WO1990011754A1 - Aerosolized azole antifungals - Google Patents
Aerosolized azole antifungals Download PDFInfo
- Publication number
- WO1990011754A1 WO1990011754A1 PCT/GB1990/000513 GB9000513W WO9011754A1 WO 1990011754 A1 WO1990011754 A1 WO 1990011754A1 GB 9000513 W GB9000513 W GB 9000513W WO 9011754 A1 WO9011754 A1 WO 9011754A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical formulation
- microns
- propellant
- formulation according
- weight
- Prior art date
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the active ingredients in finely divided form may be used in admixture with a larger sized carrier comprising particles, eg of up to 400 microns diameter.
- a larger sized carrier comprising particles, eg of up to 400 microns diameter.
- Effective particle size for particles below 30 microns may be measured by a Coulter counter.
- Effective particle size for particles above 30 microns may be measured by an Alpine air jet sieve.
Abstract
There are described pharmaceutical formulations comprising as active ingredient, an azole antifungal in a form suitable for administration by inhalation. Such formulations include pressurised aerosol formulations, non-pressurised aerosol formulations and solutions/suspensions for use with a nebuliser device. Also described is finely divided powdered azole antifungal with a mass median diameter in the range 0.1 to 10 microns and a method of prophylaxis of a fungal pulmonary infection which comprises administering by inhalation a therapeutically effective amount of an azole antifungal to a patient predisposed to such an infection.
Description
Aerosolized Azole Antifungals
This invention relates to novel pharmaceutical formulations and a novel therapeutic method of using them. Invasive fungal infections cause significant morbidity and mortality especially in patients with impaired immune defenses. Because of the increasing number of immunocompromised patients due to organ transplantation, chemotherapy and AIDS, control of fungal infection is now a major health issue. In recent years, the development of the azole group of antifungal agents has contributed greatly to the treament of fungal infections. Such compounds are normally administered in suitable formulations orally, topically to the skin, or by pessary or suppository. When administered by such routes, however, even the potent azole antifungal agents have little or no effect on an established, invasive fungal infection of the lung of an immunocompromised patient.
We have now found that administration of an aerosolised formulation of a suitable azole antifungal agent to the lungs of immunocompromised patients prevents or greatly inhibits the onset of fungal disease.
According to the invention we provide a pharmaceutical formulation comprising, as active ingredient, an azole antifungal in a form suitable for administration by inhalation.
The prophylactic administration of azole antifungal agents to the lung will be particularly effective in the prevention of fungal infections whose main portal of entry is the respiratory system, especially those caused by asperσillus and cryptococcus species. In addition, use of low doses applied directly to the lungs will minimise the risks of the side effects seen with systemic antifungal agents.
By azole antifungal agents we mean those having an imidazole (structure I, X = CH) or triazole (structure I, X **■*- N) moiety.
Particular azole antifungal agents which may be mentioned are, for example, clotrimazole, econazole nitrate, fluconazole, itraconazole, ketoconazole, miconazole nitrate and saperconazole.
Forms suitable for administration by inhalation include aqueous solutions/suspensions, for use with a nebuliser device; dry powder and pressurised dry powder aerosol. Suitable nebuliser solutions/suspensions may be
prepared by adding the azole antifungal agent to water, which has preferably been distilled or sterilised. If necessary or desired the aqueous medium may include suspending agents, solubilising agents, stabilisers and/or preservatives. The formulation may additionally contain another prophylactic agent, such as pentamidine, or a bronchodilator.
For inhalation as a powder formulation the active ingredients in finely divided form may be used in admixture with a larger sized carrier comprising particles, eg of up to 400 microns diameter. We prefer at least 90% by weight of the particles of the carrier to have an effective particle size below 400 microns, and at least 50% by weight of the particles of the carrier to have an effective particle size above 30 microns. Effective particle size for particles below 30 microns may be measured by a Coulter counter. Effective particle size for particles above 30 microns may be measured by an Alpine air jet sieve.
