EP1718276A2 - Formulation pour inhalation contenant du sulfoalkyle ether cyclodextrine et un corticosteroide, a base d'une suspension en doses unitaires - Google Patents

Formulation pour inhalation contenant du sulfoalkyle ether cyclodextrine et un corticosteroide, a base d'une suspension en doses unitaires

Info

Publication number
EP1718276A2
EP1718276A2 EP05704919A EP05704919A EP1718276A2 EP 1718276 A2 EP1718276 A2 EP 1718276A2 EP 05704919 A EP05704919 A EP 05704919A EP 05704919 A EP05704919 A EP 05704919A EP 1718276 A2 EP1718276 A2 EP 1718276A2
Authority
EP
European Patent Office
Prior art keywords
corticosteroid
amino
hydroxy
sae
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05704919A
Other languages
German (de)
English (en)
Other versions
EP1718276A4 (fr
Inventor
Rupert O. Zimmerer
Diane O. Thompson
Gerold L. Mosher
James D. Pipkin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cydex Pharmaceuticals Inc
Original Assignee
Cydex Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cydex Inc filed Critical Cydex Inc
Publication of EP1718276A2 publication Critical patent/EP1718276A2/fr
Publication of EP1718276A4 publication Critical patent/EP1718276A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • 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
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a method of administering, and a formulation for administering, sulfoalkyl ether cyclodextrin (SAE-CD) and a corticosteroid, such as budesonide, by inhalation.
  • SAE-CD sulfoalkyl ether cyclodextrin
  • corticosteroid such as budesonide
  • the formulation is made by combining SAE-CD with a suspension-based unit dose formulation of corticosteroid.
  • the invention also relates to methods of treating diseases and disorders of the lung.
  • BACKGROUND OF THE INVENTION The delivery of a drug by inhalation allows deposition of the drug in different sections of the respiratory tract, e.g., throat, trachea, bronchi and alveoli. Generally, the smaller the particle size, the longer the particle will remain suspended in air and the farther down the respiratory tract the drug can be delivered.
  • Corticosteroids are delivered by inhalation using nebulizers, metered dose inhalers, or dry powder inhalers. The principle advantages of nebulizers over other methods of pulmonary installation are that patient cooperation is not required and the delivery of higher doses of medication is easier.
  • Budesonide ((R,S)-ll ⁇ , 16 ⁇ , 17, 21-tetrahydroxypregna-l, 4-diene-3, 20-dione cyclic 16, 17-acetal with butyraldehyde; C 2 5H 34 O 6 ; Mw: 430.5) is well known. It is provided commercially as a mixture of two isomers (22R and 22S).
  • Budesonide is an anti- inflammatory corticosteroid that exhibits potent glucocorticoid activity. Administration of budesonide is indicated for maintenance treatment of asthma and as prophylactic therapy in children.
  • Commercial formulations of budesonide are sold by AstraZeneca LP (Wilmington,
  • PULMICORT RESPULES® which is a sterile aqueous suspension of micronized budesonide, is administered by inhalation using a nebulizer, in particular a compressed air driven jet nebulizer that delivers from 2 to 18% of the drug mass contained in the nominal charge.
  • RHINOCORT ® NASAL INHALERTM is a metered-dose pressurized aerosol unit containing a suspension of micronized budesonide in a mixture of propellants.
  • RHINOCORT ® AQUATM is an unscented metered-dose manual-pump spray formulation containing a suspension of micronized budesonide in an aqueous medium.
  • the suspensions should not be administered with an ultrasonic nebulizer.
  • the desired properties of a liquid for nebulization generally include: 1) reduced viscosity; 2) sterile medium; 3) reduced surface tension; 4) stability toward the mechanism of the nebulizer; 5) moderate pH of about 4-10; 6) ability to form droplets with an MMAD of ⁇ 5 ⁇ m or preferably ⁇ 3 ⁇ m; 7) absence of irritating preservatives and stabilizing agents; 8) suitable tonicity.
  • suspensions possess some advantages but on the other hand solutions possess other advantages.
  • Smaldone et al. J. Aerosol Med. (1998), 11, 113-125) disclose the results of a study on the in vitro determination of inhaled mass and particle distribution of a budesonide suspension. They conclude that 2%-18% of the nebulizer's charge of budesonide was delivered from the suspension, meaning that budesonide delivery was incomplete resulting in a significant waste of drug. In the thirteen most efficient systems, the suspension can be nebulized sufficiently well for lower respiratory tract delivery. Another study further demonstrated the highly variable efficiency of nebulization from one nebulizer to another.
  • Barry et al. J. Allergy Clin. Immunol.
  • Inhaled corticosteroids are utilized in the treatment of asthma and are of significant benefit because they are delivered directly to the site of action, the lung.
  • the goal of an inhaled corticosteroid is to provide localized therapy with immediate drug activity in the lungs.
  • Inhaled corticosteroids are well absorbed from the lungs. In fact, it can be assumed that all of the drug available at the receptor site in the lungs will be absorbed systemically. However, it is well known that using current methods and formulations the greater part of an inhaled corticosteroid dose is swallowed and becomes available for oral absorption, resulting in unwanted systemic effects.
  • high pulmonary availability is more important than high oral bioavailability because the lung is the target organ.
  • a product with high pulmonary availability has greater potential to exert positive effects in the lung.
  • the ideal inhaled corticosteroid formulation would provide minimum oral delivery thereby reducing the likelihood of systemic adverse effects.
  • the majority of the corticosteroid dose delivered to the lung is absorbed and available systemically.
  • bioavailability depends upon absorption from the GI tract and the extent of first pass metabolism in the liver. Since this oral component of corticosteroid drug delivery does not provide any beneficial therapeutic effect but can increase systemic side effects, it is desirable for the oral bioavailability of inhaled corticosteroid to be relatively low. Both particle size and formulation influence the efficacy of an inhaled corticosteroid.
  • the formulation of a drug has a significant impact on the delivery of that drug to the lungs, and therefore its efficacy.
  • Most important in the delivery of drug to the lung are the aerosol vehicle and the size of the particles delivered. Additionally, a reduced degree of pulmonary deposition suggests a greater degree of oropharyngeal deposition. Due to a particular formulation employed, some corticosteroids are more likely to be deposited in the mouth and throat and may cause local adverse effects. While receptor distribution is the major determinant of bronchodilator efficacy, particle size appears to be more important in determining the efficacy of an inhaled corticosteroid. The smallest airways have an internal perimeter of 2 micrometers (mem) or less.
  • an inhaler with particles having a mean aerodynamic diameter of 1 mem should have a greater respirable fraction than an inhaler with particles that have an average diameter of 3.5 to 4 mem.
  • all particles should ideally be no greater than 2 to 3 mem.
  • a particle that is small (less than 5 mem) is more likely to be inhaled into the smaller airways of the lungs, thus improving efficacy.
  • particles that are larger than 5 mem can be deposited in the mouth and throat, both reducing the proportion of particles that reach the lungs and potentially causing local adverse effects such as oral candidiasis and hoarseness (dysphonia).
  • Particles having a mass median aerodynamic diameter (MMAD) of close to 1 mem are considered to have a greater respirable fraction per dose than those with a diameter of 3.5 mem or greater.
  • MMAD mass median aerodynamic diameter
  • a further disadvantage to the nebulization of budesonide suspensions is the need to generate very small droplets, MMAD of about ⁇ 3 ⁇ m. Since the nebulized droplets are so small, then the micronized budesonide must be even smaller or in the range of 0.5-2.0 ⁇ m and the particles should have a narrow particle size distribution. Generation of such particles is difficult.
  • O'Callaghan (Thorax, (1990), 45, 109-111), Storr et al. (Arch. Dis. Child (1986), 61, 270-273), and Webb et al. (Arch. Dis. Child (1986), 61, 1108-1110) suggest that nebulization of corticosteroid (in particular beclomethasone) solutions may be preferred over that of suspensions because the latter may be inefficient if the nebulized particles are too large to enter the lung in therapeutically effective amounts.
  • O'Callaghan J. Pharm. Pharmacol. (2002), 54, 565-569
  • nebulization of a solution is preferred over that of a suspension. Accordingly, there is a widely recognized need for a non-suspension formulation comprising a corticosteroid for administration via nebulization.
  • the PULMICORT® suspension unit dose formulation is widely available and accepted in the field of inhalation therapy. It would be of great benefit to this field of therapy to provide a method of improving the administration of the PULMICORT® suspension unit dose formulation, or more generally, of a suspension unit dose formulation containing a corticosteroid.
  • nebulizer therapy is to administer higher concentrations of drug, use solution, preferably predominantly aqueous-based solutions in preference to non-aqueous or alcoholic or non-aqueous alcoholic solutions or suspensions if possible, minimize treatment time, synchronize nebulization with inhalation, and administer smaller droplets for deeper lung deposition of drug.
  • Corticosteroid-containing solutions for nebulization are known.
  • solutions for nebulization There are a number of different ways to prepare solutions for nebulization. These generally have been prepared by the addition of a cosolvent, surfactant, or buffer.
  • cosolvents such as ethanol, polyethylene glycol and propylene glycol are only tolerated in low amounts when administered by inhalation due to irritation of the respiratory tract.
  • the cosolvents make up less than about 35% by weight of the nebulized composition, although it is the total dose of cosolvent as well as its concentration that determines these limits.
  • the limits are set by the propensity of these solvents either to cause local irritation of lung tissue, to form hyperosmotic solutions that would draw fluid into the lungs, and/or to intoxicate the patient.
  • most potential hydrophobic therapeutic agents are not sufficiently soluble in these cosolvent mixtures.
  • Saidi et al. U.S. Patent No. 6,241,969 disclose the preparation of corticosteroid- containing solutions for nasal and pulmonary delivery.
  • the dissolved corticosteroids are present in a concentrated, essentially non-aqueous form for storage or in a diluted, aqueous-based form for administration.
  • Lintz et al. (AAPS Annual Meeting and Exposition, 2004) disclose the preparation of liquid formulations containing budesonide, water, citrate salt, sodium chloride and alcohol, propylene glycol and/or surfactant, such as Tween, Pluronic, or phospholipids with HLB-values between 10 and 20.
  • An alternative approach to administration of the PULMICORTTM suspension is administration of a liposome formulation. Waldrep et al. (J. Aerosol Med.
  • Cyclodextrins are cyclic carbohydrates derived from starch.
  • the unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure.
  • the parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as ⁇ -, ⁇ -, and ⁇ -cyclodextrin respectively.
  • Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3 positions and a primary hydroxyl group at the 6-position.
  • the cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug.
  • the complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.
  • Equations 1 and 2 This dynamic and reversible equilibrium process can be described by Equations 1 and 2, where the amount in the complexed form is a function of the concentrations of the drug and cyclodextrin, and the equilibrium or binding constant, K .
  • K the equilibrium or binding constant
  • Binding constants of cyclodextrin and an active agent can be determined by the equilibrium solubility technique (T. Higuchi et al. in "Advances in Analytical Chemistry and Instrumentation Vol. 4"; CN. Reilly ed.; John Wiley & Sons, Inc, 1965, pp. 117-212). Generally, the higher the concentration of cyclodextrin, the more the equilibrium process of Equations 1 and 2 is shifted to the formation of more complex, meaning that the concentration of free drug is generally decreased by increasing the concentration of cyclodextrin in solution.
  • the underivatized parent cyclodextrins are known to interact with human tissues and extract cholesterol and other membrane components, particularly upon accumulation in the kidney tubule cells, leading to toxic and sometimes fatal renal effects.
  • the parent cyclodextrins often exhibit a differing affinity for any given substrate.
  • ⁇ -cyclodextrin often forms complexes with limited solubility, resulting in solubility curves of the type Bs. This behavior is known for a large number of steroids which imposes serious limitations towards the use of ⁇ -CD in liquid preparations.
  • ⁇ -CD does not complex well with a host of different classes of compounds. It has been shown for ⁇ -CD and ⁇ -CD that derivatization, e.g.
  • CAPTISOL ® has been commercialized by CyDex, Inc. as CAPTISOL ® .
  • the anionic sulfobutyl ether substituent dramatically improves the aqueous solubility of the parent cyclodextrin.
  • the presence of the charges decreases the ability of the molecule to complex with cholesterol as compared to the hydroxypropyl derivative.
  • Reversible, non-covalent, complexation of drugs with CAPTISOL ® cyclodextrin generally allows for increased solubility and stability of drugs in aqueous solutions. While CAPTISOL ® is a relatively new but known cyclodextrin, its use in the preparation of corticosteroid-containing solutions for nebulization has not previously been evaluated.
  • Hemolytic assays are generally used in the field of parenteral formulations to predict whether or not a particular formulation is likely to be unsuitable for injection into the bloodstream of a subject. If the formulation being tested induces a significant amount of hemolysis, that formulation will generally be considered unsuitable for administration to a subject. It is generally expected that a higher osmolality is associated with a higher hemolytic potential. As depicted in FIG.
  • the hemolytic behavior of the CAPTISOL ® is compared to the same for the parent ⁇ -cyclodextrin, the commercially available hydroxypropyl derivatives, ENCAPSINTM cyclodextrin (degree of substitution ⁇ 3-4) and MOLECUSOL ® cyclodextrin (degree of substitution ⁇ 7-8), and two other sulfobutyl ether derivatives, SBEl- ⁇ -CD and SBE4- ⁇ -CD.
  • SAE-CD sulfoalkyl ether
  • the osmolality of a formulation is generally associated with its hemolytic potential: the higher the osmolality (or the more hypertonic), the greater the hemolytic potential.
  • Zannou et al. ("Osmotic properties of sulfobutyl ether and hydroxypropyl cyclodextrins", Pharma. Res. (2001), 18(8), 1226-1231) compared the osmolality of solutions containing SBE-CD and HP-CD. As depicted in FIG. 2, the SBE-CD containing solutions have a greater osmolality than HP-CD containing solutions comprising similar concentrations of cyclodextrin derivative.
  • U.S. Pregrant Patent Publication No. 20020055496 to McCoy et al. discloses essentially non-aqueous intra-oral formulations containing HP- ⁇ -CD. The formulations may be administered with an aerosol, spray pump or propellant.
  • Russian Patent No. 2180217 to Chuchalin discloses a stable budesonide-containing solution for inhalation. The solution comprises budesonide, propylene glycol, poly(ethylene oxide), succinic acid, Trilon B, nipazole, thiourea, water, and optionally HP- ⁇ -CD. Muller et al.
  • the HP- ⁇ -CD was evaluated as a complex or physical mixture with the drug in a study of in vitro deposition of the emitted dose from a MICRO-HALERTM inhalation device.
  • the amount of respirable drug fraction was reportedly highest with the complex and lowest with the micronized drug alone.
  • Rajewski et al. J. Pharm. Sci. (1996), 85(11), 1142-1169) provide a review of the pharmaceutical applications of cyclodextrins. In that review, they cite studies evaluating the use of cyclodextrin complexes in dry powder inhalation systems. Shao et al (Eur. J. Pharm. Biopharm.
  • HP- ⁇ -CD was formulated in a pMDI as a lyophilized inclusion complex or a physical mixture with aspirin.
  • Aspirin in the lyophilized inclusion complex exhibited the most significant degree of degradation during the 6-months storage, while aspirin alone in the pMDI demonstrated a moderate degree of degradation.
  • Aspirin formulated in the physical mixture displayed the least degree of degradation.
  • HP- ⁇ -CD may be used to enhance the stability of a chemically labile drug, but the drug stability may be affected by the method of preparation of the formulation. Gudmundsdottir et al.
  • cyclodextrin Two types of cyclodextrin were chosen; gamma cyclodextrin ( ⁇ -CD) and dimethyl-beta-cyclodextrin (DMCD) as carriers in dry powder formulations.
  • Salbutamol was used as a model drug and a control formulation containing lactose and the drug was included.
  • patents 5,942,251 and 5,756,483 to Merkus cover pharmaceutical compositions for the intranasal administration of dihydroergotamine, apomorphine and morphine comprising one of these pharmacologically active ingredients in combination with a cyclodextrin and/or a disaccharide and/or a polysaccharide and/or a sugar alcohol.
  • U.S. patent 5,955,454 discloses a pharmaceutical preparation suitable for nasal administration containing a progestogen and a methylated ⁇ -cyclodextrin having a degree of substitution of between 0.5 and 3.0.
  • a dry powder inhaler device contains a preparation consisting of a dry powder comprising (i) a parathyroid hormone (PTH), and (ii) a substance that enhances the absorption of PTH in the lower respiratory tract, wherein at least 50% of (i) and (ii) consists of primary particles having a diameter of up to 10 microns, and wherein the substance is selected from the group consisting of a salt of a fatty acid, a bile salt or derivative thereof, a phospholipid, and a cyclodextrin or derivative thereof.
  • PTH parathyroid hormone
