WO1992014473A1 - Steroid formulations - Google Patents

Steroid formulations Download PDF

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Publication number
WO1992014473A1
WO1992014473A1 PCT/GB1992/000290 GB9200290W WO9214473A1 WO 1992014473 A1 WO1992014473 A1 WO 1992014473A1 GB 9200290 W GB9200290 W GB 9200290W WO 9214473 A1 WO9214473 A1 WO 9214473A1
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WO
WIPO (PCT)
Prior art keywords
formulation
tipredane
formulation according
surfactant
active ingredient
Prior art date
Application number
PCT/GB1992/000290
Other languages
French (fr)
Inventor
Joy Elaine Saunders
Original Assignee
Fisons Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fisons Ag filed Critical Fisons Ag
Priority to ITMI920393A priority Critical patent/IT1254627B/en
Publication of WO1992014473A1 publication Critical patent/WO1992014473A1/en

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Classifications

    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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

Definitions

  • This invention relates to novel pharmaceutical formulations, in particular to aqueous suspension formulations containing tipredane.
  • US Patent No 4,361,559 discloses a large number of 3-ketoandrostenes which are described as having useful anti-inflammatory activity, including useful activity in the topical treatment of allergy and asthma. This patent also specifically discloses (11)3,17 ⁇ )-17-(ethylthio)-9 ⁇ - fluoro-ll/9-hydroxy-17-(methylthio)-androsta-1,4-diene-3-one, which is known by the INN generic name tipredane.
  • tipredane has useful anti-inflammatory activity when administered to the nose.
  • tipredane has a water solubility below 0.002 mg/ml at room temperature. Although it may be possible to increase water solubility by the use of co-solvents or solubilising agents, such co-solvents and agents frequently cause nasal stinging and/or interact with the active ingredient. Attempts at increasing the aqueous solubility of tipredane using /8-cyclodextrin derivatives were also unsuccessful. Tipredane has a relatively poor oil solubility, which prevents the preparation of satisfactory emulsion formulations.
  • powder formulations of non water soluble drugs for application to the nose are not favoured, in that the drug is being presented to the nose in a form that is unlikely to be readily bioavailable.
  • Propellant driven powder formulations are not favoured for tipredane, in that CFC driven formulations are unsatisfactory environmentally and HFC propellants are difficult to formulate.
  • tipredane as an aqueous suspension and control nasal inflammatory conditions.
  • an aqueous suspension formulation containing, as active ingredient, tipredane.
  • the formulation according to the invention is advantageous in that it is more efficacious, has a longer effect, produces fewer or less severe side-effects, or has other advantageous properties when compared with comparable formulations of other compounds or with other, known formulations of the active ingredient.
  • the stability of the active ingredient may be enhanced in the 5 formulation of the invention, which is surprising in view of the known tendency of the active ingredient to oxidise.
  • the active ingredient is preferably present in the formulation at a concentration of from 0.005% to 1.5% w/w, more preferably from 0.01 to 0.1% and especially from 0.2% 0 to 0.4% w/w.
  • the formulation will generally contain a surfactant.
  • ionic surfactants such as sodium lauryl sulphate may be used, we prefer the surfactant to be a non-ionic surfactant.
  • Non-ionic surfactants that may be mentioned sinclude glycol and glycerol esters, acetoglycerides, macrogol esters, macrogol ethers and sorbiton esters.
  • poloxamers with the general formula HO(C 2 H 4 0) a (C 3 H 6 0) b (C 2 H 4 0) a H, in dwhich a is 2 to 130 and b is 15 to 67 give particularly stable formulations.
  • poloxamers with an average molecular weight of between 4000 and 20,000, more particularly between 6000 and 15,000.
  • a particularly preferred poloxamer that may be snentioned is that known as poloxamer 188 (poloxalkol) in which a in the general formula averages 75 and b averages 30. This has a molecular weight of about 8350.
  • the concentration of the surfactant in the formulation will depend inter alia on the particular surfactant used, but will in general be from 0.05% to 10% w/w, more preferably from 0.05% to 5% w/w, especially from 0.05% to 0.5% w/w. We have found that the use of such low concentrations of surfactant, eg about 0.1 %w/w, leads to particularly stable formulations which show improved resistance to oxidation.
  • the formulation may, if desired, contain an effective proportion of a pharmaceutically acceptable preservative or sterilising agent.
  • Suitable preservatives include pharmaceutically acceptable quarternary ammonium compounds.
