US20070197489A1 - Composition of matter - Google Patents

Composition of matter Download PDF

Info

Publication number
US20070197489A1
US20070197489A1 US11/690,537 US69053707A US2007197489A1 US 20070197489 A1 US20070197489 A1 US 20070197489A1 US 69053707 A US69053707 A US 69053707A US 2007197489 A1 US2007197489 A1 US 2007197489A1
Authority
US
United States
Prior art keywords
powder composition
glucocorticosteroid
heat sterilization
budesonide
temperature
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/690,537
Inventor
Ann-Kristin Karlsson
Cheryl Larrivee-Elkins
Ove Molin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=20408992&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070197489(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to US11/690,537 priority Critical patent/US20070197489A1/en
Assigned to ASTRA AKTIEBOLAG reassignment ASTRA AKTIEBOLAG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LARRIVEE-ELKINS, CHERYL, MOLIN, OVE, KARLSSON, ANN-KRISTIN
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB CERTIFICATE OF REGISTRATION Assignors: AKTIEBOLAG, ASTRA
Publication of US20070197489A1 publication Critical patent/US20070197489A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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
    • A61K31/58—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0023—Heat
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids

Definitions

  • This invention relates to a process for sterilization of a powdered form of a glucocorticosteroid, sterile glucocorticosteroids, sterile formulations containing glucocorticosteroids and use thereof in the treatment of an allergic and/or inflammatory condition of the nose or lungs.
  • glucocorticosteroids discloses the cold sterilization of micronized glucocorticosteroids using mixtures of ethylene oxide and carbon dioxide, since, according to PT-A-69652, steroids in powder form are not stable at temperatures above 60° C.
  • Specific examples of glucorticorsteroids are prednacindone, dexamethasone and prednisolone, and salts, esters and fluoro derivatives thereof, including dexamethasone acetate, dexamethasone phosphate, prednisolone pivalate and 9-alphafluoro prednisolone.
  • ethylene oxide is toxic and when it is used to sterilize glucocorticosteroids it has been found that the residual amounts of the ethylene oxide contravene pharmaceutical guidelines which require very low levels of residual ethylene oxide. Accordingly this method has been found to be unsuitable for producing therapeutically acceptable glucocorticosteroids and formulations thereof.
  • U.S. Pat. No. 3,962,430 discloses a method for the production of sterile isotonic solutions of medicinal agents, which comprises adding the agent to a saturated solution of sodium chloride in water at 100° C. and then heating the mixture at 100-130° C.
  • This method is not suitable for suspensions of fine particles of glucocorticosteroids which are intended for inhalation because the water, and the heating and cooling involved, produce unfavorable changes in the size of the particles. Indeed it can lead to the formation of bridges between the fine particles producing large, hard aggregates which will not deaggregate into the desired fine particles upon administration.
  • a putative alternative is dry heat sterilization.
  • European Pharmacopoeia (1996, pp. 283-4) a normal heat sterilization process runs at 180° C. for 30 min or at a minimum of 160° C. for at least 2 hours.
  • Pharmacopoeia Nordica (1964, pp. 16) such a sterilization can be carried out at 140° C. for 3 hours.
  • glucocorticosteroids suffer significant degradation and are subject to changes in their surface structure.
  • WO-A-96/09814 to Andaris Ltd. relates to spray-dried particles of a water-soluble material with a mass median particle size of 1 to 10 ⁇ m.
  • the aim of the invention is to produce uniform and reproducible particles for use in dry powder inhalers.
  • the water-soluble material is preferably a human protein or a fragment thereof, in natural or recombinant form, e.g. human serum albumin (HSA), alpha-1 antitrypsin or alcohol dehydrogenase.
  • HSA human serum albumin
  • alpha-1 antitrypsin or alcohol dehydrogenase also combinations of an active material with a carrier were produced e.g. budesonide and lactose. It is stated generally that the microparticles produced can be sterile without teaching now this could or would be achieved nor showing any proof thereof.
  • WO-A-96/32905 to Astra AB relates to a process for the preparation of respirable particles by dissolving an inhalation compound in a solvent, introducing the resulting solution containing the inhalation compound in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation.
  • Budesonide with a mass median diameter (MMD) of less than 10 ⁇ m is produced with the process.
  • MMD mass median diameter
  • WO-A-92/11280 to Instytut Farmaceutyczny relates to a method of obtaining (22R) diasteroisomer of budesonide by a condensation reaction followed by crystallizing the crude product of condensaton from ethanol.
  • the obtained 21-acetate of budesonide (22R) is hydrolyzed and the product thus obtained is crystallized from ethyl acetate.
  • the content of (22S) diasteroisomer of budesonide is 1% or less.
  • aqueous suspensions of finely divided glucocorticosteroids are known, e.g. the budesonide-containing product known as Pulmicort® nebulising suspension.
  • Pulmicort® is a trademark of Astra AB of Sweden.
  • Similar formulations of fluticasone propionate are known from WO-A-95/31964.
  • a process for the sterilization of a glucocorticosteroid which process comprises heat treating the glucocorticosteroid in the form of a powder at a temperature of from 100 to 130° C.
  • the process is preferably carried out at a temperature of from 110 to 120° C., more preferably at about 110° C., preferably for up to about 24 hours, more preferable up to 10 hours, e.g. from 1 to 10 hours.
  • the process is conveniently carried out under atmospheric conditions, i.e. in air, but may also be carried out under an inert gas atmosphere, e.g. an atmosphere of argon or nitrogen.
  • the unexpectedly low temperature at which the glucocorticosteroids can be sterilized indicates that the glucocorticosteroid may provide some synergistic effect, when taken together with the heat treatment, in destroying the spores.
  • the glucocorticosteroid used in the invention is preferably an anti-inflammatory glucocorticosteroid, e.g. for use in nasal and oral inhalation.
  • glucocorticosteroids which may be used in the present invention include betamethasone, fluticasone (e.g. as propionate), budesonide, tipredane, dexamethasone, beclomethasone (e.g. as dipropionate), prednisolone, fluocinolone, triamcinolone (e.g. as acetonide), momethasone (e.g. as furoate), rofleponide (e.g.
  • momethasone furoate beclomethasone dipropionate or fluticasone propionate or glucocorticosteroids with an asymmetric acetal structure, i.e. comprising 16 ⁇ ,17 ⁇ -butylidenedioxy, such as budesonide, rofleponide or rofleponide palmitate.
  • asymmetric acetal structure i.e. comprising 16 ⁇ ,17 ⁇ -butylidenedioxy
  • budesonide, rofleponide or rofleponide palmitate Preferably, use is made of budesonide, rofleponide or rofleponide palmitate and most preferably of budesonide.
  • the glucocorticosteroid is preferably used in the form of a finely divided, e.g. micronized, powder, particularly in the form of finely divided particles having a mass median diameter of less than 10 ⁇ m, more preferably less than 5 ⁇ m.
  • the glucocorticosteroid may alternatively be in an ultra fine form, e.g. having a mass median diameter of less than 1.0 ⁇ m.
  • the finely divided particles may be produced by conventional techniques known per se. e.g. by micronization or by direct precipitation. Information about micronization can be found e.g. in “The Theory and Practice of Industrial Pharmacy”, Lachman, Liebermann and Klang, 2 nd Ed., 1976, Lea & Febiger, Philadelphia, USA.
  • the temperature, time, batch size and type of sterilizer used will be interdependent. Thus generally the higher the temperature used in the process according to the invention, the less time is required to sterilize the glucocorticosteroid.
  • the process is preferably carried out for no more than 8 hours, e.g. from 1 to 8 hours, when the temperature is greater than about 110° C., more preferably no more than 4 hours. At a temperature of about 120° C. the process is preferably carried out for no more than 4 hours, e.g. from 1 to 4 hours, more preferably no more than 2 hours, e.g. from 1 to 2 hours.
  • glucocorticosteroid At temperatures of from about 110° C. up to 130° C., a batch of 50 g of glucocorticosteroid may suitably be heat treated from 1 to 4 hours. If desired sub-batches, e.g. of 4 ⁇ 50 g, may be used.
  • the present process may be carried out such that it results in a more than log 4 reduction in the amount of heat resistant spores.
  • the process of the present invention is suitably carried out such that it results in a log 6 reduction in the amount of heat resistant spores.
  • the present process is preferably carried out such that it results in a more than log 6 reduction, and more preferably such that it results in a more than log 7 reduction in the amount of heat resistant spores.
  • the D value also known as the D T value, is the time (in minutes) required to reduce (“kill”) a standardized population of spores by 90% or 1 log cycle, i.e. to a survival fraction of 1/10, at a specific temperature T (in °C.).
  • the present process may be carried out such that the D value is less than about 240 min at the preselected temperature T, wherein T is in the range of from 100 to 130° C.
  • the process of the present invention is suitably carried out such that the D value is less than 150 min at the preselected temperature T.
  • the process of the present invention is carried out such that the D value is less than 90 min at the preselected temperature T, and more preferably such that the D value is less than 30 min at the preselected temperature T.
  • T is suitably 100, 110, 120 or 130° C.
  • the sterilization process is desirably carried out in such a manner that all parts of the bulk of the glucocorticosteroid reaches, and is maintained within, the desired temperature for the desired time.
  • the present process may be carried out batch wise or continuously, preferably batch wise.
  • the glucocorticosteroid starting material for the process which material may be in finely divided form, is suitably substantially dry, i.e. containing less than about 1% (w/w) of water.
  • the starting material for the process contains less than 0.5% (w/w) of water, and more preferably less than 0.3% (w/w) of water.
  • the glucocorticosteroid starting material for the process suitably has a bioburden of less than 50 CFU (colony forming units) per gram.
  • the glucocorticosteroid starting material for the process preferably has a bioburden of less than 10 CFU per gram, more preferably of less than 1 CFU per gram.
  • a sterile glucocorticosteroid e.g. budesonide
  • a sterile glucocorticosteroid suitably dry and preferably in the form of finely divided particles, e.g. having a mass median diameter of less than 10 ⁇ m, and more preferably less than 5 ⁇ m.
  • sterile we mean a product which meets the criteria of sterility according to the US Pharmacopoeia 23/NF18, 1995, pp. 1686-1690 and 1963-1975 and which provides a therapeutically acceptable glucocorticosteroid and formulations thereof.