  • U.S. patent 6,518,239 to Kuo et al. discloses a dispersible aerosol formulation comprising an active agent and a dipeptide or tripeptide for aerosolized administration to the lung.
  • compositions may also include polymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropyl methylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin and sulfobutylether- ⁇ -cyclodextrin), polyethylene glycols, and pectin.
  • polymeric excipients/additives e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropyl methylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxy
  • nebulizable composition comprising a drug, in particular a corticosteroid, and SBE-CD.
  • a drug in particular a corticosteroid
  • SBE-CD a nebulizable composition
  • the two most common types of nebulizers are the ultrasonic nebulizer and the air driven jet nebulizer. There are significant differences between the two. For example, jet nebulizers cool rather than heat the liquid in the reservoir, whereas ultrasonic nebulizers heat the liquid. While heating of the solution in reservoir can reduce the viscosity of the solution and enhance formation of droplets, excessive heating could lead to drug degradation.
  • the ultrasonic nebulizer is quieter and provides faster delivery than the jet nebulizer, but ultrasonic nebulizers are more expensive and are not advised for the administration of the currently available steroid for nebulization. Most importantly, however, ultrasonic nebulizers generally provide a significantly higher rate of administration than do jet nebulizers. Patients with asthma are often treated with inhaled short acting or long acting ⁇ 2- agonists, inhaled anticholinergics, and inhaled corticosteroids alone, sequentially or in combination.
  • Combinations of inhaled corticosteroids and long acting ⁇ 2-agonists are known, for example budesonide plus formoterol or fluticasone plus salmeterol are available in a dry powder inhaler.
  • budesonide plus formoterol or fluticasone plus salmeterol are available in a dry powder inhaler.
  • Combining the medications into one solution would reduce the time required to administer the medications separately.
  • nebulization of solutions may be preferred over that of suspensions and that, in some cases, an ultrasonic nebulizer, vibrating mesh, electronic or other mechanism of aerosolization may be preferred over an air driven jet nebulizer depending upon the nebulization liquid formulations being compared.
  • the ideal system would consist of non-toxic ingredients and be stable for long periods of storage at room temperature. When nebulized, it would produce respirable droplets in the less than 10 micron or less than 5 micron or less than 3 micron and a substantial portion of extra-fine aerosol in the less than about 1 micron size range.
  • Such a method would reduce the overall time of administration, increase the overall amount of drug administered, reduce the amount of drug left in the reservoir of the nebulizer, increase the portion of pulmonary deposition relative to oropharyngeal deposition of corticosteroid, and/or enhance deep lung penetration of the corticosteroid as compared to such administration, absent the improvement, of the suspension-based unit dose formulation.
  • the present invention seeks to overcome the disadvantages present in known formulations.
  • a derivatized cyclodextrin-based, e.g., sulfoalkyl ether cyclodextrin (SAE-CD)-based, inhalable formulation is provided.
  • the present formulation includes at least one corticosteroid as a principle active agent.
  • the present formulation may provide enhanced solubility and/or enhanced chemical, thermochemical, hydrolytic and/or photochemical stability of the active agent or other ingredients in the formulation.
  • the present formulation may possess other advantages, e.g.
  • SAE-CD also complexes with corticosteroids in aqueous inhalable liquid formulations.
  • Coadministration of the corticosteroid with SAE-CD may result in increased output rate and total drug delivery as compared to a control excluding SAE-CD.
  • An SAE-CD-containing formulation can be prepared with sufficient active agent solubility and stability for a commercial product. If needed, the SAE-CD-containing formulation can be prepared as a clear aqueous solution that can be sterile filtered through a filter having a pore size of 0.45 ⁇ m or less and that is stable and preserved under a variety of storage conditions.
  • One aspect of the invention provides a liquid formulation comprising an effective amount of corticosteroid, such as budesonide, and SAE-CD, wherein the SAE-CD is present in an amount sufficient to dissolve and stabilize the corticosteroid during storage.
  • Another aspect of the invention provides a method of improving the administration of corticosteroid to a subject by nebulization, the method comprising the steps of: providing in a unit dose an aqueous suspension formulation comprising water and corticosteroid suspended therein; combining the suspension with an amount of SAE-CD sufficient to and for a period of time sufficient to solubilize the corticosteroid and form a solution; and administering the solution to the subject, wherein the amount of time required to administer a therapeutic dose of corticosteroid with the solution is less than the amount of time required to administer the same therapeutic dose of corticosteroid with the suspension under similar, or otherwise comparable, nebulization conditions.
  • a suspension for nebulization When administered with a nebulizer, a suspension for nebulization will provide a first corticosteroid output rate under a first set of nebulization conditions.
  • SAE-CD when SAE-CD is added to the suspension and mixed therein, a sufficient amount of the corticosteroid is dissolved to form a liquid formulation for nebulization that provides a greater corticosteroid output rate as compared to the formulation excluding the SAE-CD when administered under substantially the same conditions.
  • the drug output rate of the formulation is increased over that of the suspension even though the total volume of nebulized composition, i.e., the total volume of solution emitted by the nebulizer, has not increased.
  • SAE-CD is present in an amount sufficient to solubilize at least 50%, at least 75%, at least 90%, at least 95% or substantially all of the corticosteroid.
  • SAE-CD is present in an amount sufficient to decrease the amount of unsolubilized corticosteroid in the suspension formulation and to improve the administration of the suspension formulation via nebulization.
  • SAE-CD is present in an amount sufficient to solubilize enough corticosteroid such that the suspension formulation to which the SAE-CD was added is converted to a solution, substantially clear solution (containing less than 5% solid), or a clear solution. It is possible that other components of the suspension formulation will not completely dissolve in, or may separate out from, the solution formulation containing SAE-CD.
  • SAE-CD-containing solution generates smaller droplets than does the same nebulizer charged with a corticosteroid/HP- ⁇ -CD-containing solution operated under otherwise similar conditions.
  • the system comprising SAE-CD is improved over an otherwise similar system comprising HP- ⁇ -CD, since the SAE-CD based system will generate a greater proportion of respirable droplets, increase the portion of pulmonary deposition relative to oropharyngeal deposition of corticosteroid, and permit deeper lung penetration (delivery).
  • One aspect of the invention provides for the use of SAE-CD in a nebulizable unit dose liquid formulation.
  • the invention provides use of SAE-CD for converting a nebulizable corticosteroid-containing suspension-based unit dose formulation to a nebulizable corticosteroid-containing liquid unit dose formulation.
  • Specific embodiments of the invention include those wherein: 1) the budesonide to SAE-CD molar ratio is 0.5 to 0.0001 (1:2 to 1:10,000), 1:1 to 1:100, 1:1 to 1:10,000, or 0.1 to 0.03; 2) the SAE-CD is sulfobutyl ether 4- ⁇ -CD, sulfobutyl ether 7- ⁇ -CD, sulfobutyl ether 6- ⁇ -CD, sulfobutyl ether 4- ⁇ -CD, sulfobutyl ether 3 to 8- ⁇ -CD, or a sulfobutyl ether 5- ⁇ -CD; 3) the SAE-CD is a compound of the formula 1 or a mixture thereof; 4) the nebulization composition further comprises
  • the nebulization composition is visibly clear as viewed by the unaided eye.
  • Specific embodiments of the methods of preparing a liquid formulation include those wherein: 1) the method further comprises the step of sterile filtering the formulation through a filtration medium having a pore size of 0.1 microns or larger; 2) the liquid formulation is sterilized by irradiation or autoclaving; 3) the nebulization solution is purged with nitrogen or argon or other inert pharmaceutically acceptable gas prior to storage such that a substantial portion of the oxygen dissolved in, and/or in surface contact with the solution is removed.
  • the invention provides a method of stabilizing corticosteroid in an aqueous corticosteroid-containing formulation comprising the step of adding SAE-CD to an aqueous corticosteroid-containing suspension or solution formulation in an amount sufficient to reduce the rate of degradation of corticosteroid as compared to a control sample excluding SAE-CD.
  • the invention also provides a method of improving the administration of an inhalable aqueous corticosteroid-containing suspension unit dose formulation by nebulization, the method comprising the step of adding SAE-CD to an aqueous corticosteroid-containing suspension unit dose formulation in an amount sufficient to solubilize the corticosteroid to form an inhalable aqueous corticosteroid-containing solution unit dose formulation, the improvement comprising increasing the output rate and/or extent of nebulized corticosteroid.
  • the invention provides a method of reducing the amount of time required to provide a therapeutically effective amount of corticosteroid to a subject by inhalation of an corticosteroid-containing composition with a nebulizer, the method comprising the steps of: including SAE-CD in the composition in an amount sufficient to solubilize the corticosteroid to form an inhalable aqueous corticosteroid-containing solution; and administering the solution to the subject by inhalation with a nebulizer, wherein the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with the solution is reduced as compared to the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with a corticosteroid-containing suspension comprising the same amount or concentration of corticosteroid when the suspension and solution are administered under otherwise similar nebulization conditions.
  • the invention also provides an inhalable composition comprising a water soluble ⁇ -CD derivative, a corticosteroid (either esterified or unesterified) and an aqueous liquid medium.
  • Another embodiment of the invention also provides an inhalable composition comprising a water soluble ⁇ -CD derivative, a corticosteroid (unesterified) and an aqueous liquid medium.
  • the invention provides an improved system for administering a corticosteroid-containing inhalable formulation by inhalation, the improvement comprising including SAE-CD in the inhalable formulation such that SAE-CD is present in an amount sufficient to provide an increased rate of inhaled corticosteroid as compared to administration of a control inhalable formulation excluding SAE-CD but otherwise being administered under approximately the same conditions.
  • the invention can be used to provide a system for administration of a corticosteroid by inhalation, the system comprising an inhalation device, such as a nebulizer, and a drug composition comprising a therapeutically effective amount of corticosteroid, liquid carrier and SAE-CD present in an amount sufficient solubilize the corticosteroid when presented to an aqueous environment, wherein the molar ratio of corticosteroid to SAE-CD is in the range of about 0.072 to 0.0001 or 0.063 to 0.003.
  • the system forms droplets having a MMAD in the range of about 1-8 ⁇ or 3-8 ⁇ .
  • the corticosteroid is delivered at a rate of at least about 20-50 ⁇ g/min, wherein this range may increase or decrease according to the concentration of corticosteroid in the nebulization solution in the reservoir of the nebulizer.
  • SAE-CD corticosteroid therapy with an inhalable nebulization solution, one can expect advantages such as enhanced drug delivery, enhanced delivery especially to the peripheral or small airways facilitated by the finer aerosol produced, potentially improved treatment of nocturnal, asymptomatic asthma and recovery from acute asthma attacks, increased rate of drug administration, reduced treatment time, improved formulation stability and/or improved patient compliance as compared to comparable corticosteroid therapy with an inhalable nebulization suspension or suspension chlorofluorocarbon (CFC) or hydrofluoroalkanes (HFA) pressurized metered-dose inhaler (pMDI).
  • CFC chlorofluorocarbon
  • HFA hydrofluoroalkanes
  • pMDI pressurized metered-dose inhal
  • kits are detailed below.
  • the invention provides the potential to accommodate combination products to overcome incompatibilities with a suspension by other solution dosage forms.
  • Figure 1 depicts a graph of the hemolytic behavior of the CAPTISOL ® as compared to the same for the parent ⁇ -cyclodextrin, the commercially available hydroxypropyl derivatives, ENCAPSINTM (degree of substitution -3-4) and
  • FIG. 1 depicts a graph of the osmolality of SBE-CD containing solutions of various degrees of substitution and HP- ⁇ -CD containing solutions comprising similar concentrations of cyclodextrin derivative.
  • Figure 3 depicts a phase solubility graph of the concentration (molar) of cyclodextrin versus the concentration (molar) of budesonide for ⁇ -CD, HP- ⁇ -CD and SBE7- ⁇ -CD.
  • Figure 4 depicts a chart of the estimated percentage of nebulization composition emitted from three different nebulizers (PARI LC PLUS, HUDSON UPDRAFT II
  • Figures 5a-5b depict droplet size data for nebulization of solutions with a PARI LC PLUS nebulizer.
  • Figure 6 depicts droplet size data for nebulization of solutions with a HUDSON UPDRAFT II EBUMIST nebulizer.
  • Figure 7 depicts droplet size data for nebulization of solutions with a MYSTIQUE ultrasonic nebulizer.
  • Figure 8 depicts comparative DV 50 droplet size data for nebulization of composition with the three nebulizers PARI LC PLUS, HUDSON UPDRAFT II NEBUMIST, and MYSTIQUE.
  • Figure 9 is a graph depicting the relationship between concentration of SAE-CD versus output rate of SAE-CD in various different nebulizers.
  • Figures 10a- 10b depict comparative droplet size data for nebulization solutions with the PARI LC PLUS and MYSTIQUE nebulizers of PULMICORT RESPULES suspension and a modified PULMICORT RESPULES-based SAE-CD solution.
  • Figure 11 depicts a semi-log plot of the % of initial concentration of the R- and S- isomers of budesonide in solutions with and without CAPTISOL versus time at 60 C in solution.
  • Figure 12 depicts a semi-log plot of the % of initial concentration of budesonide versus Lux hours when the samples are exposed to fluorescent lamps.
  • Figure 13 depicts a phase solubility diagram for fluticasone propionate in the presence of several different cyclodextrins.
  • Figure 14 depicts a phase solubility diagram for mometasone furoate in the presence of several different cyclodextrins.
  • Figure 15 depicts a phase solubility diagram for esterified and non-esterified fluticasone in the presence of SAE(5-6)- ⁇ -CD.
  • Figure 16 depicts a bar chart summarizing the aqueous solubility of beclomethasone dipropionate in the presence of various SAE-CD derivatives.
  • the presently claimed formulation overcomes many of the undesired properties of other known aqueous inhalable solution or suspension corticosteroid-containing formulations.
  • SAE-CD in an inhalable liquid formulation containing corticosteroid
  • the corticosteroid is dissolved.
  • the nebulization of corticosteroid is improved in both an air driven jet nebulizer and an ultrasonic nebulizer.
  • the corticosteroid exhibits greater stability in the presence of SAE-CD than it does in its absence.
  • the corticosteroid would be present in an amount sufficient for single dose or multi-dose administration.
  • SAE-CD would be present in an amount sufficient to solubilize the corticosteroid when the two are placed in the aqueous carrier.
  • the aqueous carrier would be present in an amount sufficient to aid in dissolution of the corticosteroid and form a nebulization solution of sufficient volume and sufficiently low viscosity to permit single dose or multi-dose administration with a nebulizer.
  • SAE-CD would be present in solid form or in solution in the aqueous carrier.
  • the corticosteroid would be present in dry powder/particle form or in suspension in the aqueous carrier.
  • Air driven jet, ultrasonic or pulsating membrane nebulizers include the AERONEBTM (Aerogen, San Francisco, CA), PARI LC PLUSTM, PARI BOYTM N and PARI DURANEBTM (PARI Respiratory Equipment, Inc., Monterey, CA), MICROAIRTM (Omron Healthcare, Inc, Vernon Hills, Illinois), HALOLITETM (Profile Therapeutics Inc, Boston, MA), RESPIMATTM (Boehringer Ingelheim ⁇ ngelheim, Germany) AERODOSETM (Aerogen, Inc, Mountain View, CA), OMRON ELITETM (Omron Healthcare, Inc, Vernon Hills, Illinois), OMRON MICROAIRTM (Omron Healthcare, Inc, Vernon Hills, Illinois ), MABISMIST TM II (Mabis Healthcare, Inc, Lake Forest, Illinois), LUMISCOPE TM 6610, (The Lumiscope Company, Inc, East Brunswick, New Jersey), AIRSEP MYSTIQUETM, (AirSep Corporation
  • Nebulizers that nebulize liquid formulations containing no propellant are suitable for use with the compositions provided herein. Nebulizers are available from, e.g., Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd.
  • Nebulizers for use herein include, but are not limited to, jet nebulizers (optionally sold with compressors), ultrasonic nebulizers, and others.
  • Exemplary jet nebulizers for use herein include Pari LC plus/ProNeb, Pari LC plus/ProNeb Turbo, Pari LC Plus Dura Neb 1000 & 2000 Pari LC plus/Walkhaler, Pari LC plus/Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer System (NE-C18 and JetAir Disposable nebulizer), Omron compare Elite Compressor Nebulizer System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star nebulizer with Proneb Ultra compressor, Pulomo- aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traverler, DeVilbiss 646, Whisper Jet, Acorn II, Misty-Neb, Allied aerosol, Schuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand Held
  • Exemplary ultrasonic nebulizers for use herein include MicroAir, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer.
  • nebulizers for use herein include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, AerodoseTM Inhaler, and AeroEclipse Breath Actuated Nebulizer.
  • the present invention provides SAE-CD based formulations, wherein the SAE-CD is a compound of the Formula 1 :
  • n 4, 5 or 6;
  • Ri, R 2 , R 3 , R 4 , R 5 , e, R 7 , R 8 and R 9 are each, independently, -O- or a -O-(C 2 - C 6 alkylene)-SO 3 " group, wherein at least one of Rt to R 9 is independently a -O-(C 2 - C 6 alkylene)-SO 3 ⁇ group, preferably a -O-(CH 2 ) m SO 3 ⁇ group, wherein m is 2 to 6, preferably 2 to 4, (e.g.-OCH 2 CH 2 CH 2 SO 3 _ or-OCH 2 CH 2 CH 2 CH 2 SO 3 ⁇ ); and
  • Si, S , S 3 , S 4 , S 5 , S 6 , S , S 8 and S are each, independently, a phannaceutically acceptable cation which includes, for example, H + , alkali metals (e.g. Li + , Na + , K + ), alkaline earth metals (e.g., Ca +2 , Mg +2 ), ammonium ions and amine cations such as the cations of ( - C 6 )- alkylamines, piperidine, pyrazine, (Ci - C 6 )-alkanolamine and (C - C 8 )-cycloalkanolamine.
  • SAE-CD derivative of the invention include derivatives of the Formula II (SAEx- ⁇ -CD), wherein "x" ranges from 1 to 18; of the
  • SAEx- ⁇ -CD SAEv- ⁇ -CD SAEz- ⁇ -CD Name SEEx- ⁇ -CD SEEy- ⁇ -CD SEEz- ⁇ -CD Sulfoethyl ether CD SPEx- ⁇ -CD SPEy- ⁇ -CD SPEz- ⁇ -CD Sulfopropyl ether CD SBEx- ⁇ -CD SBEy- ⁇ -CD SBEz- ⁇ -CD Sulfobutyl ether CD SPtEx- ⁇ -CD SPtEy- ⁇ -CD SPtEz- ⁇ -CD Sulfopentyl ether CD SHEx- ⁇ -CD SHEy- ⁇ -CD SHEz- ⁇ -CD Sulfohexyl ether CD "SAE" represents a sulfoalkyl ether substituent bound to a cyclodextrin.
  • the SAE-CD can contain from 0% to less than 50% wt. of underivatized parent cyclodextrin.
  • alkylene and alkyl as used herein (e.g., in the -0-(C 2 - C 6 - alkylene)SO 3 " group or in the alkylamines), include linear, cyclic, and branched, saturated and unsaturated (i.e., containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively.
  • alkanol in this text likewise includes both linear, cyclic and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl groups may be situated at any position on the alkyl moiety.
  • cycloalkanol includes unsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.
  • An embodiment of the present invention provides compositions containing a mixture of cyclodextrin derivatives, having the structure set out in formula (I), where the composition overall contains on the average at least 1 and up to 3n + 6 alkylsulfonic acid moieties per cyclodextrin molecule.
  • the present invention also provides compositions containing a single type of cyclodextrin derivative, or at least 50% of a single type of cyclodextrin derivative.
  • the invention also includes formulations containing cyclodextrin derivatives having a narrow or wide and high or low degree of substitution. These combinations can be optimized as needed to provide cyclodextrins having particular properties.
  • the present invention also provides compositions containing a mixture of cyclodextrin derivatives wherein two or more different types of cyclodextrin derivatives are included in the composition.
  • cyclodextrins derivatized with different types of functional groups e.g., hydroxyalkyl and sulfoalkyl, and not to the heterogeneous nature of derivatized cyclodextrins due to their varying degrees of substitution.
  • Each independent different type can contain one or more functional groups, e.g. SBE-CD where the cyclodextrin ring has only sulfobutyl functional groups, and hydroxypropyl-ethyl- ⁇ -CD where the cyclodextrin ring has both hydroxypropyl functional groups and ethyl functional groups.
  • Suitable SAE-CD derivatives also include those having an average DS of about 3 to about 8. These SAE-CD derivatives increase the solubility of poorly water soluble active agents to varying degrees. Since SAE-CD is a poly-anionic cyclodextrin, it can be provided in different salt forms. Suitable counterions include cationic organic atoms or molecules and cationic inorganic atoms or molecules. The SAE-CD can include a single type of counterion or a mixture of different counterions. The properties of the SAE-CD can be modified by changing the identity of the counterion present.
  • a first salt form of SAE-CD can have a greater corticosteroid stabilizing and/or solubilizing power than a different second salt form of SAE-CD.
  • an SAE-CD having a first degree of substitution can have a greater corticosteroid stabilizing and/or solubilizing power than a second SAE- CD having a different degree of substitution.
  • SAE- ⁇ -CD is particularly suitable for use in complexing esterified and non-esterified corticosteroids as compared to complexation of the same corticosteroids with SAE- ⁇ -CD or SAE- ⁇ -CD.
  • the table above also summarizes the phase solubility data depicted in FIG. 15 for fluticasone and fluticasone propionate with various different SAE- ⁇ -CD species having a degree of substitution in the range of 5-10.
  • SAE- ⁇ -CD is also much more effective at binding with a particular regioisomer of esterified corticosteroids than is SAE- ⁇ -CD or SAE- ⁇ -CD.
  • Example 18 details the comparative evaluation of the binding of SAE- ⁇ -CD and SAE- ⁇ -CD with a series of structurally related corticosteroid derivatives.
  • the table below summarizes the results of a study comparing the binding of SBEx- ⁇ -CD, wherein x represents the average degree of substitution, derivatives and SBE- ⁇ -CD derivative with different forms of beclomethasone.
  • a formulation according to the present invention may contain an active agent of which more than about 50% by weight is complexed with a cyclodextrin. The actual percent of active agent that is complexed will vary according to the complexation equilibrium constant characterizing the complexation of a specific cyclodextrin to a specific active agent.
  • the invention also includes embodiments wherein the active agent is not complexed with the cyclodextrin or wherein a minor portion of the active agent is complexed with the derivatized cyclodextrin.
  • an SAE-CD or any other anionic derivatized cyclodextrin, can form one or more ionic bonds with a positively charged compound. This ionic association can occur regardless of whether the positively charged compound is complexed with the cyclodextrin either by inclusion in the cavity or formation of a salt bridge.
  • the binding of a drug to the derivatized cyclodextrin can be improved by including an acid or base along with the drug and cyclodextrin.
  • the binding of a basic drug with the cyclodextrin might be improved by including an acid along with the basic drug and cyclodextrin.
  • the binding of an acidic drug with the cyclodextrin might be improved by including a base (alkaline material) along with the acidic drug and cyclodextrin.
  • the binding of a neutral drug might be improved by including a basic, acidic or other neutral compound along with the neutral drug and cyclodextrin.
  • Suitable acidic compounds include inorganic and organic acids. Examples of inorganic acids are mineral acids, such as hydrochloric and hydrobromic acid. Other suitable acids include sulfuric acid, sulfonic acid, sulfenic acid, and phosphoric acid.
  • organic acids are aliphatic carboxylic acids, such as acetic acid, ascorbic acid, carbonic acid, citric acid, butyric acid, fumaric acid, glutaric acid, glycolic acid, ⁇ -ketoglutaric acid, lactic acid, malic acid, mevalonic acid, maleic acid, malonic acid, oxalic acid, pimelic acid, propionic acid, succinic acid, tartaric acid, or tartronic acid.
  • Aliphatic carboxylic acids bearing one or more oxygenated substituents in the aliphatic chain are also useful.
  • a combination of acids can be used.
  • Suitable basic compounds include inorganic and organic bases. Suitable inorganic bases include ammonia, metal oxide and metal hydroxide.
  • Suitable organic bases include primary amine, secondary amine, tertiary amine, imidazole, triazole, tefrazole, pyrazole, indole, diethanolamine, triethanolamine, diethylamine, methylamine, tromethamine (TRIS), aromatic amine, unsaturated amine, primary thiol, and secondary thiol.
  • a combination of bases can be used.
  • An anionic derivatized cyclodextrin can complex or otherwise bind with an acid- ionizable agent.
  • acid-ionizable agent is taken to mean any compound that becomes or is ionized in the presence of an acid.
  • An acid-ionizable agent comprises at least one acid-ionizable functional group that becomes ionized when exposed to acid or when placed in an acidic medium.
  • Exemplary acid-ionizable functional groups include a primary amine, secondary amine, tertiary amine, quaternary amine, aromatic amine, unsaturated amine, primary thiol, secondary thiol, sulfonium, hydroxyl, enol and others known to those of ordinary skill in the chemical arts.
  • the degree to which an acid-ionizable agent is bound by non-covalent ionic binding versus inclusion complexation formation can be determined spectrophotometrically using methods such as 1 HNMR, 13 CNMR, or circular dichroism, for example, and by analysis of the phase solubility data for the acid-ionizable agent and anionic derivatized cyclodextrin.
  • the artisan of ordinary skill in the art will be able to use these conventional methods to approximate the amount of each type of binding that is occurring in solution to determine whether or not binding between the species is occurring predominantly by non-covalent ionic binding or inclusion complex formation.
  • an acid- ionizable agent that binds to derivatized cyclodextrin by both means will generally exhibit a bi-phasic phase solubility curve. Under conditions where non-covalent ionic bonding predominates over inclusion complex formation, the amount of inclusion complex formation, measured by NMR or circular dichroism, will be reduced even though the phase solubility data indicates significant binding between the species under those conditions; moreover, the intrinsic solubility of the acid-ionizable agent, as determined from the phase solubility data, will generally be higher than expected under those conditions.
  • the term non-covalent ionic bond refers to a bond formed between an anionic species and a cationic species.
  • the bond is non-covalent such that the two species together form a salt or ion pair.
  • An anionic derivatized cyclodextrin provides the anionic species of the ion pair and the acid-ionizable agent provides the cationic species of the ion pair. Since an anionic derivatized cyclodextrin is multi-valent, an SAE-CD can form an ion pair with one or more acid-ionizable agents.
  • the parent cyclodextrins have limited water solubility as compared to SAE-CD and HPCD. Underivatized ⁇ -CD has a water solubility of about 14.5% w/v at saturation.
  • Underivatized ⁇ -CD has a water solubility of about 1.85% w/v at saturation. Underivatized ⁇ -CD has a water solubility of about 23.2% w/v at saturation.
  • Dimethyl- beta-cyclodextrin (DMCD) forms a 43% w/w aqueous solution at saturation.
  • the SAE-CD can be combined with one or more other cyclodextrins or cyclodextrin derivatives in the inhalable solution to solubilize the corticosteroid.
  • water soluble cyclodextrin derivatives that can be used according to the invention include the hydroxyethyl, hydroxypropyl (including 2- and 3 -hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methylhydroxyethyl, ethyl-hydroxyethyl and ethyl- hydroxypropyl ethers of alpha-, beta- and gamma-cyclodextrin; and the maltosyl, glucosyl and maltotriosyl derivatives of alpha, beta- and gamma-cyclodextrin, which may contain one or more sugar residues, e.g.
  • Specific cyclodextrin derivatives for use herein include hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, hydroxyethyl- gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextr
  • cyclodextrin derivatives suitable for use in the present invention include the carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 made by ORGANON (AKZO-NOBEL), hydroxybutenyl ether derivatives made by EASTMAN, sulfoalkyl-hydroxyalkyl ether derivatives, sulfoalkyl-alkyl ether derivatives, other derivatives as described in US Pregrant Patent Application Publications No. 2002/0128468, No. 2004/0106575, No.
  • HP- ⁇ -CD can be obtained from Research Diagnostics Inc. (Flanders, NJ).
  • HP- ⁇ -CD is available with different degrees of substitution.
  • Exemplary products include ENCAPSINTM (degree of substitution ⁇ 4; HP4- ⁇ -CD) and MOLECUSOLTM (degree of substitution ⁇ 8; HP8- ⁇ -CD); however, embodiments including other degrees of substitution are also available. Since HPCD is non-ionic, it is not available in salt form. Dimethyl cyclodextrin is available from FLUKA Chemie (Buchs, CH) or Wacker
  • cyclodextrins suitable in the invention include water soluble derivatized cyclodextrins.
  • Exemplary water-soluble derivatized cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy- ⁇ -cyclodextrins, e.g. succinyl- ⁇ - cyclodextrin (SCD), and 6 A -amino-6 A -deoxy-N-(3-carboxypropyl)- ⁇ -cyclodextrin. All of these materials can be made according to methods known in the prior art.
  • Suitable derivatized cyclodextrins are disclosed in Modified Cyclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends m Cyclodextrins and Derivatives (Ed. Anthony Duchene, Editions de Sante, Paris, France, 1991).
  • FIG. 3 depicts a molar phase solubility curve for budesonide with HP- ⁇ -CD, SBE7- ⁇ -CD, and ⁇ -CD as compared to water.
  • SAE-CD is superior to other cyclodextrins and cyclodextrin derivatives at solubilizing budesonide.
  • SBE- ⁇ -CD is a better solubilizer of budesonide than HP- ⁇ -CD.
  • solubilizing power among the SAE-CD derivatives followed about this rank order for budesonide over a SAE-CD concentration range of 0.04 to 0.1 M SBE5.2- ⁇ -CD ⁇ SPE5.4- ⁇ -CD > SBE6.1- ⁇ -CD > SBE7- ⁇ -CD > SBE9.7- ⁇ -CD - SBE6.7- ⁇ -CD > SPE7- ⁇ - CD.
  • a 0.1 M concentration of SBE7- ⁇ -CD was able to solubilize a greater amount of budesonide than either ⁇ -CD or HP- ⁇ -CD.
  • SAE-CD-containing nebulizable formulations provide a greater output rate for corticosteroid by nebulization as compared to ⁇ -CD or HP- ⁇ -CD administered under otherwise similar conditions. It was unexpectedly discovered that the nebulization of Captisol solutions provides several advantages with respect to other cyclodextrins. The droplets leaving the nebulizer are of a more advantageous size and the Captisol solutions are nebulized faster than similar solutions of other Cyclodextrins. The table below shows that the average particle size (Dv50) of Captisol solutions is smaller than that of HP- ⁇ -CD or ⁇ -CD.
  • the Dv90 shows that the other cyclodextrins had significant number of very large droplets.
  • the data (Malvern particle size) was obtained for each formulation as emitted from a PARI LC PLUS nebulizer equipped with a PARI PRONEB ULTRA air compressor.
  • the smaller droplet size is favored for an inhalable composition as it permits deeper lung delivery of active agents such as a corticosteroid.
  • Nebulization is stopped when the sound changes (time to sputter) or visible particles are no longer produced.
  • the advantage(s) of SAE-CD was further demonstrated by preparing solutions containing budesonide dissolved in various cyclodextrins and comparing their performance in nebulization to the performance of commercial PULMICORT® RESPULES®, a commercially available suspension-based unit dose formulation.
  • the suspension obtained from several unit dose ampoules of PULMICORT® was pooled to form a multi-use suspension based unit dose formulation, and SAE-CD (specifically, CAPTISOL), HP- ⁇ - or ⁇ - cyclodextrin powder was added to achieve a 0.25mg/ml budesonide solution concentration.
  • budesonide-containing solutions contained 5%w/v Captisol (P5C), l%w/v gamma-CD (Pl ⁇ CD) and 5%w/v hydroxypropyl-beta- cyclodextrin (P5HP ⁇ CD). Each was prepared at least 30 minutes prior to all testing. All three formulations were clear, colorless solutions. (Note: a 250 mg/mL solution of budesonide cannot be achieved in a 5% w/v solution of ⁇ -cyclodextrin as it exhibits "B" type solubility behavior).
  • the output rate is highest for the Captisol solution indicating that an equivalent amount of drug can be delivered in a shorter period of time.
  • ⁇ - CD is unable to solubilize an equivalent amount of corticosteroid due to the limited solubility of ⁇ -CD in water.
  • the present invention can be used with other suspension-based aqueous formulations, which formulations may be adapted for nasal delivery or pulmonary delivery.
  • Exemplary suspension-based aqueous formulations include the UDB formulation (Sheffield Pharmaceuticals, Inc.), VANCENASETM AQ (beclomethasone dipropionate aqueous suspension; Schering Corporation, Kenilworth, NJ), ATOMASETM (beclomethasone dipropionate aqueous suspension; Douglas Pharmaceuticals Ltd., Aukland, Australia), BECONASETM (beclomethasone dipropionate aqueous suspension; Glaxo Wellcome, NASACORT AQTM (triamcinolone acetonide nasal spray, Aventis Pharmaceuticals), TRI-NASALTM (triamcinolone acetonide aqueous suspension; Muro Pharmacaceuticals Inc.) and AEROBID-MTM, (flunisolide inhalation aerosol, Forest Pharmaceuticals), NASALIDETM and NASARELTM (flunisolide nasal spray, Ivax Corporation), FLONASETM (fluticasone propionate, GlaxoSmithKline), and NASONEXTM (mome
  • the suspension formulation can comprise corticosteroid present in particulate, microparticulate, nanoparticulate or nanocrystalline form. Accordingly, an SAE-CD can be used to improve the administration of a corticosteroid suspension-based unit dose formulation. Moreover, the SAE-CD outperforms other cyclodextrin derivatives. According to one embodiment, a method of the invention is practiced as follows. SAE-CD (in solid or liquid form) and a suspension-based unit dose formulation comprising corticosteroid are mixed. The SAE-CD is present in an amount sufficient to increase the amount of solubilized corticosteroid, i.e. decrease the amount of unsolubilized corticosteroid, therein.
  • the liquid Prior to administration, the liquid may be optionally aseptically filtered or terminally sterilized. The liquid is then administered to a subject by inhalation using a nebulizer. As a result, the amount of drug that the subject receives is higher than the subject would have received had the unaltered suspension formulation been administered.
  • SAE-CD in liquid form, as ready-to-use liquid or as a concentrate
  • a solid unit dose formulation comprising corticosteroid are mixed to form a liquid formulation.
  • the SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid.
  • the liquid is then administered via inhalation using a nebulizer.
  • SAE-CD in solid form
  • a solid unit dose formulation comprising corticosteroid
  • SAE-CD in solid form
  • a solid unit dose formulation comprising corticosteroid
  • SAE-CD in solid form
  • a solid unit dose formulation comprising corticosteroid
  • SAE-CD in solid form
  • a solid unit dose formulation comprising corticosteroid
  • SAE-CD in solid form
  • Mixing and/or heating are optionally employed upon addition of the liquid carrier to form the formulation.
  • the SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid.
  • the formulation is then administered via inhalation using a nebulizer.
  • the size of the reservoir varies from one type of nebulizer to another.
  • the volume can be adjusted by adding additional liquid carrier or additional solution containing SAE-CD.
  • a single-use suspension-based unit dose formulation of corticosteroid contains about 0.125, 0.25, 0.5, 1, 2, or about 0.125 to about 2 mg of corticosteroid suspended in about 50 ⁇ l to 10 ml of liquid carrier.
  • the corticosteroid is present at a concentration of about 20 meg to about 30 mg of corticosteroid per ml of suspension.
  • a multi-use suspension-based unit dose formulation of corticosteroid contains approximately 0.125 to 2 mg per mL of corticosteroid suspended in 1 to 100 ml of liquid carrier.
  • a multi-use formulation actually contains two or more unit doses of corticosteroid.
  • Single unit dose aliquots are taken from a multi-use unit dose formulation, and the single unit dose are typically administered one-at-a-time to a subject.
  • about 10 to 500 mg of SAE-CD be it in solid form or dissolved in a liquid carrier, is added to each mL the suspension in order to dissolve a substantial portion of the corticosteroid and form a multi-use unit dose liquid formulation that is then administered to a subject in single unit dose aliquots.
  • a key aspect of the invention is that a suspension-based unit dose formulation is converted to a liquid unit dose formulation prior to pulmonary administration via inhalation (of a nebulized mist) to a subject.
  • the conversion can take place in the same container in which the suspension is provided, in a different container, or in the reservoir of a nebulizer.
  • a substantial portion of the corticosteroid must be dissolved.
  • a "substantial portion" is at least 20% wt., at least 30% wt., at least 40% wt., or at least 20% wt and less than 50% wt. of the corticosteroid.
  • a "major portion” is at least 50% wt. of the corticosteroid.
  • a subject (patient) undergoing corticosteroid treatment may convert the suspension-based formulation to a liquid formulation of the invention by employing a method described herein.
  • a kit containing the suspension formulation and SAE-CD can be prepared.
  • the concentration of SAE-CD in solution can be expressed on a weight to weight or weight to volume basis; however, these two units are interconvertible.
  • the %w/w cyclodextrin concentration is determined by dividing the cyclodextrin weight in grams by the total weight (cyclodextrin + water weight) in like units and multiplying by 100.
  • the %w/v cyclodextrin concentration is determined by dividing the cyclodextrin weight in grams by the total volume in milliliters and multiplying by 100.
  • %w/v [(%w/w * slope) + y-intercept] * %w/w where the slope and intercept values are determined from a linear regression of the density data in the table.
  • %w/v [(%w/w * slope) + y-intercept] * %w/w where the slope and intercept values are determined from a linear regression of the density data in the table.
  • a 40%w/w CAPTISOL solution would be equivalent to a -48.3% w/v CAPTISOL solution.
  • the performance of an inhalable solution of the invention in a nebulizer may depend upon the viscosity of the solution in its reservoir, the nebulization solution.
  • Viscosity of an aqueous solution of SBE7- ⁇ -CD changes with respect to concentration approximately as indicated in the table above. Viscosity of the inhalable composition can have an impact on percentage of nebulization composition emitted from a nebulizer, output rate of nebulized corticosteroid and droplet size distribution. The amount of residual nebulization inhalable composition left in the reservoir of the nebulizer may be greater for solutions containing SAE-CD than for a budesonide- containing suspension.
  • Figure 4 depicts a chart of the estimated percentage of nebulization composition emitted from three different nebulizers (PARI LC PLUS, HUDSON UPDRAFT II NEB-U-MIST, and MYSTIQUE) for each of four different nebulization compositions (PULMICORT RESPULES suspension, 5% w/w SBE7- ⁇ -CD solution, 10% w/w SBE7- ⁇ -CD solution and 20% w/w SBE7- ⁇ -CD solution).
  • the PULMICORT RESPULES suspension was used as the control.
  • the PARI LC PLUS, MYSTIQUE and HUDSON nebulizers were used for the comparison.
  • the MYSTIQUE nebulizer was unable to nebulize the suspension and concentrated SAE-CD solution (20% w/w) efficiently so they were not evaluated with that nebulizer.
  • the results suggest that, under the conditions tested, nebulization of PULMICORT RESPULES suspension results in a greater percentage of nebulized composition, meaning that, with the suspension, less nebulization composition is left in the reservoir of the nebulizer upon completion of nebulization as compared to with the solution. In some cases, nebulization of the suspension resulted in the greatest percentage by weight of total composition emitted by a nebulizer.
  • nebulization of the SAE-CD-containing solution provided a higher budesonide output rate than nebulization of the PULMICORT RESPULES suspension even though the nebulizer emitted a greater total amount of the suspension.
  • the nebulizer preferentially nebulizes the water of the suspension rather than the particles of the suspension thereby causing an increase in the molar concentration of budesonide in the suspension in the reservoir.
  • Higher SAE-CD concentrations, above 25% w/v led to slightly longer nebulization times and lower output rates once the viscosity exceeded an approximate upper limit.
  • SBE7- ⁇ -CD concentration 21.5+5% w/w SBE7- ⁇ -CD concentration was identified as the approximate upper acceptable level for the nebulizer tested, "acceptable” being defined as the upper concentration of SBE7- ⁇ -CD that can be used without building up excessive viscosity, which may adversely affect the nebulization time and output rate.
  • concentration of SAE-CD will vary among the nebulizer formats.
  • the upper acceptable concentration of SAE-CD in a liquid formulation for use in a nebulizer may vary according to the DS of the derivative, the alkyl chain length of the sulfoalkyl functional group, and/or the CD ring size of the SAE-CD.
  • a nebulizer is used to produce appropriately sized droplets.
  • the particle size of the droplet produced by a nebulizer for inhalation is in the range between about 0.5 to about 5 microns. If it is desired that the droplets reach the lower regions of the respiratory tract, i.e., the alveoli and terminal bronchi, the preferred particle size range is between about 0.5 and about 2.5 microns. If it is desired that the droplets reach the upper respiratory tract, the preferred particle size range is between 2.5 microns and 5 microns.
  • viscosity of the nebulization composition can impact droplet size and droplet size distribution.
  • FIGS. 5a-5b depict droplet size data for nebulization of inhalable compositions with a PARI LC PLUS nebulizer.
  • a MALVERN laser light scattering device Mastersizer S, Malvern Instruments Ltd. Malvern, Worcs, U.K. was used to measure MMAD.
  • FIG. 5a depicts the results obtained using ⁇ -CD solutions of varying concentrations (5% w/v, 10% w/v and 20% w/v) in the absence of budesonide.
  • 5b depicts the results obtained using the same nebulizer with PULMICORT RESPULES suspension or a modified PULMICORT RESPULES solution containing SAE-CD of different concentrations (5% w/v, 10% w/v and 20% w/v). With each of these samples, a significant portion of the nebulized mass is of a respirable size range. Moreover, the solutions containing SAE-CD apparently form droplets that are comparable in size to those of the nebulized suspension.
  • Figure 6 depicts droplet size data for nebulization of inhalable compositions with a HUDSON UPDRAFT II NEBUMIST nebulizer charged with PULMICORT RESPULES suspension or a solution containing SAE-CD at different concentrations. (5% w/v, 10% w/v and 20% w/v).
  • the NEB-U-MIST forms a slightly larger particle size distribution, a significant portion of the nebulized mass is still in the appropriate size range. Accordingly, the nebulization solution made from the suspension and containing SAE-CD is suitable for use in a variety of different air driven jet nebulizers.
  • the package insert for PULMICORT RESPULES suspension states that the suspension should not be nebulized with an ultrasonic nebulizer.
  • Figure 7 depicts droplet size data for nebulization of inhalable compositions with a MYSTIQUE ultrasonic nebulizer.
  • the compositions include three different SAE-CD containing solutions. Unlike the suspension, the SAE-CD containing solution can be nebulized with an ultrasonic nebulizer.
  • the invention provides a method of improving the pulmonary delivery of corticosteroid in a suspension-based unit dose formulation from an ultrasonic nebulizer, the method comprising the step of including SAE-CD in the formulation in an amount sufficient to decrease the amount of undissolved corticosteroid in the suspension-based unit dose formulation.
  • the performance of nebulization compositions across a range of nebulizers is typically compared by comparing the Dv50 of the droplet size distribution for the respective compositions.
  • Figure 8 depicts comparative Dv50 droplet size data for nebulization of an inhalable composition with the three above-mentioned nebulizers.
  • the SAE-CD containing solutions are suitable for administration by nebulization across a range of concentrations.
  • the droplet size distribution can be partially controlled by adjusting the concentration of SAE-CD.
  • Figure 9 is a graph depicting the relationship between concentration of SAE-CD versus output rate of SAE-CD in various different nebulizers with different sources of compressed air required for the specific setup: the RAINDROP-Rat, RAINDROP-Dog, PARI LC STAR-UNC, PARI LC STAR-Rat PARI LC PLUS and DEVILBISS PULMO AIDE air jet driven nebulizers.
  • the nebulizers were used in a variety of setups including free standing as well as animal exposure chambers and/or individual exposure masks. In general, the data demonstrate that output of SAE-CD increases with increasing SAE-CD concentration. Depending upon the nebulizer used, the conditions under which the nebulizer is operated and the concentration of SAE-CD in solution, different maximum output rates can be achieved. For example, the maximum output rate in the Raindrop- Dog setup is from a 250 mg/mL CAPTISOL concentration. Even though nebulization of PULMICORT RESPULES suspension with an ultrasonic nebulizer is not recommended, it can be achieved.
  • FIG. 10a depicts the DvlO and Dv50 data for the solutions run on the PARI LC PLUS air driven jet nebulizer and FIG. 10b depicts the DvlO and Dv50 data for the solutions run on the MYSTIQUE ultrasonic nebulizer.
  • the droplet size data for the two different solutions is comparable.
  • the budesonide output rate for the two solutions was significantly different.
  • Use of SAE-CD in a nebulization composition results in an increased output rate of budesonide regardless of the format of the nebulizer.
  • the invention thus, provides a method of increasing the output rate of a corticosteroid-containing suspension-based unit dose formulation being delivered by a nebulizer, the method comprising the step of including SAE-CD in the formulation in an amount sufficient to increase the amount of dissolved corticosteroid in the formulation to form an altered formulation, whereby the output rate of corticosteroid for the altered formulation is greater than the output rate of corticosteroid for the suspension formulation.
  • corticosteroids that are useful in the present invention generally include any steroid produced by the adrenocortex, including glucocorticoids and mineralocorticoids, and synthetic analogs and derivatives of naturally occurring corticosteroids having anti- inflammatory activity.
  • Suitable synthetic analogs include prodrugs, ester derivatives
  • corticosteroids that can be used in the compositions of the invention include aldosterone, beclomethasone, betamethasone, budesonide, ciclesonide (Altana Pharma AG), cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, rof
  • corticosteroid compound is present in the final, diluted corticosteroid composition designed for inhalation in an amount from about 1 ⁇ g/ml to about 10 mg/ml, about 10 ⁇ g/ml to about 1 mg/ml, or about 20 ⁇ g/ml to about 500 ⁇ g/ml.
  • the drug concentration can be between about 30 and 1000 ⁇ g/ml for triamcinolone acetonide, and between about 50 and 2000 ⁇ g/ml for budesonide, depending on the volume to be administered.
  • relatively high concentrations of the corticosteroid can be achieved in an aqueous-based composition.
  • the corticosteroid compound is present in the final, diluted corticosteroid composition designed for nasal administration in an amount from about 50 ⁇ g/ml to about 10 mg/ml, about 100 ⁇ g/ml to about 2 mg/ml, or about 300 ⁇ g/ml to about 1 mg/ml.
  • the drug concentration is between about 250 ⁇ g/ml and 1 mg/ml for triamcinolone acetonide, and between about 400 ⁇ g/ml and 1.6 mg/ml for budesonide, depending on the volume to be administered.
  • the diluted corticosteroid composition is prepared as described herein.
  • the corticosteroid for such treatment is preferably either beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone propionate, mometasone furoate, or triamcinolone acetonide, and is formulated in the concentrations set forth herein.
  • the daily dose of the corticosteroid is generally about 0.05 to 10 mg, depending on the drug and the disease, in accordance with the Physician's Desk Reference.
  • the corticosteroid can be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, isomeric, isomeric, enantiomerically pure, racemic, solvate, anhydrous, hydrate, chelate, derivative, analog, esterified, non-esterfied, or other common form.
  • an active agent is named herein, all such forms available are included. For example, all known forms of budesonide are considered within the scope of the invention.
  • the formulation of the invention can be used to deliver two or more different active agents.
  • Particular combinations of active agents can be provided by the present formulation.
  • Some combinations of active agents include: 1) a first drug from a first therapeutic class and a different second drug from the same therapeutic class; 2) a first drug from a first therapeutic class and a different second drug from a different therapeutic class; 3) a first drug having a first type of biological activity and a different second drug having about the same biological activity; 4) a first drug having a first type of biological activity and a different second drug having a different second type of biological activity.
  • a corticosteroid such as budesonide, can be administered in combination with one or more other drugs.
  • Such other drugs include: ⁇ 2 adrenoreceptor agonist, dopamine D 2 receptor agonist, anticholinergic agent, or topical anesthetic.
  • ⁇ 2 -Adrenoreceptor agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol (alpha 1 -(((1,1 dimethylethyl)amino)methyl)-4-hydroxy-l,3-benzenedimethanol); Bambuterol
  • Pirbuterol (.alpha..sup.6-(((l,l-dimethylethyl)-amino)methyl)-3-hydroxy-2,6- pyridinemethanol); Procaterol (((R*,S*)-(.+-.)-8-hydroxy-5-(l-hydroxy-2-((l- methylethyl)amino- )butyl)-2(lH)-quinolin-one); Reproterol ((7-(3-((2-(3,5- dihydroxyphenyl)-2-hydroxyethyl)amino)-propyl)-3,7-dihydro-l,3-dimethyl-lH-purine- 2,6-dione)- ; Rimiterol (4-(hydroxy-2-piperidinylmethyl)-l,2-benzenediol); Salbutamol ((.+-.)-alpha 1 -((( 1 , 1 -dimethylethyl)amino)methyl)-4
  • Dopamine (D 2 ) receptor agonists include, but are not limited to, Apomorphine ((r)- 5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo[de,glquinoli- ne-10,11 -diol); Bromocriptine ((5'.alpha.)-2-bromo-12'-hydroxy-2 , -(l-methylethyl)-5'-(2-methylpropyl)ergotaman-3',6', 18-trione); Cabergoline ((8.beta.)-N-(3-(dimethylamino)propyl)-N-((ethylamino)carbony- l)-6-(2-propenyl)ergoline-8-carboxamide); Lisuride (N'-((8-alpha-)-9,10-di- dehydro-6- methylergolin-8-yl)-N,N-diethylurea); Pergolide
  • Ropinirole (4-(2-(dipropylamino)ethyl)-l,3-dihydro-2H-indol-2-one); and Talipexole (5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thia-zolo[4,5-d]azepin-2-amine).
  • Other dopamine D 2 receptor agonists for use herein are disclosed in International Patent Application Publication No. WO 99/36095, the relevant disclosure of which is hereby inco ⁇ orated by reference.
  • Anticholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladonna extract, scopolamine, scopolamine methobromide, homatropine methobromide, hyoscyamine, isopriopramide, orphenadrine, benzalkonium chloride, tiofropium bromide and glycopyrronium bromide.
  • the compositions contain an anticholinergic agent, such as ipratropium bromide or tiofropium bromide, at a concentration of about 5 ⁇ g/mL to about 5 mg/mL, or about 50 ⁇ g/mL to about 200 ⁇ g/mL.
  • the compositions for use in the methods herein contain an anticholinergic agent, including ipratropium bromide and tiofropium bromide, at a concentration of about 83 ⁇ g/mL or about 167 ⁇ g/mL.
  • Other active ingredients for use herein in combination therapy include, but are not limited to, IL-5 inhibitors such as those disclosed in U.S. Patents No. 5,668,110, No.
  • leukotriene receptor antagonists such as montelukast sodium (SingularTM, R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl-
  • anti-IgE antibodies such as XolairTM (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025 A; rhuMAb-E25), Genentech, Inc., South San Francisco, Calif.), and topical anesthetics such as lidocaine, N- arylamide, aminoalkylbenzoate, prilocaine, etidocaine (U.S. Patents No. 5,510,339, No.
  • the invention includes methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconsfrictive disorders.
  • the method further includes administering one or more of (a), (b), (c) or (d) as follows: (a) a ⁇ 2 -adrenoreceptor agonist;
  • a dopamine (D 2 ) receptor agonist (b) a dopamine (D 2 ) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; or
  • an anticholinergic agent simultaneously with, prior to or subsequent to the composition provided herein.
  • Embodiments of the present invention allow for combinations to be prepared in a variety of ways: 1) Mixing ready to use solutions of a ⁇ 2-agonist such as levalbuterol or anticholinergic such as ipatropium bromide with a ready to use solution of a corticosteroid in SAE-CD; 2) Mixing ready to use solutions of a ⁇ 2-agonist or anticholinergic with a concentrated solution of a corticosteroid dissolved using SAE-CD; 3) Mixing a ready to use solution of a ⁇ 2-agonist or anticholinergic with substantially dry SAE-CD and a substantially dry corticosteroid; 4) Mixing a ready to use solution of a ⁇ 2-agonist or anticholinergic with a substantially dry mixture of SAE-CD and a corticosteroid or more conveniently a pre- measured amount of the mixture in a unit container such as a capsule (empty a capsule into ready to use
  • solutions or powders may optionally contain other ingredients such as buffers and/or tonicity adjusters and/or antimicrobials and/or additives or other such excipients as set forth herein or as presently used in inhalable liquid formulations to improve the output of the nebulizer.
  • Dosing, use and administration of the therapeutic agents disclosed herein is generally intended to follow the guidelines set forth in the Physician's Desk Reference, 55 th Edition (Thompson Healthcare, Montvale, NJ, 2005) the relevant disclosure of which is hereby incorporated by reference.
  • the bronchoconsfrictive disorder to be treated, prevented, or whose one or more symptoms are to be ameliorated is associated with asthma, including, but not limited to, bronchial asthma, allergic asthma and intrinsic asthma, e.g., late asthma and airway hyper- responsiveness; and, particularly in embodiments where an anticholinergic agent is used, other chronic obstructive pulmonary diseases (COPDs), including, but not limited to, chronic bronchitis, emphysema, and associated cor pulmonale (heart disease secondary to disease of the lungs and respiratory system) with pulmonary hypertension, right ventricular hypertrophy and right heart failure.
  • COPD chronic obstructive pulmonary diseases
  • COPD chronic obstructive pulmonary diseases
  • a formulation according to the invention will have a storage shelf life of no less than 6 months.
  • shelf life is determined only as regards the increase in the amount of budesonide degradation by-products or a reduction in the amount of budesonide remaining in the formulation.
  • the formulation will not demonstrate an unacceptable and substantial increase in the amount of degradants during the storage period of at least six months.
  • the criteria for acceptable shelf-life are set as needed according to a given product and its storage stability requirements. In other words, the amount of degradants in a formulation having an acceptable shelf-life will not increase beyond a predetermined value during the intended period of storage.
  • Example 3 The method of Example 3 was followed to determine the stability of budesonide in solution.
  • the shelf-life was defined as the time to loss of 10% potency. Under the conditions tested, the loss of potency was first order.
  • the shelf life of a Captisol- Enabled® Budesonide Inhalation Solution is greater than about 3 years at a pH between 4 and 5, i.e.
  • Figure 11 is a semi-log plot of the % of initial concentration at each time point for the samples stored at 60 °C. Loss of budesonide was first order at each temperature. The table below shows the pseudo-first order rate constants calculated for each isomer at 60 °C and 80 °C.
  • SBE7- ⁇ -CD stabilized both R- and S-isomers of budesonide in solutions at both pH 4 and 6.
  • the with/without CAPTISOL ratio of rate constants was much less than 1 at all temperatures.
  • SBE7- ⁇ -CD had a greater effect on the stability of both the R and S- isomer at pH 6 than at pH 4.
  • the ratio of rate constants with/without SBE7- ⁇ -CD was less at pH 6 than at pH 4.
  • SBE7- ⁇ -CD stabilized both isomers, the S-isomer appears to be stabilized to an even greater extent than the R.
  • the ratio of rate constants with/without SBE7- ⁇ -CD was lower for the S isomer.
  • the degree of stabilization affected by SBE7- ⁇ -CD at 60°C is greater than at 80°C. An even greater degree of stabilization would be expected at 40°C and/or room temperature (20-30 C).
  • Samples of the above solutions were also placed in a chamber under a bank of fluorescent lights. Vials were periodically removed and assayed for budesonide.
  • Figure 12 shows the semi-log plot of the % of initial value remaining as a function of light exposure (light intensity * time).
  • SBE7- ⁇ -CD significantly reduced the photodecomposition of budesonide. The loss of budesonide was first order and independent of pH.
  • the formulation of the invention can be provided as a kit adapted to form an inhalable solution for nebulization.
  • the kit would comprise a corticosteroid, SAE-CD, an aqueous carrier, and optionally one or more other components.
  • the corticosteroid and SAE-CD can be provided together or separately in solid, suspended or dissolved form. After mixing SAE-CD with corticosteroid in the presence of an aqueous carrier, the solids will dissolve to form an inhalable solution rather than suspension for nebulization.
  • Each component can be provided in an individual container or together with another component.
  • SAE-CD can be provided in an aqueous solution while budesonide is provided in dry solid form or wet suspended form.
  • SAE-CD is provided in dry form and budesonide is provided as an aqueous suspension, e.g., PULMICORT RESPULESTM.
  • the kit can instead comprise an admixture of a solid derivatized cyclodextrin and solid corticosteroid and, optionally, at least one solid pharmaceutical excipient, such that a major portion of the active agent is not complexed with the derivatized cyclodextrin prior to reconstitution of the admixture with an aqueous carrier.
  • the composition can comprise a solid mixture comprising the inclusion complex of a derivatized cyclodextrin and an active agent, wherein a major portion of the active agent is complexed with the derivatized cyclodextrin prior to reconstitution of the solid mixture with an aqueous carrier.
  • the aqueous carrier may be a liquid or frozen solid.
  • the kit excludes the aqueous carrier during storage, but the aqueous carrier is added to the SAE-CD and corticosteroid prior to use to form, the nebulization solution.
  • the corticosteroid and SAE- CD can be complexed and present in aqueous concentrated form prior to addition of the aqueous carrier, which is later added to bring the solution to volume and proper viscosity and concentration for nebulization.
  • a reconstitutable formulation can be prepared according to any of the following processes. A liquid formulation of the invention is first prepared, then a solid is formed by lyophilization (freeze-drying), spray-drying, spray freeze-drying, antisolvent precipitation, various processes utilizing supercritical or near supercritical fluids, or other methods known to those of ordinary skill in the art to make a solid for reconstitution.
  • a liquid vehicle included in a formulation of the invention comprises an aqueous liquid carrier, such as water, aqueous alcohol, or aqueous organic solvent.
  • the formulation of the present invention may include a conventional preservative, antioxidant, buffering agent, acidifying agent, alkalizing agent, colorant, solubility-enhancing agent, complexation-enhancing agent, electrolyte, glucose, stabilizer, tonicity modifier, bulking agent, antifoaming agent, oil, emulsifying agent, cryoprotectant, plasticizer, flavors, sweeteners, a tonicity modifier, surface tension modifier, viscosity modifier, density modifier, volatility modifier, other excipients known by those of ordinary skill in the art for use in preserved formulations, or a combination thereof.
  • alkalizing agent is intended to mean a compound used to provide alkaline medium, such as for product stability.
  • alkaline medium such as for product stability.
  • Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, friethanolamine, diethanolamine, organic amine base, alkaline amino acids and trolamine and others known to those of ordinary skill in the art.
  • acidifying agent is intended to mean a compound used to provide an acidic medium for product stability.
  • Such compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and others known to those of ordinary skill in the art.
  • a conventional preservative in the inhalable solution formulation is optional, since the formulation is self-preserved by SAE-CD depending upon its concentration in solution. Nonetheless, a conventional preservative can be further included in the formulation if desired.
  • Preservatives can be used to inhibit microbial growth in the compositions. The amount of preservative is generally that which is necessary to prevent microbial growth in the composition for a storage period of at least six months.
  • a conventional preservative is a compound used to at least reduce the rate at which bioburden increases, but preferably maintains bioburden steady or reduces bioburden after contamination has occurred.
  • Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamma picolinium chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl, propyl or butyl parabens and others known to those of ordinary skill in the art.
  • antioxidant is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process.
  • Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite and others known to those of ordinary skill in the art.
  • buffering agent is intended to mean a compound used to resist change in pH upon dilution or addition of acid or alkali. Buffers are used in the present compositions to adjust the pH to a range of between about 2 and about 8, about 3 to about 7, or about 4 to about 5.
  • Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in the art.
  • buffers include citric acid/phosphate mixture, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate, mecanical-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)imino- tris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N- (carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES (piperazine-N,N'-bis(2- ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS- TRIS PROPANE (l,
  • a complexation-enhancing agent can be added to a formulation of the invention. When such an agent is present, the ratio of cyclodexfrin /active agent can be changed.
  • a complexation-enhancing agent is a compound, or compounds, that enhance(s) the complexation of the active agent with the cyclodexfrin.
  • Suitable complexation enhancing agents include one or more pharmacologically inert water soluble polymers, hydroxy acids, and other organic compounds typically used in liquid formulations to enhance the complexation of a particular agent with cyclodextrins.
  • Hydrophilic polymers can be used as complexation-enhancing, solubility- enhancing and/or water activity reducing agents to improve the performance of formulations containing a cyclodextrin.
  • Loftsson has disclosed a number of polymers suitable for combined use with a cyclodexfrin (underivatized or derivatized) to enhance the performance and/or properties of the cyclodexfrin.
  • Suitable polymers are disclosed in Pharmazie (2001), 56(9), 746-747; International Journal of Pharmaceutics (2001), 212(1), 29-40; Cyclodextrin: From Basic Research to Market, International Cyclodexfrin Symposium, 10th, Ann Arbor, MI, United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp.: Adrian, Mich.); PCT International Publication No. WO 9942111; Pharmazie, 53(11), 733-740 (1998); Pharm. Technol.
  • the natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g. sodium alginate) and agar, and polypeptides such as casein and gelatin.
  • the semi-synthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and other mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose, hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethylcellulose.
  • the synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (e.g. carbomer).
  • polyoxyethylene derivatives polyethylene glycols
  • polyvinyl derivatives polyvinyl alcohol, polyvinylpyrrolidone and polystyrene sulfonate
  • acrylic acid e.g. carbomer
  • Other natural, semi-synthetic and synthetic polymers not named here which meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are likewise considered to be within the ambit of the present invention.
  • An emulsifying agent is intended to mean a compound that aids the formation of an emulsion.
  • An emulsifier can be used to wet the corticorsteroid and make it more amenable to dissolution.
  • Emulsifiers for use herein include, but are not limited to, polyoxyetheylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan firstearate), polyoxyethylene (20) sorbitan mono-oleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane- 1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; fragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose
  • stabilizer is intended to mean a compound used to stabilize the therapeutic agent against physical, chemical, or biochemical process that would reduce the therapeutic activity of the agent.
  • Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharin and other known to those of ordinary skill in the art.
  • tonicity modifier is intended to mean a compound or compounds that can be used to adjust the tonicity of the liquid formulation.
  • Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those of ordinary skill in the art.
  • Other tonicity modifiers include both inorganic and organic tonicity adjusting agents.
  • Tonicity modifiers include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tarfrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, proplyene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate
  • the tonicity of the liquid formulation approximates the tonicity of the tissues in the respiratory fract.
  • An osmotic agent can be used in the compositions to enhance the overall comfort to the patient upon delivery of the corticosteroid composition.
  • Osmotic agents can be added to adjust the tonicity of SAE-CD containing solutions.
  • Osmolality is related to concentration of SAE-CD in water. At SBE7- ⁇ -CD concentrations below about 11-13% w/v, the solutions are hypotonic or hypoosmotic with respect to blood and at SBE7- ⁇ -CD concentrations above about 11-13% w/v the SBE7- ⁇ -CD containing solutions are hypertonic or hyperosmotic with respect to blood.
  • Suitable osmotic agents include any low molecular weight water-soluble species pharmaceutically approved for pulmonary and nasal delivery such as sodium chloride, lactose and glucose.
  • the formulation of the invention can also include biological salt(s), potassium chloride, or other electrolyte(s).
  • antifoaming agent is intended to mean a compound or compounds that prevents or reduces the amount of foaming that forms on the surface of the liquid formulation.
  • Suitable antifoaming agents include dimethicone, simethicone, octoxynol, ethanol and others known to those of ordinary skill in the art.
  • the term "bulking agent” is intended to mean a compound used to add bulk to the lyophilized product and/or assist in the control of the properties of the formulation during lyophilization.
  • Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and others known to those of ordinary skill in the art.
  • the term "cryoprotectant” is intended to mean a compound used to protect an active therapeutic agent from physical or chemical degradation during lyophilization. Such compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and others known to those of ordinary skill in the art.
  • a solubility-enhancing agent can be added to the formulation of the invention.
  • a solubility-enhancing agent is a compound, or compounds, that enhance(s) the solubility of the active agent when in a liquid formulation. When such an agent is present, the ratio of cyclodexfrin/active agent can be changed.
  • Suitable solubility enhancing agents include one or more organic solvents, detergents, soaps, surfactant and other organic compounds typically used in parenteral formulations to enhance the solubility of a particular agent.
  • Suitable organic solvents that can be used in the formulation include, for example, ethanol, glycerin, polyethylene glycols, propylene glycol, poloxomers, and others known to those of ordinary skill in the art. It should be understood, that compounds used in the art of pharmaceutical formulations generally serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used to define more than one term herein, its purpose or function should not be construed as being limited solely to that named purpose(s) or function(s).
  • an active agent contained within the present formulation can be present as its pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the active agent is modified by reacting it with an acid or base as needed to form an ionically bound pair.
  • pharmaceutically acceptable salts include conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those of ordinary skill in the art.
  • the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and others known to those of ordinary skill in the art.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent active agent which contains a basic or acidic moiety by conventional chemical methods.
  • the term "patient” or “subject” are taken to mean warm blooded animals such as mammals, for example, cats, dogs, mice, guinea pigs, horses, bovine cows, sheep and humans.
  • a formulation of the invention will comprise an active agent present in an effective amount.
  • effective amount is meant the amount or quantity of active agent that is sufficient to elicit the required or desired response, or in other words, the amount that is sufficient to elicit an appreciable biological response when administered to a subject.
  • EXAMPLE 1 Exemplary formulations according to the invention were made according to the following general procedures.
  • Method A Cyclodexfrin is dissolved in water (or buffer) to form a solution containing a known concentration of cyclodextrin. This solution is mixed with an active agent in solid, suspension, gel, liquid, paste, powder or other form while mixing, optionally while heating to form an inhalable solution.
  • Method B A known amount of substantially dry cyclodexfrin is mixed with a known amount of substantially dry active agent.
  • a liquid is added to the mixture to form a suspension, gel, solution, syrup or paste while mixing, optionally while heating and optionally in the presence of one or more other excipients, to form an inhalable solution.
  • Method C Method C.
  • a known amount of substantially dry cyclodextrin is added to a suspension, gel, solution, syrup or paste comprising a known amount of active agent while mixing, optionally while heating and optionally in the presence of one or more other excipients, to form an inhalable solution.
  • the methods of this example may be modified by the inclusion of a wetting agent in the composition in order to facilitate dissolution and subsequent inclusion complexation of the corticosteroid.
  • a surfactant, soap, detergent or emulsifying agent can be used as a wetting agent.
  • other excipients typically incorporated into inhalable formulations are optionally included in the present formulations.
  • EXAMPLE 2 The MMD of nebulized solutions containing SBE7- ⁇ -CD and budesonide was determined as follows. Placebo solutions of three different cyclodextrins were prepared at different concentrations. Two ml of the solutions were added to the cup of a Pari LC Plus nebulizer supplied with air from a Pari Proneb Ultra compressor. The particle size of the emitted droplets was determined using a Malvern Mastersizer S laser light scattering instrument.
  • EXAMPLE 3 The stability of liquid formulations containing SAE-CD was determined by HPLC chromatography of aliquots periodically drawn from the liquid in storage.
  • Citrate-phosphate (Mcllvaines) buffer solutions at a pH of 4, 5, 6, 7, or 8 were prepared by mixing various portions of 0.01M citric acid with 0.02 M Na 2 HPO 4 . These stock solutions contained 5% w/w Captisol. Approximately 250 ⁇ g /mL of budesonide was dissolved in each buffer solution. Aliquots of the solutions were stored at 40 °C, 50 °C and 60 °C. Control samples were stored at 5 °C but are not reported here. HPLC analysis of the samples was performed initially and after 1, 2, and 3 months storage. The HPLC conditions included:
  • EXAMPLE 4 The viscosity of aqueous solutions containing SAE-CD were measured using a cone and plate viscometer. A Brookfield Programmable DV-III+ Rheometer, CPE-40 cone and CPE 40Y plate
  • EXAMPLE 6 Preparation of an inhalable solution containing budesonide.
  • a buffer solution containing 3mM Citrate Buffer and 82mM NaCl at pH 4.45 is prepared. -12.5 grams of CAP ⁇ SOL was placed into a 250 ml volumetric flask. -62.5 mg of budesonide was placed into the same flask. Flask was made to volume with the 3mM mecanicte buffer/82mM NaCl solution. The flask was well-mixed on a vortexer for 10 minutes and sonicated for 10 minutes. The flask was stirred over weekend with magnetic stirrer.
  • EXAMPLE 7 Preparation of an inhalable solution containing budesonide. Approximately 5 grams of CAP ⁇ SOL was placed into a 100 mL volumetric flask. -26.3 mg of budesonide was placed into the same flask. The flask was made to volume with the 3mM citrate buffer/82mM NaCl solution. The mixture was well-mixed on a vortexer for 10 minutes and sonicated for 10 minutes. The mixture was stirred overnight with a magnetic stirrer. Stirring was stopped after -16 hours and flask was revortexed and resonicated again for 10 minutes each. The solution was filtered through 0.22 ⁇ m Durapore Millex-GV Millipore syringe filter unit. The first 5 drops were discarded before filter rest of solution into an amber glass jar with a Teflon-lined screw cap. Sample was analyzed to be 233 ⁇ g budesonide/ml.
  • EXAMPLE 8 Preparation of an inhalable solution containing budesonide. The procedure of Example 7 was followed except that 12.5 g of CAPTISOL, 62.5 mg of budesonide and about 250 ml of buffer were used. Sufficient disodium EDTA was added to prepare a solution having an EDTA concentration of about 0.01 or 0.05 % wt/v EDTA.
  • EXAMPLE 9 Preparation of a solution containing SAE-CD and budesonide as prepared from a PULMICORT RESPULES suspension.
  • Method A To the contents of one or more containers of the Pulmicort Respules (nominally 2 mL of the suspension), about 50 mg (corrected for water content) of CAPTISOL was added per mL of Respule and mixed or shaken well for several minutes. After standing from about 30 minutes to several hours, the solution was used as is for in vitro characterization.
  • the PULMICORT RESPULE (suspension) also contains the following in active ingredients per the label: citric acid, sodium citrate, sodium chloride, disodium EDTA and polysorbate 80.
  • Method B Weigh approximately 200 mg amounts of CAPTISOL (corrected for water content) into 2-dram amber vials. Into each vial containing the weighed amount of CAPTISOL empty the contents of two Pulmicort Respules containers (0.5 mg/2 mL, Lot # 308016 Feb05) by gently squeezing the deformable plastic container to the last possible drop. The Respules were previously swirled to re-suspend the budesonide particles.
  • the vials are screw capped, mixed vigorously by vortex and then foil wrapped.
  • the material can be kept refrigerated until use.
  • the inhalable liquid composition prepared according to any of these methods can be used in any known nebulizer. By converting the suspension to a liquid, an improvement in delivery of budesonide (a corticosteroid) is observed.
  • EXAMPLE 11 Clarity of solutions was determined by visual inspection or insfrumentally. A clear solution is at least clear by visual inspection with the unaided eye.
  • EXAMPLE 12 The following method was used to determine the performance of nebulization compositions emitted from a nebulizer according to FIGS. 10a- 10b. Two ml of the test CD solution or Pulmicort suspension was accurately pipetted by volumetric pipettes into a clean nebulizer cup prior to starting each experiment. The test nebulizer was assembled and charged with the test inhalation solution or suspension according to the manufacturer instructions.
  • the end of the mouthpiece was placed at a height of approximately 18 cm from the platform of the MALVERN MASTERSIZER to the middle point of tip of the nebulizer mouthpiece.
  • a vacuum source was positioned opposite the mouthpiece approximately 6 cm away to scavenge aerosol after sizing.
  • the distance between the mouthpiece and the detector was approximately 8 cm.
  • the center of the mouthpiece was level with the laser beam (or adjusted as appropriate, depending on the individual design of each nebulizer).
  • the laser passed through the center of the emitted cloud when the nebulizer was running. Measurements were manually started 15 seconds into nebulization. Data collection started when beam obscuration reached 10% and was averaged over 15,000 sweeps (30 seconds).
  • Cifrate buffers (50mM) at each pH value were prepared by mixing differing portions of 50mM citric acid and 50mM sodium citrate (tribasic, dihydrate) solutions.
  • the budesonide was dissolved first in 100% ethyl alcohol. An aliquot of the ethanol/budesonide solution was then added drop-wise with stirring to each buffer solution. The theoretical budesonide concenfration was 100 ⁇ g/mL with a final ethanolic content of 5% in each buffer. All solution preps and procedures involving budesonide were done in a darkened room under red light.
  • both buffer solutions were filtered through Millipore Millex-GV 0.22 ⁇ m syringe filters to remove any solid that had precipitated (no significant amounts observed) from the solutions.
  • the final budesonide concenfration was about 50 ⁇ g/mL.
  • Both the pH 4 and 6 solutions were split in two, and solid SBE7- ⁇ -CD was added to one of the portions to create solutions with and without 1% w/v SBE7- ⁇ -CD at each pH.
  • Each solution was aliquoted into individual amber vials. They were then placed in ovens at 60 °C and 80 °C. Sample vials were removed from the ovens and analyzed by HPLC at 0, 96, 164, and 288 hours. The HPLC assay conditions are summarized below.
  • EXAMPLE 14 Preparation and use of a combination solution containing SAE-CD. budesonide, and albuterol sulfate. A budesonide solution is prepared per EXAMPLE 9 (mixing SAE-CD with the
  • PULMICORT RESPULES suspension and added to 3 ml of a solution containing 2.5 mg albuterol (The World Health Organization recommended name for albuterol base is salbutamol) provided as albuterol sulfate.
  • the albuterol solution is commercially available prediluted and sold under the name PROVENTIL ® Inhalation Solution, 0.083%, or prepared from a commercially available concentrate 0.5% (sold under the names: PROVENTIL ® Solution for inhalation and VENTOLIN ® Inhalation Solution).
  • the initial dosing should be based upon body weight (0.1 to 0.15 mg/kg per dose), with subsequent dosing titrated to achieve the desired clinical response.
  • Dosing should not exceed 2.5 mg three to four times daily by nebulization.
  • the appropriate volume of the 0.5% inhalation solution should be diluted in sterile normal saline solution to a total volume of 3 mL prior to administration via nebulization.
  • 0.5 mL of the concentrate is diluted to 3 mL with sterile normal saline.
  • the albuterol aqueous solutions also contain benzalkonium chloride; and sulfuric acid is used to adjust the pH to between 3 and 5.
  • an aqueous solution of an appropriate sfrength of albuterol may be prepared from albuterol sulfate, USP with or without the added preservative benzalkonium chloride and pH adjustment using sulfuric acid may also be unnecessary when combining with the corticosteroid solution.
  • the volume containing the appropriate dose of corticosteroid may be decreased four-fold as described in the following example allowing the total volume to be less and the time of administration to diminish accordingly.
  • citric acid Approximately 62.5 mg was dissolved in and brought to volume with water in one 100 ml volumetric flask. Approximately 87.7 mg of sodium turite was dissolved in and brought to volume with water in another 100 mL volumetric flask. In a beaker the sodium mecanicte solution was added to the citric acid solution until the pH was approximately 4.5. Approximately 10.4 mg of budesonide and 1247.4 mg of Captisol were ground together with a mortar and pestle and fransferred to a 10 mL flask. Buffer solution was added, and the mixture was vortexed, sonicated and an additional 1.4 mg budesonide added.
  • the solution was filtered through a 0.22 ⁇ m Durapore Millex-GV Millipore syringe filter unit.
  • the resulting budesonide concentration was -1 mg/ml Approximately 0.5 ml of the budesonide solution was added to a unit dose of either Proventil (2.5 mg/3 mL) or Xopenex (1.25 mg/3 mL) thereby forming the combination clear liquid dosage form of the invention.
  • the resulting mixture remained essentially clear for a period of at least 17 days at ambient room conditions protected from light.
  • EXAMPLE 16 Preparation and use of a combination solution containing SAE-CD, budesonide, and formoterol (FORADIL® (formoterol fumarate inhalation powder)).
  • the contents of the vial were vortexed to dissolve the solids present.
  • the budesonide concentrate was prepared as described in the previous example to provide a concentration of -1 mg/mL.
  • the purpose of the study was to determine, by gamma scintigraphy, the infra-pulmonary deposition of radiolabeled budesonide following nebulization of a budesonide suspension (Pulmicort Respules ® , Asfra Zeneca, reference formulation) and a Captisol ® -Enabled budesonide solution (test formulation) in healthy male volunteers. Dosing was conducted using a Pari LC Plus air-jet nebulizer. The use of gamma scintigraphy in conjunction with radiolabeled study drug and/or vehicle is the standard technique for the quantitative assessment of pulmonary deposition and clearance of inhaled drugs and/or vehicle.
  • the study dosage forms consisted of: 1) lmg Budesonide as 2mL x 0.5mg/mL
  • Pulmicort Respules ® or 2) 1 mg Budesonide as 2mL x 0.5mg/mL Pulmicort Respules to which 7.5% w/v Captisol ® has been added.
  • Each subject received each of four study administrations of radiolabeled Budesonide in a non-randomized manner.
  • a non-randomized design was utilized for this study since the reference formulation (Pulmicort Respule ® ) must be administered first to all subjects in order to determine the time to sputter (TTS).
  • TTS time to sputter
  • the TTS differed between subjects.
  • the dose administered was controlled by the length of administration, expressed as a fraction of the time to sputter determined following administration of the reference formulation (i.e.
  • One aspect of the method and dosage form of the invention thus provides an improved method of administering a corticosteroid suspension-based unit dose, the method comprising the step of adding a sufficient amount of SAE-CD to convert the suspension to a clear solution and then administering the clear solution to a subject.
  • the method of the invention provides increased rate of administration as well as increased total pulmonary delivery of the corticosteroid as compared to the initial unit dose suspension formulation.
  • EXAMPLE 18 Comparative evaluation of various forms of SAE-CD in the solubilization of corticosteroid derivatives .
  • BDP, B17P and B21P were obtained from Hovione.
  • Beclomethasone was obtained from Specfrum Chemicals.
  • CAPTISOL, SBE(3.4) ⁇ -CD, SBE(5.23) ⁇ -CD and SBE(6.1) ⁇ -CD were provided by CyDex, Inc.
  • Beclomethasone forms were weighed in amounts in excess of the anticipated solubilites directly into 2-dram teflon-lined screw-capped vials. These amounts typically provided approximately 6 mg/mL of solids. Each vial then received 2 mL of the appropriate CD solution. The vials were vortexed and sonicated for about 10 minutes to aid in wetting the solids with the fluid. The vials were then wrapped in aluminum foil to protect from light and placed on a lab quake for equilibration. The vials were visually inspected periodically to assure that the solids were adequately being wetted and in contact with the fluid. The time points for sampling were at 24 hrs for all samples and 72 hours for BDP only.
  • Solutions of SBE(6.1) ⁇ -CD were prepared at 0.04, 0.08, and 0.1M and solutions of SBE (5.23) ⁇ -CD were prepared at only 0.04 and 0.08M.
  • Beclomethasone dipropionate was weighed in amounts in excess of the anticipated solubilities directly into 2-dram teflon-lined screw-capped vials. These amounts typically provided approximately 2 mg/mL of solids.
  • the vials were vortexed and sonicated for about 10 minutes to aid in wetting the solids with the fluid.
  • the vials were then wrapped in aluminum foil to protect from light and placed on a lab quake for a five-day equilibration.
  • the removed supernatant was then filtered using the Durapore PVDF 0.22 ⁇ m syringe filter (discarded first few drops), and diluted with the mobile phase to an appropriate concenfration within the standard curve.
  • the samples were then analyzed by HPLC to determine concentration of solubilized corticosteroid.
  • EXAMPLE 19 Preparation and use of a combination solution containing SAE-CD, budesonide, and formoterol fumarate.
  • Formoterol fumarate dry powder is blended with Captisol dry powder which are both sized appropriately to provide for content uniformity at a weight ratio of 12 meg formoterol fumarate/100 mg Captisol.
  • An amount of powder blend corresponding to a unit dose of formoterol fumarate is placed in a suitable unit dose container such as a HPMC capsule for later use or is added directly to a unit dose of Pulmicort Respules budesonide inhalation suspension (500 meg / 2 mL), then mixed to achieve dissolution of all solids (a clear solution) and placed in the nebulizer reservoir for administration.
  • a suitable unit dose container such as a HPMC capsule for later use or is added directly to a unit dose of Pulmicort Respules budesonide inhalation suspension (500 meg / 2 mL), then mixed to achieve dissolution of all solids (a clear solution) and placed in the nebulizer reservoir for administration.
  • EXAMPLE 20 Preparation and use of a combination solution containing SAE-CD, budesonide, and ipratropium bromide.
  • a budesonide solution is prepared as per EXAMPLE 9 and added to a ipratropium bromide solution that is commercially available and sold under the name ATROVENT® Inhalation Solution Unit Dose.
  • ATROVENT® (ipratropium bromide) Inhalation solution is 500 meg (1 unit dose Vial) administered three to four times a day by oral inhalation, with doses 6 to 8 hours apart.
  • ATROVENT® inhalation solution unit dose Vials contain 500 meg ipatropium bromide anhydrous in 2.5 ml sterile , preservative-free, isotonic saline solution, pH-adjusted to 3.4 (3 to 4) with hydrochloric acid. Furthermore the volume containing the appropriate dose of corticosteroid may be decreased four-fold as described in the above example (budesonide concentrate - 1 mg/mL) allowing the total volume to be less and the time of administration to diminish accordingly.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Nanotechnology (AREA)
  • Otolaryngology (AREA)
  • Emergency Medicine (AREA)
  • Rheumatology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une formulation liquide sous forme unitaire inhalable. Cette formulation contient du SAE-CD et un corticostéroïde, elle est conçue pour être administrée à un sujet par nébulisation au moyen d'un nébuliseur usuel, elle peut être comprise dans un kit, elle est administrée sous forme de solution aqueuse ou de composition concentrée, elle est utilisée dans un système de nébulisation perfectionné pour l'administration de corticostéroïde par inhalation. Le SAE-CD présent dans la formulation augmente de manière notable la stabilité chimique du corticostéroïde tel que le budésonide. La présente invention porte également sur une méthode pour administrer cette formulation par inhalation, ladite formulation pouvant également être administrée au moyen d'un appareil classique d'administration nasale. La formulation est obtenue par mélange d'un SAE-CD, sous forme solide ou liquide (dissoute), avec une formulation inhalable en doses unitaires à base d'une suspension.
EP05704919A 2003-12-31 2005-01-03 Formulation pour inhalation contenant du sulfoalkyle ether cyclodextrine et un corticosteroide, a base d'une suspension en doses unitaires Withdrawn EP1718276A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US53362803P 2003-12-31 2003-12-31
PCT/US2005/000084 WO2005065651A1 (fr) 2003-12-31 2005-01-03 Formulation pour inhalation contenant du sulfoalkyle ether cyclodextrine et un corticosteroide, a base d'une suspension en doses unitaires

Publications (2)

Publication Number Publication Date
EP1718276A2 true EP1718276A2 (fr) 2006-11-08
EP1718276A4 EP1718276A4 (fr) 2008-07-23

Family

ID=34794240

Family Applications (4)

Application Number Title Priority Date Filing Date
EP17161913.3A Withdrawn EP3238708A1 (fr) 2003-12-31 2004-12-31 Formulation pour inhalation à base de cyclodextrine et de corticostéroïde
EP05704917.3A Active EP1732512B1 (fr) 2003-12-31 2004-12-31 Formulation d'inhalation contenant une sulfoalkyl ether cyclodextrine et un corticosteroide
EP05704920A Withdrawn EP1729724A4 (fr) 2003-12-31 2004-12-31 Formulation inhalable contenant de l'ether sulfoalkyle g-cyclodextrine et un corticosteroide
EP05704919A Withdrawn EP1718276A4 (fr) 2003-12-31 2005-01-03 Formulation pour inhalation contenant du sulfoalkyle ether cyclodextrine et un corticosteroide, a base d'une suspension en doses unitaires

Family Applications Before (3)

Application Number Title Priority Date Filing Date
EP17161913.3A Withdrawn EP3238708A1 (fr) 2003-12-31 2004-12-31 Formulation pour inhalation à base de cyclodextrine et de corticostéroïde
EP05704917.3A Active EP1732512B1 (fr) 2003-12-31 2004-12-31 Formulation d'inhalation contenant une sulfoalkyl ether cyclodextrine et un corticosteroide
EP05704920A Withdrawn EP1729724A4 (fr) 2003-12-31 2004-12-31 Formulation inhalable contenant de l'ether sulfoalkyle g-cyclodextrine et un corticosteroide

Country Status (15)

Country Link
EP (4) EP3238708A1 (fr)
JP (6) JP2007517067A (fr)
KR (3) KR20070007075A (fr)
CN (3) CN1921830A (fr)
AU (3) AU2004311478A1 (fr)
BR (3) BRPI0418276B8 (fr)
CA (3) CA2552641A1 (fr)
DK (1) DK1732512T3 (fr)
HU (1) HUE032527T2 (fr)
IL (6) IL176577A0 (fr)
MX (2) MXPA06007581A (fr)
NZ (1) NZ548225A (fr)
PT (1) PT1732512T (fr)
RU (3) RU2006127432A (fr)
WO (3) WO2005065649A1 (fr)

Families Citing this family (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070020299A1 (en) * 2003-12-31 2007-01-25 Pipkin James D Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
RU2006141358A (ru) 2004-04-23 2008-05-27 Сайдекс, Инк. (Us) Препаративная форма для ингалятора сухого порошка, содержащая простой сульфоалкиловый эфир циклодекстрина
DE102005041860A1 (de) * 2005-09-02 2007-03-08 Schering Ag Nanopartikulärer Einschluss- und Ladungskomplex für pharmazeutische Formulierungen
DK2581078T3 (en) * 2005-10-26 2015-03-02 Cydex Pharmaceuticals Inc Sulfoalkylætercyclodekstrinsammensætninger and processes for the preparation thereof
US7629331B2 (en) 2005-10-26 2009-12-08 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
PL1948678T3 (pl) 2005-11-09 2013-09-30 Onyx Therapeutics Inc Związki do hamowania enzymów
BRPI0618653A2 (pt) * 2005-11-15 2011-09-06 Baxter Int composições compreendendo inibidores da lipoxigenase e ciclodextrina
EP1959953A2 (fr) * 2005-12-02 2008-08-27 Alembic Limited Composition pharmaceutique stabilisée de pramipexole et son procédé de préparation
EP1971348A2 (fr) * 2005-12-20 2008-09-24 Tika Läkemedel AB Systèmes et méthodes d'administration de corticostéroïdes à dépôt pulmonaire accru
AU2006329042B2 (en) * 2005-12-21 2012-02-02 Meda Pharma Gmbh & Co Kg Combination of anticholinergics, glucocorticoids, beta2-agonists, PDE4 inhibitor and antileukotriene for the treatment of inflammatory diseases
TR201807714T4 (tr) * 2006-02-10 2018-06-21 Pari Pharma Gmbh İnhalasyon tedavisine yönelik nebülize antibiyotikler.
JP2009526858A (ja) * 2006-02-15 2009-07-23 ティカ レーケメデル アーベー コルチコステロイド溶液を製造する方法
ES2913483T3 (es) * 2006-04-03 2022-06-02 Ceva Animal Health Pty Ltd Formulaciones estabilizadas de polisulfato de pentosano (PPS)
DK2041158T3 (da) 2006-06-19 2013-06-24 Onyx Therapeutics Inc Peptid-epoxidketoner til proteasom inhibering
WO2009003199A1 (fr) * 2007-06-28 2008-12-31 Cydex Pharmaceuticals, Inc. Administration nasale et ophtalmique de solutions aqueuses de corticostéroïdes
EP1894568A1 (fr) * 2006-08-31 2008-03-05 Novartis AG Composées pharmaceutiques destinées au traitement des maladies inflammatoires ou obstructives des bronches
EP1894559A1 (fr) * 2006-09-01 2008-03-05 PARI Pharma GmbH Stabilisation de stéroides destinées à être inhalées
US20090325917A1 (en) * 2006-10-19 2009-12-31 Cipla Limited Pharmaceutical Compositions and Nasal Spray Incorporating Anhydrous Mometasone Furoate
WO2008065142A1 (fr) * 2006-11-29 2008-06-05 N.V. Organon Solution stabilisée de rocuronium comprenant un dérivé de l'éther sulfoalkylique de bêta-cyclodextrine
KR20150041173A (ko) 2007-04-27 2015-04-15 사이덱스 파마슈티칼스, 인크. 클로피도그렐 및 설포알킬 에테르 사이클로덱스트린을 함유하는 제형 및 사용 방법
KR20150131405A (ko) 2007-10-04 2015-11-24 오닉스 세라퓨틱스, 인크. 결정형 펩티드 에폭시 케톤 프로테아제 저해제 및 아미노산 케토-에폭시드의 합성
MX2010005100A (es) * 2007-11-09 2010-11-12 Map Pharmaceuticals Inc Metodos para administrar formulaciones de corticoesteroides.
EP2349313A4 (fr) 2008-10-21 2012-08-29 Onyx Therapeutics Inc Thérapie de combinaison avec des peptides époxycétones
US10463677B2 (en) 2008-11-07 2019-11-05 Cydex Pharmaceuticals, Inc. Composition containing sulfoalkyl ether cyclodextrin and latanoprost
US20100196483A1 (en) * 2009-02-04 2010-08-05 Activaero Gmbh Research & Development Method for treatmentof severe and uncontrollable asthma
EP2400987B1 (fr) * 2009-02-25 2014-09-03 Supratek Pharma, Inc. Compositions de cyclopolysaccharide et de bendamustine
AR075899A1 (es) 2009-03-20 2011-05-04 Onyx Therapeutics Inc Tripeptidos epoxicetonas cristalinos inhibidores de proteasa
KR101743591B1 (ko) 2009-05-13 2017-06-20 사이덱스 파마슈티칼스, 인크. 프라수그렐 및 사이클로덱스트린 유도체를 포함하는 약학 조성물 및 그의 제조 및 사용 방법
RU2580315C3 (ru) 2009-05-29 2021-06-18 Перл Терапьютикс, Инк. Композиции для респираторной доставки активных веществ и связанные с ними способы и системы
MX343193B (es) * 2009-06-18 2016-10-26 Allergan Inc Administracion segura de desmopresina.
US8853147B2 (en) 2009-11-13 2014-10-07 Onyx Therapeutics, Inc. Use of peptide epoxyketones for metastasis suppression
MX2012010017A (es) 2010-03-01 2012-10-01 Onyx Therapeutics Inc Compuestos de para la inhibicion de inmunoproteasomas.
RU2445119C2 (ru) * 2010-05-25 2012-03-20 Сергей Викторович Чепур Фармацевтическая композиция и способ ее ингаляционного введения
WO2012146642A1 (fr) * 2011-04-26 2012-11-01 Activaero Gmbh Administration d'iloprost comme bolus sous forme d'aérosol
CN102188371B (zh) * 2011-05-11 2013-01-23 台州职业技术学院 一种环索奈德纳米粒水溶液及其制备方法
CN102973574A (zh) * 2011-09-02 2013-03-20 北京燕锋晨医药技术发展有限公司 一种用于治疗哮喘的药物组合物及制备方法
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
CN104411334A (zh) * 2012-05-08 2015-03-11 欧尼斯治疗公司 用于配制肽蛋白酶体抑制剂的环糊精络合法
DK3517541T3 (da) 2012-05-08 2020-09-07 Nicox Ophthalmics Inc Polymorf form af fluticasonpropionat
RU2504382C1 (ru) * 2012-06-13 2014-01-20 Шолекс Девелопмент Гмбх Ингаляционный препарат для лечения бронхиальной астмы и хронической обструктивной болезни легких и способ его получения
US20140105921A1 (en) 2012-07-09 2014-04-17 Onyx Therapeutics, Inc. Prodrugs of Peptide Epoxy Ketone Protease Inhibitors
RU2506080C1 (ru) * 2012-09-25 2014-02-10 Государственное бюджетное образовательное учреждение высшего профессионального образования "Нижегородская государственная медицинская академия" Министерства здравоохранения и социального развития Российской Федерации (ГБОУ ВПО НижГМА Минздравсоцразвития России) Способ лечения и профилактики осложнений в полости рта, вызванных приемом ингаляционных гормональных препаратов у больных бронхиальной астмой
RU2493827C1 (ru) * 2012-10-03 2013-09-27 Шолекс Девелопмент Гмбх Стабильный комбинированный раствор фенотерола гидробромида и ипратропия бромида
BR112015010601B1 (pt) * 2012-11-09 2022-07-19 Civitas Therapeutics, Inc. Composição farmacêutica e uso da composição
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
CN106413759B (zh) * 2014-03-28 2022-02-22 列日大学 用于治疗和预防肺部炎症的包含环糊精和布地奈德衍生物的组合物
EP2923702A1 (fr) * 2014-03-28 2015-09-30 Universite De Liege Composition de cyclodextrine avec des dérivés de budésonide pour le traitement et la prévention d'une maladie inflammatoire pulmonaire
AU2016218976B2 (en) * 2015-02-13 2021-04-01 Cumberland Pharmaceuticals, Inc. Milrinone composition and method for administering same
MA45276A (fr) * 2015-06-18 2018-04-25 Sage Therapeutics Inc Solutions de stéroïdes neuroactifs et leurs méthodes d'utilisation
WO2017193110A1 (fr) * 2016-05-06 2017-11-09 Stites Adam Compositions cannabinoïdes pour nébuliseur à pulvérisation sublinguale
KR20220119529A (ko) 2016-06-02 2022-08-29 애브비 인코포레이티드 글루코코르티코이드 수용체 작용제 및 이의 면역접합체
WO2019106609A1 (fr) 2017-12-01 2019-06-06 Abbvie Inc. Agoniste du récepteur des glucocorticoïdes et immunoconjugués de celui-ci
WO2019147154A1 (fr) * 2018-01-23 2019-08-01 Александр Григорьевич ЧУЧАЛИН Composition pharmaceutique (variantes) utilisation de la composition pharmaceutique (variantes)
US11007185B2 (en) 2019-08-01 2021-05-18 Incarda Therapeutics, Inc. Antiarrhythmic formulation
CN115811978B (zh) * 2020-06-23 2024-04-26 广州谷森制药有限公司 包含奥达特罗、噻托溴铵和布地奈德的药物组合物的制备
CN115835885A (zh) * 2020-06-23 2023-03-21 广州谷森制药有限公司 包含奥达特罗和布地奈德的药物组合物的制备
CN113018280A (zh) * 2021-03-01 2021-06-25 石家庄四药有限公司 一种异丙托溴铵吸入用溶液制剂及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3008875A (en) * 1960-01-08 1961-11-14 Upjohn Co Neomycin and mirystyl-gamma-picolinium halide compositions
US3219533A (en) * 1962-11-29 1965-11-23 Merck & Co Inc Aerosol solid medicament in propellant and low-level ethanol avoiding higher-level ethanol dispersed-solid reflocculation
US6358935B1 (en) * 1998-09-02 2002-03-19 Allergan Sales, Inc. Preserved cyclodextrin-containing compositions
US20020198174A1 (en) * 2001-05-07 2002-12-26 Allergan Sales, Inc. Disinfecting and solubilizing steroid compositions

Family Cites Families (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3426011A (en) 1967-02-13 1969-02-04 Corn Products Co Cyclodextrins with anionic properties
US6407079B1 (en) 1985-07-03 2002-06-18 Janssen Pharmaceutica N.V. Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
US5002935A (en) 1987-12-30 1991-03-26 University Of Florida Improvements in redox systems for brain-targeted drug delivery
KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
US5376645A (en) * 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
US5977070A (en) 1992-07-14 1999-11-02 Piazza; Christin Teresa Pharmaceutical compositions for the nasal delivery of compounds useful for the treatment of osteoporosis
US5472954A (en) 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
US5324718A (en) 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US5510339A (en) 1993-02-02 1996-04-23 Mayo Foundation For Medical Education And Research Method for the treatment of bronchial asthma by administration of topical anesthetics
US5525623A (en) 1993-03-12 1996-06-11 Arris Pharmaceutical Corporation Compositions and methods for the treatment of immunomediated inflammatory disorders
WO1994022445A2 (fr) 1993-03-26 1994-10-13 Merkus Franciscus W H M Compositions pharmaceutiques pour l'administration intranasale de dihydroergotamine, d'apomorphine et de morphine
BE1007402A5 (nl) 1993-03-26 1995-06-06 Adir Nasale farmaceutische preparaten met progestagene stof.
TW385308B (en) 1994-03-04 2000-03-21 Merck & Co Inc Prodrugs of morpholine tachykinin receptor antagonists
EP1283035A3 (fr) 1994-12-22 2003-03-19 AstraZeneca AB Préparation thérapeutique à inhaler contenant de l' hormone parathyroidienne
DE4446891A1 (de) * 1994-12-27 1996-07-04 Falk Pharma Gmbh Stabile wäßrige Budesonid-Lösung
US5840713A (en) * 1995-04-03 1998-11-24 Weisz; Paul B. Therapy for tissue membrane insufficiency
US5576645A (en) * 1995-06-05 1996-11-19 Hughes Aircraft Company Sample and hold flip-flop for CMOS logic
US5654276A (en) 1995-06-07 1997-08-05 Affymax Technologies N.V. Peptides and compounds that bind to the IL-5 receptor
US5683983A (en) 1995-06-07 1997-11-04 Glaxo Group Limited Peptides and compounds that bind to the IL-5 receptor
US5668110A (en) 1995-06-07 1997-09-16 Affymax Technologies N.V. Peptides and compounds that bind to the IL-5 receptor
US5677280A (en) 1995-06-07 1997-10-14 Glaxo Group Limited Peptides and compounds that bind to the IL-5 receptor
US5750549A (en) 1996-10-15 1998-05-12 Merck & Co., Inc. Cycloalkyl tachykinin receptor antagonists
GB9625843D0 (en) 1996-12-12 1997-01-29 Merck & Co Inc Phenyl spiroethercycloalkyl tachykinn receptor antagonists
US5929094A (en) 1996-10-25 1999-07-27 Merck & Co., Inc. Heteroaryl spiroethercycloalkyl tachykinin receptor antagonists
JP2001503406A (ja) * 1996-10-28 2001-03-13 ファーマーク、ニーダーランド、ベスローテン、フェンノートシャップ 医薬組成物
US6071910A (en) 1996-12-05 2000-06-06 Mayo Foundation For Medical Education And Research Use of agents to treat eosinophil-associated pathologies
US5837713A (en) 1997-02-26 1998-11-17 Mayo Foundation For Medical Education And Research Treatment of eosinophil-associated pathologies by administration of topical anesthetics and glucocorticoids
US6046177A (en) * 1997-05-05 2000-04-04 Cydex, Inc. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations
PT889056E (pt) 1997-07-01 2006-07-31 Pfizer Prod Inc Processo para produzir um,a ciclodextrina.
JP2002509119A (ja) 1998-01-13 2002-03-26 アストラゼネカ ユーケイ リミテッド ドーパミン（Ｄ２）レセプターアゴニスト活性を有する化合物およびβ２−アドレナリンレセプターアゴニスト活性を有する化合物（Ｂ）を含有する薬学的組成物
CA2320772A1 (fr) 1998-02-23 1999-08-26 Cyclops, Ehf. Complexes de cyclodextrine extremement energetiques
US6241969B1 (en) 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
US6509323B1 (en) 1998-07-01 2003-01-21 California Institute Of Technology Linear cyclodextrin copolymers
WO2000047203A1 (fr) 1999-02-12 2000-08-17 Mqs, Inc. Formulation et systeme pour administration intra-orale de principes actifs
FR2789685B1 (fr) 1999-02-15 2001-05-04 Univ Lille Sciences Tech Procede de fabrication de polymeres solubles et insolubles a base de cyclodextrine(s) et/ou de derives de cyclodextrine(s) et polymeres solubles a base de cyclodextrine(s) et/ou de derives de cyclodextrine(s)
US6136603A (en) 1999-03-26 2000-10-24 Isis Pharmaceuticals Inc. Antisense modulation of interleukin-5 signal transduction
ES2343124T3 (es) 1999-10-29 2010-07-23 Novartis Ag Composiciones de polvo seco con dispersabilidad mejorada.
US6479467B1 (en) 1999-12-16 2002-11-12 Eastman Chemical Company Cyclodextrin ethers
RU2180217C2 (ru) 2000-03-21 2002-03-10 Закрытое акционерное общество "Пульмомед" Стабильный водный раствор противовоспалительного действия, содержащий будесонид
JP2003532757A (ja) 2000-05-11 2003-11-05 イーストマン ケミカル カンパニー アシル化シクロデキストリン：ゲスト分子包接錯体
JP2005503446A (ja) 2001-01-11 2005-02-03 イーストマン ケミカル カンパニー シクロデキストリンスルホネート、ゲスト包接錯体、その製造方法及び関連物質
WO2002064635A1 (fr) 2001-02-14 2002-08-22 Akzo Nobel N.V. Derives de cyclodextrine 2-alkylee : agents d'inversion du blocage neuromusculaire d'origine medicamenteuse
US7034013B2 (en) * 2001-03-20 2006-04-25 Cydex, Inc. Formulations containing propofol and a sulfoalkyl ether cyclodextrin
US20030055026A1 (en) * 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
WO2004032862A2 (fr) 2002-10-09 2004-04-22 Insert Therapeutics, Inc. Materiaux et compositions a base de cyclodextrine, et utilisations correspondantes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3008875A (en) * 1960-01-08 1961-11-14 Upjohn Co Neomycin and mirystyl-gamma-picolinium halide compositions
US3219533A (en) * 1962-11-29 1965-11-23 Merck & Co Inc Aerosol solid medicament in propellant and low-level ethanol avoiding higher-level ethanol dispersed-solid reflocculation
US6358935B1 (en) * 1998-09-02 2002-03-19 Allergan Sales, Inc. Preserved cyclodextrin-containing compositions
US20020198174A1 (en) * 2001-05-07 2002-12-26 Allergan Sales, Inc. Disinfecting and solubilizing steroid compositions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ASHWINKUMAR C. JAIN ET AL.: "hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether beta-cyclodextrins (SBE) and danazol-SBE inclusion complexes" INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 212, 2001, pages 177-186, XP008092986 *
R. WILLIAMS ET AL.: "study of solubility of steroids in hydrofluoroalkanes propellants" DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 25, no. 12, 1999, pages 1227-1234, XP008093135 *
See also references of WO2005065651A1 *

Also Published As

Publication number Publication date
IL176576A0 (en) 2006-10-31
CA2552641A1 (fr) 2005-07-21
EP1732512A2 (fr) 2006-12-20
EP1718276A4 (fr) 2008-07-23
KR20070005586A (ko) 2007-01-10
RU2388462C2 (ru) 2010-05-10
IL225946A0 (en) 2013-06-27
RU2006127467A (ru) 2008-02-10
WO2005065435A3 (fr) 2005-09-01
EP3238708A1 (fr) 2017-11-01
BRPI0418276B8 (pt) 2021-05-25
HUE032527T2 (en) 2017-09-28
WO2005065435A2 (fr) 2005-07-21
DK1732512T3 (en) 2017-07-10
CA2551749A1 (fr) 2005-07-21
RU2006127432A (ru) 2008-02-10
IL176575A0 (en) 2006-10-31
WO2005065651A1 (fr) 2005-07-21
JP2016172774A (ja) 2016-09-29
BRPI0418276A (pt) 2007-05-02
BRPI0418276B1 (pt) 2017-02-14
JP5782413B2 (ja) 2015-09-24
AU2004312095A1 (en) 2005-07-21
CN1976679B (zh) 2011-08-31
JP2007517067A (ja) 2007-06-28
CN1921834A (zh) 2007-02-28
CA2551749C (fr) 2014-02-11
EP1729724A1 (fr) 2006-12-13
IL225946A (en) 2017-04-30
IL176577A0 (en) 2006-10-31
JP2007517068A (ja) 2007-06-28
JP2015129173A (ja) 2015-07-16
AU2004311478A1 (en) 2005-07-21
MXPA06007581A (es) 2007-03-09
RU2006127443A (ru) 2008-02-10
CN1921830A (zh) 2007-02-28
CN1976679A (zh) 2007-06-06
EP1732512B1 (fr) 2017-03-22
BRPI0418386A (pt) 2007-05-22
IL251496B (en) 2021-04-29
EP1732512A4 (fr) 2008-07-23
JP2012224648A (ja) 2012-11-15
AU2004312096A1 (en) 2005-07-21
MX348041B (es) 2017-05-25
IL251496A0 (en) 2017-05-29
WO2005065649A1 (fr) 2005-07-21
PT1732512T (pt) 2017-07-24
JP6186478B2 (ja) 2017-08-23
CA2551826A1 (fr) 2005-07-21
RU2390330C2 (ru) 2010-05-27
KR20070007075A (ko) 2007-01-12
NZ548225A (en) 2012-12-21
EP1729724A4 (fr) 2008-07-23
BRPI0418232A (pt) 2007-04-27
JP2007517069A (ja) 2007-06-28
KR20070007076A (ko) 2007-01-12

Similar Documents

Publication Publication Date Title
US10799599B2 (en) Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
JP6186478B2 (ja) スルホアルキルエーテルシクロデキストリンおよびコルチコステロイドを含む吸入製剤
US20110008325A1 (en) Inhalant Formulation Containing Sulfoalkyl Ether Cyclodextrin and Corticosteroid Prepared from a Unit Dose Suspension
US20070020298A1 (en) Inhalant formulation containing sulfoalkyl ether gamma-cyclodextrin and corticosteroid
AU2014227557B2 (en) Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
MXPA06007583A (en) Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid prepared from a unit dose suspension

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060629

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1090311

Country of ref document: HK

DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20080625

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/08 20060101AFI20080619BHEP

Ipc: A61K 47/48 20060101ALI20080619BHEP

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CYDEX PHARMACEUTICALS, INC.

17Q First examination report despatched

Effective date: 20081201

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090714

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1090311

Country of ref document: HK