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
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  • 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
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  • 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 and a corticosteroid, such as budesonide, by inhalation.
• 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)-l l ⁇ , 16 , 17, 21-tetrahydroxypregna-l, 4-diene-3, 20-dione cyclic 16, 17-acetal with butyraldehyde; C 2 5H 34 0 6 ; Mw: 430.5) is well known. It is provided commercially as a mixture of two isomers (22R and 22 S).
• 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, DE) under the trademarks ENTOCORT TM EC, PULMICORT RESPULES®, Rhinocort Aqua®, Rhinocort® Nasal Inhaler and Pulmicort Turbuhaler®, and under its generic name.
• 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.
• 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. For inhaled corticosteroids, 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.
• 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 corticodsteroid.
• 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. For patients with obstructive lung disease, all particles should ideally be no greater than 2 to 3 mem.
• a particle that is small 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.
• the micronized budesonide 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. Even so, efforts have been made to improve the nebulization of budesonide suspensions with ultrasonic nebulizers by using submicron-sized particles (Keller et al. in Respiratory Drug Delivery VIII (2002), 197-206). A suspension of nanoparticles (0.1-1.0 ⁇ m) of the corticosteroid might be used to increase the proportion of respirable particles as compared to a coarser suspension as in the PULMICORTTM suspension.
• O'Riordan (Respiratory Care (2002 Nov), 47(11), 1305-1313) states that drugs can be delivered by nebulization of either solutions or suspensions, but that in general, nebulization of a solution is preferred over that of a suspension. He states that ultrasonic nebulizers should not be used on suspensions and should be used only on solutions. O'Callaghan (Thorax, (1990), 45, 109-111), Storr et al. (Arch. Dis. Child (1986), 61, 270-273), and Webb et al. (Arch. Dis.
• 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. However, 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. (1994), 7(2), 135-145) reportedly succeeded in preparing a liposome formulation of budesonide and phosphatidylcholine derivatives. Solubilization of drugs by cyclodextrins and their derivatives is well known.
• 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.
• 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.
• 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 b .
• 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"; C.N. 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.
• SAE-CD is less suitable for solubilizing compounds than are HP- ⁇ -CD, DM- ⁇ -CD, ⁇ -CD or ⁇ -CD.
• the anionic sulfobutyl ether substituent dramatically improves the aqueous solubility of the parent cyclodextrin.
• CAPTISOL ® is a relatively new but known cyclodextrin
• 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.
• 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
• CAPTISOL ® degree of substitution-7
• SBE4- ⁇ -CD degree of substitution-4
• 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.
• M ⁇ ller et al. discloses the results of a study on the preparation of budesonide microparticles by an ASES(Aerosol Solvent Extraction System) supercritical carbon dioxide process for use in a dry powder inhaler.
• HP- ⁇ -CD is suggested as a carrier for a powder.
• M ⁇ ller et al. U.S. Patent No. 6,407,079) discloses pharmaceutical compositions containing HP- ⁇ -CD. They suggest that nasal administration of a solution containing the cyclodextrin is possible.
• 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.
• nebulized 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.
• the need continues to remain for a method of improving the administration, by nebulization, of a suspension-based unit dose formulation. 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 gamma- 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 is systemically absorbed following administration via inhalation. It is also eliminated from the lungs. 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 mometasone furoate, fluticasone propionate or budesonide, and SAE- ⁇ -CD, wherein the SAE- ⁇ -CD is present in an amount sufficient to dissolve and stabilize the corticosteroid during storage.
• corticosteroid such as mometasone furoate, fluticasone propionate or budesonide
• SAE- ⁇ -CD SAE- ⁇ -CD
• 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 added to the suspension and mixed therein, a sufficient amount of the corticosteroid is dissolved to form a liquid formulation for nebulization that should provide a greater corticosteroid output rate as compared to the formulation excluding the SAE- ⁇ -CD when administered under substantially the same conditions.