  • Further regulations for sterility of the final product include the European Pharmacopoeia (Ph. Eur. 1998, Chapters 2.6.1 and 5.1.1), the British Pharmacopoeia (BP 1993, Appendix XVI A. p. A180 and Appendix XVIII A, p. A184) and the Japanese Pharmacopoeia (JP, 13 th ed., pp. 69-71 and 181-182).
  • the therapeutically acceptable glucocorticosteroid and formulation thereof have been produced by a method which provides assurance of sterility according to the US Pharmacopoeia 23/NF18, 1995, pp. 1686-1690 and 1963-1975.
  • the glucocorticosteroid according to the invention will essentially maintain the same pharmacological activity and physico-chemical properties/its chemical purity and physical form as the starting material from which it is prepared, i.e. the degradation, and especially the chemical degradation, caused by the present sterilization process will be limited.
  • the glucocorticosteroid according to the invention is preferably at least 98.5% by weight pure, more preferably at least 99% by weight pure, and most preferably at least 99.2% by weight pure.
  • the invention further provides a sterile glucocorticosteroid, preferably an anti-inflammatory glucocorticosteroid, more preferably budesonide, rofleponide or rofleponide palmitate, and most preferably budesonide, for use in the treatment of an allergic and/or inflammatory condition of the nose or lungs, e.g. chronic obstructive pulmonary disease (COPD), rhinitis or asthma.
  • COPD chronic obstructive pulmonary disease
  • the invention also provides the use of such a sterile glucocorticosteroid, preferably an anti-inflammatory glucocorticosteroid, more preferably budesonide, in the manufacture of a medicament (preferably a sterile medicament) for use in the treatment of such conditions.
  • a sterile pharmaceutical formulation comprising a glucocorticosteroid in an aqueous suspension, wherein the glucocorticosteroid is preferably a sterile finely divided glucocorticosteroid, such as budesonide.
  • a sterile pharmaceutical formulation comprising a glucocorticosteroid and one or more pharmaceutically acceptable additives, diluents or carries.
  • additives include surfactants, pH regulating agents, chelating agents, agents rendering the suspension isotonic and thickening agents.
  • a surfactant may be used, optionally in combination with e.g. lecithin.
  • the surfactants may also function as stabilizing agents in the formulations according to the present invention
  • suitable surfactants include non-ionic surfactants of the alkyl aryl polyether alcohol type, specifically TyloxapolTM—a polymer of 4-(1,1,3,3-tetramethylbutyl)phenol with ethylene oxide and formaldehyde.
  • suitable surfactants include sorbitan derivatives, e.g.
  • polyoxyethylene sorbitan fatty acid esters preferably of the Polysorbate or TweenTM groups, more preferably polysorbate 80 or polyoxyethylene 20 sorbitan mono-oleate (Tween TM 80).
  • Suitable surfactants also include polyoxyethylene ethers, especially polyoxyethylene alkyl ethers, preferably pentaethyleneglycol mono n-dodecylether or C 12 E 5 .
  • Further suitable surfactants include poloxamers, polyoxyethylene castor oil derivatives, polyvinylalcohol and block copolymers of polyethyleneoxides, polypropyleneoxides, polybutyleneoxides and polyethyleneglycols (PEGs) or mixtures of any of these.
  • Further suitable surfactants include polyethylene glycol derivatives, especially polyethylene glycol 660 hydroxystearate or SolutolTM HS 15, povidone, polyvinylpyrrolidone (PVP) and polyethyleneglycols (PEGs).
  • the surfactant may be present at about 0.0002 to 2% w/w of the formulation.
  • the pH of the suspension may be adjusted as required.
  • suitable pH regulating agents are weak organic acids, e.g. citric acid, strong mineral acids, e.g. hydrochloric acid, and strong alkaline agents, e.g. NaOH.
  • the pH of the system can be adjusted by balancing the acid and salt forms of buffers such as citric acid, sodium citrate, acetic acid, sodium acetate and sodium phosphate.
  • the formulation may also contain a suitable chelating agent, e.g. disodium edetate (EDTA).
  • EDTA disodium edetate
  • the chelating agent may be present at about 0.005 to 0.1% w/w of the formulation.
  • Agents which make the suspension isotonic may be added. Examples are dextrose, glycerol, mannitol, sodium chloride, potassium chloride and sodium bromide.
  • a thickening agent may be included in the formulation.
  • suitable thickening agents are cellulose derivatives, suitably cellulose ethers, or microcrystalline cellulose.
  • Preferred cellulose ethers include ethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylecellulose (CMC), e.g. the sodium salt thereof.
  • Suitable thickening agents also include cyclodextrin and dextrin.
  • Suitable thickening agents further include xanthan gum, guar gum and carbomer.
  • Preferred thickening agents in the formulations of the invention are povidone, polyvinylpyrrolidone (PVP) and polyethyleneglycols (PEGs).
  • the thickening agent may be present at about 0.1 to 3.0% w/w of the formulation.
  • microcrystalline cellulose and sodium carboxymethyl cellulose (CMC) are present at about 0.5 to 2.5%, xanthan gum at about 0.3 to 3%, carbomer at about 0.1 to 2%, guar gum at about 0.3 to 2% and hydroxypropyl methyl cellulose at about 0.5 to 3.0%, w/w of the formulation.
  • the suspension that active constituent, e.g. budesonide, is present as small particles, where at least 90% of the small particles have a mass median diameter (MMD) of less than 20 ⁇ m, suitably at least 80% less than 10 ⁇ m, preferably at least 70% less than 7 ⁇ m and most preferably at least 60% less than 4 ⁇ m.
  • MMD mass median diameter
  • the suspension to contain from about 0.05 to about 20 mg/ml of glucocortiosteroid. More preferably the suspension contains from 0.08 to 10 mg/ml of the glucocorticosteroid and most preferably from 0.1 to 5 mg/ml of the glucocorticosteroid.
  • a sterile pharmaceutical formulation comprising a glucocorticosteroid, such as finely divided budesonide, rofleponide or rofleponide palmitate, sterilized according to the present process, can be prepared by mixing the sterilized glucocorticosteroid with any suitable additional ingredient, e.g. a surfactant, a pH regulating or chelating agent, an agent rendering the suspension isotonic or a thickening agent. All components, other than the glucocorticosteroid, can be produced by sterile filtration of their aqueous solutions.
  • the resulting sterile suspension may be stored under an over pressure of a sterile and inert gas, e.g. nitrogen or argon, and should be filled under aseptic conditions into pre-sterilized containers to produce a sterile pharmaceutical product, e.g. using a blow/fill/seal system.
  • the invention further provides a method for treatment of an inflammatory condition of the nose or lungs by administering to a mammal, especially a human being, suffering from such a condition a therapeutically effective amount of a sterile glucocorticosteroid or a sterile formulation containing a glucocorticosteroid, preferably a sterile formulation containing a sterile glucocorticosteroid produced according to the present invention.
  • the invention provides a method for treatment of chronic obstructive pulmonary disease (COPD), rhinitis, asthma or other allergic and/or inflammatory conditions by administering to a mammal, especially a human being, suffering from such a condition a therapeutically effective amount of a sterile glucocorticosteroid or a sterile formulation containing a glucocorticosteroid, preferably a sterile formulation containing a sterile glucocorticosteroid produced according to the present invention.
  • COPD chronic obstructive pulmonary disease
  • rhinitis asthma or other allergic and/or inflammatory conditions
  • sample nos. 2-10 in Table 1 below were subjected to the heat treatment shown in Table 1 in a dry sterilizer, Lytzen model CB 1200. Sample 1 was not subjected to such treatment and was used as the reference sample. After the treatment the samples were analyzed for chemical and physical properties. TABLE 1 No. 1 2 3 4 5 6 7 8 9 10 Temp/° C.
  • BET Brunauer, Emett and Teller
  • the sterilization of budesonide was compared with that of calcium stearate.
  • Tests were performed to evaluate the heat resistance of various naturally occurring microorganisms.
  • All the components, other than the budesonide, were produced by sterile filtration of their aqueous solutions and an appropriate volume of the resulting suspension (about 2 ml) was filled under aseptic conditions into pre-sterilized 5 ml containers to produce a sterile product.
  • the resulting suspension may be stored under an over-pressure of sterile nitrogen and may be filled into containers using a blow/fill/seal system.
  • a sterile formulation comprising finely divided budesonide sterilized by the method of Example 2, can be prepared by mixing the following ingredients: TABLE 5 Micronized budesonide 2-3 mg Disodium edetate 0.1 mg Sodium chloride 8.5 mg Stabilizing agent 0.02-2 mg Anhydrous citric acid 0.28 mg Sodium citrate 0.5 mg Purified water to 1 ml
  • All the components, other than the budesonide, can be produced by sterile filtration of their aqueous solutions and an appropriate volume of the resulting suspension (about 2 ml) filled under aseptic conditions into pre-sterilized 5 ml containers to produce a sterile product.
  • the resulting suspension may be stored under an over-pressure of sterile nitrogen and may be filled into containers using a blow/fill/seal system.
  • the substance and the spore suspension were mixed and dried for approximately 3 hours at 55° C.
  • the inoculated and dried budesonide was mixed with 20-40 g of non-inoculated micronized budesonide.
  • the number of spores before heat treatment were determined in samples heated at 80° C. for 10 min in order to kill the vegetative cells.
  • the samples were heat treated at 110° C. A sample was withdrawn after various heating times. The number of spores/g were determined by a pour plate technique according to US Pharmacopoeia 23/NF18, 1995, pp. 1681-1686, especially p. 1684.
  • Table 7 clearly shows that the present process is very efficient in reducing the number of spores in samples containing glucocorticosteroids.
  • the process is especially efficient with budesonide and rofleponide.
  • budesonide and rofleponide yielded total kill at very short cycle times ( ⁇ 5 minutes at 110° C.), where a D 110 value could not be calculated.
  • micronized budesonide substance stored in a plastic container, were subjected to irradiation. The substance was exposed to ⁇ -irradiation at 2.5 to 25 kGy and ⁇ -irradiation at 8 to 32 kGy. After the exposure the budesonide content and the amount of related substances were determined by liquid chromatography. The chemical stability of budesonide was considered to be the most critical parameter to study. TABLE 8 Stability of micronized budesonide substance during sterilization by irradiation Exposure Ref.
  • micronized budesonide can not be satisfactorily sterilized with ⁇ - or ⁇ -irradiation, due to significant chemical degradation.

Abstract

The invention provides a process for the sterilization of a powdered form of a glucocorticosteroid, sterile glucocorticosteroids, sterile formulations containing glucocorticosteroids and use thereof in the treatment of an allergic and/or inflammatory condition of the nose or lungs.