Desirably, at least 95% by weight of the particles of the active ingredients have an effective particle size in the range 0.1 to 10 microns. Preferably at least 90% and more desirably at least 95% by weight thereof, have an effective particle size in the range 1 to 10 microns. Suitably at least 50% by weight of the particles of the active ingredients have an effective particle size in the
range 1 to 5 microns.
The particle size spectrum of the carrier will depend on the particular inhalation device from which the formulation is to be dispersed. It is however desirable to avoid carrier particles of less than 10 microns in size, thus minimising the number of non-drug particles which penetrate deep into the lung. A large proportion of very large particles may also cause a gritty feel in the mouth of the user and is therefore less preferred. Use of a carrier of large particle size may also cause problems in filling- when using filling machines which involve a dosator which picks up powder by dipping into a powder bed from above. However, use of a carrier of large particle size may ease filling when using machines in which a die is filled from above, but may incline the composition to segregate during transport or storage. Thus , desirably, at least 95% by weight of the particles of the carrier have an effective particle size below 400 microns. Preferably at least 50%, and more desirably at least 70%, by weight of the carrier particles have an effective particle size in the range 30 to 150, especially 30 to 80 microns.
The composition preferably contains from 2 to 50% by weight, more especially from 5 to 25% by weight and particularly from 10 to 15% by weight of the active ingredient, and from 50 to 98% by weight, more especially
from 75 to 95% by weight and particularly from 85 to 90% by weight of the carrier.
The finely divided active ingredients may be prepared in the desired particle size range for example using a ball mill, a fluid energy mill, by precipitation or by spray drying. The carrier may be prepared by spray drying or grinding and subsequently separating out the desired fraction, for example by air classification and/or seiving. The powder compositions may be prepared by mixing the ingredients together in one or, preferably, more (eg two) steps in a mixer, such as a planetary or other stirred mixer.
The carrier may be any non-toxic material which is chemically inert to the active ingredients and is acceptable for inhalation. Examples of carriers which may be used include inorganic salts, eg sodium chloride or calcium carbonate; organic salts, eg sodium tartrate or calcium lactate; organic compounds, eg urea or propylidone; monosaccharides, eg lactose, mannitol, arabinose or dextrose monohydrate; disaccharides, eg maltose or sucrose; polysaccharides, eg starches, dextrins or dextrans. A particularly preferred carrier is lactose, eg crystalline lactose.
The powder compositions will generally be put in sealed gelatine, plastic or other capsules. The container
is preferably loosely filled to less than about 80% by volume, preferably less than about 50% by volume with the powder composition.
Alternatively, for inhalation the active ingredients may be used in pellet or granule form, wherein the pellet or granule is soft, is from 10 to 1,000, preferably from 30 to 500 microns in diameter and comprises an agglomeration of individual medicament particles, at least 90% by weight of which have a diameter of less than 10 microns. The soft pellet or granule preferably has an internal coherence such that the pellet or granule remains intact when filled into a container, eg a capsule, using automatic or semi-automatic filling machines, under conditions of transport and storage, and when fluidised within a container in the device from which it is intended to dispense the pellets or granules and yet may be broken up into particles of a therapeutically effective size outside the container as it discharges from the container.
We have found that satisfactory soft pellets or granules for use in insufflators of the type described in British Patent No. 1,182,779 (commercially available under the Registered Trade Mark "Spinhaler") and powdered by human inhalation have a mean size in the range of from 50 to 250 microns, preferably a mean size in the range 120 to 160 microns and most preferably a mean size of about 140
microns .
For pressurised aerosol formulations, the active ingredients are preferably finely divided, eg at least 95% by weight of the paticles of the active ingredient have an effective particle size of from 1 to 10 microns (and these finely divided forms of the active ingredients are a feature of the invention) . We particularly prefer the active ingredient to have a mass median diameter of less than 5 microns and especially of less than 4 microns and most preferably of less than 3.5 microns. We also prefer not more than 5% by weight of the particles to have a diameter of greater than 10 microns, and more preferably not less than 90% by weight of the particles to have a diameter of less than 6 microns. we prefer the composition to contain from 0.1 to 12%, more preferably from 0.2 to 5%, eg about 1 to 3.5% by weight of the finely divided active ingredients.
