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
  • A61K9/0012—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
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • 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
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
• • 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
• • 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]

Definitions

• the invention generally relates to pharmaceutical formulations suitable for inhalation which employ lactose and methods of administering the same.
• Inhalers are well known devices for administering medicinal products to the respiratory tract. They are commonly used for local relief of respiratory diseases, but the pulmonary route also provides a conduit for the potential systemic delivery of a variety of medicinal products such as analgesics and hormones.
• the two main types of inhalers are the pressurized metered dose inhaler ( DI) and the dry powder inhaler (DPI).
• DI pressurized metered dose inhaler
• DPI dry powder inhaler
• the MDI uses a volatile propellant to produce an aerosol cloud containing the active ingredient for inhalation. DPIs deliver the active ingredient in the form of dry powder particles to the respiratory tract.
• the active ingredient used within an inhaler is typically less than 5 ⁇ m, and consequently inherently cohesive._Dispersion upon aerosolisation is achieved by a combination of the inhaler dispersion mechanics and the formulation.
• Dry powder formulations for inhalation commonly comprise at least one micronised active substance and a biologically inert carrier. The latter is used in dry powders for inhalation as a diluent, to facilitate manufacture, and as an aerosolisation aid. It typically comprises defined proportions of finely divided and coarser particles to optimise and control the manufacture of the drug product and delivery of the active ingredient to the lung.
• the carrier may include any acceptable pharmacologically inert material or combination of materials.
• Lactose can exist as either the alpha or beta form of the crystal.
• Beta lactose is an anhydrate and is non-hygroscopic below 97% relative humidity (RH). Above 97%RH, it absorbs moisture and mutarotates to form the alpha- monohydrate.
• Alpha monohydrate is non hygroscopic.
• Angberg et al, Int. J. Pharm. 73, 209-220 (1991 ) disclose employing microcalorimetry at 25°C to investigate the incorporation of hydrate water in roller-dried anhydrous lactose that consisted of 31% alpha- and 69% beta-lactose.
• J. Pharm, 130, 13-24, 1996) disclose a comparison of aerosols formed by three salts and the free base of albuterol following their formation from similarly micronized crystalline powders held in a model dry powder inhaler under varying environmental conditions.
• Jashnani et al disclose that albuterol stearate, the most hydrophobic salt, emptied and aerosolized best from the inhaler and showed least sensitivity to temperature and humidity.
• Various methodologies have been employed in an attempt to assess and prevent the drop in physical performance induced by adverse environmental storage. Maggi et a/ (Int. J. Pharm.
• a desiccant integral to the device has also been shown to enhance chemical stability of inhaled products.
• Wu et al disclose a medicinal aerosol steroid solution formulation product with enhanced chemical stability.
• the steroid is a 20-ketosteroid having an OH group at the C-17 or C-21 position and the aerosol container has a non- metal interior surface which has been found to reduce chemical degradation of such steroids.
• the susceptibility of physical performance dry powder formulations to environmental humidity may be potentially reduced by increasing the moisture resistance of the dry powder formulation to the environment.
• fine particle fraction refers to the percentage of particles within a given dose of aerosolized medicament that is of "respirable” size, as compared to the total emitted dose. It is highly desirable to provide a pharmaceutical formulation which produces a consistent FP Fraction throughout the life of the product.
• the invention provides a pharmaceutical formulation suitable for inhalation comprising at least one pharmaceutically active medicament and lactose anhydrate.
• the invention provides a method for treating a respiratory disorder in a mammal. The method comprising administrating a therapeutically effective amount of the pharmaceutical formulation to the mammal.
• the invention provides an inhalation device employing a pharmaceutical formulation.
• the present invention offers a number of surprising advantages and benefits. For example, the present invention is highly advantageous in that it provides inhalable pharmaceutical formulations which are capable of displaying improved desiccating ability, particularly at lower relative humidity conditions. Moreover, the inhalable pharmaceutical formulations are capable of exhibiting improved FP Fraction stability relative to conventional inhalable formulations.
• the chemical degradation of the active material can be mediated by the presence of moisture in such formulations.