• the SAE- ⁇ -CD When compared to the SAE- ⁇ -CD, the SAE- ⁇ -CD solubilizes esterified and non-esterified corticosteroid better, thereby allowing one to prepare more concentrated solutions and resulting in faster delivery rate of drug due to the smaller volume of liquid being nebulized. Moreover, SAE- ⁇ -CD requires a lower amount of cyclodextrin than does SAE- ⁇ -CD to solubilize the same amount of drug, i.e. less mmoles of CD per mmole of drug, thereby resulting in less CD mass being delivered to lung for the same mass of drug delivered.
• the drug output rate of the formulation should be 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, may not have 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 the corticosteroid.
• 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% precipitated solid), or a clear solution.
• a nebulizer charged with a corticosteroid/ SAE- ⁇ -CD-containing solution should generate 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 and permit deeper lung penetration.
• 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 or sulfobutyl ether 7- ⁇ -CD, sulfobutyl ether 6- ⁇ -CD, sulfobutyl ether 4- ⁇ -CD, sulfobutyl ether 3 to 8- ⁇ -CD, or a sulfobutyl ether 5- ⁇ -CD
• 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 formulation by nebulization, the method comprising the step of adding SAE- ⁇ -CD to an aqueous corticosteroid-containing suspension formulation in an amount sufficient to solubilize the corticosteroid to form an inhalable aqueous corticosteroid-containing solution 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
• a corticosteroid either esterified or unesterified
• an aqueous liquid medium e.g., water soluble ⁇ -CD derivative, a corticosteroid (either esterified or 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 should be 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 surprisingly 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, reduced frequency of exacerbations and emergency room visits, 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
• the invention can be employed in a kit comprising SAE- ⁇ -CD, an aqueous carrier, and corticosteroid, wherein the kit is adapted for the preparation of a nebulization solution. Embodiments of the kit are detailed below.
• Figure 1 depicts a phase solubility graph of the concentration (molar) of cyclodextrin versus the concentration (molar) of budesonide for ⁇ -CD, ⁇ -CD, HP- ⁇ -CD, SBE5- ⁇ -CD, SBE7- -CD, and SBE7- ⁇ -CD in water.
• Figure 2 depicts a phase solubility diagram for fluticasone propionate in the presence of several different cyclodextrins.
• Figure 3 depicts a phase solubility diagram for mometasone furoate in the presence of several different cyclodextrins.
• Figure 4 depicts a phase solubility diagram for esterified and non-esterified fluticasone in the presence of SAE(5-6)- ⁇ -CD.
• Figure 5 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.
• HALOLITETM Profile Therapeutics Inc, Boston, MA
• RESPIMATTM Boehringer Ingelheim Ingelheim, 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, Buffalo, NY), ACORN- 1 and ACORN-II (Vital Signs, Inc, Totowa, New Jersey), AQUATOWERTM ( Medical Industries America, Adel, Iowa), AVA-NEB (Hudson Respiratory Care Incorporated, Temecula, California), CIRRUS (Intersurgical Incorporated, Liverpool, New York), DART (Professional Medical Products,
• 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
• 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:
• Ri, R , R 3 , R t , R 5 , Re, R 7 , R 8 and R are each, independently, -O- or a -0-(C 2 - C 6 alkylene)-S0 3 " group, wherein at least one of Ri to R 9 is independently a -0-(C 2 - C 6 alkylene)-S0 3 " group, preferably a -0-(CH 2 ) m S0 3 ⁇ group, wherein m is 2 to 6, preferably 2 to 4, (e.g.-OCH 2 CH 2 CH 2 S0 3 ⁇ or-OCH 2 CH 2 CH 2 CH 2 S0 3 ⁇ ); and
• Si, S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8 and S 9 are each, independently, a pharmaceutically 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 (Ci - C 6 )- alkylamines, piperidine, pyrazine, (Ci - C 6 )-alkanolamine and (C 4 - C 8 )-cycloalkanolamine.
• exemplary embodiments of the SAE- ⁇ -CD derivative of the invention include derivatives of the Formula II (SAEz- ⁇ -CD), wherein "z" ranges from 1 to 24 such as:
• SAE represents a sulfoalkyl ether substituent bound to a cyclodextrin
• U.S. Patent No. 3,426,011 to Parmerter et al. discloses anionic cyclodextrin derivatives having sulfoalkyl ether substituents.