Description

    FIELD OF THE INVENTION
  • This invention relates to a process for sterilization of a powdered form of a glucocorticosteroid, sterile glucocorticosteroids, sterile formulations containing glucocorticosteroids and use thereof in the treatment of an allergic and/or inflammatory condition of the nose or lungs.
    • BACKGROUND OF THE INVENTION
  • Various methods have been proposed in the past for the sterilization of glucocorticosteroids. PT-A-69652 discloses the cold sterilization of micronized glucocorticosteroids using mixtures of ethylene oxide and carbon dioxide, since, according to PT-A-69652, steroids in powder form are not stable at temperatures above 60° C. Specific examples of glucorticorsteroids are prednacindone, dexamethasone and prednisolone, and salts, esters and fluoro derivatives thereof, including dexamethasone acetate, dexamethasone phosphate, prednisolone pivalate and 9-alphafluoro prednisolone. However, ethylene oxide is toxic and when it is used to sterilize glucocorticosteroids it has been found that the residual amounts of the ethylene oxide contravene pharmaceutical guidelines which require very low levels of residual ethylene oxide. Accordingly this method has been found to be unsuitable for producing therapeutically acceptable glucocorticosteroids and formulations thereof.
  • U.S. Pat. No. 3,962,430 discloses a method for the production of sterile isotonic solutions of medicinal agents, which comprises adding the agent to a saturated solution of sodium chloride in water at 100° C. and then heating the mixture at 100-130° C. This method is not suitable for suspensions of fine particles of glucocorticosteroids which are intended for inhalation because the water, and the heating and cooling involved, produce unfavorable changes in the size of the particles. Indeed it can lead to the formation of bridges between the fine particles producing large, hard aggregates which will not deaggregate into the desired fine particles upon administration.
  • A putative alternative is dry heat sterilization. According to the European Pharmacopoeia (1996, pp. 283-4) a normal heat sterilization process runs at 180° C. for 30 min or at a minimum of 160° C. for at least 2 hours. According to Pharmacopoeia Nordica (1964, pp. 16) such a sterilization can be carried out at 140° C. for 3 hours. However at the temperatures of these processes glucocorticosteroids suffer significant degradation and are subject to changes in their surface structure.
  • Sterilization by β- or γ-irradiation is also known. Indeed Illum and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174 recommend the use of such irradiation to sterilize glucocorticosteroids. However when such irradiation is used to sterilize certain finely divided, e.g. micronized, glucocorticosteroids, they are significantly degraded.
  • WO-A-96/09814 to Andaris Ltd. relates to spray-dried particles of a water-soluble material with a mass median particle size of 1 to 10 μm. The aim of the invention is to produce uniform and reproducible particles for use in dry powder inhalers. The water-soluble material is preferably a human protein or a fragment thereof, in natural or recombinant form, e.g. human serum albumin (HSA), alpha-1 antitrypsin or alcohol dehydrogenase. Also combinations of an active material with a carrier were produced e.g. budesonide and lactose. It is stated generally that the microparticles produced can be sterile without teaching now this could or would be achieved nor showing any proof thereof.
  • WO-A-96/32905 to Astra AB relates to a process for the preparation of respirable particles by dissolving an inhalation compound in a solvent, introducing the resulting solution containing the inhalation compound in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation. Budesonide with a mass median diameter (MMD) of less than 10 μm is produced with the process. There is no information in WO-A-96/32095 about sterilization or sterile particles.
  • WO-A-92/11280 to Instytut Farmaceutyczny relates to a method of obtaining (22R) diasteroisomer of budesonide by a condensation reaction followed by crystallizing the crude product of condensaton from ethanol. The obtained 21-acetate of budesonide (22R) is hydrolyzed and the product thus obtained is crystallized from ethyl acetate. The content of (22S) diasteroisomer of budesonide is 1% or less. There is no information in WO-A-92/11280 about sterilization or sterile particles.
  • We have also found that attempts at terminal sterilization of the pharmaceutical formulations, especially suspensions, e.g. aqueous suspensions, of glucocorticosteroids have all proved unsatisfactory. Such suspensions can not normally be sterilized by sterile filtration as most of the particles of glucocorticosteroid will be retained on the filter. We have also shown that moist heat sterilization, e.g. steam treatment of glass vials containing the product, leads to an unacceptable change in particle size.
  • Various aqueous suspensions of finely divided glucocorticosteroids are known, e.g. the budesonide-containing product known as Pulmicort® nebulising suspension. (Pulmicort® is a trademark of Astra AB of Sweden). Similar formulations of fluticasone propionate are known from WO-A-95/31964.
  • According a new process for the sterilization of glucocorticosteroids (and formulations containing them) is required.
  • Surprisingly we have now found that effective sterilization of dry glucocorticosteroids can be carried out at a signficantly lower temperature than that considered necessary for the heat sterilization of other substances. Such sterile glucocorticosteroids can be used in the preparation of sterile formulations containing them.
    • DESCRIPTION OF THE INVENTION
  • According to the invention there is provided a process for the sterilization of a glucocorticosteroid, which process comprises heat treating the glucocorticosteroid in the form of a powder at a temperature of from 100 to 130° C. The process is preferably carried out at a temperature of from 110 to 120° C., more preferably at about 110° C., preferably for up to about 24 hours, more preferable up to 10 hours, e.g. from 1 to 10 hours. The process is conveniently carried out under atmospheric conditions, i.e. in air, but may also be carried out under an inert gas atmosphere, e.g. an atmosphere of argon or nitrogen.
  • Surprisingly we have found that this process kills many more spores when applied to the glucocorticosteroid budesonide than when applied to the comparison substance calcium stearate. Even better results were obtained with the glucocorticosteroid rofleponide.
  • It is believed, but we do not intend to be limited by this explanation, that the unexpectedly low temperature at which the glucocorticosteroids can be sterilized indicates that the glucocorticosteroid may provide some synergistic effect, when taken together with the heat treatment, in destroying the spores.
  • The glucocorticosteroid used in the invention is preferably an anti-inflammatory glucocorticosteroid, e.g. for use in nasal and oral inhalation. Examples of glucocorticosteroids which may be used in the present invention include betamethasone, fluticasone (e.g. as propionate), budesonide, tipredane, dexamethasone, beclomethasone (e.g. as dipropionate), prednisolone, fluocinolone, triamcinolone (e.g. as acetonide), momethasone (e.g. as furoate), rofleponide (e.g. as palmitate), flumethasone, flunisolide, ciclesonide, deflazacort, cortivazol, 16α, 17α-butylidenedioxy-6α,9α-difluoro-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione; 6α, 9α-difluoro-11β-hydroxy-16α, 17α-butylidenedioxy-17β-methylthioandrosta-4-ene-3-one; 16α,17α- butylidenedioxy-6α,9α-difluoro-11β-hydroxy-3oxoandrosta-1,4-diene-17β-carbothioic acid S-methyl ester; methyl 9α-chloro-6α-chloro-6α-fluoro-11β-hydroxy-16α-methyl -3oxo-17α-propionyloxy-androsta-1,4-diene-17αcarboxylate; 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydrofuran-3-yl) ester; optionally in their pure isomeric forms (where such forms exist) and/or in the form of their esters, acetals or salts, where applicable. Suitably, use is made of momethasone furoate, beclomethasone dipropionate or fluticasone propionate or glucocorticosteroids with an asymmetric acetal structure, i.e. comprising 16α,17α-butylidenedioxy, such as budesonide, rofleponide or rofleponide palmitate. Preferably, use is made of budesonide, rofleponide or rofleponide palmitate and most preferably of budesonide.
  • The glucocorticosteroid is preferably used in the form of a finely divided, e.g. micronized, powder, particularly in the form of finely divided particles having a mass median diameter of less than 10 μm, more preferably less than 5 μm. The glucocorticosteroid may alternatively be in an ultra fine form, e.g. having a mass median diameter of less than 1.0 μm. The finely divided particles may be produced by conventional techniques known per se. e.g. by micronization or by direct precipitation. Information about micronization can be found e.g. in “The Theory and Practice of Industrial Pharmacy”, Lachman, Liebermann and Klang, 2nd Ed., 1976, Lea & Febiger, Philadelphia, USA.
  • The temperature, time, batch size and type of sterilizer used will be interdependent. Thus generally the higher the temperature used in the process according to the invention, the less time is required to sterilize the glucocorticosteroid. The process is preferably carried out for no more than 8 hours, e.g. from 1 to 8 hours, when the temperature is greater than about 110° C., more preferably no more than 4 hours. At a temperature of about 120° C. the process is preferably carried out for no more than 4 hours, e.g. from 1 to 4 hours, more preferably no more than 2 hours, e.g. from 1 to 2 hours.
  • At temperatures of from about 110° C. up to 130° C., a batch of 50 g of glucocorticosteroid may suitably be heat treated from 1 to 4 hours. If desired sub-batches, e.g. of 4×50 g, may be used.
  • The present process may be carried out such that it results in a more than log 4 reduction in the amount of heat resistant spores. The process of the present invention is suitably carried out such that it results in a log 6 reduction in the amount of heat resistant spores. The present process is preferably carried out such that it results in a more than log 6 reduction, and more preferably such that it results in a more than log 7 reduction in the amount of heat resistant spores.
  • A different way of characterizing the efficiency of a sterilizing process is by using the D value. The D value, also known as the DT value, is the time (in minutes) required to reduce (“kill”) a standardized population of spores by 90% or 1 log cycle, i.e. to a survival fraction of 1/10, at a specific temperature T (in °C.).
  • The present process may be carried out such that the D value is less than about 240 min at the preselected temperature T, wherein T is in the range of from 100 to 130° C. The process of the present invention is suitably carried out such that the D value is less than 150 min at the preselected temperature T. Preferably, the process of the present invention is carried out such that the D value is less than 90 min at the preselected temperature T, and more preferably such that the D value is less than 30 min at the preselected temperature T. T is suitably 100, 110, 120 or 130° C.
  • The sterilization process is desirably carried out in such a manner that all parts of the bulk of the glucocorticosteroid reaches, and is maintained within, the desired temperature for the desired time.
  • The present process may be carried out batch wise or continuously, preferably batch wise.
  • The glucocorticosteroid starting material for the process, which material may be in finely divided form, is suitably substantially dry, i.e. containing less than about 1% (w/w) of water. Preferably, the starting material for the process contains less than 0.5% (w/w) of water, and more preferably less than 0.3% (w/w) of water.
  • The glucocorticosteroid starting material for the process suitably has a bioburden of less than 50 CFU (colony forming units) per gram. The glucocorticosteroid starting material for the process preferably has a bioburden of less than 10 CFU per gram, more preferably of less than 1 CFU per gram.