• the inhalable pharmaceutical formulations are thus capable of increased chemical stability of the active material relative to conventional formulations.
• the pharmaceutical formulations of the invention are capable of exhibiting little, if any, aggregation upon storage, notwithstanding the moisture absorption capabilities of the formulations.
• Figure 1 is a chart illustrating the X-Ray diffraction patterns for anhydrous lactose in comparison with alpha lactose monohydrate.
• Figure 2 is a graph illustrating GVS moisture uptake for various types of lactose.
• Figure 3 is a graph illustrating the weight change of various types of anhydrous lactose upon extended storage at 25°C/75%RH.
• Figure 4 is a graph illustrating FP Fraction values for various formulation blends containing different levels of various types of anhydrous and monohydrate lactose.
• Figure 5 is a graph illustrating the moisture uptake of anhydrous lactose (coarse and fines) and monohydrate lactose.
• Figure 6 is a graph illustrating the moisture uptake of various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose upon exposure to 25°C/40%RH.
• Figure 7 is a graph illustrating the calculated percent rehydration for various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose upon storage at 25°C/40%RH.
• Figure 8 is a graph illustrating the equilibrium relative humidity (ERH) of various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose.
• Figure 9 is a graph illustrating the desiccant capacity of various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose.
• Figure 10 is a graph illustrating FP Fraction values for various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose with storage at 25°C/75%RH.
• Figure 11 is a graph illustrating FP Fraction values for various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose with storage at 40°C/75%RH.
• Figure 12 is a graph illustrating the desiccant capacity of various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose.
• Figure 13 is a graph illustrating FP Fraction values for various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose with storage at 25°C/75%RH.
• Figure 14 is a graph illustrating FP Fraction values for various formulation blends containing different levels of anhydrous (fine and coarse) and monohydrate lactose with storage at 40°C/75%RH.
• the pharmaceutical formulation comprises at least one pharmaceutically active medicament and lactose anhydrate.
• the pharmaceutical formulation consists essentially of at least one pharmaceutically active medicament and lactose anhydrate.
• the pharmaceutical formulation consists of at least one pharmaceutically active medicament and lactose anhydrate.
• the pharmaceutical formulation exhibits a weight gain of at least 0.3 percent when equilibrated at 25°C and 40 percent RH. More preferably, the formulation exhibits a weight gain of at least 0.2 percent when equilibrated 25°C and 30 percent RH. Most preferably, the formulation exhibits a weight gain of at least 0.1 percent when equilibrated at 25°C and 20 percent RH.
• the term "equilibrated” is defined as a weight change of less than 0.1% w/w following storage for 4 hours.
• lactose As used herein is to be broadly construed. As an example, lactose is intended to encompass crystalline, amorphous, isomeric and polymorphic forms of lactose, including, but not limited to, lactose monohydrate, the stereoisomers -lactose monohydrate and ⁇ -anhydrous lactose, as well as alpha-anhydrous lactose. Lactose (i.e., milk sugar) is preferably obtained from cheese whey, which can be manufactured in different forms depending on the process employed.
• lactose anhydrate is defined to encompass lactose having various levels of water content.
• the lactose anhydrate includes less than 1 mole of water (e.g., including, without limitation, water) per mole of lactose.
• lactose anhydrate may encompass anhydrous lactose.
• the pharmaceutical formulation contains varying levels of water.
• the pharmaceutical formulation is free of water.
• the pharmaceutical formulation is substantially free of water. In another embodiment, the pharmaceutical formulation contains less than or equal to about 1 , 2, 3, 4, or 5 %w/w of water. In accordance with the invention, the amount of lactose employed in the formulation is believed to assist in achieving the benefits described herein.
• the lactose includes at least 1 , 3, or 5 %w/w lactose anhydrate, more preferably at least 10 %w/w lactose anhydrate.
• the lactose includes from, at a lower end 1 , 2, 3, 5, 10, 20, 30, or 40 %w/w to, at a higher end, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 %w/w lactose anhydrate.
• the balance of the lactose present is monohydrate lactose.