  • the preferred preservatives amongst the quarternary ammonium compounds are the alkyl benzyl dimethyl ammonium chlorides and mixtures thereof, eg that known generically as * benzalkonium chloride' .
  • the preservative may be used at a concentration of from about 0.005% to 0.10%, preferably 0.005% to 0.05%, eg about 0.01% w/w.
  • the formulation will generally also contain a pseudoplastic thixotropic viscosity modifying agent.
  • Suitable thixotropic viscosity modifying agents which may be used include carboxy vinyl polymers, alginates, cellulose and its derivatives, for example hydroxypropyl methylcellulose and dispersible cellulose, which is a co-blend of microcrystalline cellulose and sodium carboxymethyl cellulose sold commercially as Avicel RC-591. If present, the thixotropic viscosity modifying agent will be at a concentration at which the resulting viscosity of the formulation is suitable for its intended use.
  • the viscosity of the formulation may be varied between quite wide limits (typically between 0.5 and 5.0% w/w) but, in general, will be relatively low at high shear rates (to enable dispensing, eg as a spray from a conventional nasal pump) and relatively high at low shear rates.
  • the formulation may therefore contain a tonicity adjusting agent, eg glycerol, at a concentration of from about 0.1% to 2.0%, more preferably 0.5% to 1.0% w/w. 0
  • the formulation may additionally contain conventional excipients eg electrolytes.
  • a particularly preferred electrolyte is sodium chloride.
  • Sodium chloride is useful as a flocculating agent and may also alter the tonicity of the formulation. 5
  • the overall proportion and concentration of excipients may be varied within fairly wide ranges, provided that the resulting solution is stable and non-irritant when applied to the nasal tissues.
  • an aqueous formulation comprising a) from 0.1 to 1.25% w/w of tipredane as active ingredient, b) from 0.05% to 10% w/w of a non-ionic surfactant, c) from 0.5 to 5% w/w of a thixotropic viscosity 5 modifying agent, and d) from 0.1 to 2.0% w/w of a tonicity adjusting agent.
  • the formulation of the invention may be made up, for example, by dispersing the active ingredient, using the surfactant as wetting agent, and dispersing or dissolving othe thixotropic viscosity modifying agent (if included) and other excipients (if included) in freshly distilled water, adding to this solution an aqueous solution of the preservative (if included) , making the solution up to the desired volume with distilled water, and stirring.
  • the 5formulation is preferably made up under aseptic conditions.
  • a method of treatment of conditions of the nose in which conditions allergic or immune reactions play a contributory part, which method comprises administration of a formulation according to the invention to a patient suffering from, or susceptible to, such a condition.
  • the dosage administered will of course vary with the condition to be treated and with its severity. However, in general, a dosage of about 400 ⁇ g is indicated.
  • the dose may be administered up to four times to each nostril at any one dosing session and from 1 to 4 times a days. We prefer to administer the formulation once or twice daily.
  • Conditions of the nose in which may be treated the ethod of the invention include seasonal rhinitis, eg hay fever; perenial rhinitis; nasal polyps and allergic manifestations of the nasopharynx.
  • the formulation has been found to be chemically and physically stable when using an identical vehicle containing tipredane at the following strengths: 0.0096% w/w (equivalent to 12.5 ⁇ g per actuation) 0.0192% W/W (equivalent to 25 ⁇ g per actuation) 0.0385% W/W (equivalent to 50 ⁇ g per actuation) 0.0770% W/W (equivalent to lOO ⁇ g per actuation) 0.1540% W/W (equivalent to 200 ⁇ g per actuation) 0.692% W/W (equivalent to 800 ⁇ g per actuation) 1.231% W/W (equivalent to 1600 ⁇ g per actuation)
  • Tipredane is dispersed in an aqueous solution of poloxamer 188, glycerol, sodium chloride and benzalkonium chloride. This is added to a dispersion of microcrystalline cellulose co-blend in water and mixed until homogeneous. The suspension is made to weight with more water before filling into bottles. 5
  • the tipredane is preferably micronised material, with a mean particle size of 5 ⁇ g and not more than 20% by weight of the tipredane having a particle size of > lO ⁇ m.
  • the pH of the aqueous suspension can be Q adjusted by addition of acid or base as appropriate, to give a pH of between 4.5 and 7.5.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

An aqueous suspension formulation containing, as active ingredient, tipredane. The formulation is useful for the treatment of conditions of the nose in which allergic or immune reactions play a contributary part.