  • According to the invention there is further provided a sterile glucocorticosteroid (e.g. budesonide), suitably dry and preferably in the form of finely divided particles, e.g. having a mass median diameter of less than 10 μm, and more preferably less than 5 μm.
  • By the term “sterile” we mean a product which meets the criteria of sterility according to the US Pharmacopoeia 23/NF18, 1995, pp. 1686-1690 and 1963-1975 and which provides a therapeutically acceptable glucocorticosteroid and formulations thereof. Further regulations for sterility of the final product include the European Pharmacopoeia (Ph. Eur. 1998, Chapters 2.6.1 and 5.1.1), the British Pharmacopoeia (BP 1993, Appendix XVI A. p. A180 and Appendix XVIII A, p. A184) and the Japanese Pharmacopoeia (JP, 13th ed., pp. 69-71 and 181-182). Preferably, the therapeutically acceptable glucocorticosteroid and formulation thereof have been produced by a method which provides assurance of sterility according to the US Pharmacopoeia 23/NF18, 1995, pp. 1686-1690 and 1963-1975.
  • The glucocorticosteroid according to the invention will essentially maintain the same pharmacological activity and physico-chemical properties/its chemical purity and physical form as the starting material from which it is prepared, i.e. the degradation, and especially the chemical degradation, caused by the present sterilization process will be limited.
  • The glucocorticosteroid according to the invention is preferably at least 98.5% by weight pure, more preferably at least 99% by weight pure, and most preferably at least 99.2% by weight pure.
  • The invention further provides a sterile glucocorticosteroid, preferably an anti-inflammatory glucocorticosteroid, more preferably budesonide, rofleponide or rofleponide palmitate, and most preferably budesonide, for use in the treatment of an allergic and/or inflammatory condition of the nose or lungs, e.g. chronic obstructive pulmonary disease (COPD), rhinitis or asthma. The invention also provides the use of such a sterile glucocorticosteroid, preferably an anti-inflammatory glucocorticosteroid, more preferably budesonide, in the manufacture of a medicament (preferably a sterile medicament) for use in the treatment of such conditions.
  • According to the invention there is further provided a sterile pharmaceutical formulation comprising a glucocorticosteroid in an aqueous suspension, wherein the glucocorticosteroid is preferably a sterile finely divided glucocorticosteroid, such as budesonide.
  • According to the invention there is also provided a sterile pharmaceutical formulation comprising a glucocorticosteroid and one or more pharmaceutically acceptable additives, diluents or carries. Examples of such additives include surfactants, pH regulating agents, chelating agents, agents rendering the suspension isotonic and thickening agents.
  • To obtain an efficient dispersion of the glucocorticosteroid particles in the suspension, a surfactant may be used, optionally in combination with e.g. lecithin. The surfactants may also function as stabilizing agents in the formulations according to the present invention Examples of suitable surfactants include non-ionic surfactants of the alkyl aryl polyether alcohol type, specifically Tyloxapol™—a polymer of 4-(1,1,3,3-tetramethylbutyl)phenol with ethylene oxide and formaldehyde. Further suitable surfactants include sorbitan derivatives, e.g. polyoxyethylene sorbitan fatty acid esters, preferably of the Polysorbate or Tween™ groups, more preferably polysorbate 80 or polyoxyethylene 20 sorbitan mono-oleate (Tween ™ 80). Suitable surfactants also include polyoxyethylene ethers, especially polyoxyethylene alkyl ethers, preferably pentaethyleneglycol mono n-dodecylether or C12E5. Further suitable surfactants include poloxamers, polyoxyethylene castor oil derivatives, polyvinylalcohol and block copolymers of polyethyleneoxides, polypropyleneoxides, polybutyleneoxides and polyethyleneglycols (PEGs) or mixtures of any of these. Further suitable surfactants include polyethylene glycol derivatives, especially polyethylene glycol 660 hydroxystearate or Solutol™ HS 15, povidone, polyvinylpyrrolidone (PVP) and polyethyleneglycols (PEGs).
  • The surfactant may be present at about 0.0002 to 2% w/w of the formulation. We prefer the polyoxyethylene sorbitan fatty acid esters to be present at about 0.005 to 0.5% w/w, poloxamers at about 0.01 to 2% w/w, and polyoxyethylene alkyl ethers of the polyoxyethylene castor oil derivatives at about 0.01 to 1.0% w/w of the formulation.
  • The pH of the suspension may be adjusted as required. Examples of suitable pH regulating agents are weak organic acids, e.g. citric acid, strong mineral acids, e.g. hydrochloric acid, and strong alkaline agents, e.g. NaOH. Alternatively, the pH of the system can be adjusted by balancing the acid and salt forms of buffers such as citric acid, sodium citrate, acetic acid, sodium acetate and sodium phosphate. We prefer the formulations intended for inhalation to have a pH in the range of from about 3.5 to about 6.0, more preferably from 4.0 to 5.0, and most preferably from 4.2 to 4.8.
  • We also prefer the formulation to contain a suitable chelating agent, e.g. disodium edetate (EDTA). The chelating agent may be present at about 0.005 to 0.1% w/w of the formulation.
  • Agents which make the suspension isotonic may be added. Examples are dextrose, glycerol, mannitol, sodium chloride, potassium chloride and sodium bromide.
  • In order to form a stable suspension with a minimal tendency to agglomerate of form a sediment, a thickening agent may be included in the formulation. Examples of suitable thickening agents are cellulose derivatives, suitably cellulose ethers, or microcrystalline cellulose. Preferred cellulose ethers include ethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylecellulose (CMC), e.g. the sodium salt thereof. Suitable thickening agents also include cyclodextrin and dextrin. Suitable thickening agents further include xanthan gum, guar gum and carbomer. Preferred thickening agents in the formulations of the invention are povidone, polyvinylpyrrolidone (PVP) and polyethyleneglycols (PEGs).
  • The thickening agent may be present at about 0.1 to 3.0% w/w of the formulation. Preferably microcrystalline cellulose and sodium carboxymethyl cellulose (CMC) are present at about 0.5 to 2.5%, xanthan gum at about 0.3 to 3%, carbomer at about 0.1 to 2%, guar gum at about 0.3 to 2% and hydroxypropyl methyl cellulose at about 0.5 to 3.0%, w/w of the formulation.
  • In the suspension that active constituent, e.g. budesonide, is present as small particles, where at least 90% of the small particles have a mass median diameter (MMD) of less than 20 μm, suitably at least 80% less than 10 μm, preferably at least 70% less than 7 μm and most preferably at least 60% less than 4 μm.
  • We prefer the suspension to contain from about 0.05 to about 20 mg/ml of glucocortiosteroid. More preferably the suspension contains from 0.08 to 10 mg/ml of the glucocorticosteroid and most preferably from 0.1 to 5 mg/ml of the glucocorticosteroid.
  • A sterile pharmaceutical formulation comprising a glucocorticosteroid, such as finely divided budesonide, rofleponide or rofleponide palmitate, sterilized according to the present process, can be prepared by mixing the sterilized glucocorticosteroid with any suitable additional ingredient, e.g. a surfactant, a pH regulating or chelating agent, an agent rendering the suspension isotonic or a thickening agent. All components, other than the glucocorticosteroid, can be produced by sterile filtration of their aqueous solutions. The resulting sterile suspension may be stored under an over pressure of a sterile and inert gas, e.g. nitrogen or argon, and should be filled under aseptic conditions into pre-sterilized containers to produce a sterile pharmaceutical product, e.g. using a blow/fill/seal system.
  • The invention further provides a method for treatment of an inflammatory condition of the nose or lungs by administering to a mammal, especially a human being, suffering from such a condition a therapeutically effective amount of a sterile glucocorticosteroid or a sterile formulation containing a glucocorticosteroid, preferably a sterile formulation containing a sterile glucocorticosteroid produced according to the present invention. More specifically, the invention provides a method for treatment of chronic obstructive pulmonary disease (COPD), rhinitis, asthma or other allergic and/or inflammatory conditions by administering to a mammal, especially a human being, suffering from such a condition a therapeutically effective amount of a sterile glucocorticosteroid or a sterile formulation containing a glucocorticosteroid, preferably a sterile formulation containing a sterile glucocorticosteroid produced according to the present invention.
    • EXAMPLES
  • The invention is illustrated by reference to the following Examples which are not intended to limit the invention.
    • EXAMPLE 1
  • Experiments were carried out to determine the effect of heat treatment upon the chemical purity and physical form of samples of micronized budesonide.
  • Nine 50 g batches of micronized budesonide (sample nos. 2-10 in Table 1 below) were subjected to the heat treatment shown in Table 1 in a dry sterilizer, Lytzen model CB 1200. Sample 1 was not subjected to such treatment and was used as the reference sample. After the treatment the samples were analyzed for chemical and physical properties.
    TABLE 1
    No. 1 2 3 4 5 6 7 8 9 10
    Temp/° C. — 100 100 100 110 110 110 120 120 120
    Time/hours 0 4 6 10 2 4 10 1 2 4
    Size/μm 2.0 2.2 2.2 2.2 2.2 2.2 2.3 2.2 2.2 2.3
    Size range (10- 2.6 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
    90%)/μm
    Epimer A/% by wt 48.8 48.8 48.7 48.7 48.7 48.8 48.7 48.7 48.7 48.7
    Budesonide 99.4 99.3 99.3 99.2 99.2 99.3 98.9 99.2 99.2 99.0
    content/% by wt
    Total of known 0.13 0.14 0.16 0.15 0.16 0.15 0.18 0.14 0.15 0.17
    foreign steroids
    Total of unknown 0.04 0.04 0.05 0.05 0.04 0.08 0.18 0.04 0.07 0.16
  • After the heat treatment there was no change in the Brunauer, Emett and Teller (BET) surface value (as measured using a Micrometrics Gemini 2375 device; see also British Standard 4359 (1969)part 1) of the budesonide or in its X-ray diffraction pattern for each sample compared to sample 1. The size for each sample was measured as the mass median diameter (MMD) using a Coulter counter.
    • EXAMPLE 2
  • The sterilization of budesonide was compared with that of calcium stearate.
  • Samples of 0.5 g of budesonide and of 0.5 g of calcium stearate were each inoculated with 0.1 ml of a Steris Bacillus subtilis (globigii) (Lot# LG126B) spore suspension containing 1.5×107 spores. Each sample was subjected to a temperature of 110° C. for 3 hours and 10 min in a Baxter Constant Temperature Oven using the same technique as in Example 1. The spore population of the samples was measured and the results obtained are shown below in Table 2.
    TABLE 2
    Compound Before After
    Calcium stearate 1.5 × 107 spores 3.3 × 106 spores
    Budesonide 1.5 × 107 spores <10 spores
  • As a result of the heat treatment, a spore log reduction of greater than 6.2 was obtained in the inoculated sample of budesonide, whereas the log reduction was less than 0.7 in the inoculated sample of calcium stearate.
    • EXAMPLE 3
  • Tests were performed to evaluate the heat resistance of various naturally occurring microorganisms.
  • Samples of 0.5 g of budesonide powder were each inoculated with approximately 102-103 viable ATCC microorganisms in 120 ml open-ended polypropylene container. Each sample was subjected to a temperature of 110° C. for 3 hours and 10 min. The microorganism population of the samples was measured before and after heat treatment and the results obtained are shown below in Table 3.
    TABLE 3
    Microorganism Before After
    E. coli 450 0
    B. subtilis ATCC 6633 300 0
    Salmonella typhi 270 0
    C. albicans 780 0
    A. niger 260 0
    M. luteus 300 0
    S. epidermidis 240 0
    C. sporogenes 160 0
    Ps. Aeruginosa 350 0
    B. subtilis ATCC 6633 1.2 × 105 11