• Lammers et al. (Reel. Trav. Chim. Pays- Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) disclose sulfoalkyl ether derivatized cyclodextrins.
• SAE- ⁇ -CD can be made according to the disclosures of Stella et al., Parmerter et al., Lammers et al. or Qu et al., and if processed to remove the major portion (>50%) of the underivatized parent cyclodextrin, used according to the present invention.
• the key aspect in the manufacture of SAE- ⁇ -CD is that the parent underivatized cyclodextrin must be ⁇ -CD.
• alkylene and alkyl as used herein (e.g., in the -0-(C 2 - C 6 - alkylene)S0 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.
• 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.
• the amount of each type of cyclodextrin derivative present can be varied as desired to provide a mixture having the desired properties.
• Exemplary SAE- ⁇ -CD derivatives include SBE3.4- ⁇ -CD, SBE4.2- ⁇ -CD, SBE4.9- ⁇ - CD, SBE5.2- ⁇ -CD, SBE6.1- ⁇ -CD, SBE7.5- ⁇ -CD, SBE7.8- ⁇ -CD, and SBE5- ⁇ -CD.
• 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. 3 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 useful for solubilizing corticosteroids, it is unexpectedly more useful at solubilizing esterified corticosteroids than are the corresponding SAE- ⁇ - CD and SAE- ⁇ -CD derivatives.
• the invention provides an inhalable formulation comprising esterified corticosteroid, SAE- ⁇ -CD and an aqueous carrier.
• SAE- ⁇ -CD is surprisingly even more effective at solubilizing unesterified corticosteroids as compared to esterified corticosteroids having the same core structure as depicted in FIGS. 2-5.
• SAE- ⁇ -CD is also much more effective at binding with a particular regioisomer of esterified corticosteroids than is SAE- ⁇ -CD or SAE- ⁇ -CD.
• the procedure set forth in 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 SBEz- ⁇ -CD, wherein z represents the average degree of substitution, derivatives and SBE- ⁇ -CD derivative with different forms of beclomethasone.
• complexed is meant “being part of a clathrate or inclusion complex with”, i.e., a complexed therapeutic agent is part of a clathrate or inclusion complex with a cyclodextrin derivative.
• major portion is meant at least about 50% by weight.
• 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, tetrazole, 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.
• the term 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, and 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 (Iowa).
• Other derivatized 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
• 6 ⁇ -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 in Cyclodextrins and Derivatives (Ed. Dominique Duchene, Editions de Sante, Paris, France, 1991).
• FIG. 1 depicts a molar phase solubility curve for budesonide with HP- ⁇ -CD, SBE7- ⁇ -CD, SBE5- ⁇ -CD, SBE7- ⁇ -CD, ⁇ -CD, and ⁇ -CD as compared to water.
• SAE- ⁇ -CD is superior to other SAE-CD derivatives, cyclodextrins and cyclodextrin derivatives at solubilizing budesonide.
• the 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- ⁇ -CD > SBE7- ⁇ -CD » SBE7- ⁇ -CD > HP- ⁇ - CD » ⁇ -CD .
• a 0.1 M concentration of SBE5- ⁇ -CD was able to solubilize a greater amount of budesonide than SBE7- ⁇ -CD or ⁇ -CD or HP- ⁇ -CD.
• SAE- CD-containing nebulizable formulations should 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 SAE-CD solutions can provide several advantages with respect to other cyclodextrins. The droplets leaving the nebulizer are of a more advantageous size and the SAE-CD solutions are nebulized faster than similar solutions of other cyclodextrins. In general, the average particle size (Dv50) of SAE-CD 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 comparative evaluation data (Malvern particle size) can be obtained for each formulation as it is 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. This advantage is further shown in the output rate of these solutions.
• SAE-CD is emitted from the nebulizer faster and also to a greater extent than the other non-SAE-CD cyclodextrin derivatives, thus the output rate of the nebulizer is greater when SAE-CD is nebulized than when other cyclodextrin derivatives are nebulized.
• the formulation of the invention provides substantial advantages over other aqueous formulations containing corticosteroid and cyclodextrin, such as HP- ⁇ -CD, ⁇ -CD.