• the lactose anhydrate is preferably present as hygroscopic alpha anhydrous lactose or ⁇ ?H anhydrous lactose.
• hygroscopic alpha anhydrous lactose is characterized by having a crystallographic structure, and anomeric ratio consistent with that of the predominantly alpha form of lactose whilst being essentially anhydrous in nature (represented by the lack of water of crystallization).
• the alpha- anhydrous form is also hygroscopic in nature as demonstrated by the propensity of the material to sorb water (at least 1 % w/w) under low environmental relative humidity (RH) conditions (20%RH) at 25°C.
• RH environmental relative humidity
• the lactose anhydrate may possess various physical properties.
• the lactose anhydrate has a surface area ranging from, at a lower end, about 0.1 , 1 , 2, 3, or 4 m 2 /g to, at a higher end, about 6, 7, 8, 9, or 10 m 2 /g.
• the lactose anhydrate has a porosity ranging from, at a lower end, about 0.0001 , 0.005, or 0.001 ml/g to, at a higher end, about 0.05 or 0.01 ml/g, measured using BET N 2 adsorption.
• the lactose anhydrate has a beta content ranging from, at a lower end, about 0, 5, 10, 15, 20, or 25 %w/w to, at a higher end, about 20, 25, 30, 35, or 40 %w/w measured using gas chromatography.
• the lactose anhydrate possesses a water content ranging from about 0.001 to about 5 percent measured using thermo-gravimetric analysis.
• the lactose anhydrate has a dispersive surface energy ( D s) ranging from about 30 to about 60 mJm "2 measured using inverse gas chromatography.
• the lactose anhydrate may encompass both coarse and fine fractions. The relative amounts of coarse and fines employed may be varied in accordance with the present invention.
• the coarse and fine fractions have preferred size profiles.
• the coarse fraction when employed in a dry powder device (e.g., Diskus®), the coarse fraction preferably has a volume median diameter (D 5 o) ranging from about 60 to about 90 ⁇ m, and a volume of sub-14.2 ⁇ m particles ranging from about 0 to about 10%v/v.
• the fine fraction preferably has a volume median diameter (D50) particle size ranging from about 1 to about 30 ⁇ m and a volume of sub 14.2 ⁇ m particles ranging from about 30 to about 100 %v/v, measured using laser diffraction.
• the pharmaceutical formulation of the invention is free or substantially free of particle size change as a result of water uptake when exposed a variety of humidity conditions including, without limitation, those set forth herein.
• the lactose anhydrate employed in accordance with the invention may optionally further be present, to a certain level, in amorphous form.
• the lactose anhydrate includes at least 1 %w/w of amorphous lactose. In one embodiment, the lactose anhydrate includes at least 10 %w/w of amorphous lactose.
• the anhydrous lactose includes from, at a lower end 0, 1, 5, 10, 20, 30, or 40 %w/w to, at a higher end, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 %w/w amorphous lactose, based on the lactose weight.
• the balance in the above embodiments is crystalline lactose anhydrate. The above weight percentages are based on the weight of the lactose.
• lactose may be formed by various processes known in the art. One example is set forth in Figura, L.O. and Epple M., J, Thermal Anal., (1995) 44-53.
• hygroscopic anhydrous lactose i.e., an anhydrous lactose
• anhydrous lactose may be manufactured by a rapid thermal dehydration by heating at 120°C under 20 mbar pressure for 3 hours.
• Other processes may also be employed.
• Medicaments for the purposes of the invention, include a variety of pharmaceutically active ingredients, such as, for example, those which are useful in inhalation therapy.
• the term "medicament” is to be broadly construed and include, without limitation, actives, drugs and bioactive agents, as well as biopharmaceuticals.
• medicament may be present in micronized form.
• Appropriate medicaments may thus be selected from, for example, analgesics, (e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine); anginal preparations, (e.g., diltiazem; antiallergics, e.g., cromoglicate, ketotifen or nedocromil); antiinfectives (e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine); antihistamines, (e.g., methapyrilene); anti-inflammatories, (e.g., beclometasone dipropionate, fluticasone propionate, flunisolide, budesonide, rofleponide, mometasone furcate, ciclesonide, triamcinolone acetonide or 6 ⁇ , 9 ⁇ -difluoro-11 ⁇
• the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the medicament. It will be further clear to a person skilled in the art that where appropriate, the medicaments may be used in the form of a pure isomer, for example, R-salbutamol or RR-formoterol.