    1A singular bacillus species was found, verified by Gram stain in the 100 dilution plate.
  • As is evident from Table 3, heat treatment of budesonide at 110° C. for 3 hours and 10 min, is an effective sterilizing method for a substantial variety of microorganisms.
    • EXAMPLE 4
  • A formulation comprising finely divided budesonide sterilized by the method of Example 2, and meeting the criteria of sterility according to the US Pharmacopoeia 23/NF18, 1995, was prepared by mixing the following ingredients:
    TABLE 4
    Micronized budesonide 0.125 mg
    Disodium edetate 0.1 mg
    Sodium chloride 8.5 mg
    Polysorbate 80 0.2 mg
    Anhydrous citric acid 0.28 mg
    Sodium citrate 0.5 mg
    Purified water to 1 ml
  • All the components, other than the budesonide, were produced by sterile filtration of their aqueous solutions and an appropriate volume of the resulting suspension (about 2 ml) was filled under aseptic conditions into pre-sterilized 5 ml containers to produce a sterile product.
  • The resulting suspension may be stored under an over-pressure of sterile nitrogen and may be filled into containers using a blow/fill/seal system.
    • EXAMPLE 5
  • A sterile formulation comprising finely divided budesonide sterilized by the method of Example 2, can be prepared by mixing the following ingredients:
    TABLE 5
    Micronized budesonide 2-3 mg
    Disodium edetate 0.1 mg
    Sodium chloride 8.5 mg
    Stabilizing agent 0.02-2 mg
    Anhydrous citric acid 0.28 mg
    Sodium citrate 0.5 mg
    Purified water to 1 ml
  • All the components, other than the budesonide, can be produced by sterile filtration of their aqueous solutions and an appropriate volume of the resulting suspension (about 2 ml) filled under aseptic conditions into pre-sterilized 5 ml containers to produce a sterile product.
  • The resulting suspension may be stored under an over-pressure of sterile nitrogen and may be filled into containers using a blow/fill/seal system.
    • EXAMPLE 6
  • 5 g of micronized budesonide was inoculated with approximately 2 ml of a spore suspension of Bacillus subtilis.
  • The substance and the spore suspension were mixed and dried for approximately 3 hours at 55° C. The inoculated and dried budesonide was mixed with 20-40 g of non-inoculated micronized budesonide.
  • 5 g portions of this sample were heat treated at 100° C., 110° C. in a Heraeus ST 5060 heating apparatus. A 1 g sample was withdrawn after various heating times at the respective heating temperatures. Each such 1 g sample was transferred to 10 ml of dilution medium pH 7.2. Appropriate dilutions were made in 0.1% Peptone Aqueous solution and the number of spores/g were determined by a pour plate technique according to US Pharmacopoeia 23/NF18. 1995, pp. 1681-1686, especially p. 1684.
  • The number of spores before heat treatment were determined in samples heated at 80° C. for 10 min in order to kill the vegetative cells.
  • The results are shown in Table 6, where the DT value is the amount of time in minutes required to obtain a log 1 reduction in the number of spores before and after heat treatment at the temperature T (in ° C.).
    TABLE 6
    Heating at 100° C.
    80° C. Heating time at 100° C.
    10 min 15 min 45 min 75 min
    spores/g 6.5 × 106 4.8 × 103 7.1 × 102 1.7 × 102
    log spores/g 6.81 3.68 2.85 2.23
    D100 = 41.5 min; correlation coefficient = −0.0996
    This means that it takes 6 × 41.5 minutes to obtain a log 6 reduction in
    the number of spores at a temperature of 100° C.
    Heating at 110° C.
    80° C. Heating time at 110° C.
    10 min 5 min 15 min 20 min
    spores/g 2 × 106 2.08 × 104 9.25 × 102 3.55 × 102
    log spores/g 6.20 4.32 2.97 2.55
    D110 = 8.3 min; correlation coefficient = −0.995
    This means that it takes 6 × 8.3 minutes to obtain a log 6 reduction in
    the number of spores at a temperature of 110° C.
    Heating at 120° C.
    80° C. Heating time at 120° C.
    10 min 4 min 6 min 8 min
    spores/g 1.5 × 106 1.9 × 102 5.5 × 101 2 × 101
    log spores/g 6.19 2.28 1.74 1.30
    D120 = 4.1 min; correlation coefficient = −0.998
    This means that it takes 6 × 4.1 minutes to obtain a log 6 reduction in
    the number of spores at a temperature of 120° C.
    • EXAMPLE 7
  • 1 g of micronized budesonide, prednisolone and beclomethasone dipropionate and 0.5 g of rofleponide were inoculated with a different spore suspension to the one used in Example 6.
  • The samples were heat treated at 110° C. A sample was withdrawn after various heating times. The number of spores/g were determined by a pour plate technique according to US Pharmacopoeia 23/NF18, 1995, pp. 1681-1686, especially p. 1684.
  • From the number of spores before and after heat treatment the log reduction of spores and decimal reduction time (time needed at a specified temperature to reduce the number of microorganisms with one log) was calculated.
  • The results are shown in Table 7.
    TABLE 7
    Heating at 110° C.
    Glucocorticosteroid D110 value in min
    Budesonide 41
    Rofleponide 9.8
    Beclomethasone dipropionate 72.7
    Prednisolone 73.8
  • Table 7 clearly shows that the present process is very efficient in reducing the number of spores in samples containing glucocorticosteroids. The process is especially efficient with budesonide and rofleponide. In fact analysis conducted on a full 1.0 g sample of rofleponide yielded total kill at very short cycle times (≧5 minutes at 110° C.), where a D110 value could not be calculated.
    • COMPARATIVE EXAMPLE 8
  • Irradiation
  • About 3 g of micronized budesonide substance stored in a plastic container, were subjected to irradiation. The substance was exposed to β-irradiation at 2.5 to 25 kGy and γ-irradiation at 8 to 32 kGy. After the exposure the budesonide content and the amount of related substances were determined by liquid chromatography. The chemical stability of budesonide was considered to be the most critical parameter to study.
    TABLE 8
    Stability of micronized budesonide substance during
    sterilization by irradiation
    Exposure Ref. β β β β β γ γ
    Intensity (kGy) 1) 2.5 5 10 17 25 7.8 31.9
    Budesonide 99.5- 99.1 98.9 98.9 98.8 98.8 97.9 95.0
    content (%) 99.8
    Related
    substances
    Total of known 0.13- 0.19 0.19 0.18 0.20 0.21 0.34 0.51
    foreign steroids 0.15
    Total of 0.03- 0.19 0.24 0.26 0.36 0.43 0.68 1.8
    unknown 0.04
    foreign steroids

    1) The analysis was done on different days and the reference was analyzed at all occasions
  • From the results in Table 8, it can be seen that the budesonide content decreases in samples exposed to β- and y-irradiation. Several new degradation products were observed, especially for the γ-irradiated sample. In addition the mass balance for both β- and γ-irradiated samples is poor. The budesonide content has decreased by 0.5-4.6 per cent, when exposed to β- or γ-irradiation.
  • It can be concluded that micronized budesonide can not be satisfactorily sterilized with β- or γ-irradiation, due to significant chemical degradation.

Claims (51)