• the present formulation should provide enhanced corticosteroid output rate, improved droplet size distribution for enhanced pulmonary delivery and deeper lung penetration, higher concentration solutions resulting in a reduction in the total volume of solution that needs to be administered to a subject.
• 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.
• the correlation between the two cyclodextrin concentration percentages is experimentally determined by preparing various %w/w cyclodextrin solutions and measuring the density of each with a pycnometer at 25°C.
• 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.
• the viscosity of an aqueous solution of SBE- ⁇ -CD changes with respect to concentration. 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 formulation of the invention provides substantial advantages over other aqueous suspension-based formulations containing corticosteroid suspended therein, such as the PULMICORT RESPULES suspension containing budesonide.
• the present formulation should provide enhanced corticosteroid output rate compared to that of the PULMICORT RESPULES suspension even though the total volume of liquid or suspension may be different.
• Use of SAE-CD in a nebulization composition results in an increased output rate of budesonide regardless of the format of the nebulizer.
• Other advantages of the suspension should also include utility of the present solution in a wider range of different nebulizer formats.
• the output of SAE-CD increases with increasing SAE-CD concentration.
• SAE-CD concentrations above 25% w/v may lead to slightly longer nebulization times and lower output rates once the viscosity exceeded an approximate upper limit.
• a 20% - 30% wt./vol. concentration of SAE-CD should be the approximate upper acceptable level for the nebulizers tested, "acceptable” being defined as the upper concentration of SAE-CD that can be used without building up excessive viscosity, which may adversely affect the nebulization time and output rate.
• accepted being defined as the upper concentration of SAE-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.
• 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.
• the package insert for PULMICORT RESPULES suspension states that the suspension should not be nebulized with an ultrasonic nebulizer.
• the SAE-CD containing solution can be nebulized with an ultrasonic nebulizer.
• 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.
• SAE-CD-containing solutions are suitable for administration by nebulization across a range of concentrations.
• the droplet size distribution may be partially controlled by adjusting the concentration of SAE-CD.
• the 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 formulation of the invention can be prepared by mixing an
• the exemplary suspension-based aqueous formulations which formulations may be adapted for nasal delivery or pulmonary delivery, 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
• 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 suspension-based unit dose formulation may be converted, by addition of SAE- ⁇ -CD, 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 suspension-based unit dose formulation comprising corticosteroid.
• Such pharmacists will now be able to prepare a single use or multi-use liquid unit dose formulation by employing a method described herein.
• 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 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.
• 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
• Such other drugs include: B 2 adrenoreceptor agonist, topical anesthetic, dopamine D 2 receptor agonist, anticholinergic agent.
• B 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
• Isoetharine (4-( 1 -hydroxy-2-(( 1 -methy lethyl)amino)butyl)- 1 ,2-benzenediol) ;
• Isoprenaline (4-( 1 -hydroxy-2-(( 1 -methylethyl)amino)ethyl)- 1 ,2-benzenediol) ;
• Meta-proterenol (5 -( 1 - hydroxy-2-((l-methylethyl)amino)ethyl)-l,3-benzenediol); Picumeterol (4-amino-3,5- dichloro-alpha-(((6-(2-(2-pyridinyl)ethoxy)hexyl)-amino)methyl) benzenemethanol); Pirbuterol (.alpha, .sup .6-((( 1 , 1 -dimethylethyl)-amino)methyl)-3 -hydroxy
• (R)-Salbutamol Salmeterol ((.+-.)-4-hydroxy-.alpha 1 -(((6-(4-phenylbutoxy)hexyl)- amino)methyl)-l,3-benzenedimethanol); (R)-Salmeterol; Terbutaline (5-(2-((l,l- dimethylethyl)amino)- 1 -hydroxyethyl)- 1 ,3-benzenediol); Tulobuterol (2-chloro-.alpha.- (((1,1 -dimethylethyl)amino)methyl)benzenemethanol); and TA-2005 (8-hydroxy-5-((lR)- l-hydroxy-2-(N-((lR)-2-(4-methoxyphenyl)-l-methylethyl)amino)ethyl)carbostyril hydrochloride).