By mass median diameter we mean the diameter such that half the particulate mass is in particles of lesser diameter and half in particles of greater diameter. The mass median diameter is essentially a Stokes diameter and may be determined using a Joyce Loebl sedimentation disc centrifuge either in a two layer or line start photometric mode (Bagness J and Ottaway A, Proc. Soc. Analyt. Chem. Part 4, Vol 9, 1972 pages 83 -86).
The active ingredients of mass median diameter less than 4 microns when formulated as aerosol units and when the units are examined using a single stage liquid impinger (modification of that described in J. Pharm. Pharmac. 1973,
- 25, Suppl. 32P-36P) produce a greater dispersion than exactly analogous units containing active ingredients of larger mass median diameter. The single stage liquid impinger samples the whole cloud delivered from the aerosol and separates it into two fractions by inertial impaction. 0 The fraction of smaller particle size is less than 10 microns in aerodynamic diameter and represents material which is likely to penetrate into the deeper regions of the human airways.
By providing a large proportion of fine particles of
,- active ingredient the invention enables effective lung penetration to potential sites of organism colonisation.
The fine active ingredient(s) may be made by grinding or milling and is (are) preferably dried thoroughly before they are incorporated into the liquefied propellant medium.
2Q The liquefied propellant is preferably a gas at room temperature (20°C) and atmospheric pressure ie it should have a boiling point below 20°C at atmospheric pressure. The liquefied propellant should also be non-toxic. Among the suitable liquefied propellants which may be employed are dimethyl ether and alkanes containing up to 5 carbon
atoms, eg butane or pentane, or a lower alkyl chloride, eg methyl, ethyl or propyl chlorides. The most suitable liquefied propellants are the fluorinated and fluorochlorinated lower alkanes such as those sold under the Registerd Trade Mark "Freon". Mixtures of the above mentioned propellants may be suitably employed. Examples of these propellants are: dichlorodifluoromethane ("Propellant 12") ; 1,2-dichlorotetrafluoroethane ("Propellant 114"); trichloromonofluoromethane ("Propellant 11") ; dichloromonofluoromethane ("Propellant 21") monochlorodifluoromethane ("Propellant 22") trichlorotrifluoroethane ("Propellant 113") monochlorotrifluoromethane ("Propellant 13") . asymmetric dihydrotetrafluoroethane ("Propellant 134a")
Propellants with improved vapour pressure characteristics may be obtained by using certain mixtures of these compounds, eg "Propellant 11" with "Propellant 12" or "Propellant 12" with "Propellant 114". For example, "Propellant 12", which has a vapour pressure of about 570kPa (absolute) at 20°C, may be mixed in various proportions to form a propellant having a desired intermediate vapour pressure. We prefer compositions which do not contain trichloromonofluoromethane.
It is desirable that the vapour pressure of the propellant employed be between 380 and 500, and preferably between 410 and 470kPa (absolute) at 20°C. Such a propellant mixture is usable safely with metallic containers. Other mixtures of "Propellant 12" with
"Propellant 114", or of "Propellant 12" with "Propellant 11", or of "Propellant 12" with "Propellant 11" and "Propellant 114" with absolute vapour pressures at 20°C in the range 230 to 380kPa are usable safely with reinforced glass containers.
The composition may also contain a surface active agent. The surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. The preferred solid anionic surface active agent is sodium dioctylsulphosuccinate.
The amount of the surface active agent required is related to the solids content of the suspension and to the particle size of the solids. In general it is only necessary to use 5-15%, and preferably 5-8% of the solid surface active agent by weight of the solids content of the suspension.