Description

Steroid formulations
This invention relates to novel pharmaceutical formulations, in particular to aqueous suspension formulations containing tipredane.
US Patent No 4,361,559 discloses a large number of 3-ketoandrostenes which are described as having useful anti-inflammatory activity, including useful activity in the topical treatment of allergy and asthma. This patent also specifically discloses (11)3,17α)-17-(ethylthio)-9α- fluoro-ll/9-hydroxy-17-(methylthio)-androsta-1,4-diene-3-one, which is known by the INN generic name tipredane.
We have now found that tipredane has useful anti-inflammatory activity when administered to the nose.
The most favoured vehicle for administering a drug to the nose is water as this is likely to give maximum bioavailability. However, tipredane has a water solubility below 0.002 mg/ml at room temperature. Although it may be possible to increase water solubility by the use of co-solvents or solubilising agents, such co-solvents and agents frequently cause nasal stinging and/or interact with the active ingredient. Attempts at increasing the aqueous solubility of tipredane using /8-cyclodextrin derivatives were also unsuccessful. Tipredane has a relatively poor oil solubility, which prevents the preparation of satisfactory emulsion formulations.
In general, powder formulations of non water soluble drugs for application to the nose are not favoured, in that the drug is being presented to the nose in a form that is unlikely to be readily bioavailable.
Propellant driven powder formulations are not favoured for tipredane, in that CFC driven formulations are unsatisfactory environmentally and HFC propellants are difficult to formulate. Surprisingly, we have now found that it is possible to formulate tipredane as an aqueous suspension and control nasal inflammatory conditions.
According to the invention there is provided an aqueous suspension formulation containing, as active ingredient, tipredane.
The formulation according to the invention is advantageous in that it is more efficacious, has a longer effect, produces fewer or less severe side-effects, or has other advantageous properties when compared with comparable formulations of other compounds or with other, known formulations of the active ingredient. In addition, the stability of the active ingredient may be enhanced in the 5formulation of the invention, which is surprising in view of the known tendency of the active ingredient to oxidise.
The active ingredient is preferably present in the formulation at a concentration of from 0.005% to 1.5% w/w, more preferably from 0.01 to 0.1% and especially from 0.2% 0to 0.4% w/w.
The formulation will generally contain a surfactant. Although ionic surfactants such as sodium lauryl sulphate may be used, we prefer the surfactant to be a non-ionic surfactant. Non-ionic surfactants that may be mentioned sinclude glycol and glycerol esters, acetoglycerides, macrogol esters, macrogol ethers and sorbiton esters. We have found that the block copolymers of poloxyethylene- polyoxypropylene, known as poloxamers with the general formula HO(C2H40)a(C3H60)b(C2H40)aH, in dwhich a is 2 to 130 and b is 15 to 67 give particularly stable formulations.
We prefer poloxamers with an average molecular weight of between 4000 and 20,000, more particularly between 6000 and 15,000. A particularly preferred poloxamer that may be snentioned is that known as poloxamer 188 (poloxalkol) in which a in the general formula averages 75 and b averages 30. This has a molecular weight of about 8350.
The concentration of the surfactant in the formulation will depend inter alia on the particular surfactant used, but will in general be from 0.05% to 10% w/w, more preferably from 0.05% to 5% w/w, especially from 0.05% to 0.5% w/w. We have found that the use of such low concentrations of surfactant, eg about 0.1 %w/w, leads to particularly stable formulations which show improved resistance to oxidation.
The formulation may, if desired, contain an effective proportion of a pharmaceutically acceptable preservative or sterilising agent. Suitable preservatives include pharmaceutically acceptable quarternary ammonium compounds. The preferred preservatives amongst the quarternary ammonium compounds are the alkyl benzyl dimethyl ammonium chlorides and mixtures thereof, eg that known generically as *benzalkonium chloride' . The preservative may be used at a concentration of from about 0.005% to 0.10%, preferably 0.005% to 0.05%, eg about 0.01% w/w.
The formulation will generally also contain a pseudoplastic thixotropic viscosity modifying agent. Suitable thixotropic viscosity modifying agents which may be used include carboxy vinyl polymers, alginates, cellulose and its derivatives, for example hydroxypropyl methylcellulose and dispersible cellulose, which is a co-blend of microcrystalline cellulose and sodium carboxymethyl cellulose sold commercially as Avicel RC-591. If present, the thixotropic viscosity modifying agent will be at a concentration at which the resulting viscosity of the formulation is suitable for its intended use. The viscosity of the formulation may be varied between quite wide limits (typically between 0.5 and 5.0% w/w) but, in general, will be relatively low at high shear rates (to enable dispensing, eg as a spray from a conventional nasal pump) and relatively high at low shear rates.
We prefer the formulation according to the invention to be isotonic with the nasal mucosa. The formulation may therefore contain a tonicity adjusting agent, eg glycerol, at a concentration of from about 0.1% to 2.0%, more preferably 0.5% to 1.0% w/w. 0 The formulation may additionally contain conventional excipients eg electrolytes. A particularly preferred electrolyte is sodium chloride. Sodium chloride is useful as a flocculating agent and may also alter the tonicity of the formulation. 5 In general, the overall proportion and concentration of excipients may be varied within fairly wide ranges, provided that the resulting solution is stable and non-irritant when applied to the nasal tissues.
As a particularly preferred aspect of the invention, othere is provided an aqueous formulation comprising a) from 0.1 to 1.25% w/w of tipredane as active ingredient, b) from 0.05% to 10% w/w of a non-ionic surfactant, c) from 0.5 to 5% w/w of a thixotropic viscosity 5modifying agent, and d) from 0.1 to 2.0% w/w of a tonicity adjusting agent. The formulation of the invention may be made up, for example, by dispersing the active ingredient, using the surfactant as wetting agent, and dispersing or dissolving othe thixotropic viscosity modifying agent (if included) and other excipients (if included) in freshly distilled water, adding to this solution an aqueous solution of the preservative (if included) , making the solution up to the desired volume with distilled water, and stirring. The 5formulation is preferably made up under aseptic conditions. According to another aspect of the invention there is provided a method of treatment of conditions of the nose, in which conditions allergic or immune reactions play a contributory part, which method comprises administration of a formulation according to the invention to a patient suffering from, or susceptible to, such a condition.
The dosage administered will of course vary with the condition to be treated and with its severity. However, in general, a dosage of about 400μg is indicated. The dose may be administered up to four times to each nostril at any one dosing session and from 1 to 4 times a days. We prefer to administer the formulation once or twice daily.
Conditions of the nose in which may be treated the ethod of the invention include seasonal rhinitis, eg hay fever; perenial rhinitis; nasal polyps and allergic manifestations of the nasopharynx.
The invention is illustrated, but in no way limited, by the following Example. Example Ingredients
Active ingredient 0.308 w/w
(equivalent to 400μg per actuation)
Poloxamer 188 0.100 Sodium chloride Ph.Ew/USP 0.584
Glycerol 1.000
Benzalkonium chloride1 0.010
Avicel RC-591 2.000
Purified water Ph.Ew/BP/USP to 100.00
1 added as a 50% w/v solution
The formulation has been found to be chemically and physically stable when using an identical vehicle containing tipredane at the following strengths: 0.0096% w/w (equivalent to 12.5μg per actuation) 0.0192% W/W (equivalent to 25μg per actuation) 0.0385% W/W (equivalent to 50μg per actuation) 0.0770% W/W (equivalent to lOOμg per actuation) 0.1540% W/W (equivalent to 200μg per actuation) 0.692% W/W (equivalent to 800μg per actuation) 1.231% W/W (equivalent to 1600μg per actuation)
Manufacturing process
Tipredane is dispersed in an aqueous solution of poloxamer 188, glycerol, sodium chloride and benzalkonium chloride. This is added to a dispersion of microcrystalline cellulose co-blend in water and mixed until homogeneous. The suspension is made to weight with more water before filling into bottles. 5 The tipredane is preferably micronised material, with a mean particle size of 5μg and not more than 20% by weight of the tipredane having a particle size of > lOμm.
If necessary, the pH of the aqueous suspension can be Qadjusted by addition of acid or base as appropriate, to give a pH of between 4.5 and 7.5.
5
0

Claims

Claims
1. An aqueous suspension formulation containing, as active ingredient, tipredane.
2. A formulation according to claim 1 which includes a surfactant.
3. A formulation according to claim 2, wherein the surfactant is a non-ionic surfactant.
4. A formulation according to claim 2 or claim 3, wherein the surfactant is a poloxamer.
5. A formulation according to any one of the preceding claims, which includes a pharmaceutically acceptable preservative.
6. A formulation according to any one of the preceding claims, which includes a thixotropic viscosity modifying agent.
7. A formulation according to claim 6, wherein the viscosity modifying agent is cellulose or a derivative thereof.
208. A formulation according to any one of the preceding claims which is isotonic with the nasal mucosa.
9. An aqueous suspension formulation which comprises a) from 0.1 to 1.25% w/w of tipredane as active ingredient,
25b) from 0.05% to 10% w/w of a non-ionic surfactant, c) from 0.5 to 5% w/w of a thixotropic viscosity modifying agent, and d) from 0.1 to 2.0% w/w of a tonicity adjusting agent.
10. The use of tipredane in the manufacture of a
30medicament for the treatment of the nose in which allergic or immune reactions play a contributory part.
35
PCT/GB1992/000290 1991-02-23 1992-02-19 Steroid formulations WO1992014473A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
ITMI920393A IT1254627B (en) 1991-02-23 1992-02-21 Steroid formulations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9103824.0 1991-02-23
GB919103824A GB9103824D0 (en) 1991-02-23 1991-02-23 Formulation

Publications (1)

Publication Number Publication Date
WO1992014473A1 true WO1992014473A1 (en) 1992-09-03

Family

ID=10690478

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Application Number Title Priority Date Filing Date
PCT/GB1992/000290 WO1992014473A1 (en) 1991-02-23 1992-02-19 Steroid formulations

Country Status (13)

Country Link
CN (1) CN1065010A (en)
AU (1) AU1247192A (en)
BE (1) BE1004177A4 (en)
FR (1) FR2673104A1 (en)
GB (1) GB9103824D0 (en)
GR (1) GR1001511B (en)
IE (1) IE920516A1 (en)
IL (1) IL101010A0 (en)
IT (1) IT1254627B (en)
MX (1) MX9200748A (en)
PT (1) PT100150A (en)
WO (1) WO1992014473A1 (en)
ZA (1) ZA921247B (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0551626A1 (en) * 1991-12-19 1993-07-21 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Thermoreversible gel as a liquid pharmaceutical carrier for a galenic formulation
EP0938345A1 (en) * 1996-07-03 1999-09-01 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Aqueous-based pharmaceutical composition
WO2001028562A1 (en) * 1999-10-20 2001-04-26 Byk Gulden Lomberg Chemische Fabrik Gmbh Ciclesonide contained pharmaceutical composition for application to mucosa
DE10064950A1 (en) * 2000-12-23 2002-07-11 Impetus Ag Basel Thixotropic nasal spray
WO2004024122A1 (en) * 2002-09-13 2004-03-25 Zicam, Llc Composition and method for moisturizing nasal tissue
US6939559B1 (en) 1998-04-21 2005-09-06 Teijin Limited Pharmaceutical composition for application to mucosa
JP2005281315A (en) * 1997-07-02 2005-10-13 Aventis Pharmaceuticals Holdings Inc Aqueous pharmacological composition
EP1645266A1 (en) * 2004-10-08 2006-04-12 Hisamitsu Medical Co., Ltd. Aqueous suspension for nasal drops
JP2011503044A (en) * 2007-11-09 2011-01-27 アルキメデス・デベロップメント・リミテッド Intranasal composition
US8383611B1 (en) 1999-10-20 2013-02-26 Nycomed Gmbh Ciclesonide containing aqueous pharmaceutical composition
WO2013049539A1 (en) * 2011-09-30 2013-04-04 Mcneil-Ppc, Inc. A method of blocking or trapping allergens
WO2019073298A1 (en) * 2017-10-11 2019-04-18 Lifescience As N-acetylneuraminic acid compositions and methods of use
WO2020165578A1 (en) * 2019-02-11 2020-08-20 Reckitt Benckiser Health Limited Novel composition

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0073026A1 (en) * 1981-08-20 1983-03-02 E.R. Squibb & Sons, Inc. 17,17-Bis(substituted thio)-3-ketoandrostenes and pharmaceutical compositions
EP0246652A2 (en) * 1986-05-22 1987-11-25 Syntex Pharmaceuticals International Limited Aqueous steroid formulations for nasal administration
US4868170A (en) * 1987-11-13 1989-09-19 E. R. Squibb & Sons, Inc. Steriod lotion formulation
WO1991011173A1 (en) * 1990-02-02 1991-08-08 Fisons Plc Propellant compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0073026A1 (en) * 1981-08-20 1983-03-02 E.R. Squibb & Sons, Inc. 17,17-Bis(substituted thio)-3-ketoandrostenes and pharmaceutical compositions
EP0246652A2 (en) * 1986-05-22 1987-11-25 Syntex Pharmaceuticals International Limited Aqueous steroid formulations for nasal administration
US4868170A (en) * 1987-11-13 1989-09-19 E. R. Squibb & Sons, Inc. Steriod lotion formulation
WO1991011173A1 (en) * 1990-02-02 1991-08-08 Fisons Plc Propellant compositions