• Dopamine (D 2 ) receptor agonists include, but are not limited to, Apomorphine ((r)- 5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,glquinoline-10,l 1-diol); Bromocriptine ((5'- ⁇ )-2-bromo-12'-hydroxy-2'-(l-methylethyl)-5'-(2-methylpropyl)ergotaman-3',6',18- trione); Cabergoline ((8 ⁇ )-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 ((8-beta-)-8-((methylthi
• 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 incorporated 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, tiotropium bromide and glycopyrronium bromide.
• the compositions contain an anticholinergic agent, such as ipratropium bromide or tiotropium 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 tiotropium 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)]- 1 -[[[1 -[3-[2-(7-chloro-2-quinolinyl)ethenyl-]phenyl]-3-[2-(l -hydroxy- l-methylethyl)phenyl]-propyl]thio]methyl] cyclopropaneacetic acid, monosodium salt), 5- lypoxygenase inhibitors such as zileuton (ZyfloTM, Abbott Laboratories, Abbott Park, 111.), anti-IgE antibodies such as XolairTM (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMA
• the invention includes methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders.
• the method further includes administering one or more of (a), (b), (c) or (d) as follows: (a) a b 2 -adrenoreceptor agonist; (b) a dopamine (D 2 ) receptor agonist; (c) a prophylactic therapeutic, such as a steroid; or (d) 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 solution); 5) Mixing a ready to use solution of a corticosteroid such as
• 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 bronchoconstrictive 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.
• SBE- ⁇ -CD is suitable for stabilizing corticosteroids in aqueous solutions.
• a stability study was conducted using fluticasone propionate in aqueous solutions stored at 25 °C or 40 °C having a pH of 4.5 or 6.0. The data is summarized in the table below.
• the results were substantially the same as for fluticasone propionate. In general, a more acidic pH and lower temperature are preferred.
• the estimated shelf-life for a mometasone furoate formulation of the invention is greater than two years.
• the shelf-life of a SBE( ⁇ ) ⁇ -CD-Enabled Mometasone furoate Inhalation Solution at 25 °C storage is estimated to exceed a target of 2 years (projected to be at least 48 months without any other stabilizers added) at a pH of 4.5.
• the T90 of both pH's at 25 °C is estimated to exceed two years of stability but pH 4.5 is stable for almost seven years.
• SAE- ⁇ -CD may be capable of stabilizing the isomers of budesonide or of another corticosteroid to different extents. This is true even though SAE- ⁇ -CD is capable of stabilizing both isomers of budesonide sufficiently well for use in a commercial pharmaceutical liquid formulation. SAE- ⁇ -CD should be able to provide stabilization of a corticosteroid against photolytic degradation.
• 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.
• 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, 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, triethanolamine, 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, citrate-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,3-
• a complexation-enhancing agent is a compound, or compounds, that enhance(s) the complexation of the active agent with the cyclodextrin.
• 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 cyclodextrin (underivatized or derivatized) to enhance the performance and/or properties of the cyclodextrin.
• 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 Cyclodextrin 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 tristearate), 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; tragacanth; 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 tartrate, 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, sodium
• the tonicity of the liquid formulation approximates the tonicity of the tissues in the respiratory tract.
• 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 SAE-CD concentrations below about 11-13% w/v, the solutions are hypotonic or hypoosmotic with respect to blood and at SAE-CD concentrations above about 11-13% w/v the 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 cyclodextrin/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 Cyclodextrin 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 cyclodextrin 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 SAE- ⁇ -CD and budesonide is determined as follows. Placebo solutions of three different cyclodextrins are prepared at different concentrations. Two ml of the solutions are 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 is determined using a Malvern Mastersizer S laser light scattering instrument.
• EXAMPLE 3 The stability of liquid formulations containing SAE-CD is determined by HPLC analysis of aliquots periodically drawn from the liquid in storage.