When a liquid non-ionic surface active agent is employed it should have an hydrophile-lipophile balance (HLB) ratio of less than 10. The HLB ratio is an empirical
number which provides a guide to the surface active properties of a surface active agent. The lower the HLB ratio, the more lipophilic is the agent and, conversely, the higher the HLB ratio, the more hydrophilic is the agent. The HLB ratio is well known and understood by the colloid chemist and its method of determination is described by W C Griffin in the Journal of the Society of Cosmetic Chemists, Vol 1, No 5, pages 311-326 (1949). Preferably the surface active agent employed should have an HLB ratio of 1 to 5. It is possible to employ mixtures of surface active agents, the mixture having an HLB ratio within the prescribed range.
Those surface active agents which are soluble or dispersible in the propellant are effective. The more propellant soluble surface active agents are the most effective.
We prefer the liquid non-ionic surface active agent to comprise from 0.1 to 2%, and more preferably from 0.2 to 1% by weight of the total composition. Such compositions tend to be more physically stable on storage.
Among the liquid non-ionic surface active agents which may be employed are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, oleostearic and oleic acids with an aliphatic
polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the Registered Trade Mark "span") and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides, may be employed. The preferred liquid non-ionic surface active agents are the oleates of sorbitan, eg those sold under the Registered Trade Marks "Arlacel C" (sorbitan sesquioleate) , "Span 80" (sorbitan monooleate) and "Span 85" (Sorbitan trioleate) . Specific examples of other liquid non-ionic surface active agents which may be employed are sorbitan monolaurate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol pentaoleate and polyoxypropylene mannitol dioleate. A solid non-ionic surface active agent which may be mentioned is lecithin, eg soya lecithin, a vegetable lecithin extracted from soya beans, but lecithin is not preferred. We particularly prefer compositions containing a sorbitan or sorbitol ester, eg sorbitan trioleate in a mixture of propellants 12 and 114. We prefer the ratio of propellant 12 to 114 to be in the range 2 to 1:1 and preferably 1.5:1 by weight, ie we prefer an excess of propellant 12 over propellant 114.
The preferred dosages of active drug will be dependent on several factors including the particular azole antifungal agent used and the patient's diagnosis. However, when the treatment is to be used prophylactically, we prefer that adequate levels of the drug are maintained in the lung to prevent invasive fungal colonisation.
When the formulation is in the form of a non-pressurised dry powder, eg a capsule for inhalation, a unit dose of active ingredient may be from 0.05 to 40 g, more preferably 1 to 30 mg, particularly 5 to 20 mg.
When the formulation is in the form of a pressurised aerosol formulation, the aerosol dispensing pack is preferably provided with a valve adapted to deliver unit dosages of between 0.025 and 0.25mls, and preferably 0.05 or O.lmls of composition. We prefer the valve to deliver o.i, l, 2, 3, 4 or 5mg of active ingredient and unit doses of these quantities of the drug are provided.
The pressurised aerosol formulations of the invention may be made by mixing the various components at a temperature and pressure at which the propellant is in the liquid phase and the active ingredients are in the solid phase.
In producing the pressurised aerosol compositions and packages of the invention, a container equipped with a valve is filled with a propellant containing the finely
divided active ingredient in suspension. A container may first. e charged with a weighed amount of dry active ingredients which have been ground to a predetermined particle size, or with a slurry of powder in the cooled liquid propellant. A container may also be filled by introducing powder and propellant by the normal cold filling method, or a slurry of the powder in that component of the propellant which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellant may be introduced by pressure filling through the valve nozzle. As a further alternative a bulk of the total composition may be made and portions of this bulk compositon may be filled into the container through the valve. Throughout the preparation of the product care is desirably exercised to minimise the absorption of moisture. On operating the valve, the powder will be dispensed in a stream of propellant which will vaporise providing an aerosol of dry powder.
It has not previously been suggested that azole antifungals may be used as inhalation medicaments. As such finely divided powdered azole antifungal is novel. According to the invention, there is provided finely divided powdered azole antifungal with a mass median diameter in the range 0.1 to 10 microns. We prefer at least 95% of such powdered antifungal to have a mass median
diameter in this range.
The compositions of the invention may be used in the remedial treatment or, more preferably, in the prophylaxis of fungal infections of the airways. The compositions of the invention, when administered via inhalation, will be particularly useful for the prophylaxis of systemic fungal infections whose portal of entry is the respiratory system.
According to a further aspect of the invention we provide a composition for the prophylaxis of fungal infections whose main portal of entry is the respiratory system.
The formulations of the invention are advantageous in that they are less toxic, more efficacious, give rise to fewer side effects are better tolerated or have other useful properties compared to known therapies.
Asperσillus and cryptococcus are significant mycotic pathogens which enter the body via the lungs. The compositions of the invention may, therefore, be used for the prophylaxis and/or treatment of aspergillosis and cryptococcosis. Patients particularly susceptible to invasive aspergillosis are those with defective neutrophil function and/or neutropenia, for example those with hematologic and lymphoreticular malignancy, organ transplants, or high dose steroid use. Some asthmatic patients are also predisposed to allergic bronchopulmonary
aspergillosis (ABPA) for which there is no established therapy. Treatment of the symptoms of asthma and/or ABPA using steroids increases the risk of developing invasive disease. Patients particularly at risk of developing cryptococcosis are those with AIDS, lymphoreticular malignancies, organ transplants, chronic steroid use, sarcoidosis,. chronic active hepatitis, connective tissue disorders or severe diabetes mellitus. The treatment may be administered by nasal inhalation; however we prefer oral inhalation.
The dosage to be given will clearly vary with the patient and with their condition. In general, however, relatively low doses administered at an interval to maintain adequate pulmonary drug concentration are indicated.
According to the invention there is also provided a method of prophylaxis of a fungal pulmonary infection, especially infections caused by aspergillosis or cryptococcosis, which comprises administering by inhalation a therapeutically effective amount of an azole antifungal agent to a patient predisposed to such an infection.
Claims
, Claims
1. A pharmaceutical formulation comprising, as active ingredient, an azole antifungal in a form suitable for administration by inhalation. 5 2. A pharmaceutical formulation according to claim 1, in the form of a dry powder.
3. A pharmaceutical formulation according to Claim 2 which contains a pharmaceutically acceptable liquefied gas aerosol propellant. 104. A pharmaceutical formulation according to Claim 3 which contains from 0.1 to 12% by weight of the active ingredient.
5. A pharmaceutical formulation according to Claim 3, wherein at least 95% by weight of the particles of active
15 ingredient have a mass median diameter of from 0.1 to 10 microns.
6. A pharmaceutical formulation according to Claim 2 which is non-pressurised.
7. A pharmaceutical formulation according to Claim 6, 20wherein the active ingredient is in admixture with a pharmaceutically acceptable carrier.
8. A pharmaceutical formulation according to Claim 6, wherein at least 95% by weight of the particles of the active ingredient have a mass median diameter of from 0.1
25to 10 microns.
9. A pharmaceutical formulation according to claim 1, in the form of. an aqueous solution or suspension for use with a nebuliser device.
10. Finely divided powdered azole antifungal with a mass median diameter in the range 0.1 to 10 microns.
11. A pharmaceutical formulation according to any one of Claims 1 to 8, wherein the azole antifungal is selected from clotrimazole, econazole nitrate, fluconazole, itraconazole, ketoconazole, miconazole nitrate and saperconazole.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8908250.7 | 1989-04-12 | ||
GB898908250A GB8908250D0 (en) | 1989-04-12 | 1989-04-12 | Formulations |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1990011754A1 true WO1990011754A1 (en) | 1990-10-18 |
Family
ID=10654880
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1990/000513 WO1990011754A1 (en) | 1989-04-12 | 1990-04-05 | Aerosolized azole antifungals |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0467916A1 (en) |
JP (1) | JPH04504419A (en) |
CA (1) | CA2014401A1 (en) |
GB (1) | GB8908250D0 (en) |
GR (1) | GR900100280A (en) |
PT (1) | PT93739A (en) |
WO (1) | WO1990011754A1 (en) |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992000061A1 (en) * | 1990-06-29 | 1992-01-09 | Fisons Plc | Pressurised aerosol compositions |
EP0518601A1 (en) * | 1991-06-10 | 1992-12-16 | Schering Corporation | Non-chlorofluorocarbon aerosol formulations |
EP0634166A1 (en) * | 1993-07-15 | 1995-01-18 | Hoechst Aktiengesellschaft | Drug compositions containing coated, poorly watersoluble drugs for use in pharmaceutical inhalation forms and method to produce them |
EP0666077A1 (en) * | 1993-08-16 | 1995-08-09 | Meiji Seika Kabushiki Kaisha | Anti-mrsa composition |
US5474997A (en) * | 1993-01-27 | 1995-12-12 | Sepracor, Inc. | Methods and compositions of (2R,4S) itraconazole for treating fungal yeast and dermatophyte infections |
NL1006103C2 (en) * | 1997-05-21 | 1998-11-25 | Nutricia Nv | Powder-based skin spray. |
WO1999029522A1 (en) | 1997-12-09 | 1999-06-17 | The Goodyear Tire & Rubber Company | Pneumatic tyre with an antenna for radio transponder |
US5998413A (en) * | 1992-03-18 | 1999-12-07 | Janssen Pharmaceutica, N.V. | Itraconazole and stereoisomers |
US6086376A (en) * | 1998-01-30 | 2000-07-11 | Rtp Pharma Inc. | Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant |
US6485743B1 (en) | 1997-12-31 | 2002-11-26 | Choongwae Pharma Corporation | Method and composition of an oral preparation of itraconazole |
WO2006026502A1 (en) * | 2004-08-27 | 2006-03-09 | The Dow Chemical Company | Enhanced delivery of drug compositions to treat life threatening infections |
US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
US7473433B2 (en) | 2000-12-21 | 2009-01-06 | Nektar Therapeutics | Pulmonary delivery of polyene antifungal agents |
US20100298394A1 (en) * | 2007-04-05 | 2010-11-25 | The Johns Hopkins University | Antifungal agents as neuroprotectants |
WO2014106727A1 (en) | 2013-01-03 | 2014-07-10 | Vectura Limited | Inhaler and formulation |
US9616060B2 (en) | 2002-04-17 | 2017-04-11 | Nektar Therapeutics | Particulate materials |
US9833451B2 (en) | 2007-02-11 | 2017-12-05 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1253711B (en) * | 1991-12-17 | 1995-08-23 | Alfa Wassermann Spa | VAGINAL PHARMACEUTICAL FORMULATIONS CONTAINING RIFAXIMIN AND THEIR USE IN THE TREATMENT OF VAGINAL INFECTIONS |
CN104983701A (en) * | 2008-04-15 | 2015-10-21 | 默沙东公司 | ORAL PHARMACEUTICAL COMPOSITIONS IN A SOLID DISPERSION COMPRISING PREFERABLY POSACONAZOLE AND HPMCAs |
EP2601973A1 (en) | 2011-12-09 | 2013-06-12 | Laboratoires SMB SA | Dry powder formulation of azole derivative for inhalation |
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EP0156508A1 (en) * | 1984-02-23 | 1985-10-02 | Ortho Pharmaceutical Corporation | Antifungal aerosol solution |
EP0320002A1 (en) * | 1987-12-10 | 1989-06-14 | Kyorin Seiyaku Kabushiki Kaisha | Inhalant |
-
1989
- 1989-04-12 GB GB898908250A patent/GB8908250D0/en active Pending
-
1990
- 1990-04-05 EP EP90905606A patent/EP0467916A1/en not_active Withdrawn
- 1990-04-05 JP JP2505638A patent/JPH04504419A/en active Pending
- 1990-04-05 WO PCT/GB1990/000513 patent/WO1990011754A1/en not_active Application Discontinuation
- 1990-04-10 GR GR900100280A patent/GR900100280A/en unknown
- 1990-04-11 CA CA002014401A patent/CA2014401A1/en not_active Abandoned
- 1990-04-11 PT PT93739A patent/PT93739A/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0156508A1 (en) * | 1984-02-23 | 1985-10-02 | Ortho Pharmaceutical Corporation | Antifungal aerosol solution |
EP0320002A1 (en) * | 1987-12-10 | 1989-06-14 | Kyorin Seiyaku Kabushiki Kaisha | Inhalant |
Non-Patent Citations (2)
Title |
---|
Biological Abstracts, Volume 88, No. 10, 1989, J. VAN CUTSEM et al.: "The Treatment of Experimental Aspergillosis with Enilconazole and Itraconazole", see Abstract 105355, & Bull Soc. Fr. Mycol. Med. 18(1): 55-60 1989. see the Abstract * |
The Journal of International Medical Research, Volume 10, No. 1. 1982, Cambridge Medical Publications Limited, W.V.R. SHELLOW: "2% Miconazole Nitrate Powder in Aerosol Spray Form: Its Efficacy in Treating Tinea Pedis", pages 28-31 see pge 28, column 2; pages 29, column 2, page 30, column 2; page 31, paragraph 1 * |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5846521A (en) * | 1990-06-29 | 1998-12-08 | Fisons Plc | Pressurized solvent-free drug aerosol compositions containing hydrofluorocarbon propellants |
WO1992000061A1 (en) * | 1990-06-29 | 1992-01-09 | Fisons Plc | Pressurised aerosol compositions |
EP0518601A1 (en) * | 1991-06-10 | 1992-12-16 | Schering Corporation | Non-chlorofluorocarbon aerosol formulations |
WO1992022287A1 (en) * | 1991-06-10 | 1992-12-23 | Schering Corporation | Non-chlorofluorocarbon aerosol formulations |
US6503482B1 (en) | 1991-06-10 | 2003-01-07 | Schering Corporation | Non-chlorofluorocarbon aerosol formulations |
US6416743B1 (en) | 1991-06-10 | 2002-07-09 | Schering Corporation | Aerosol formulations of albuterol and 1,1,1,2-tetrafluoroethane |
US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
US5998413A (en) * | 1992-03-18 | 1999-12-07 | Janssen Pharmaceutica, N.V. | Itraconazole and stereoisomers |
US5474997A (en) * | 1993-01-27 | 1995-12-12 | Sepracor, Inc. | Methods and compositions of (2R,4S) itraconazole for treating fungal yeast and dermatophyte infections |
US5663198A (en) * | 1993-07-15 | 1997-09-02 | Hoechst Aktiengesellschaft | Drug formulations comprising coated, very sparingly water-soluble drugs for inhalational pharmaceutical forms, and process for their preparation |
EP0634166A1 (en) * | 1993-07-15 | 1995-01-18 | Hoechst Aktiengesellschaft | Drug compositions containing coated, poorly watersoluble drugs for use in pharmaceutical inhalation forms and method to produce them |
EP0666077A4 (en) * | 1993-08-16 | 1995-09-06 | ||
EP0666077A1 (en) * | 1993-08-16 | 1995-08-09 | Meiji Seika Kabushiki Kaisha | Anti-mrsa composition |
EP0884043A1 (en) * | 1997-05-21 | 1998-12-16 | N.V. Nutricia | Powder-based skin spray |
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Also Published As
Publication number | Publication date |
---|---|
GR900100280A (en) | 1991-09-27 |
GB8908250D0 (en) | 1989-05-24 |
PT93739A (en) | 1990-11-20 |
EP0467916A1 (en) | 1992-01-29 |
JPH04504419A (en) | 1992-08-06 |
CA2014401A1 (en) | 1990-10-12 |
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