• Particular medicaments for administration using pharmaceutical formulations in accordance with the invention include anti-allergies, bronchodilators, beta agonists (e.g., long-acting beta agonists), and anti- inflammatory steroids of use in the treatment of respiratory conditions as defined herein by inhalation therapy, for example cromoglicate (e.g. as the sodium salt), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as the xinafoate salt), bitolterol, formoterol (e.g. as the fumarate salt), terbuta ⁇ ne (e.g. as the sulphate salt), reproterol (e.g.
• cromoglicate e.g. as the sodium salt
• salbutamol e.g. as the free base or the sulphate salt
• salmeterol e.g. as the xinafoate salt
• bitolterol e.g. as the
• a beclometasone ester e.g. the dipropionate
• a fluticasone ester e.g. the propionate
• a mometasone ester e.g., the furoate
• budesonide dexamethasone, flunisolide, triamcinolone, tripredane, (22R)-6. alpha. ,9.alpha.- difluoro-11.beta.,21-dihydroxy-16.alpha.,17.alpha. -propylmethyienedioxy-4- pregnen-3,20-dione.
• Medicaments useful in erectile dysfunction treatment may also be employed.
• PDE-V inhibitors such as vardenafil hydrochloride, along with alprostadil and sildenafil citrate
• the medicaments that may be used in conjunction with the inhaler are not limited to those described herein.
• Salmeterol especially salmeterol xinafoate, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred.
• the formulations according to the invention may, if desired, contain a combination of two or more medicaments.
• Formulations containing two active ingredients are known for the treatment of respiratory disorders such as asthma, for example, formoterol (e.g. as the fumarate) and budesonide, salmeterol (e.g. as the xinafoate salt) and fluticasone (e.g. as the propionate ester), salbutamol (e.g. as free base or sulphate salt) and beclometasone (as the dipropionate ester) are preferred.
• a particular combination that may be employed is a combination of a beta agonist (e.g., a long-acting beta agonist) and an anti- inflammatory steroid.
• One embodiment encompasses a combination of fluticasone propionate and salmeterol, or a salt thereof (particularly the xinafoate salt).
• the ratio of salmeterol to fluticasone propionate in the formulations according to the present invention is preferably within the range 4:1 to 1 :20.
• the two drugs may be administered in various manners, simultaneously, sequentially, or separately, in the same or different ratios.
• each metered dose or actuation of the inhaler will typically contain from 25 ⁇ g to 100 ⁇ g of salmeterol and from 25 ⁇ g to 500 ⁇ g of fluticasone propionate.
• the pharmaceutical formulation may be administered as a formulation according to various occurrences per day. In one embodiment, the pharmaceutical formulation is administered twice daily.
• the pharmaceutical formulation may include various amounts of the one or more excipient and lactose anhydrate.
• the formulation may include, at a lower end, from 0.05, 0.1 , 1 , 2 3, 5, 10, 15, 20, 25 or 30 to, at a higher end 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 or 50 % w/w of the at least one pharmaceutically active medicament.
• the remaining portion of the formulation includes lactose anhydrate, as well as optionally other pharmaceutically inert ingredients.
• the pharmaceutical formulations may be present in the form of various inhalable formulations. In one embodiment, the pharmaceutical formulation is present in the form of a dry powder formulation, the formulation of such may be carried out according to known techniques.
• Dry powder formulations for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
• Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base which includes lactose and, optionally, at least one additional excipient (e.g., carrier, diluent, etc.).
• each capsule or cartridge may generally contain between 20 ⁇ g and 10 mg of the at least one medicament.
• the formulation may be formed into particles comprising at least one medicament, and excipient material(s), such as by co-precipitation or coating.
• packaging of the formulation may be suitable for unit dose or multi-dose delivery.