1.-31. (canceled)
32. A method of manufacturing a sterile composition, the method comprising
(a) providing a powder composition comprising a glucocorticosteroid or an ester, acetal, or salt thereof, wherein the glucocorticosteroid contains an asymmetric acetal structure comprising 16α,17α-butylidenedioxy; and
(b) sterilizing the powder composition by a method comprising heat sterilization.
33. The method of claim 32, wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 130° C.
34. The method of claim 32, wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 120° C.
35. The method of claim 32, wherein the heat sterilization comprises heating the powder composition to a temperature of about 110° C.
36. The method of claim 32, wherein the glucocorticosteroid is an anti-inflammatory glucocorticosteroid.
37. The method of claim 32, wherein the glucocorticosteroid or ester, acetal, or salt thereof is selected from the group consisting of budesonide, rofleponide, and rofleponide palmitate.
38. The method of claim 32, wherein the heat sterilization is performed or no longer than 10 hours.
39. The method of claim 32, wherein the heat sterilization is carried out in air.
40. The method of claim 63, wherein the heat sterilization is carried out under an inert gas atmosphere.
41. The method of claim 32, wherein the heat sterilization comprises a dry-heat treatment.
42. The method of claim 32, wherein the glucocorticosteroid is budesonide.
43. The method of claim 32, wherein the glucocorticosteroid is isomerically pure budesonide.
44. The method of claim 43, wherein the budesonide is in the form of the (22R) diasteroisomer.
45. The method of claim 32, wherein the powder composition contains less than about 1% (w/w) of water at a point just before the heat sterilization.
46. The method of claim 32, wherein the powder composition consists of particles having a mass median diameter of less than 10 μm.
47. The method of claim 32, wherein the powder composition consists of particles having a mass median diameter of less than 5 μm.
48. The method of claim 32, wherein the number of heat resistant spores in the powder composition is reduced by more than log 6 by the heat sterilization.
49. The method of claim 32, wherein the number of heat resistant spores in the powder composition is reduced by more than log 7 by the heat sterilization.
50. The method of claim 32, wherein the heat sterilization comprises heating the powder composition for a time less than 90 minutes and at a temperature in the range of 100 to 130° C.
51. A method of manufacturing a sterile composition, comprising
(a) providing a powder composition comprising particles of budesonide or an ester, acetal or salt thereof, wherein the particles have a mass median diameter of less than 10 μm; and
(b) dry-heating the powder composition at a temperature in the range of 100 to 130° C., thereby producing the sterile powder composition.
52. The method of claim 51, wherein the temperature is in the range of from 100 to 120° C.
53. The method of claim 51, wherein the temperature is in the range of about 110° C.
54. The method of claim 51, wherein the powder composition is dry-heated for no longer than 10 hours.
55. The method of claim 51, wherein the dry-heating is carried out in air.
56. The method of claim 51, wherein the dry-heating is carried out under an inert gas atmosphere.
57. The method of claim 51, wherein the budesonide is isomerically pure.
58. The method of claim 57, wherein the budesonide is in the form of the (22R) diastereoisomer.
59. The method of claim 51, wherein the powder composition contains less than about 1% (w/w) of water at a pint just before the dry-heating.
60. The method of claim 51, wherein the particles of budesonide have a mass median diameter of less than 5 μm.
61. The method of claim 51, wherein the number of heat resistant spores in the powder composition is reduced by more than log6 by the dry-heating.
62. The method of claim 51, wherein the amount of heat resistant spores in the powder composition is reduced by more than log7 by the dry heating.
63. A method of manufacturing a sterile composition, the method comprising
(a) manufacturing a powder composition comprising a glucocorticosteroid or an ester, acetal, or salt thereof, wherein the glucocorticosteroid contains an asymmetric acetal structure comprising 16α,17α-butylidenedioxy, and
(b) sterilizing the powder composition by a method comprising heat sterilization.
64. The method of claim 63, further comprising combining the sterilized powder composition produced in step (b) with a sterile aqueous solution to produce a sterile aqueous suspension of the powder.
65. The method of claim 63, wherein step (a) comprises micronizing the glucocorticosteroid or ester, acetal, or salt thereof to produce particles having a mass median diameter of less than 10 μm.
66. The method of claim 63, wherein step (a) comprises micronizing the glucocorticosteroid or ester, acetal, or salt thereof to produce particles having a mass median diameter of less than 5 μm.
67. The method of claim 63, wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 130° C.
68. The method of claim 63, wherein the heat sterilization comprises heating the powder composition to a temperature in the range of 100 to 120° C.
69. The method of claim 63, wherein the heat sterilization comprises heating the powder composition to a temperature of about 110° C.
70. The method of claim 63, wherein the glucocorticosteroid is an anti-inflammatory glucocorticosteroid.
71. The method of claim 63, wherein the glucocorticosteroid or ester, acetal, or salt thereof is selected from the group consisting of budesonide, rofleponide, and rofleponide palmitate.
72. The method of claim 63, wherein the heat sterilization is performed for no longer than 10 hours.
73. The method of claim 63, wherein the heat sterilization is carried out in air.
74. The method of claim 63, wherein the heat sterilization is carried out under an inert gas atmosphere.
75. The method of claim 63, wherein the heat sterilization comprises a dry-heat treatment.
76. The method of claim 63, wherein the glucocorticosteroid is budesonide.
77. The method of claim 63, wherein the glucocorticosteroid is isomerically pure budesonide.
78. The method of claim 77, wherein the budesonide is in the form of the (22R) diastereoisomer.
79. The method of claim 63, wherein the powder composition contains less than about 1% (w/w) of water at a point just before the heat sterilization.
80. The method of claim 63, wherein the number of heat resistant spores in the powder composition is reduced by more than log6 by the heat sterilization.
81. The method of claim 63, wherein the number of heat resistant spores in the powder composition is reduced by more than log7 by the heat sterilization.
US11/690,537 1997-11-14 2007-03-23 Composition of matter Abandoned US20070197489A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/690,537 US20070197489A1 (en) 1997-11-14 2007-03-23 Composition of matter

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
SE9704186-7 1997-11-14
SE9704186A SE9704186D0 (en) 1997-11-14 1997-11-14 New composition of matter
PCT/SE1998/002039 WO1999025359A1 (en) 1997-11-14 1998-11-11 New composition of matter
US09/230,781 US6392036B1 (en) 1997-11-14 1998-11-11 Dry heat sterilization of a glucocorticosteroid
US09/993,669 US7524834B2 (en) 1997-11-14 2001-11-27 Sterile powders, formulations, and methods for producing the same
US11/690,537 US20070197489A1 (en) 1997-11-14 2007-03-23 Composition of matter

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09/993,669 Continuation US7524834B2 (en) 1997-11-14 2001-11-27 Sterile powders, formulations, and methods for producing the same

Publications (1)

Publication Number Publication Date
US20070197489A1 true US20070197489A1 (en) 2007-08-23

Family

ID=20408992

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/230,781 Expired - Lifetime US6392036B1 (en) 1997-11-14 1998-11-11 Dry heat sterilization of a glucocorticosteroid
US09/993,669 Expired - Fee Related US7524834B2 (en) 1997-11-14 2001-11-27 Sterile powders, formulations, and methods for producing the same
US11/690,537 Abandoned US20070197489A1 (en) 1997-11-14 2007-03-23 Composition of matter

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US09/230,781 Expired - Lifetime US6392036B1 (en) 1997-11-14 1998-11-11 Dry heat sterilization of a glucocorticosteroid
US09/993,669 Expired - Fee Related US7524834B2 (en) 1997-11-14 2001-11-27 Sterile powders, formulations, and methods for producing the same

Country Status (24)

Country Link
US (3) US6392036B1 (en)
EP (1) EP1032396B1 (en)
JP (2) JP4598268B2 (en)
KR (1) KR100571075B1 (en)
CN (1) CN1173702C (en)
AR (1) AR013765A1 (en)
AT (1) ATE259642T1 (en)
AU (1) AU744992B2 (en)
BR (1) BR9814118A (en)
CA (1) CA2310222C (en)
DE (1) DE69821796T2 (en)
DK (1) DK1032396T3 (en)
ES (1) ES2214749T3 (en)
HK (1) HK1030549A1 (en)
IL (1) IL136086A (en)
MY (1) MY118856A (en)
NO (1) NO327391B1 (en)
NZ (1) NZ504273A (en)
PT (1) PT1032396E (en)
SA (1) SA99190966B1 (en)
SE (1) SE9704186D0 (en)
TW (1) TWI242436B (en)
WO (1) WO1999025359A1 (en)
ZA (1) ZA9810217B (en)