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0551626A1 (en) * 1991-12-19 1993-07-21 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Thermoreversible gel as a liquid pharmaceutical carrier for a galenic formulation
EP0938345A1 (en) * 1996-07-03 1999-09-01 Rhone-Poulenc Rorer Pharmaceuticals, Inc. Aqueous-based pharmaceutical composition
EP0938345A4 (en) * 1996-07-03 1999-12-29 Rhone Poulenc Rorer Pharma Aqueous-based pharmaceutical composition
US7977045B2 (en) 1996-07-03 2011-07-12 Aventis Pharmaceuticals Inc. Aqueous-based pharmaceutical composition
CZ299689B6 (en) * 1996-07-03 2008-10-22 Aventis Pharmaceuticals Inc. Water-based pharmaceutical composition
EP1382330A1 (en) * 1996-07-03 2004-01-21 Aventis Pharmaceuticals Inc. Aqueous-Based pharmaceutical composition
JP2005281315A (en) * 1997-07-02 2005-10-13 Aventis Pharmaceuticals Holdings Inc Aqueous pharmacological composition
BG64919B1 (en) * 1998-04-21 2006-09-29 Teijin Ltd. Pharmaceutical composition for mucous membrane application
US7235247B2 (en) 1998-04-21 2007-06-26 Teijin Pharma Limited Pharmaceutical composition for application to mucosa
US6939559B1 (en) 1998-04-21 2005-09-06 Teijin Limited Pharmaceutical composition for application to mucosa
CZ297779B6 (en) * 1999-10-20 2007-03-28 Altana Pharma Ag Aqueous pharmaceutical composition
HRP20020346B1 (en) * 1999-10-20 2011-06-30 Nycomed Gmbh Ciclesonide contained pharmaceutical composition for application to mucosa
US6767901B1 (en) 1999-10-20 2004-07-27 Altana Pharma Ag Ciclesonide contained pharmaceutical composition for application to mucosa
US8383611B1 (en) 1999-10-20 2013-02-26 Nycomed Gmbh Ciclesonide containing aqueous pharmaceutical composition
WO2001028562A1 (en) * 1999-10-20 2001-04-26 Byk Gulden Lomberg Chemische Fabrik Gmbh Ciclesonide contained pharmaceutical composition for application to mucosa
BG65818B1 (en) * 1999-10-20 2010-01-29 Byk Gulden Lomberg Chemische Fabrik Gmbh Ciclesonide contained pharmaceutical composition for applicdtion to mucosa
DE10064950A1 (en) * 2000-12-23 2002-07-11 Impetus Ag Basel Thixotropic nasal spray
WO2004024122A1 (en) * 2002-09-13 2004-03-25 Zicam, Llc Composition and method for moisturizing nasal tissue
EP1645266A1 (en) * 2004-10-08 2006-04-12 Hisamitsu Medical Co., Ltd. Aqueous suspension for nasal drops
JP2011503044A (en) * 2007-11-09 2011-01-27 アルキメデス・デベロップメント・リミテッド Intranasal composition
WO2013049539A1 (en) * 2011-09-30 2013-04-04 Mcneil-Ppc, Inc. A method of blocking or trapping allergens
WO2019073298A1 (en) * 2017-10-11 2019-04-18 Lifescience As N-acetylneuraminic acid compositions and methods of use
WO2020165578A1 (en) * 2019-02-11 2020-08-20 Reckitt Benckiser Health Limited Novel composition
CN113557009A (en) * 2019-02-11 2021-10-26 雷克特本克斯尔健康有限公司 Novel compositions

Also Published As

Publication number Publication date
PT100150A (en) 1993-05-31
CN1065010A (en) 1992-10-07
GB9103824D0 (en) 1991-04-10
BE1004177A4 (en) 1992-10-06
IL101010A0 (en) 1992-11-15
GR1001511B (en) 1994-02-28
IT1254627B (en) 1995-09-28
ITMI920393A0 (en) 1992-02-21
FR2673104A1 (en) 1992-08-28
ZA921247B (en) 1992-10-28
AU1247192A (en) 1992-09-15
ITMI920393A1 (en) 1993-08-21
IE920516A1 (en) 1992-08-26
MX9200748A (en) 1992-10-01

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