• the formulation can be pre-metered (e.g., as in Diskus®, see GB 2242134/ U.S. Patent Nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and 6,536,427 or Diskhaler, see GB 2178965, 2129691 and
• the Diskus® inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing the at least one medicament, the lactose, optionally with other excipients.
• the strip is sufficiently flexible to be wound into a roll.
• the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width.
• the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the base sheet.
• the formulations may be employed in or as suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g.
• Such formulations may be delivered via a pressurized inhaler, e.g., a Metered Dose Inhaler (MDI).
• MDIs typically include canisters suitable for delivering the pharmaceutical formulations.
• Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example an aluminum can which may optionally be anodised, lacquer-coated and/or plastic-coated, which container is closed with a metering valve.
• Aluminum cans which have their inner surfaces coated with a fluorocarbon polymer are particularly preferred.
• Such polymers can be made of multiples of the following monomeric units: tetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (EFTE), vinyldienefluoride (PVDF), and chlorinated ethylene tetrafluoroethylene.
• PTFE tetrafluoroethylene
• FEP fluorinated ethylene propylene
• PFA perfluoroalkoxyalkane
• EFTE ethylene tetrafluoroethylene
• PVDF vinyldienefluoride
• chlorinated ethylene tetrafluoroethylene Embodiments of coatings used on all or part of the internal surfaces of an MDI are set forth in U.S. Patent Nos. 6,143,277; 6,511,653; 6,253,762; 6,532,955; and 6,546,928.
• MDIs may also include metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.
• the gasket may comprise any suitable elastomeric material such as for example low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
• Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser ⁇ M).
• Embodiments of metering valves are set forth in U.S. Patent Nos. 6,170,717; 6,315,173; and 6,318,603.
• the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Patent No. 6,390,291, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431,168.
• the invention relates to a container suitable for use in conjunction with a pharmaceutical formulation.
• the container comprises at least one pharmaceutically active medicament and lactose anhydrate.
• the container is structured such that the formulation possesses moisture sorption properties as described herein.
• the container may be employed in conjunction with the various inhalation devices described, e.g., dry powder inhalers and metered dose inhalers.
• the container may be present in various forms such as, without limitation, those described hereinabove such as a capsule, cartridge, reservoir, as well as a container formed from a base sheet and a lid sheet. If used in a metered dose inhaler, the container may be present as described herein, e.g., as a canister.
• the pharmaceutical formulation of the invention may be used to treat a number of respiratory conditions. Such respiratory conditions include, without limitation, diseases and disorders associated with reversible airways obstruction such as asthma, chronic obstructive pulmonary diseases (COPD) (e.g. chronic and whez bronchitis, emphysema), respiratory tract infection and upper respiratory tract disease (e.g.
• COPD chronic obstructive pulmonary diseases
• the invention provides a method for treating a respiratory disorder in a mammal such as a human.
• the method comprises administrating a pharmaceutically effective amount of a pharmaceutical formulation as defined herein.
• pharmaceutically effective amount is to be broadly interpreted and encompass the prophylaxis and/or treatment of the disorder.
• the invention provides a method of treating a respiratory condition. The method comprises administering to a patient by oral or nasal inhalation a pharmaceutically effective amount of a pharmaceutical formulation by using a device as defined herein.
• the medicament(s) present in the pharmaceutical formulation is believed to exhibit a more stable FP Fraction relative to medicaments present in conventional inhalable formulations.
• the medicament(s) may experience a decrease in FP Fraction of not greater than 10% from initial following 2.5 months storage at 40°C/75%RH, and/or a drop of no more than 15% from initial following 3 months storage at 25°C/75%RH.
• the pharmaceutical formulation may exhibit increased chemical stability relative to a similar formulation employing lactose monohydrate.
• the medicament(s) experiences at least 25 percent less degradation as measured by impurity content.
• Fine Particle Fraction described within the following examples is defined as the amount of active ingredient as a proportion of the total emitted dose, depositing in Stage 2 of a Twin Impinger or Stages 1 to 5 of an Andersen Cascade Impactor, both impactors operating at a vacuum flow rate of 60 Imin "1 - Example 1
• Use of anhydrous lactose within dry powder formulations The effect of various types of anhydrous lactose on FP Fraction stability of dry powder inhalers is illustrated herein. Two batches of anhydrous lactose were manufactured by thermally dehydrating a coarse classification of lactose monohydrate (MPS 92 ⁇ m) under vacuum. This method of dehydration was carried out according to the teachings of Figura, L.O.