• Citrate-phosphate (Mcllvaines) buffer solutions at a pH of 4, 5, 6, 7, or 8 are prepared by mixing various portions of 0.01M citric acid with 0.02 M Na 2 HP0 4 . These stock solutions would contain SAE- ⁇ -CD. Approximately 250 ⁇ g /mL of budesonide is dissolved in each buffer solution. Aliquots of the solutions are stored at 40 °C, 50 °C and 60 °C. Control samples are stored at 5 °C. HPLC analysis of the samples iss performed initially and after 1, 2, and 3 months storage. The HPLC conditions include:
• EXAMPLE 4 The viscosity of aqueous solutions containing SAE-CD is 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 SAE- ⁇ -CD is placed into a 250 ml volumetric flask.
• -62.5 mg of budesonide is placed into the same flask.
• Flask is made to volume with the 3mM citrate buffer/82mM NaCl solution.
• the flask is well-mixed on a vortexer for 10 minutes and sonicated for 10 minutes.
• the flask can be stirred over weekend with magnetic stirrer.
• -25 mg of budesonide is placed into the same flask.
• the flask is made to volume with the
• Example 7 The procedure of Example 7 is followed except that about 6.25 g of SAE- ⁇ -CD, 62.5 mg of budesonide and about 250 ml of buffer are used. Sufficient disodium EDTA is added, if needed, 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 SAE- ⁇ -CD is added per mL of Respule and mixed or shaken well for several minutes. After standing from about 30 minutes to several hours, the solution is 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 SAE- ⁇ -CD (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, ) by gently squeezing the deformable plastic container to the last possible drop. The Respules are 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.
• Dilute Concentrate A at a ratio of 1 to 4 with pH 4.5 salinated citrate buffer (4 mM containing 109 mM sodium chloride) containing 1.25% w/v SAE- ⁇ -CD on an anhydrous basis. Filter the diluted concentrate through a 0.22 ⁇ m Millipore Durapore Millex-GV syringe filter unit. Assay the filtered solution by HPLC then add supplemental budesonide as needed to give a solution final concentration of about 250 ⁇ g/mL ( ⁇ ⁇ 5%).
• Dilute Concentrate B at a ratio of 1 to 4 with pH 4.5 salinated citrate buffer (4 mM containing 109 mM sodium chloride) containing 1.25% w/v SAE- ⁇ -CD on an anhydrous basis. Filter the diluted concentrate through a 0.22 ⁇ m Millipore Durapore Millex-GV syringe filter unit. Assay the filtered solution by HPLC then dilute further with pH 4.5 salinated citrate buffer (3 mM containing 82 mM sodium chloride) as required to give a final solution concentration of about 250 ⁇ g/mL ( ⁇ ⁇ 5%). This technique takes advantage of the excess solid budesonide used to saturate the solution. EXAMPLE 11 Clarity of solutions was determined by visual inspection or instrumentally. A clear solution is at least clear by visual inspection with the unaided eye.
• EXAMPLE 12 The following method is used to determine the performance of nebulization compositions emitted from a nebulizer.
• Two ml of the test CD solution or Pulmicort suspension is accurately pipetted by volumetric pipettes into a clean nebulizer cup prior to starting each experiment.
• the test nebulizer is assembled and charged with the test inhalation solution or suspension according to the manufacturer instructions.
• the end of the mouthpiece is 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 is positioned opposite the mouthpiece approximately 6 cm away to scavenge aerosol after sizing. The distance between the mouthpiece and the detector is approximately 8 cm.
• the center of the mouthpiece is level with the laser beam (or adjusted as appropriate, depending on the individual design of each nebulizer).
• the laser is passed through the center of the emitted cloud when the nebulizer is running. Measurements are manually started 15 seconds into nebulization. Data collection is started when beam obscuration reached 10% and is averaged over 15,000 sweeps (30 seconds). Scatted light intensity data on the detector rings is modeled using the "Standard- Wef ' model. Channels 1 and 2 are killed due to low relative humidity during measurement to prevent beam steering.
• the volume diameter of droplets defining 10, 50 (volume median), and 90% of the cumulative volume undersize is determined. (DvlO is the size below which 10% of the volume of material exists, Dv50 is the size below which 50% of the volume of material exists and Dv90 is the size below which 90% of the volume of material exists.
