calculations.
• the FPF is representative of the drug that might be delivered to the desired area, such as the lung.
• Fine particle dose is the drug analyzed from plates 3 to 7 and the filter (microgams).
• Mean metered dose is the total recovery of drug from all diluent samples (micrograms).
• ACI data has provided evidence that the formulation may have undergone a degree of Ostwald ripening.
• Ostwald Ripening refers to the growth of larger particles from those of smaller size which have a higher solubility than the larger ones. In the process, the larger particles begin to grow at the expense of the smaller particles. This results in an increase of larger fine particle distribution and a corresponding decline in smaller size fine particle distribution. This is consistent with the observed reduction in FPD seen on stability.
• An example of mometasone furoate ACI deposition profile is shown in Figure 2.
• Samples in Table 3 are prepared using a pressure fill process, such as a pressure fill process such as described in US2004/0042973, which is incorporated herein.
• a pressure fill process such as a pressure fill process such as described in US2004/0042973, which is incorporated herein.
• the excipients such as oleic acid and a portion of ethanol are mixed in a beaker and then added to the chilled batching vessel.
• the active pharmaceutical agent(s) such as formoterol fumarate and then mometasone furoate are added to the chilled batching vessel.
• the remaining ethanol is then used to rinse any residual APA that adheres to the charging port into the batching vessel.
• Sufficient HFA-227 propellant is added to the batching vessel to cover the head of the in dwelling homogenizer.
• the homogenizer head When the homogenizer head is immersed, the homogenizer is turned on and the formulation is mixed at full speed. The remaining HFA-277 propellant is continuously added to the batching vessel while mixing at full speed. Once all of the propellant is added, the speed of the homogenizer is reduced. The formulation is mixed and chilled to -5°C. The requisite quantity of formulation is pressure filled through the metering chamber into the canister such as a FEP internally coated aluminum canisters, which had been previously sealed by vacuum crimping to the metering valve. The units are check-weighed and heat stressed in a water bath. The units are stored for a minimum of one week to allow for valve equilibration. The units are stabilized at 40°C/ambient RH for a period of 6 weeks.

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• 2007
  • 2007-02-09 EP EP07750471A patent/EP2117504A1/en not_active Ceased
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