• Example 2 Physical properties of anhydrous lactose
• the physical properties of the three anhydrous lactose batches are detailed in Table 1 . Included are physical properties of the monohydrate batch used as the input material to produce the two dehydrated lactose batches.
• Figure 1 provides a chart illustrating the X-Ray diffraction patterns for the anhydrous lactose in comparison with the lactose monohydrate.
• the anhydrous nature of the dehydrated forms of lactose is exemplified by the low water contents, whilst the predominance of alpha lactose within the material is demonstrated by the anomeric purity i.e. low beta lactose content.
• the commercial lactose is anhydrous in nature, it contains a high level of beta lactose.
• Example 3 Moisture uptake of anhydrous lactose batches The moisture uptake of the lactose batches was measured.
• Figure 2 shows the moisture uptake of the two manufactured anhydrous lactose batches, in comparison with the monohydrate control, measured using gravimetric vapor sorption (GVS), and demonstrates different degrees of hygroscopicity between the material.
• the hygroscopic anhydrous lactose manifests a weight change at significantly lower relative humidity (RH) than the stable anhydrous lactose, although both materials undergo a weight change of approximately 5% w/w, consistent with rehydration.
• RH relative humidity
• Figure 3 illustrates the weight change of the three batches of anhydrous lactose over several days storage at 25°C/75%RH, and demonstrates the differences in hygroscopicity of the materials. This was measured by storing samples of each material at this condition and measuring the weight change from initial at regular timepoints. The hygroscopic alpha anhydrous lactose increases in weight by about 5% within 24 hours, whilst the stable alpha anhydrous lactose achieved this weight gain after nine days. However, the commercial anhydrous lactose only underwent a weight change of less than 1% after nine days storage. This illustrates the differences in hygroscopicity between the different batches of anhydrous lactose in terms of rate of moisture uptake and critical RH for moisture uptake.
• Example 4 Fine Particle Fraction of pharmaceutical formulations Dry powder blends containing 0.58% w/w salmeterol xinafoate and 0.8%w/w fluticasone propionate were manufactured using a combination of anhydrous lactose and lactose monohydrate with the anhydrous lactose component present in the concentrations described in Table 2.
• the particle size distributions of the blends were matched using lactose monohydrate. Control batches were manufactured using lactose monohydrate. The lactose blends were manufactured in situ using a high shear blender, and sufficient lactose blend removed to enable addition of the active ingredients in order to achieve to desired drug concentrations. The formulation was manufactured according to methodology described in EP416951 and filled into MDPI foil strips (see e.g., U.S. Patent No. 5,860,419) using perforated bed filling methodology. The change in Fine Particle Fraction of the dry powder formulations following storage at elevated temperature and humidity are shown in Figure 4 and Table 3.
• Example 5 Use of hygroscopic anhydrous lactose within dry powder formulations Fine and coarse classifications of lactose monohydrate (MPS 23 ⁇ m and 92 ⁇ m respectively) were thermally dehydrated under vacuum (120°C, 20mbar) until they had achieved a weight loss of 5%w/w. This dehydration method is purported to produce a hygroscopic form of anhydrous lactose (Figura, L.O. and Epple M., J, Thermal Anal. ,(1995) 44-53) Physical properties of dehydrated lactose Effect of dehydration on physical properties The physical properties of the following types of lactose are determined and compared as set forth in Table 4.
• Moisture uptake of dehydrated lactose The results are set forth in Figure 5. As shown, anhydrous lactose is capable of being significantly more hygroscopic than the monohydrate taking up of greater than 5 %w/w water at an RH of up to approximately 90 percent. As shown from Figure 5, the rate and magnitude of water uptake appear to be not significantly dependent on particle size.
• Example 6 Effect of storage on physical properties of dehydrated lactose Samples of the two dehydrated lactose batches were stored at 33 and 58% RH, for about 5 days, until they had undergone a weight increase of 5%, consistent with rehydration.
• Example 7 Use of dehydrated lactose in dry powder formulations
• the dehydrated coarse and fine lactose batches were used to make dry powder blends containing 0.58% w/w salmeterol xinafoate and 0.8% fluticasone propionate according to an experimental design devised to investigate the effect of anhydrous lactose concentration and particle size on Fine Particle Fraction stability.
• the particle size distributions of the blends were matched using lactose monohydrate (Table 6).
• the lactose blends were manufactured in situ using a high shear blender, and sufficient lactose blend removed to enable addition of the active ingredients in order to achieve to desired drug concentrations.
• the formulation was manufactured according to methodology described in EP416951 and filled into MDPI foil strips (see e.g., U.S. Patent No. 5,860,419) using perforated bed filling methodology (WO00/71419).
• Particle size of pharmaceutical formulations following storage Samples of the formulations described in Table 6 containing 0.58% salmeterol xinafoate and 0.8% w/w fluticasone propionate were stored at ambient temperature/58%RH for 7 days.
• the particle size of the formulations defined here as the volume percentage of particles less the 14.2 ⁇ m measured using laser diffraction, are shown in Table 7.
• the formulations using anhydrous lactose undergo a similar small reduction in fines following storage following storage at 58%RH, to a control lactose monohydrate formulation.
• Eguilibrium relative humidity (ERH) of pharmaceutical formulations The Equilibrium Relative Humidity (ERH) was measured during the manufacuring process in order to determine the relative humidity within the powder. This parameter represents the relative humidity within the interparticulate void spaces and as such, gives an indication of the ability of the powder to absorb moisture from the immediate storage environment to the extent that it reduces the relative humidity of the bulk powder.
• the ERH data or the pharmaceutical formulations described in Table 6 were determined as a function of the filling process.
• the formulations each contain 0.58% salmeterol xinafoate and 0.8% fluticasone propionate.
• the ERH was measured by inserting an RH probe into the powder blend on the filling apparatus.
• Desiccant capacity of pharmaceutical formulations Desiccant capacities of pharmaceutical formulations (0.8% fluticasone propionate and 0.58% salmeterol xinafoate) are determined for various levels of fine and coarse alpha anhydrous lactose, as well as for those employing conventional lactose, i.e., 0/0 AF/AC percent. Desiccant capacity was assessed as the propensity of samples of each formulation to undergo a further water induced weight change upon storage at 58%RH, and is used as an indication of the ability of a formulation to retain a degree of dehydration during a manufacturing process. Naked blends and those blends present in blister strips are evaluated.
• Blends were taken at the start of the filling process and having been exposed to the environment on the filling apparatus for approximately one hour (labeled 1 and 2 respectively). Blend was tested from two batches of MDPI strip - one manufactured upon immediate exposure of blend, and one after the blend had been exposed to the environment for approximately one hour. The strips were tested approximately 4 weeks after filling, having been stored under ambient environment conditions. Figure 9 illustrates the results. The text represents the expected percentage weight change, had no rehydration occurred during the filling process. These data suggest that the dry powder formulations containing anhydrous lactose appear to not significantly rehydrate during the manufacturing process, such that they retained their desiccant capacity within the MDPI strip up to four weeks post filling. As shown, the blends and strips having the fine and coarse fractions generally demonstrate greater desiccating ability relative to those utilizing conventional monohydrate lactose.
• Fine Particle Fraction of pharmaceutical formulations The FP Fraction for salmeterol and fluticasone propionate of formulations following storage at 25°C/75%RH and 40°C/75%RH are determined for dry powder formulations containing various levels of fine and coarse alpha anhydrous lactose, as well as for those employing conventional lactose, i.e., 0/0 AF/AC percent.
• the formulations are employed in strips for use in a dry powder Diskus® inhaler.
• Figures 10 and 11 illustrate the results.
• the drop in Fine Particle Fraction from initial following storage at 25°C/75%RH and 40°C/75%RH are tabulated in Tables 8 and 9.