Families Citing this family (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0810853B1 (en) * 1995-02-24 2004-08-25 Elan Pharma International Limited Aerosols containing nanoparticle dispersions
SE9704186D0 (en) * 1997-11-14 1997-11-14 Astra Ab New composition of matter
US20090297602A1 (en) * 1998-11-02 2009-12-03 Devane John G Modified Release Loxoprofen Compositions
IT1303692B1 (en) * 1998-11-03 2001-02-23 Chiesi Farma Spa PROCEDURE FOR THE PREPARATION OF SUSPENSIONS OF PARTICLES OF DRUGS TO BE ADMINISTERED BY INHALATION.
AR026073A1 (en) * 1999-10-20 2002-12-26 Nycomed Gmbh PHARMACEUTICAL COMPOSITION AQUATIC CONTAINING CICLESONIDE
AR026072A1 (en) * 1999-10-20 2002-12-26 Nycomed Gmbh PHARMACEUTICAL COMPOSITION CONTAINING CICLESONIDE FOR MUCOSA APPLICATION
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
GB0019172D0 (en) 2000-08-05 2000-09-27 Glaxo Group Ltd Novel compounds
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6787532B2 (en) * 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
EP1337279B1 (en) * 2000-11-24 2006-06-21 Breath Limited Sterilisation of glucocorticosteriode suspensions
UA77656C2 (en) 2001-04-07 2007-01-15 Glaxo Group Ltd S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent
US6667344B2 (en) * 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US20030055026A1 (en) * 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
GB0130055D0 (en) * 2001-12-14 2002-02-06 Technology Innovation Ltd Medicament packaging
US20030129242A1 (en) * 2002-01-04 2003-07-10 Bosch H. William Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer
PT1471887E (en) 2002-02-04 2010-07-16 Elan Pharma Int Ltd Nanoparticulate compositions having lysozyme as a surface stabilizer
EP1476201B1 (en) * 2002-02-19 2008-12-24 Resolution Chemicals Limited Solvent-based sterilisation of steroids
GB2389530B (en) 2002-06-14 2007-01-10 Cipla Ltd Pharmaceutical compositions
CN100366256C (en) * 2002-07-02 2008-02-06 奥坦纳医药公司 Ciclesonide-containing sterile aqueous suspension
US20040023935A1 (en) * 2002-08-02 2004-02-05 Dey, L.P. Inhalation compositions, methods of use thereof, and process for preparation of same
US20040105778A1 (en) * 2002-10-04 2004-06-03 Elan Pharma International Limited Gamma irradiation of solid nanoparticulate active agents
US20040109826A1 (en) * 2002-12-06 2004-06-10 Dey, L.P. Stabilized albuterol compositions and method of preparation thereof
WO2004052374A1 (en) 2002-12-12 2004-06-24 Altana Pharma Ag Combination medicament
US20040208833A1 (en) * 2003-02-04 2004-10-21 Elan Pharma International Ltd. Novel fluticasone formulations
EP1454636A1 (en) * 2003-03-04 2004-09-08 Dompé S.P.A. Sterilization of glucocorticoid drug particles for pulmonary delivery
DE602004028585D1 (en) * 2003-03-15 2010-09-23 Brin Tech Internat Ltd Packaging for medicines
US7811606B2 (en) * 2003-04-16 2010-10-12 Dey, L.P. Nasal pharmaceutical formulations and methods of using the same
US8912174B2 (en) 2003-04-16 2014-12-16 Mylan Pharmaceuticals Inc. Formulations and methods for treating rhinosinusitis
US9808471B2 (en) * 2003-04-16 2017-11-07 Mylan Specialty Lp Nasal pharmaceutical formulations and methods of using the same
JP2007501683A (en) * 2003-05-22 2007-02-01 エラン ファーマ インターナショナル リミテッド Sterilization of nanoparticle active substance dispersions by gamma irradiation
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
GB0319500D0 (en) 2003-08-19 2003-09-17 Resolution Chemicals Ltd Particle-size reduction apparatus,and use thereof
PT1670482E (en) 2003-09-16 2014-03-12 Takeda Gmbh Use of ciclesonide for the treatment of respiratory diseases
PE20050941A1 (en) * 2003-12-16 2005-11-08 Nycomed Gmbh AQUEOUS CYCLESOUND SUSPENSIONS FOR MISTING
ATE446581T1 (en) * 2004-03-12 2009-11-15 Trinity College Dublin MAGNETORRESISTIVE MEDIUM
US7892483B2 (en) * 2004-03-12 2011-02-22 Cipla Limited Sterilization process
US20070134165A1 (en) * 2004-04-20 2007-06-14 Altana Pharma Ag Use of Ciclesonide for the Treatment of Respiratory Disease in a Smoking Patient
ITMI20040795A1 (en) * 2004-04-23 2004-07-23 Eratech S R L DRY SOLID PHARMACEUTICAL COMPOSITION ON ITS STABLE WATER PREPARATION AND SUSPENSION PROCESS OBTAINED BY ITSELF
GB0410995D0 (en) 2004-05-17 2004-06-23 Norton Healthcare Ltd Heat sterilization of glucocorticosteroids
ITSA20040012A1 (en) * 2004-09-07 2004-12-07 Genetec S P A STERILIZATION PROCESS OF A GLUCOCORTICOSTEROID.
GB0425266D0 (en) 2004-11-16 2004-12-15 Norton Healthcare Ltd Pharmaceutical manufacturing process
GB0427568D0 (en) 2004-12-16 2005-01-19 Resolution Chemicals Ltd Particle-size reduction apparatus, and the use thereof
EP1782839A1 (en) 2005-11-03 2007-05-09 Genetic S.p.A. Sterilization process of Glucocorticosteroid by supercritical CO2
US8497258B2 (en) 2005-11-12 2013-07-30 The Regents Of The University Of California Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract
US20090252801A1 (en) * 2005-11-29 2009-10-08 Farmbios S.P.A. Process for the Preparation of Micronised Sterile Steroids
US20070178049A1 (en) * 2005-12-20 2007-08-02 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids having an enhanced pharmacokinetic profile
US20070197486A1 (en) * 2005-12-20 2007-08-23 Verus Pharmaceuticals, Inc. Methods and systems for the delivery of corticosteroids
US20070160542A1 (en) * 2005-12-20 2007-07-12 Verus Pharmaceuticals, Inc. Methods and systems for the delivery of corticosteroids having an enhanced pharmacokinetic profile
US20070185066A1 (en) * 2005-12-20 2007-08-09 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids
US20070249572A1 (en) * 2005-12-20 2007-10-25 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids
US20070166184A1 (en) * 2006-01-13 2007-07-19 Zimmer Technology, Inc. Methods for cleaning and sterilizing devices
US20070178051A1 (en) * 2006-01-27 2007-08-02 Elan Pharma International, Ltd. Sterilized nanoparticulate glucocorticosteroid formulations
CA2642577A1 (en) * 2006-02-15 2007-08-23 Tika Lakemedel Ab Methods of manufacturing corticosteroid solutions
FR2898273B1 (en) * 2006-03-07 2013-11-08 Merck Generiques DRY-HEATING STERILIZATION PROCESS OF A POWDER COMPRISING A GLUCOCORTICOSTEROID
EP2043698A2 (en) * 2006-07-20 2009-04-08 Sicor, Inc. Process for the preparation of solid sterile active pharmaceutical ingredient
CN101265342B (en) * 2007-03-12 2014-04-02 广东炜林纳功能材料有限公司 Composite beta crystal-type nucleater of polypropylene
CN102226026B (en) * 2007-03-12 2013-12-18 广东炜林纳功能材料有限公司 Compound beta-crystal nucleating agent used for polypropylene
AU2008323676B2 (en) * 2007-11-09 2014-04-03 Map Pharmaceuticals, Inc. Methods for administering corticosteroid formulations
GB2458403B (en) * 2007-11-13 2010-01-13 Meritage Pharma Inc Stabilised corticosteroid compositions
US20090123390A1 (en) 2007-11-13 2009-05-14 Meritage Pharma, Inc. Compositions for the treatment of gastrointestinal inflammation
KR20190026056A (en) * 2008-04-21 2019-03-12 오토노미, 인코포레이티드 Auris formulations for treating otic diseases and conditions
WO2009139924A2 (en) 2008-05-14 2009-11-19 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8648119B2 (en) * 2008-05-23 2014-02-11 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
US20090311335A1 (en) * 2008-06-12 2009-12-17 Scott Jenkins Combination of a triptan and an nsaid
US8846770B2 (en) 2008-06-18 2014-09-30 Otonomy, Inc. Controlled release aural pressure modulator compositions and methods for the treatment of OTIC disorders
WO2010011466A2 (en) 2008-06-27 2010-01-28 Otonomy, Inc. Controlled-release cns modulating compositions and methods for the treatment of otic disorders
US8349353B2 (en) * 2008-06-27 2013-01-08 Otonomy, Inc. Controlled release cytotoxic agent compositions and methods for the treatment of otic disorders
AU2009271129B2 (en) * 2008-07-14 2013-10-10 Otonomy, Inc. Controlled-release apoptosis modulating compositions and methods for the treatment of otic disorders
US8318817B2 (en) 2008-07-21 2012-11-27 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US8399018B2 (en) * 2008-07-21 2013-03-19 Otonomy, Inc. Controlled release ion channel modulator compositions and methods for the treatment of otic disorders
US8496957B2 (en) * 2008-07-21 2013-07-30 Otonomy, Inc Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
JP5421366B2 (en) * 2008-07-21 2014-02-19 オトノミ―，インク． Controlled release otic structure modulating and innate immune system modulating compounds and methods for treatment of otic disorders
US20100016450A1 (en) * 2008-07-21 2010-01-21 Otonomy, Inc. Controlled release delivery devices for the treatment of otic disorders
US8784870B2 (en) * 2008-07-21 2014-07-22 Otonomy, Inc. Controlled release compositions for modulating free-radical induced damage and methods of use thereof
AU2009307825A1 (en) 2008-10-22 2010-04-29 Rick FRIEDMAN Treatment and/or prevention of inner ear conditions by modulation of a metabotropic glutamate receptor
KR20100079830A (en) * 2008-12-31 2010-07-08 삼성정밀화학 주식회사 Method for preparing toner having narrow particle size distribution
US20180009767A9 (en) 2009-03-19 2018-01-11 The Johns Hopkins University Psma targeted fluorescent agents for image guided surgery
EP3964498A1 (en) 2009-03-19 2022-03-09 The Johns Hopkins University Psma-targeting compounds and uses thereof
US8273725B2 (en) 2009-09-10 2012-09-25 Genzyme Corporation Stable hyaluronan/steroid formulation
WO2011135585A2 (en) * 2010-04-28 2011-11-03 Cadila Healthcare Limited Aqueous pharmaceutical solution of ciclesonide
WO2012150131A1 (en) 2011-05-03 2012-11-08 Chiesi Farmaceutici S.P.A. Improved suspension formulation of a corticosteroid for administration by inhalation
MX362187B (en) * 2013-03-15 2019-01-08 Oakwood Laboratories Sustained release microspheres and method of producing the same.
AU2014311358A1 (en) 2013-08-27 2016-04-07 Otonomy, Inc. Treatment of pediatric otic disorders
NO3193835T3 (en) * 2014-09-15 2018-08-04
US11040004B2 (en) 2016-09-16 2021-06-22 Otonomy, Inc. Otic gel formulations for treating otitis externa
WO2018232280A1 (en) 2017-06-15 2018-12-20 The Johns Hopkins University Psma targeted fluorescent agents for image guided surgery
AU2018318123A1 (en) 2017-08-15 2020-03-19 Nephron Pharmaceuticals Corporation Aqueous nebulization composition
CN107510687B (en) * 2017-08-18 2020-07-03 南京海纳医药科技股份有限公司 Inhalation suspension containing formoterol and budesonide for atomization and preparation method thereof
CN108175763B (en) * 2017-12-19 2020-09-11 亿腾医药（苏州）有限公司 Budesonide sterile raw material and preparation method of suspension for inhalation thereof

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337400A (en) * 1965-10-08 1967-08-22 Joel P Smith Aqueous post-surgical injection by infiltration with a local anesthetic, a substantially water-insoluble, local anti-inflammatory gluco corticoid, and an antibiotic
US3692430A (en) * 1971-06-18 1972-09-19 John W Timmons Liquid pumping system
US3992534A (en) * 1972-05-19 1976-11-16 Ab Bofors Compositions and method of treating with component B of stereoisomeric mixtures of 2'-unsymmetrical 16,17-methylenedioxy steriods
US4263253A (en) * 1978-08-25 1981-04-21 Bayer Aktiengesellschaft Process for rendering solids sterile
US5049389A (en) * 1988-12-14 1991-09-17 Liposome Technology, Inc. Novel liposome composition for the treatment of interstitial lung diseases
US5192528A (en) * 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
US5407926A (en) * 1987-12-29 1995-04-18 Alcon Laboratories, Inc. Ophthalmic composition
US5521168A (en) * 1994-10-13 1996-05-28 Alcon Laboratories, Inc. Estrogen metabolites for lowering intraocular pressure
US5540930A (en) * 1993-10-25 1996-07-30 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
US5556964A (en) * 1989-10-02 1996-09-17 Aktiebolaget Astra Process for the manufacture of budesonide
US5637620A (en) * 1993-08-27 1997-06-10 Astra Aktiebolag Micro formoterol particles
US5700794A (en) * 1994-10-13 1997-12-23 Alcon Laboratories Inc. Treatment of ocular hypotony
US5792758A (en) * 1995-12-08 1998-08-11 G. D. Searle & Co. Steroid nitrite ester derivatives useful as anti-inflammatory drugs
US5824668A (en) * 1996-11-07 1998-10-20 Supergen, Inc. Formulation for administration of steroid compounds
US5837699A (en) * 1994-01-27 1998-11-17 Schering Corporation Use of mometasone furoate for treating upper airway passage diseases
US5858998A (en) * 1997-09-26 1999-01-12 Dr. Falk Pharma Gmbh Budesonide alone or in combination with ursodeoxycholic acid in the therapy of cholestatic liver diseases
US6066292A (en) * 1997-12-19 2000-05-23 Bayer Corporation Sterilization process for pharmaceutical suspensions
US6153607A (en) * 1995-12-04 2000-11-28 University Of Miami Non-preserved topical corticosteroid for treatment of dry eye, filamentary keratitis, and delayed tear clearance (or turnover)
US6187765B1 (en) * 1997-10-09 2001-02-13 Schering Corporation Mometasone furoate suspensions for nebulization
US6241969B1 (en) * 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
US6291445B1 (en) * 1996-12-05 2001-09-18 Astra Aktiebolag Low dose budesonide formulations and uses thereof
US6468958B2 (en) * 1995-03-15 2002-10-22 Ciba Specialty Chemicals Corporation Biphenyl-substituted triazines
US6863865B2 (en) * 2000-11-24 2005-03-08 Breath Limited Sterilization of pharmaceuticals
US20050089476A1 (en) * 2003-10-22 2005-04-28 MONTERESEARCH S.r.I. Process for the preparation of pharmaceutical suspensions for inhalation
US20050201888A1 (en) * 2004-03-12 2005-09-15 Cipla Limited Sterilization process