• EXAMPLE 13 Determination of the stability of corticosteroid in an aqueous solution containing SBE6.1- ⁇ -CD. Fluticasone propionate.
• a citrate buffer solution at a pH of 4.5 was prepared by mixing various portions of 0.003M citric acid with 0.003M of trisodium citrate.
• 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. To provide 2.5 mg, 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 strength 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.
• EXAMPLE 15 Preparation and use of a combination solution containing SAE-CD, budesonide, and albuterol sulfate or levalbuterol HCl (Xopenex).
• a citrate buffer (3 mM pH 4.5) is prepared as follows. Approximately 62.5 mg of citric acid is dissolved in and brought to volume with water in one 100 ml volumetric flask. Approximately 87.7 mg of sodium citrate is dissolved in and brought to volume with water in another 100 mL volumetric flask. In a beaker the sodium citrate solution is added to the citric acid solution until the pH is approximately 4.5.
• budesonide and 1247.4 mg of SAE- ⁇ -CD are ground together with a mortar and pestle and transferred to a 10 mL flask. Buffer solution is added, and the mixture is vortexed, sonicated and an additional 1.4 mg budesonide added. After shaking overnight, the solution is filtered through a 0.22 ⁇ m Durapore Millex-GV Millipore syringe filter unit.
• the resulting budesonide concentration is -1 mg/ml Approximately 0.5 ml of the budesonide solution is 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 should remain essentially clear for a suitable period of time when stored 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 one capsule containing 12 meg of formoterol fumarate blended with 25 mg of lactose is emptied into a vial to which is added 3-mL of 3 mM citrate buffer (pH 4.5) prepared as described in the previous example.
• the contents of the vial are vortexed to dissolve the solids present.
• the budesonide concentrate is prepared as described in the previous example to provide a concentration of -1 mg/mL.
• Approximately 1 ml of the budesonide solution is added to the formoterol fumarate buffered solution.
• the resulting solution should remain essentially clear for a suitable period when stored at room ambient conditions protected from light.
• EXAMPLE 17 Clinical evaluation of a dosage form according to the invention is conducted by performing gamma scintigraphy analyses on subjects before and after administration of the dosage form by nebulization.
• a single centre, four-way crossover gamma scintigraphy study to compare pulmonary delivery of budesonide via Pulmicort Respules®, and SAE- ⁇ -CD-containing budesonide formulations using a Pari LC air-jet nebulizer is conducted.
• the purpose of the study is to determine, by gamma scintigraphy, the intra-pulmonary deposition of radio labeled budesonide following nebulization of a budesonide suspension (Pulmicort Respules ® , Astra Zeneca, reference formulation) and a SAE- ⁇ -CD-containing budesonide solution (test formulation) in healthy male volunteers. Dosing is 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 may consist 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 2.5% w/v SAE- ⁇ -CD is been added.
• Each subject may receive each of four study administrations of radiolabeled Budesonide in a non-randomized manner.
• a non-randomized design is 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 dose administered is controlled by the length of administration, expressed as a fraction of the time to sputter determined following administration of the reference formulation (i.e. 25% TTS, 50% TTS and 75% TTS). It is expected that even though the same concentration of budesonide would be nebulized for a shorter time, the amount of drug reaching the volunteers lungs would be essentially the same as the reference suspension for one of the legs of the study. Scintigraphic images are acquired using a gamma camera immediately after completion of dosing the volunteers. Comparison of the image from the reference product and the 25% TTS leg should indicate that a greater percentage of the budesonide from the Respule is in the stomach and throat immediately after administration.
• 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.
• the solubility of beclomethasone dipropionate (BDP), beclomethasone 17- monopropionate (B 17P), beclomethasone 21 -monopropionate (B21 P) and beclomethasone (unesterifed) in solutions containing CAPTISOL and various SBE n ⁇ -CD was evaluated.
• BDP, B17P and B21P were obtained from Hovione.
• Beclomethasone was obtained from Spectrum 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 solubilites 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 concentration 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 SAE- ⁇ -CD dry powder which are both sized appropriately to provide for content uniformity at a weight ratio of 12 meg formoterol fumarate/25 mg SAE- ⁇ -CD.
• 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.

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