• the dry powder formulations containing hygroscopic anhydrous lactose generally exhibit a lower drop in Fine Particle Fraction of both salmeterol and fluticasone on storage in comparison with the lactose monohydrate formulation.
• Chemical stability of dry powder formulations The chemical stability of formulations following storage at 40°C/75%RH is determined for dry powder formulations containing various levels of fine and coarse alpha anhydrous lactose, as well as for those employing conventional lactose, i.e., 0/0 AF/AC percent. This was assessed by performing a drug related impurity analysis on dry powder blend emptied from MDPI strips that had been on stability for 2.5 months.
• Table 10 1-Hydroxy-4-(2-hydroxy-5- ⁇ 1-hydroxy-2-[6-(4-phenyl- butoxy)-hexylamino]-ethyl ⁇ -benzyl)-naphthalene-2-carboxylic acid content of dry powder formulations containing anhydrous lactose following 2.5 months storage at 40°C/75%RH Anhydrous lactose (%/% AF/AC) 1 -Hydroxy-4-(2-hydroxy-5- ⁇ 1 ⁇ hydroxy-2-[6-(4-phenyl-
• the concentration of 1-Hydroxy-4-(2-hydroxy-5- ⁇ 1-hydroxy-2-[6-(4- phenyl-butoxy)-hexylamino]-ethyl ⁇ -benzyl)-naphthalene-2-carboxylic acid is highest in the dry powder formulation containing conventional lactose monohydrate i.e. 0/0 AF/AC percent.
• the chromatographic data show that the dry powder formulations employing anhydrous lactose contain lower levels of drug related impurities, particularly 1-Hydroxy-4-(2-hydroxy-5- ⁇ 1-hydroxy-2-[6- (4-phenyl-butoxy)-hexylamino]-ethyl ⁇ -benzyl)-naphthalene-2-carboxylic acid, than the monohydrate based dry powder formulation.
• Example 9 Use of hygroscopic anhydrous lactose within dry powder formulations
• the dehydrated coarse and fine lactose batches described in Example 5 were used to make dry powder blends containing 0.58% w/w salmeterol xinafoate and 0.4% fluticasone propionate with varying concentration of anhydrous fine and coarse lactose, as described in Table 11.
• the particle size distributions of the blends were matched using lactose monohydrate.
• the lactose blends were manufactured in situ using a high shear blender, and sufficient lactose blend removed to enable addition of the active ingredients in order to achieve to desired drug concentrations.
• the formulation was manufactured according to methodology described in EP416951 and filled into MDPI foil strips (see e.g., U.S. Patent No. 5,860,419) using perforated bed filling methodology (WOOO/71419).
• Desiccant Capacity of Pharmaceutical Formulations Desiccant capacities of pharmaceutical formulations (0.4% w/w fluticasone propionate and 0.58% w/w salmeterol xinafoate) are determined for various levels of fine and coarse alpha anhydrous lactose, as well as for those employing conventional lactose, i.e., 0/0 AF/AC percent. Desiccant capacity was assessed as the propensity of samples of each formulation to undergo a further water induced weight change upon storage at 58%RH, and is used as an indication of the ability of a formulation to retain a degree of dehydration during a manufacturing process. Naked blends and those blends present in blister strips are evaluated.
• Fine Particle Fraction of Pharmaceutical Formulations The FP Fraction for salmeterol and fluticasone propionate following storage at 25°C/75%RH and 40°C/75%RH are determined for dry powder formulations, as well as for those employing conventional lactose, i.e., 0/0 AF/AC percent. The formulations are employed in strips for use in a dry powder Diskus® inhaler. Figures 13 and 14 illustrate the results. The drop in Fine Particle Fraction from initial following storage at 25°C/75%RH and 40°C/75%RH are tabulated in Tables 12 and 13. The dry powder formulations containing hygroscopic anhydrous lactose exhibit a lower drop in Fine Particle Fraction of both salmeterol and fluticasone on storage in comparison with the lactose monohydrate formulation.
• Table 12 Drop in Fine Particle Fraction of dry powder formulations following 3 months storage at 25°C/75%RH.

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