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US396430A (en) * 1889-01-22 Helm reichel
US3962430A (en) * 1974-08-07 1976-06-08 Merck & Co., Inc. Sterilization of solid non-electrolyte medicinal agents employing sodium chloride
PT69652A (en) 1979-05-22 1979-06-01 Quatrum Empresa Nacional De Qu PROCESS FOR THE STERILIZATION OF NON-STABLE PRODUCTS AT HIGH TEMPERATURES NAMELY STEROID IN POWDER FORM CONTAINED IN A CLOSED PACKAGING
JPS5732212A (en) 1980-08-07 1982-02-20 Mitsui Toatsu Chem Inc Sterilizing method of acetylsalicylate salt
JPH0660106B2 (en) 1985-11-14 1994-08-10 徳男 斎藤 Manufacturing method of sterile pills mainly composed of crude drugs
US5380645A (en) * 1989-03-16 1995-01-10 The Johns Hopkins University Generalized method for assessment of colorectal carcinoma
IE912365A1 (en) * 1990-07-23 1992-01-29 Zeneca Ltd Continuous release pharmaceutical compositions
PL164294B1 (en) 1990-12-20 1994-07-29 Inst Farmaceutyczny Method of obtaining a diasteroisomer (22r) of budezonide
US5491062A (en) * 1993-11-23 1996-02-13 Stratagene Polynucleotide amplification mycoplasma assay, primers, and kits therefore
US5843644A (en) * 1994-03-01 1998-12-01 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Isolation of cellular material under microscopic visualization using an adhesive/extraction reagent tipped probe
GB9410222D0 (en) * 1994-05-21 1994-07-06 Glaxo Wellcome Australia Ltd Medicaments
US5580728A (en) * 1994-06-17 1996-12-03 Perlin; Mark W. Method and system for genotyping
WO1996009410A1 (en) * 1994-09-23 1996-03-28 Finkelstein Sydney D Topographic genotyping
JPH10506406A (en) 1994-09-29 1998-06-23 アンダリス、リミテッド Spray-dried fine particles as therapeutic vehicles
SE9501384D0 (en) * 1995-04-13 1995-04-13 Astra Ab Process for the preparation of respirable particles
AU6290396A (en) * 1995-06-29 1997-01-30 Mcneil-Ppc, Inc. The combination of topical nasal mast cell stabilizers and topical nasal steroids
JPH0930988A (en) * 1995-07-21 1997-02-04 Sumitomo Osaka Cement Co Ltd Sustained release porous ceramic molding for medicine and its production
WO1999018971A1 (en) 1997-10-09 1999-04-22 Schering Corporation Mometasone furoate suspensions for nebulization
SE9704186D0 (en) * 1997-11-14 1997-11-14 Astra Ab New composition of matter
EP1476201B1 (en) 2002-02-19 2008-12-24 Resolution Chemicals Limited Solvent-based sterilisation of steroids
ITMI20022674A1 (en) 2002-12-18 2004-06-19 Chiesi Farma Spa PROCEDURE FOR THE PREPARATION OF STERILE FORMULATIONS BASED ON MICRONIZED CRYSTALLINE PHARMACEUTICAL ACTIVE SUBSTANCES TO BE ADMINISTERED AS WATER SUSPENSION BY INHALATION.

Patent Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337400A (en) * 1965-10-08 1967-08-22 Joel P Smith Aqueous post-surgical injection by infiltration with a local anesthetic, a substantially water-insoluble, local anti-inflammatory gluco corticoid, and an antibiotic
US3692430A (en) * 1971-06-18 1972-09-19 John W Timmons Liquid pumping system
US3992534A (en) * 1972-05-19 1976-11-16 Ab Bofors Compositions and method of treating with component B of stereoisomeric mixtures of 2'-unsymmetrical 16,17-methylenedioxy steriods
US4263253A (en) * 1978-08-25 1981-04-21 Bayer Aktiengesellschaft Process for rendering solids sterile
US5192528A (en) * 1985-05-22 1993-03-09 Liposome Technology, Inc. Corticosteroid inhalation treatment method
US5407926A (en) * 1987-12-29 1995-04-18 Alcon Laboratories, Inc. Ophthalmic composition
US5049389A (en) * 1988-12-14 1991-09-17 Liposome Technology, Inc. Novel liposome composition for the treatment of interstitial lung diseases
US5556964A (en) * 1989-10-02 1996-09-17 Aktiebolaget Astra Process for the manufacture of budesonide
US5637620A (en) * 1993-08-27 1997-06-10 Astra Aktiebolag Micro formoterol particles
US5540930A (en) * 1993-10-25 1996-07-30 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
US5837699A (en) * 1994-01-27 1998-11-17 Schering Corporation Use of mometasone furoate for treating upper airway passage diseases
US5521168A (en) * 1994-10-13 1996-05-28 Alcon Laboratories, Inc. Estrogen metabolites for lowering intraocular pressure
US5700794A (en) * 1994-10-13 1997-12-23 Alcon Laboratories Inc. Treatment of ocular hypotony
US6468958B2 (en) * 1995-03-15 2002-10-22 Ciba Specialty Chemicals Corporation Biphenyl-substituted triazines
US6153607A (en) * 1995-12-04 2000-11-28 University Of Miami Non-preserved topical corticosteroid for treatment of dry eye, filamentary keratitis, and delayed tear clearance (or turnover)
US5792758A (en) * 1995-12-08 1998-08-11 G. D. Searle & Co. Steroid nitrite ester derivatives useful as anti-inflammatory drugs
US5824668A (en) * 1996-11-07 1998-10-20 Supergen, Inc. Formulation for administration of steroid compounds
US6291445B1 (en) * 1996-12-05 2001-09-18 Astra Aktiebolag Low dose budesonide formulations and uses thereof
US5858998A (en) * 1997-09-26 1999-01-12 Dr. Falk Pharma Gmbh Budesonide alone or in combination with ursodeoxycholic acid in the therapy of cholestatic liver diseases
US6187765B1 (en) * 1997-10-09 2001-02-13 Schering Corporation Mometasone furoate suspensions for nebulization
US6066292A (en) * 1997-12-19 2000-05-23 Bayer Corporation Sterilization process for pharmaceutical suspensions
US6241969B1 (en) * 1998-06-26 2001-06-05 Elan Corporation Plc Aqueous compositions containing corticosteroids for nasal and pulmonary delivery
US6863865B2 (en) * 2000-11-24 2005-03-08 Breath Limited Sterilization of pharmaceuticals
US20050089476A1 (en) * 2003-10-22 2005-04-28 MONTERESEARCH S.r.I. Process for the preparation of pharmaceutical suspensions for inhalation
US20050201888A1 (en) * 2004-03-12 2005-09-15 Cipla Limited Sterilization process

Also Published As

Publication number Publication date
CN1285750A (en) 2001-02-28
CA2310222C (en) 2008-05-13
EP1032396B1 (en) 2004-02-18
DK1032396T3 (en) 2004-05-24
DE69821796D1 (en) 2004-03-25
JP4598268B2 (en) 2010-12-15
KR100571075B1 (en) 2006-04-14
US20020065256A1 (en) 2002-05-30
CN1173702C (en) 2004-11-03
ATE259642T1 (en) 2004-03-15
WO1999025359A1 (en) 1999-05-27
MY118856A (en) 2005-01-31
TWI242436B (en) 2005-11-01
IL136086A0 (en) 2001-05-20
NZ504273A (en) 2002-10-25
EP1032396A1 (en) 2000-09-06
AR013765A1 (en) 2001-01-10
JP2010070567A (en) 2010-04-02
ES2214749T3 (en) 2004-09-16
ZA9810217B (en) 1999-05-14
NO20002470L (en) 2000-07-05
BR9814118A (en) 2000-10-03
JP2001523638A (en) 2001-11-27
SA99190966B1 (en) 2006-03-07
HK1030549A1 (en) 2001-05-11
KR20010032088A (en) 2001-04-16
NO20002470D0 (en) 2000-05-12
NO327391B1 (en) 2009-06-22
IL136086A (en) 2005-05-17
SE9704186D0 (en) 1997-11-14
US6392036B1 (en) 2002-05-21
US7524834B2 (en) 2009-04-28
AU744992B2 (en) 2002-03-07
AU1266699A (en) 1999-06-07
DE69821796T2 (en) 2005-01-13
CA2310222A1 (en) 1999-05-27
PT1032396E (en) 2004-06-30

Similar Documents

Publication Publication Date Title
US6392036B1 (en) Dry heat sterilization of a glucocorticosteroid
EP1126823B1 (en) A process for the preparation of sterile therapeutically acceptable beclomethasone dipropionate
US7892483B2 (en) Sterilization process
EP2805712B1 (en) Heat sterilization of glucocorticoidsteriods
JP5001657B2 (en) Aqueous suspension of ciclesonide for nebulization
JP4712689B2 (en) Sterilization of beclomethasone drug particles for pulmonary delivery
MXPA00004648A (en) New composition of matter
WO2022231531A1 (en) Process for the preparation of sterilized suspensions for the inhalation by nebulization
US20150290220A1 (en) Pharmaceutical formualtions comprising a Gluococorticosteroid
MXPA06006537A (en) Aqueous suspensions of ciclesonide for nebulisation

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTRA AKTIEBOLAG, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KARLSSON, ANN-KRISTIN;LARRIVEE-ELKINS, CHERYL;MOLIN, OVE;REEL/FRAME:019110/0865;SIGNING DATES FROM 19981214 TO 19990120

AS Assignment

Owner name: ASTRAZENECA AB, SWEDEN

Free format text: CERTIFICATE OF REGISTRATION;ASSIGNOR:AKTIEBOLAG, ASTRA;REEL/FRAME:019175/0721

Effective date: 20000215

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION