CA1288048C - Aqueous steroid formulations for nasal administration - Google Patents
Aqueous steroid formulations for nasal administrationInfo
- Publication number
- CA1288048C CA1288048C CA000537690A CA537690A CA1288048C CA 1288048 C CA1288048 C CA 1288048C CA 000537690 A CA000537690 A CA 000537690A CA 537690 A CA537690 A CA 537690A CA 1288048 C CA1288048 C CA 1288048C
- Authority
- CA
- Canada
- Prior art keywords
- amount
- formulation
- formulation according
- stinging
- nasal mucosa
- 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.)
- Expired - Lifetime
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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- 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]
Abstract
ABSTRACT OF THE DISCLOSURE
A non-stinging aqueous anti-inflammatory steroid formulation suitable for intranasal administration comprises: an anti-inflammatory steroid in an amount between about 0.01% and about 0.05% (w/v); propylene glycol in an amount between about 2% and about 10% (w/v);
PEG 400 in an amount between about 10% and about 25%
(w/v); polysorbate 20 in an amount between about 1% and about 4% (w/v); an effective amount of a preservative; an effective amount of a stabilizer; an effective amount of an antioxidant; water; and pH buffering agent sufficient to adjust the pH of the resulting solution to between about 3.5 and about 7.
A non-stinging aqueous anti-inflammatory steroid formulation suitable for intranasal administration comprises: an anti-inflammatory steroid in an amount between about 0.01% and about 0.05% (w/v); propylene glycol in an amount between about 2% and about 10% (w/v);
PEG 400 in an amount between about 10% and about 25%
(w/v); polysorbate 20 in an amount between about 1% and about 4% (w/v); an effective amount of a preservative; an effective amount of a stabilizer; an effective amount of an antioxidant; water; and pH buffering agent sufficient to adjust the pH of the resulting solution to between about 3.5 and about 7.
Description
-12~3B~4~
AQUEOUS STEROID FORMULATIONS FOR NASAL ADMINISTRATION
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to aqueous anti-in~lammatory steroid formulations suitable ~or nasal administration, and to methods for treating in~lammat~on o~ the nasal mucosa by intranasal administration o~ said ~ormulations.
Related Disclosure Aqueous ~ormulations o~ anti- inflammatory steroids such as flunisolide suitable ~or nasal administration are commercially available, for example under the trademark Nasalide- (see, for example, U.K. Patent No. 1525181).
However, currently available ~ormulations, while sa~e and 25 ef~ective, are known to cause stinging upon administration in some cases, which is a side effect particularly undesirable when treating nasal inflammation. The novel formulations of the invention are suitable for nasal administration of 30 anti-in~lammatory steroids without causing stinging.
One aspect o~ the invention is a substantially non-stinging aqueous anti-inflammatory steroid 35 formulation suitable ~or nasal administration, which formulation comprises: an anti-in~lammatory steroid in 3505Y 25560-fF
an amount between about O.OlX and about 0.05% tw/v);
propylene glycol in an amount between about 2% and about 10% (w/v); PEG 400 in an amount between about 10% and about 25% (w/v); polysorbate 20 in an amount between about 1% and about 4% (w/v); and water.
Suitably, an effective amount of a preservative, preferably between about 0.02% and about 0.08% (w/v); an effective amount of a stabilizer, pre~erably between about 0.005% and about 0.05%; an effective amount of an antioxidant, preferably between about O.OOlX and about 0.05%; and a pH buffering agent sufficient to adjust the pH of the resulting solution to between about 3.5 and about 7, are also present to enhance stability and preservability.
A preferred subgenus of the invention is the formulation wherein said anti-inflammatory steroid is flunisolide, particularly in an amount of about 0.025%
(w/v) .
A preferred class is the formulation wherein said 20 preservative is benzalkonium chloride in an amount between about 0.02% and about 0.08% (w/v); said stabilizer is disodium EDTA in an amount between about 0.~05% and about 0.05% ~w/v); and said antioxidant is BHT
in an amount between about O.OOlX and about 0.05% (w/v);
25 especially the formulation which further comprises sorbitol in an amount between about 0.001% and about 5%
(w/v). A preferred subclass is the formulation wherein said pH buffering agent comprises a citrate buffer such as: citric acid in an amount between about 0.001% and 30 about 0.05% (w/v); and sodium citrate dihydrate in an a~ount between about O.OOlX and about 0.05% (w/v).
A preferred species is the non-stinging aqueous anti-inflammatory steroid formulation suitable for nasal administration, which formulation comprises:
1288~
flunisolide hemihydrate in an amount of about 0.025% (w/v);
propylene glycol in an amount of about 5% (w/v);
PEG 400 in an amount o~ about 20% (w/v);
polysorbate 20 in an amount o~ about 2.50% (w/v);
benzalkonium chloride in an amount o~ about 0.035% (w/v);
disodium EDTA in an amount of about 0.01% (w/v);
~HT in an amount of about 0.01% (w/v);
citric acid in an amount of about 0.005% (w/v);
sodium citrate dihydrate in an amount o~ about 0.00765% (w/v);
sorbitol in an amount o~ about 2.00% (w/v); and water, wherein the pH o~ the resulting solution is adjusted to about 5.2.
Another aspect o~ the invention is a method o~
treating inflammation o~ the nasal mucosa without inducing stinging, which method comprises intranasally 20 administering to a subject in need thereo~ a substantially non-stinging aqueous anti-in~lammatory steroid ~ormulation as described above.
A ~urther aspect o~ the invention is the use of the steroid formulation as described above in the treatment 25 ~ in~lammation o~ the nasal musosa.
The compositions o~ this invention have very satis~actory nasal acceptability, particularly as shown by their lack of, or low level of, nasal stinging.
The compositions o~ this invention provide good drug 30 solubility, and this solubility is retained with varying temperature.
The compositions of this invention provide excellent pumping characteristics, so reducing the need to overcome pump clogging with washing and rinsing procedures.
The compositions of this invention are also stable and preservable.
3505Y . 25560-FF
1288(~48 From these advantages, it is clear that the compositions of this invention provide very attractive nasal steroid formulations.
DEFINITIONS
As used herein, the term "anti-inflammatory steroid"
re~ers to a steroid compound which is phar~aceutically acceptable, and which is known to be use~ul in reducing inflammation. Particularly suitable anti-inflammatory 10 steroids are ~lunisolide and beclomethasone.
Dexamethasone or hydrocortisone might also be used.
Flunisolide is most advantageously used in the form of the hemihydrate, as that form is non-hygroscopic and is thus easiest to handle during ~ormulation. Flunisolide is commercially available, and can be prepared as described in U.S. Pat. No. 4,273,710. Beclomethasone is also commercially available, and can be prepared as described in G.B. Pat. No. 912,378.
Propylene glycol re~ers to 1,2-propanediol.
20 Propylene glycol is available commercially.
Polyethylene glycol 400 re~ers to commercially available mixtures o~ polymers o~ average molecular weight about 400 o~ the ~orm H-(OCH2CH2)n-OH, where the average value o~ n is between 8.2 and 9.1.
25 Polyethylene glycol 400 is abbreviated herein as "PEG
400n .
Polysorbate 20 refers to commercially available polyoxyethylene-sorbitan monolaurates having about 20 oxyethylene units per sorbitan unit, for example 30 Tween- 20.
The term ~BHT" refers to butylated hydroxytoluene, which is a commercially available preservative/anti-oxidant.
The term "BHA" re~ers to butylated hydroxyanisole, 35 which is a commercially available preservative/anti-oxidant.
3505Y , 255~0-FF
``` ~X88048 The term "preservative" refers to a compound or mixture of compounds used in a formulation which is use~ul for reducing or eliminating microbial growth in a ~ormulation. A preservative must be pharmaceutically acceptable at the concentrations used, and should not interfere with the action of the active compound in the formulation. An "effective amount" of a preservative is that amount necessary to prevent the growth o~
10 microorganisms in the formulation. The effective amount may be determined using the USP-BP modified double blind assay. Exemplary preservatives include, without limitation, BHA, BHT, benzalkonium chloride, thimerosal, potassium sorbate, methylparaben, propylparaben, sodium 15 benzoate and the like. Presently pre~erred preservatives are benzalkonium chloride and thimerosal, particularly benzalkonium chloride.
The term "antioxidant" re~ers to a compound or mixture o~ compounds used in a ~ormulation which is 20 use~ul ~or preventing the oxidation o~ active compound(s) in a ~ormulation. A antioxidant must be pharmaceutically acceptable at the concentrations used, and should not interfere with the action of the active compound in the formulation. An "ef~ective amount" o~ an antioxidant is 25 that amount necessary to prevent undue oxidation of the active compound under normal storage conditions.
Presently pre~erred antioxidants are BHA, and BHT, particularly BHT.
The term "stabilizer" refers to a compound used in a 30 formulatiQn to prevent chemical degradation by means other than oxidation or microbial digestion. An "e~ective amount n of an oxidant is that amount necessary to prevent unacceptable degradation o~ the active compound. The presently preferred stabilizer is disodium 35 EDTA.
``` ~288048 The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a hùman, and includes:
(i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it;
(ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing 10 regression o~ the disease.
ADMINISTRATION
The compositions of the invention are advantageously administered intranasally by means of a "non-propellant n type aerosol or atomizer, especially using a pump-type dispenser. ror example, the Calmar Mark II nasal pump (Calmar-Albert GmbH) and the P~eiffer pump (Ing.-erich Pfeiffer GmbH ~ Co. KG) are generally useful.
Preferably, the aerosol pump will deliver a spray in 20 which less than 1% o~ the droplets are below 16 ~m in diameter. This minimizes the amount of composition which reaches the lungs.
Su~icient amounts o~ the composition will be administered to give e~fective nasal anti-inflammatory 25 action with the steroid concerned.
PREPARATION
The compositions of this invention may be prepared in any convenient manner. Suitably the steroid is 30 dissolved in the solubilizers (propylene glycol, PEG 400 and polysorbate 20) before the required water is added.
Any desired excipients may suitably be dissolved in the -water prior to adding to the steroid solution. The pH of the final solution is adjusted to suitable levels, ~or 35 example, between 3.5 and 7.
3505Y , 25560-FF
Pre~erred compositions of the invention ma~ be prepared as ~ollows:
The desired amounts o~ propylene glycol, PE~ 400 7 and polysorbate 20 are mixed well in an appropriate vessel. To thls mixture ls added the desired amount o~
~lunisolide (pre~erably in the ~orm o~ the hernihydrate), and BHT. The resulting mixture is heated to 50-55qC and mixed until the ~lunisolide and BHT dissolve.
The desired amount o~ sorbitol (e.g., as a 70%
10 solution) is mixed with citric acid and sodium citrate (in the proper proportions ~or obtaining the desired bu~er), benzalkonium chloride ~e.g. as a 50% solution), edetate disodium, and water, to ~orm a solution which is approximately gO% water. This solution is then mixed 15 wlth the ~lu~isolide solution an~ the pH measured and adjusted with HCl soluti.on or NaOH solution as appropriate.
The resulting solution is brought to ~inal volume with puri~ied water, ~iltered through a 3 micron ~ilter, 20 and packaged.
(Example Formulations) The ~ollowing are representative compositions o~ the 25 invention. The compositions are prepared as described in the Preparation above.
(I) 3505Y , 25560-Ff ~ ~288~4~
, Compound amount%~w/v) flunisolide hemihydrate 0.025 propylene glycol 5.0 PEG 400 20.0 polysorbate 20 2.50 benzalkonium chloride 0.035 disodium EDTA 0.01 BHT 0.01 citric acid 0.005 sodium citrate-2H20 0.00765 sorbitol 2.00 water qs 100.0 pH 5.2 ( I I ) Compound amount%(w/v) flunisolide hemihydrate 0.01 propylene glycol 2.0 PEG 400 10.0 polysorbate 20 1.0 benzalkonium chloride 0.03 disodium EDTA 0.01 BHT 0.01 citric acid 0.005 sodium citrate-2H20 0.00765 - sorbitol 2.00 water qs 100.0 pH 5.3 2S ( III) Compound amount%~w/v~
beclomethasone 0.05 propylene glycol 10.0 PEG 400 25.0 polysorbate 20 4.0 benzalkonium chloride 0.03 disodium EDTA 0.01 BHT 0.01 citric acid 0.005 sodium citrate-2H20 0.00765 sorbitol 5.00 water qs 100.0 pH 5.2 .
88(~
(Nasal Acceptability) The following example illustrates a procedure for assaying the nasal acceptability of various compositions. The formulations were prepared as in Example 1. Formulation C is a vehicle according to this invention.
Eighteen volunteers were randomly divided into two groups. Group 1 received formulations A, B, and D.
10 Group 2 received formulations A, C, and E. The tests were per~ormed by applying one spray to each nostril, with a rest period o~ 4 hours between administrations o~
di~erent ~ormulations.
The ~ollowiny parameters were recorded, both 15 immediately and 15 minutes a~ter administration: nasal stinging, taste, other sensations, and willingness to use the spray three times daily. The formulations tested were as ~ollows:
- amountX(w/v) Compound A B C D E
propylene glycol20.0 7.0 5.0 0.0 0.0 PEG 3350 15.0 0.0 0.0 0.0 0.0 PEG 400 0.0 40.0 20.0 15.0 0.0 polysorbate 20 0.0 0.0 2.50 3.5 3.5 25 *benzalkonium Cl0.02 0.02 0.02 0.02 0.02 disodium EDTA 0.01 0.01 0.01 0.01 0.01 BHA 0.002 0.002 0.002 0.002 0.002 citric acid 0.005 0.005 0.005 0.005 0.005 Na citrate 0.0077 0.0077 0.0077 0.0077 0.0077 sorbitol 0.0 3.0 2.0 2.0 2.0 water qs 100.0 100.0 100.0100.0 100.0 30 pH 5.3 5.3 5.3 5.3 5.3 , *50~ solutlon The results indicated superior nasal acceptability for compositions C, D, and E.
~288048 (Accelerated Stability) The stability of ~ormulations was investigated as 5 follows:
Six ~ormulations were prepared as set out below for testing. Ten mL of each formulation was filled and sealed in amber glass ampoules and stored at 80C
(1/2 month), 60C (1.5 months), and 15C for the period 10 of time stated. In addition, 25 mL o~ each solution was filled in 1 oz round high density polyethylene bottles and screw capped. These bottles were stored at 50C (2, 3, 8, and 10 months), 40C (8 and 10 months), and room temperature (RT) (8 and 10 months). At the end of the 15 appropriate time period, the steroid content was determined using HPLC, and the pH of the solution measured. The results are normalized against the 15C
data ~or the appropriate time periods.
- -amountX~w/v) ComDosition 1 2 3 ~4 - 5 6 7 PG 20.0 5.0 5.0 0.0 5.0 5.0 0.0 PEG 335015.0 0.0 0.0 0.0 0.0 0.0 0-0 PEG 400 0.0 20.020.0 15.0 20.0 20.015.0 PS 20 0.0 2.5 2.5 3.5 2.5 2.5 3.5 25 BHA 0.01 0.010.01 0.01 o.0 o.o o.o BHT 0.0 0.0 0.0 0.0 0.01 0.010.01 citrate0.01 0.010.02 0.010.02 0.010.02 water qs 100.0 100.0 100.0 100.0 100.0 100.0 100.0 In addition, each ~ormulation contained 0.025%
30 ~lunisolide, 2% sorbitol, 0.01% EDTA, and 0.04%
benzalkonium chloride. Composition 1 corresponds to Composition A of Example 2. Compositions 2, 3, 5, and 6 are equivalent to Composition C o~ Example 2, and are according to the invention. Compositinns 4 and 7 are 35 equivalent to Co~position D o~ Example 2.
3505Y ~ 25560-FF
~ Zl~38048 The results indicated that the formulations of the invention (Compositions 2, 3, 5, and 6) display superior stability as compared to other compositions (1, 4, and 7) in this assay.
(Preservative E~icacy) The compositions listed below are tested for 10 preservative efficacy using the USP-BP modified double challenge test.
amount%(w/v) Composition A B C D E
15 ~lunisolide 0.025 0.025 0.025 0.025 0.025 propylene glycol 20.0 7.0 5.0 0.0 0.0 PEG 3350 15.0 0.0 0.0 0.0 0.0 PEG 400 0.0 40.0 20.0 15.0 0.0 polysorbate 20 0.0 0.0 2.50 3.5 3.5 disodium EDTA 0.01 0.01 0.01 0.01 0.01 BHA 0.002 0.002 0.002 0.002 0.002 20 citrate bu~er 0.01 0.01 0.01 0.01 0.01 sorbitol 0.0 3.0 2.0 2.0 2.0 water qs 100.0 100.0 100.0 100.0 100.0 pH 5.3 5.3 5.3 5.3 5.3 In addition, each composition is prepared with 0.01, 25 0.02, 0.025, 0.03, 0.035, or 0.04 %(w/v) benzalkonium chloride. These compositions correspond to compositions A-E o~ Example 2. Composition C is according to the invention.
Compositions A-E are prepared according to 30 Example lf added to culture media, and the resulting test media directly inoculated with challenge organisms.
A~ter incubation ~or 14 days, the test media are inoculated again. The number o~ colony forming units is recorded over the remaining 14 days of the test.
` ~288048 The results indicated that Compositions A and B were effectively preserved with 0.01~ benzalkonium chloride and Composition C was e~fectively preserved with 0.03%
5 benzalkonium chloride, whereas Composition D required more than 0.04X benzalkonium chloride, and Composition E
was not e~ectively preserved with any concentration of benzalkonium chloride tested.
E~AMPLE 5 (Toxicology) No adverse reactions were seen in a one month intranasal toxicity study in rabbits with Composition (I) ~rom Example 1 above.
AQUEOUS STEROID FORMULATIONS FOR NASAL ADMINISTRATION
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates to aqueous anti-in~lammatory steroid formulations suitable ~or nasal administration, and to methods for treating in~lammat~on o~ the nasal mucosa by intranasal administration o~ said ~ormulations.
Related Disclosure Aqueous ~ormulations o~ anti- inflammatory steroids such as flunisolide suitable ~or nasal administration are commercially available, for example under the trademark Nasalide- (see, for example, U.K. Patent No. 1525181).
However, currently available ~ormulations, while sa~e and 25 ef~ective, are known to cause stinging upon administration in some cases, which is a side effect particularly undesirable when treating nasal inflammation. The novel formulations of the invention are suitable for nasal administration of 30 anti-in~lammatory steroids without causing stinging.
One aspect o~ the invention is a substantially non-stinging aqueous anti-inflammatory steroid 35 formulation suitable ~or nasal administration, which formulation comprises: an anti-in~lammatory steroid in 3505Y 25560-fF
an amount between about O.OlX and about 0.05% tw/v);
propylene glycol in an amount between about 2% and about 10% (w/v); PEG 400 in an amount between about 10% and about 25% (w/v); polysorbate 20 in an amount between about 1% and about 4% (w/v); and water.
Suitably, an effective amount of a preservative, preferably between about 0.02% and about 0.08% (w/v); an effective amount of a stabilizer, pre~erably between about 0.005% and about 0.05%; an effective amount of an antioxidant, preferably between about O.OOlX and about 0.05%; and a pH buffering agent sufficient to adjust the pH of the resulting solution to between about 3.5 and about 7, are also present to enhance stability and preservability.
A preferred subgenus of the invention is the formulation wherein said anti-inflammatory steroid is flunisolide, particularly in an amount of about 0.025%
(w/v) .
A preferred class is the formulation wherein said 20 preservative is benzalkonium chloride in an amount between about 0.02% and about 0.08% (w/v); said stabilizer is disodium EDTA in an amount between about 0.~05% and about 0.05% ~w/v); and said antioxidant is BHT
in an amount between about O.OOlX and about 0.05% (w/v);
25 especially the formulation which further comprises sorbitol in an amount between about 0.001% and about 5%
(w/v). A preferred subclass is the formulation wherein said pH buffering agent comprises a citrate buffer such as: citric acid in an amount between about 0.001% and 30 about 0.05% (w/v); and sodium citrate dihydrate in an a~ount between about O.OOlX and about 0.05% (w/v).
A preferred species is the non-stinging aqueous anti-inflammatory steroid formulation suitable for nasal administration, which formulation comprises:
1288~
flunisolide hemihydrate in an amount of about 0.025% (w/v);
propylene glycol in an amount of about 5% (w/v);
PEG 400 in an amount o~ about 20% (w/v);
polysorbate 20 in an amount o~ about 2.50% (w/v);
benzalkonium chloride in an amount o~ about 0.035% (w/v);
disodium EDTA in an amount of about 0.01% (w/v);
~HT in an amount of about 0.01% (w/v);
citric acid in an amount of about 0.005% (w/v);
sodium citrate dihydrate in an amount o~ about 0.00765% (w/v);
sorbitol in an amount o~ about 2.00% (w/v); and water, wherein the pH o~ the resulting solution is adjusted to about 5.2.
Another aspect o~ the invention is a method o~
treating inflammation o~ the nasal mucosa without inducing stinging, which method comprises intranasally 20 administering to a subject in need thereo~ a substantially non-stinging aqueous anti-in~lammatory steroid ~ormulation as described above.
A ~urther aspect o~ the invention is the use of the steroid formulation as described above in the treatment 25 ~ in~lammation o~ the nasal musosa.
The compositions o~ this invention have very satis~actory nasal acceptability, particularly as shown by their lack of, or low level of, nasal stinging.
The compositions o~ this invention provide good drug 30 solubility, and this solubility is retained with varying temperature.
The compositions of this invention provide excellent pumping characteristics, so reducing the need to overcome pump clogging with washing and rinsing procedures.
The compositions of this invention are also stable and preservable.
3505Y . 25560-FF
1288(~48 From these advantages, it is clear that the compositions of this invention provide very attractive nasal steroid formulations.
DEFINITIONS
As used herein, the term "anti-inflammatory steroid"
re~ers to a steroid compound which is phar~aceutically acceptable, and which is known to be use~ul in reducing inflammation. Particularly suitable anti-inflammatory 10 steroids are ~lunisolide and beclomethasone.
Dexamethasone or hydrocortisone might also be used.
Flunisolide is most advantageously used in the form of the hemihydrate, as that form is non-hygroscopic and is thus easiest to handle during ~ormulation. Flunisolide is commercially available, and can be prepared as described in U.S. Pat. No. 4,273,710. Beclomethasone is also commercially available, and can be prepared as described in G.B. Pat. No. 912,378.
Propylene glycol re~ers to 1,2-propanediol.
20 Propylene glycol is available commercially.
Polyethylene glycol 400 re~ers to commercially available mixtures o~ polymers o~ average molecular weight about 400 o~ the ~orm H-(OCH2CH2)n-OH, where the average value o~ n is between 8.2 and 9.1.
25 Polyethylene glycol 400 is abbreviated herein as "PEG
400n .
Polysorbate 20 refers to commercially available polyoxyethylene-sorbitan monolaurates having about 20 oxyethylene units per sorbitan unit, for example 30 Tween- 20.
The term ~BHT" refers to butylated hydroxytoluene, which is a commercially available preservative/anti-oxidant.
The term "BHA" re~ers to butylated hydroxyanisole, 35 which is a commercially available preservative/anti-oxidant.
3505Y , 255~0-FF
``` ~X88048 The term "preservative" refers to a compound or mixture of compounds used in a formulation which is use~ul for reducing or eliminating microbial growth in a ~ormulation. A preservative must be pharmaceutically acceptable at the concentrations used, and should not interfere with the action of the active compound in the formulation. An "effective amount" of a preservative is that amount necessary to prevent the growth o~
10 microorganisms in the formulation. The effective amount may be determined using the USP-BP modified double blind assay. Exemplary preservatives include, without limitation, BHA, BHT, benzalkonium chloride, thimerosal, potassium sorbate, methylparaben, propylparaben, sodium 15 benzoate and the like. Presently pre~erred preservatives are benzalkonium chloride and thimerosal, particularly benzalkonium chloride.
The term "antioxidant" re~ers to a compound or mixture o~ compounds used in a ~ormulation which is 20 use~ul ~or preventing the oxidation o~ active compound(s) in a ~ormulation. A antioxidant must be pharmaceutically acceptable at the concentrations used, and should not interfere with the action of the active compound in the formulation. An "ef~ective amount" o~ an antioxidant is 25 that amount necessary to prevent undue oxidation of the active compound under normal storage conditions.
Presently pre~erred antioxidants are BHA, and BHT, particularly BHT.
The term "stabilizer" refers to a compound used in a 30 formulatiQn to prevent chemical degradation by means other than oxidation or microbial digestion. An "e~ective amount n of an oxidant is that amount necessary to prevent unacceptable degradation o~ the active compound. The presently preferred stabilizer is disodium 35 EDTA.
``` ~288048 The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a hùman, and includes:
(i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it;
(ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing 10 regression o~ the disease.
ADMINISTRATION
The compositions of the invention are advantageously administered intranasally by means of a "non-propellant n type aerosol or atomizer, especially using a pump-type dispenser. ror example, the Calmar Mark II nasal pump (Calmar-Albert GmbH) and the P~eiffer pump (Ing.-erich Pfeiffer GmbH ~ Co. KG) are generally useful.
Preferably, the aerosol pump will deliver a spray in 20 which less than 1% o~ the droplets are below 16 ~m in diameter. This minimizes the amount of composition which reaches the lungs.
Su~icient amounts o~ the composition will be administered to give e~fective nasal anti-inflammatory 25 action with the steroid concerned.
PREPARATION
The compositions of this invention may be prepared in any convenient manner. Suitably the steroid is 30 dissolved in the solubilizers (propylene glycol, PEG 400 and polysorbate 20) before the required water is added.
Any desired excipients may suitably be dissolved in the -water prior to adding to the steroid solution. The pH of the final solution is adjusted to suitable levels, ~or 35 example, between 3.5 and 7.
3505Y , 25560-FF
Pre~erred compositions of the invention ma~ be prepared as ~ollows:
The desired amounts o~ propylene glycol, PE~ 400 7 and polysorbate 20 are mixed well in an appropriate vessel. To thls mixture ls added the desired amount o~
~lunisolide (pre~erably in the ~orm o~ the hernihydrate), and BHT. The resulting mixture is heated to 50-55qC and mixed until the ~lunisolide and BHT dissolve.
The desired amount o~ sorbitol (e.g., as a 70%
10 solution) is mixed with citric acid and sodium citrate (in the proper proportions ~or obtaining the desired bu~er), benzalkonium chloride ~e.g. as a 50% solution), edetate disodium, and water, to ~orm a solution which is approximately gO% water. This solution is then mixed 15 wlth the ~lu~isolide solution an~ the pH measured and adjusted with HCl soluti.on or NaOH solution as appropriate.
The resulting solution is brought to ~inal volume with puri~ied water, ~iltered through a 3 micron ~ilter, 20 and packaged.
(Example Formulations) The ~ollowing are representative compositions o~ the 25 invention. The compositions are prepared as described in the Preparation above.
(I) 3505Y , 25560-Ff ~ ~288~4~
, Compound amount%~w/v) flunisolide hemihydrate 0.025 propylene glycol 5.0 PEG 400 20.0 polysorbate 20 2.50 benzalkonium chloride 0.035 disodium EDTA 0.01 BHT 0.01 citric acid 0.005 sodium citrate-2H20 0.00765 sorbitol 2.00 water qs 100.0 pH 5.2 ( I I ) Compound amount%(w/v) flunisolide hemihydrate 0.01 propylene glycol 2.0 PEG 400 10.0 polysorbate 20 1.0 benzalkonium chloride 0.03 disodium EDTA 0.01 BHT 0.01 citric acid 0.005 sodium citrate-2H20 0.00765 - sorbitol 2.00 water qs 100.0 pH 5.3 2S ( III) Compound amount%~w/v~
beclomethasone 0.05 propylene glycol 10.0 PEG 400 25.0 polysorbate 20 4.0 benzalkonium chloride 0.03 disodium EDTA 0.01 BHT 0.01 citric acid 0.005 sodium citrate-2H20 0.00765 sorbitol 5.00 water qs 100.0 pH 5.2 .
88(~
(Nasal Acceptability) The following example illustrates a procedure for assaying the nasal acceptability of various compositions. The formulations were prepared as in Example 1. Formulation C is a vehicle according to this invention.
Eighteen volunteers were randomly divided into two groups. Group 1 received formulations A, B, and D.
10 Group 2 received formulations A, C, and E. The tests were per~ormed by applying one spray to each nostril, with a rest period o~ 4 hours between administrations o~
di~erent ~ormulations.
The ~ollowiny parameters were recorded, both 15 immediately and 15 minutes a~ter administration: nasal stinging, taste, other sensations, and willingness to use the spray three times daily. The formulations tested were as ~ollows:
- amountX(w/v) Compound A B C D E
propylene glycol20.0 7.0 5.0 0.0 0.0 PEG 3350 15.0 0.0 0.0 0.0 0.0 PEG 400 0.0 40.0 20.0 15.0 0.0 polysorbate 20 0.0 0.0 2.50 3.5 3.5 25 *benzalkonium Cl0.02 0.02 0.02 0.02 0.02 disodium EDTA 0.01 0.01 0.01 0.01 0.01 BHA 0.002 0.002 0.002 0.002 0.002 citric acid 0.005 0.005 0.005 0.005 0.005 Na citrate 0.0077 0.0077 0.0077 0.0077 0.0077 sorbitol 0.0 3.0 2.0 2.0 2.0 water qs 100.0 100.0 100.0100.0 100.0 30 pH 5.3 5.3 5.3 5.3 5.3 , *50~ solutlon The results indicated superior nasal acceptability for compositions C, D, and E.
~288048 (Accelerated Stability) The stability of ~ormulations was investigated as 5 follows:
Six ~ormulations were prepared as set out below for testing. Ten mL of each formulation was filled and sealed in amber glass ampoules and stored at 80C
(1/2 month), 60C (1.5 months), and 15C for the period 10 of time stated. In addition, 25 mL o~ each solution was filled in 1 oz round high density polyethylene bottles and screw capped. These bottles were stored at 50C (2, 3, 8, and 10 months), 40C (8 and 10 months), and room temperature (RT) (8 and 10 months). At the end of the 15 appropriate time period, the steroid content was determined using HPLC, and the pH of the solution measured. The results are normalized against the 15C
data ~or the appropriate time periods.
- -amountX~w/v) ComDosition 1 2 3 ~4 - 5 6 7 PG 20.0 5.0 5.0 0.0 5.0 5.0 0.0 PEG 335015.0 0.0 0.0 0.0 0.0 0.0 0-0 PEG 400 0.0 20.020.0 15.0 20.0 20.015.0 PS 20 0.0 2.5 2.5 3.5 2.5 2.5 3.5 25 BHA 0.01 0.010.01 0.01 o.0 o.o o.o BHT 0.0 0.0 0.0 0.0 0.01 0.010.01 citrate0.01 0.010.02 0.010.02 0.010.02 water qs 100.0 100.0 100.0 100.0 100.0 100.0 100.0 In addition, each ~ormulation contained 0.025%
30 ~lunisolide, 2% sorbitol, 0.01% EDTA, and 0.04%
benzalkonium chloride. Composition 1 corresponds to Composition A of Example 2. Compositions 2, 3, 5, and 6 are equivalent to Composition C o~ Example 2, and are according to the invention. Compositinns 4 and 7 are 35 equivalent to Co~position D o~ Example 2.
3505Y ~ 25560-FF
~ Zl~38048 The results indicated that the formulations of the invention (Compositions 2, 3, 5, and 6) display superior stability as compared to other compositions (1, 4, and 7) in this assay.
(Preservative E~icacy) The compositions listed below are tested for 10 preservative efficacy using the USP-BP modified double challenge test.
amount%(w/v) Composition A B C D E
15 ~lunisolide 0.025 0.025 0.025 0.025 0.025 propylene glycol 20.0 7.0 5.0 0.0 0.0 PEG 3350 15.0 0.0 0.0 0.0 0.0 PEG 400 0.0 40.0 20.0 15.0 0.0 polysorbate 20 0.0 0.0 2.50 3.5 3.5 disodium EDTA 0.01 0.01 0.01 0.01 0.01 BHA 0.002 0.002 0.002 0.002 0.002 20 citrate bu~er 0.01 0.01 0.01 0.01 0.01 sorbitol 0.0 3.0 2.0 2.0 2.0 water qs 100.0 100.0 100.0 100.0 100.0 pH 5.3 5.3 5.3 5.3 5.3 In addition, each composition is prepared with 0.01, 25 0.02, 0.025, 0.03, 0.035, or 0.04 %(w/v) benzalkonium chloride. These compositions correspond to compositions A-E o~ Example 2. Composition C is according to the invention.
Compositions A-E are prepared according to 30 Example lf added to culture media, and the resulting test media directly inoculated with challenge organisms.
A~ter incubation ~or 14 days, the test media are inoculated again. The number o~ colony forming units is recorded over the remaining 14 days of the test.
` ~288048 The results indicated that Compositions A and B were effectively preserved with 0.01~ benzalkonium chloride and Composition C was e~fectively preserved with 0.03%
5 benzalkonium chloride, whereas Composition D required more than 0.04X benzalkonium chloride, and Composition E
was not e~ectively preserved with any concentration of benzalkonium chloride tested.
E~AMPLE 5 (Toxicology) No adverse reactions were seen in a one month intranasal toxicity study in rabbits with Composition (I) ~rom Example 1 above.
Claims (30)
1. A substantially non-stinging aqueous anti-inflammatory steroid formulation suitable for intranasal administration, which formulation comprises:
an anti-inflammatory steroid in an amount between about 0.01% and about 0.05% (w/v);
propylene glycol in an amount between about 2% and about 10% (w/v);
PEG 400 in an amount between about 10% and about 25%
(w/v);
polysorbate 20 in an amount between about 1% and about 4% (w/v); and water.
an anti-inflammatory steroid in an amount between about 0.01% and about 0.05% (w/v);
propylene glycol in an amount between about 2% and about 10% (w/v);
PEG 400 in an amount between about 10% and about 25%
(w/v);
polysorbate 20 in an amount between about 1% and about 4% (w/v); and water.
2. A formulation according to Claim 1, which is a stable, effectively preservable, substantially non-stinging aqueous anti-inflammatory steroid formulation suitable for intranasal administration, which formulation comprises:
an anti-inflammatory steroid in an amount between about 0.01% and about 0.05% (w/v);
propylene glycol in an amount between about 2% and about 10% (w/v);
PEG 400 in an amount between about 10% and about 25%
(w/v);
polysorbate 20 in an amount between about 1% and about 4% (w/v);
an effective amount of preservative;
an effective amount of antioxidant;
an effective amount of stabilizer;
water; and pH buffering agent sufficient to adjust the pH of the resulting solution to between about 3.5 and about 7
an anti-inflammatory steroid in an amount between about 0.01% and about 0.05% (w/v);
propylene glycol in an amount between about 2% and about 10% (w/v);
PEG 400 in an amount between about 10% and about 25%
(w/v);
polysorbate 20 in an amount between about 1% and about 4% (w/v);
an effective amount of preservative;
an effective amount of antioxidant;
an effective amount of stabilizer;
water; and pH buffering agent sufficient to adjust the pH of the resulting solution to between about 3.5 and about 7
3. The formulation of Claim 2 which comprises:
preservative in an amount between about 0.02% and about 0.08% (w/v);
antioxidant in an amount between about 0.001% and about 0.05% (w/v);
stabilizer in an amount between about 0.005% and about 0.05% (w/v).
preservative in an amount between about 0.02% and about 0.08% (w/v);
antioxidant in an amount between about 0.001% and about 0.05% (w/v);
stabilizer in an amount between about 0.005% and about 0.05% (w/v).
4. The formulation according to claim 3 wherein:
said preservative is benzalkonium chloride;
said antioxidant is BHT; and said stabilizer is disodium EDTA.
said preservative is benzalkonium chloride;
said antioxidant is BHT; and said stabilizer is disodium EDTA.
5. The formulation according to claim 1 wherein said anti-inflammatory steroid is flunisolide.
6. The formulation according to claim 2 wherein said anti-inflammatory steroid is flunisolide.
7. The formulation according to claim 3 wherein said anti-inflammatory steroid is flunisolide.
8. The formulation according to claim 4 wherein said anti-inflammatory steroid is flunisolide.
9. The formulation of claim 1 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
10. The formulation of claim 2 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
11. The formulation of claim 3 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
12. The formulation of claim 4 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
13. The formulation of claim 5 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
14. The formulation of claim 6 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
15. The formulation of claim 7 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
16. The formulation of claim 8 which further comprises sorbitol in an amount between about 0.001% and 5% (w/v).
17. A formulation according to Claim 2, which is a stable, effectively preservable, substantially non-stinging aqueous anti-inflammatory steroid formulation suitable for intranasal administration, which formulation comprises:
flunisolide hemihydrate in an amount of about 0.025%
(w/v);
propylene glycol in an amount of about 5% (w/v);
PEG 400 in an amount of about 20% (w/v);
polysorbate 20 in an amount of about 2.50% (w/v);
benzalkonium chloride in an amount of about 0.035%
(w/v);
disodium EDTA in an amount of about 0.01% (w/v);
BHT in an amount of about 0.01% (w/v);
citric acid in an amount of about 0.001% (w/v);
sodium citrate dihydrate in an amount of about 0.00765%
(w/v);
sorbitol in an amount of about 2.00% (w/v); and water; wherein the pH of the resulting solution is adjusted to about 5.2.
flunisolide hemihydrate in an amount of about 0.025%
(w/v);
propylene glycol in an amount of about 5% (w/v);
PEG 400 in an amount of about 20% (w/v);
polysorbate 20 in an amount of about 2.50% (w/v);
benzalkonium chloride in an amount of about 0.035%
(w/v);
disodium EDTA in an amount of about 0.01% (w/v);
BHT in an amount of about 0.01% (w/v);
citric acid in an amount of about 0.001% (w/v);
sodium citrate dihydrate in an amount of about 0.00765%
(w/v);
sorbitol in an amount of about 2.00% (w/v); and water; wherein the pH of the resulting solution is adjusted to about 5.2.
18. A formulation according to any one of Claims 1 to 3 for use in treating inflammation of the nasal mucosa without inducing stinging.
19. A formulation according to any one of Claims 4 to 6 for use in treating inflammation of the nasal mucosa without inducing stinging.
20. A formulation according to any one of Claims 7 to 9 for use in treating inflammation of the nasal mucosa without inducing stinging.
21. A formulation according to any one of Claims 10 to 12 for use in treating inflammation of the nasal mucosa without inducing stinging.
22. A formulation according to any one of Claims 13 to 15 for use in treating inflammation of the nasal mucosa without inducing stinging.
23. A formulation according to Claims 16 or 17 for use in treating inflammation of the nasal mucosa without inducing stinging.
24. The use of a formulation according to any one of Claims 1 to 3 for treating inflammation of the nasal mucosa without inducing stinging.
25. The use of a formulation according to any one of Claims 4 to 6 for treating inflammation of the nasal mucosa without inducing stinging.
26. The use of a formulation according to any one of Claims 7 to 9 for treating inflammation of the nasal mucosa without inducing stinging.
27. The use of a formulation according to any one of Claims 10 to 12 for treating inflammation of the nasal mucosa without inducing stinging.
28. The use of a formulation according to any one of Claims 13 to 15 for treating inflammation of the nasal mucosa without inducing stinging.
29. The use of a formulation according to Claims 16 or 17 for treating inflammation of the nasal mucosa without inducing stinging.
30. A process for preparing the formulation of Claim 1, which process comprises dissolving the stated ingredients in water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/866,171 US4782047A (en) | 1986-05-22 | 1986-05-22 | Aqueous steroid formulations for nasal administration |
| US866,171 | 1986-05-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1288048C true CA1288048C (en) | 1991-08-27 |
Family
ID=25347059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000537690A Expired - Lifetime CA1288048C (en) | 1986-05-22 | 1987-05-21 | Aqueous steroid formulations for nasal administration |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US4782047A (en) |
| EP (1) | EP0246652B1 (en) |
| JP (1) | JP2521291B2 (en) |
| KR (1) | KR950008308B1 (en) |
| AT (1) | ATE65183T1 (en) |
| AU (1) | AU609718B2 (en) |
| CA (1) | CA1288048C (en) |
| DE (1) | DE3771389D1 (en) |
| DK (1) | DK175238B1 (en) |
| ES (1) | ES2031467T3 (en) |
| FI (1) | FI88459C (en) |
| GR (1) | GR3002317T3 (en) |
| HK (1) | HK39094A (en) |
| IE (1) | IE60259B1 (en) |
| IL (1) | IL82615A (en) |
| IT (1) | IT1205667B (en) |
| NO (1) | NO173365C (en) |
| NZ (1) | NZ220394A (en) |
| ZA (1) | ZA873663B (en) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4983595A (en) * | 1986-05-22 | 1991-01-08 | Syntex (U.S.A.) Inc. | Aqueous steroid formulations for nasal administration |
| JPH0311016A (en) * | 1989-06-09 | 1991-01-18 | Tokyo Tanabe Co Ltd | Aqueous preparation of pyrido(1,2-a)pyrimidine derivative |
| GB9103824D0 (en) * | 1991-02-23 | 1991-04-10 | Fisons Ag | Formulation |
| US5338732A (en) * | 1991-06-18 | 1994-08-16 | Bristol-Myers Squibb Company | Megestrol acetate formulation |
| ES2171469T3 (en) * | 1993-10-21 | 2002-09-16 | Hisamitsu Pharmaceutical Co | COMPOSITION ADMINISTERED BY NASAL AND PREPARATION THAT CONTAINS IT. |
| US5762917A (en) * | 1994-09-27 | 1998-06-09 | Virotex Corporation | Method and composition for cleansing wounds with minimal cytotoxicity for minimal scarring |
| US5976573A (en) * | 1996-07-03 | 1999-11-02 | Rorer Pharmaceutical Products Inc. | Aqueous-based pharmaceutical composition |
| US8466134B1 (en) | 1998-06-26 | 2013-06-18 | Athena Neurosciences, Inc. | Aqueous compositions containing corticosteroids for nasal and pulmonary delivery |
| US6241969B1 (en) | 1998-06-26 | 2001-06-05 | Elan Corporation Plc | Aqueous compositions containing corticosteroids for nasal and pulmonary delivery |
| GB9918559D0 (en) * | 1999-08-07 | 1999-10-06 | Glaxo Wellcome Kk | Novel pharmaceutical formulation |
| US20060083691A1 (en) * | 2000-05-10 | 2006-04-20 | Wermeling Daniel P | Intranasal opioid compositions, delivery devices and methods of using same |
| US20040115133A1 (en) * | 2000-05-10 | 2004-06-17 | Wermeling Daniel P. | Intranasal opioid compositions |
| US6610271B2 (en) * | 2000-05-10 | 2003-08-26 | University Of Kentucky Research Foundation | System and method for intranasal administration of lorazepam |
| WO2002013886A2 (en) | 2000-08-15 | 2002-02-21 | University Of Kentucky Research Foundation | Programmable multi-dose intranasal drug delivery device |
| US20040176359A1 (en) * | 2001-02-20 | 2004-09-09 | University Of Kentucky Research Foundation | Intranasal Benzodiazepine compositions |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| JP4664071B2 (en) | 2002-08-01 | 2011-04-06 | エーザイ コーポレーション オブ ノース アメリカ | Improved treatment of cancer with glutamine |
| US7148211B2 (en) * | 2002-09-18 | 2006-12-12 | Genzyme Corporation | Formulation for lipophilic agents |
| US7404489B1 (en) | 2003-03-04 | 2008-07-29 | Qol Medical, Llc | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
| JP5238779B2 (en) * | 2003-04-25 | 2013-07-17 | ロート製薬株式会社 | Nasal drops |
| JP4632687B2 (en) * | 2003-04-25 | 2011-02-16 | ロート製薬株式会社 | Nasal drops |
| WO2005065185A2 (en) * | 2003-12-24 | 2005-07-21 | Collegium Pharmaceuticals, Inc. | Temperature-stable formulations, and methods of development thereof |
| GB0400804D0 (en) | 2004-01-14 | 2004-02-18 | Innoscience Technology Bv | Pharmaceutical compositions |
| US20060045850A1 (en) * | 2004-08-30 | 2006-03-02 | Qpharma, Llc | Nasal delivery of cyclodextrin complexes of anti-inflammatory steroids |
| PL2486942T3 (en) | 2004-11-24 | 2019-05-31 | Meda Pharmaceuticals Inc | Compositions comprising azelastine and methods of use thereof |
| WO2007022345A2 (en) | 2005-08-17 | 2007-02-22 | Fleming And Company, Pharmaceuticals | Vitamin b12 nasal spray and method of use |
| KR100767976B1 (en) | 2006-08-25 | 2007-10-18 | 한국유나이티드제약 주식회사 | Effective pharmaceutical composition for dry nose syndrome |
| CN101678112B (en) | 2007-01-19 | 2016-08-31 | 哈南亚有限公司 | For delivering the method and composition of therapeutic agent |
| US20080275030A1 (en) | 2007-01-19 | 2008-11-06 | Sveinbjorn Gizurarson | Methods and Compositions for the Delivery of a Therapeutic Agent |
| JP2011001317A (en) * | 2009-06-19 | 2011-01-06 | Fumakilla Ltd | Cleaning agent for nose |
| CA2905587A1 (en) | 2013-03-15 | 2014-09-18 | Medicis Pharmaceutical Corporation | Topical compositions of flunisolide and methods of treatment |
| JP6097787B2 (en) * | 2015-06-09 | 2017-03-15 | パル ファーマシューティカル， インコーポレーテッド | Cyanocobalamin low viscosity aqueous formulation for intranasal delivery |
| EP3324933B1 (en) | 2015-07-16 | 2020-12-16 | Marinomed Biotech AG | Method for improving aqueous solubility of water-insoluble or slightly water-soluble drugs |
| US11510859B2 (en) | 2015-07-16 | 2022-11-29 | Marinomed Biotech Ag | Method for improving aqueous solubility of water-insoluble or slightly water-soluble drugs |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2989437A (en) * | 1955-06-08 | 1961-06-20 | Upjohn Co | Anti-inflammatory and anti-bacterial decongestant nasal spray compositions |
| MX3864E (en) * | 1975-05-27 | 1981-08-26 | Syntex Corp | A PROCESS TO PREPARE THE CRYSTALLINE COMPOUND 6-FLUIRO-11B 21-DIHIROXI-16 17-ISOPROPILIDENDIOXIPREGNA-1 4-DIEN-3 20-DIONA |
| DE2750090A1 (en) * | 1976-11-19 | 1978-06-01 | Sandoz Ag | NEW FORMS OF ADMINISTRATION FOR ORGANIC COMPOUNDS |
| US4444762A (en) * | 1980-04-04 | 1984-04-24 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacyclopentan-2-ones |
| US4344940A (en) * | 1981-11-30 | 1982-08-17 | E. R. Squibb & Sons, Inc. | Steroid formulation containing dipotassium EDTA |
| US4603131A (en) * | 1982-04-26 | 1986-07-29 | Bernstein Joel E | Method and composition for treating and preventing irritation of the mucous membranes of the nose |
-
1986
- 1986-05-22 US US06/866,171 patent/US4782047A/en not_active Expired - Lifetime
-
1987
- 1987-05-21 AT AT87107416T patent/ATE65183T1/en not_active IP Right Cessation
- 1987-05-21 FI FI872231A patent/FI88459C/en not_active IP Right Cessation
- 1987-05-21 ZA ZA873663A patent/ZA873663B/en unknown
- 1987-05-21 DK DK198702586A patent/DK175238B1/en active
- 1987-05-21 NZ NZ220394A patent/NZ220394A/en unknown
- 1987-05-21 DE DE8787107416T patent/DE3771389D1/en not_active Expired - Lifetime
- 1987-05-21 KR KR1019870005032A patent/KR950008308B1/en not_active IP Right Cessation
- 1987-05-21 IL IL82615A patent/IL82615A/en not_active IP Right Cessation
- 1987-05-21 IE IE133587A patent/IE60259B1/en not_active IP Right Cessation
- 1987-05-21 CA CA000537690A patent/CA1288048C/en not_active Expired - Lifetime
- 1987-05-21 IT IT20621/87A patent/IT1205667B/en active
- 1987-05-21 ES ES198787107416T patent/ES2031467T3/en not_active Expired - Lifetime
- 1987-05-21 AU AU73273/87A patent/AU609718B2/en not_active Ceased
- 1987-05-21 JP JP62126846A patent/JP2521291B2/en not_active Expired - Lifetime
- 1987-05-21 NO NO872127A patent/NO173365C/en unknown
- 1987-05-21 EP EP87107416A patent/EP0246652B1/en not_active Expired - Lifetime
-
1991
- 1991-07-18 GR GR91400394T patent/GR3002317T3/en unknown
-
1994
- 1994-04-21 HK HK39094A patent/HK39094A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE65183T1 (en) | 1991-08-15 |
| EP0246652B1 (en) | 1991-07-17 |
| AU609718B2 (en) | 1991-05-09 |
| NO173365C (en) | 1993-12-08 |
| FI88459B (en) | 1993-02-15 |
| HK39094A (en) | 1994-04-29 |
| NO872127D0 (en) | 1987-05-21 |
| KR870010862A (en) | 1987-12-18 |
| ES2031467T3 (en) | 1992-12-16 |
| US4782047A (en) | 1988-11-01 |
| EP0246652A2 (en) | 1987-11-25 |
| AU7327387A (en) | 1987-11-26 |
| IT1205667B (en) | 1989-03-31 |
| DE3771389D1 (en) | 1991-08-22 |
| IE871335L (en) | 1987-11-22 |
| DK258687D0 (en) | 1987-05-21 |
| JP2521291B2 (en) | 1996-08-07 |
| NO173365B (en) | 1993-08-30 |
| IL82615A (en) | 1991-11-21 |
| GR3002317T3 (en) | 1992-12-30 |
| NZ220394A (en) | 1990-04-26 |
| DK258687A (en) | 1987-11-23 |
| NO872127L (en) | 1987-11-23 |
| FI88459C (en) | 1993-05-25 |
| DK175238B1 (en) | 2004-07-19 |
| IL82615A0 (en) | 1987-11-30 |
| EP0246652A3 (en) | 1988-02-03 |
| KR950008308B1 (en) | 1995-07-27 |
| JPS62283927A (en) | 1987-12-09 |
| FI872231A (en) | 1987-11-23 |
| ZA873663B (en) | 1988-12-28 |
| FI872231A0 (en) | 1987-05-21 |
| IT8720621A0 (en) | 1987-05-21 |
| IE60259B1 (en) | 1994-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1288048C (en) | Aqueous steroid formulations for nasal administration | |
| US4983595A (en) | Aqueous steroid formulations for nasal administration | |
| JP2515788B2 (en) | Remedies for eye inflammation | |
| US4711906A (en) | Liquid diclofenac preparations | |
| US20030152595A1 (en) | Stabilized antihistamine syrup | |
| EP0973501B1 (en) | Aqueous suspension for nasal administration of loteprednol | |
| EP2647380A2 (en) | Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration | |
| IL142494A (en) | Storable active substance concentrate with formoterol | |
| US5538989A (en) | Fenbendazole formulations | |
| US6949509B2 (en) | Pharmaceutical composition containing a small or medium size peptide | |
| JP4393192B2 (en) | Ribavirin syrup formulation | |
| WO2012127497A1 (en) | Stable pharmaceutical compositions of ketorolac or salts thereof | |
| EP1543826B1 (en) | Concentrated aqueous solution of ambroxol | |
| EA024475B1 (en) | Intranasal compositions of vitamin b12 | |
| US3275513A (en) | Stable calcium tetracycline compositions | |
| JP4157988B2 (en) | Water-soluble preparations with no contraindications | |
| EP1121935B1 (en) | Pharmaceutical composition containing a small or medium size peptide | |
| JPH09151127A (en) | Composition for pharyngopathy | |
| US6239165B1 (en) | Liquid pharmaceutical formulation containing zotepine | |
| AU2773892A (en) | Trimethoprim oral liquid | |
| CN115137699A (en) | Dexmedetomidine nasal spray with synergistic and antiseptic effects | |
| MXPA00007410A (en) | Liquid pharmaceutical formulation containing zotepine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |