4,782,047
`[11] Patent Number:
`[191
`United States Patent
`Benjamin et al. Nov. 1, 1988 [45] Date of Patent:
`
`
`
`
`
`[54] AQUEOUS STEROID FORMULATIONS FOR
`NASAL ADMINISTRATION
`’
`Inventors: Eric Benjamin, Sunnyvale; Shabbir
`Anik, Mountain View; Ya-Yun T.
`Lin, Cupertino, all of Calif.
`
`[75]
`
`[73] Assignee:
`.
`~
`
`Syntex Pharmaceuticals International
`Ltd., Hamilton, Bermuda
`
`[21] Appl. No.: 866,171
`
`'
`
`22
`
`[
`
`1
`
`F1 d:
`1 C
`
`M 22, 1986
`ay
`
`Int. CL4 .................... ..
`
`[52]
`_
`---------------- 514/174; 514/169
`[53] Field Of Search ---------------------- -- 514/ 174, 180, 159
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,444,762 4/1984 Rajadhyaksha ....................... 424/88
`
`OTHER PUBLICATIONS
`Physician’s Desk Reference, 38th ed. (1984), p. 1981;
`Nasahde ®’
`Primary Examiner-—-Leonard Schenkman
`Assistant Examiner—Joseph A. Lipovsky
`Attorney, Agent, or Firm-David A. Lowin; Tom M.
`Moran; Gram D‘ Green
`[57]
`ABSTRACI‘
`
`A non-stinging aqueous anti-inflammatory steroid for-
`mulation suitable for intranasal administration com-
`prises: an anti-inflammatory steroid in an amount be-
`tween 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
`polysol-batg
`in an amount betwegn
`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 buff-
`ering agentbslifficient 1:0 zidjyusst tlée EH €f7 the resulting
`soulon o eweena ou
`.
`an a on
`.
`
`15 Claims, No Drawings
`
`   
`


`
`Lannett Holdings, Inc. LAN 1023
`
`

`
`1
`
`4,782,047
`
`AQUEOUS STEROID FORMULATIONS FOR
`NASAL ADMINISTRATION
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to aqueous anti-inflammatory
`steroid formulations suitable for nasal administration,
`and to methods for treating inflammation of the nasal
`mucosa by intranasal administration of said formula-
`tions.
`2. Related Disclosure
`Acceptable formulations must be able to dissolve or
`suspend an active compound without precipitation or
`undue oxidation of the components. In other words,
`acceptable formulations must be stable. Acceptable
`formulations must also avoid creating discomfort upon
`administration, and will employ only pharrnaceutically
`acceptable components. Finally, acceptable formula-
`tions must not support the growth of microorganisms,
`and so generally include preservatives.
`Anti-inflammatory steroids are difficult to formulate
`in aqueous solutions due to their generally low solubil-
`ity in water. Aqueous formulations of anti-inflammatory
`steroids such as flunisolide suitable for nasal administra-
`tion are commercially available, for example under the
`trademark Nasalide ®. However, currently available
`formulations, while safe and effective, 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 in-
`vention are stable, effectively preservable, and are suit-
`able for nasal administration of anti-inflammatory ste-
`roids without causing stinging.
`SUMMARY OF THE INVENTION
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`One aspect of the invention is a stable, preservable,
`substantially non-stinging aqueous anti-inflammatory
`steroid formulation suitable for nasal 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 a preservative, preferably
`between about 0.02% and about 0.08% (w/v); an effec-
`tive amount of an antioxidant, preferably between about
`0.001% and‘ 0.05% (w/v); an effective amount of a
`stabilizer, preferably between about 0.005% and 0.05%;
`water; and pH buffering agent sufficient to adjust the
`pH of the resulting solution to between about 3.5 and
`about 7.
`Another aspect of the invention is a method of treat-
`ing inflammation of the nasal mucosa without inducing
`stinging, which method comprises intranasally adminis-
`tering to a subject in need thereof a substantially non-
`stinging aqueous anti-inflammatory steroid formulation
`as described above.
`
`45
`
`50
`
`55
`
`DETAILED DESCRIPTION AND PREFERRED
`EMBODIMENTS
`
`One aspect of the invention is a stable, preservable,
`substantially non-stinging aqueous anti-inflammatory
`steroid formulation suitable for nasal 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
`
`65
`
`2
`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, preferably
`between about 0.02% and about 0.08% (w/v); an effec-
`tive amount of a stabilizer, preferably between about
`0.005% and about 0.05%; an effective amount of an
`antioxidant, preferably between about 0.001% and
`about 0.05%; water; and a pH buffering agent sufficient
`to adjust the pH of the resulting solution to between
`about 3.5 and about 7. A preferred subgenus of the
`invention is the formulation wherein said anti-inflamma-
`tory steroid is flunisolide, particularly in an amount of
`about 0.025% (w/v). A preferred class is the formula-
`tion wherein said 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 0.005% and about 0.05% (w/v); and said
`antioxidant is BHT in an amount between about 0.001%
`and about 0.05% (w/v); especially the formulation
`which further comprises sorbitol in an amount between
`about 0.001% and about 5% (w/v). A preferred sub-
`class is the formulation wherein said pH buffering agent
`comprises: citric acid in an amount between about
`0.001% and about 0.05% (w/v); and sodium citrate
`dihydrate in an amount between about 0.001% 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:
`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 0.005% (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.
`~
`Another aspect of the invention is a method of treat-
`ing inflammation of the nasal mucosa without inducing
`stinging, which method comprises intranasally adminis-
`tering to a subject in need thereof a substantially non-
`stinging aqueous anti-inflammatory steroid formulation
`comprising an anti-inflammatory steroid in an amount
`between about 0.01% and about 0.05% (w/v); propy-
`lene glycol in an amount between about 2% and about
`10% (w/v); PEG 4-00 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, preferably between about
`0.02% and about 0.08% (w/v); an effective amount of a
`stabilizer, preferably between about 0.005% and about
`0.05%; an effective amount of an antioxidant, prefera-
`bly between about 0.001% and about 0.05%; water; and
`a pH buffering agent sufficient to adjust the pH of the
`resulting solution to between about 3.5 and about 7; and
`water. A preferred subgenus is the method wherein said
`anti-inflammatory steroid is flunisolide in an amount of
`about 0.025% (w/v), particularly where said preserva-
`tive is benzalkonium chloride in an amount between
`
`

`
`3
`about 0.02% and about 0.08% (w/v); said stabilizer is
`disodium EDTA in an amount between about 0.005%
`and about 0.05% (w/v); and said antioxidant is BHT in
`an amount between about 0.001% and about 0.05%
`(w/v). A preferred class is the method which further
`comprises sorbitol in an amount between about 0.001%
`and about 5% (w/v). A preferred subclass is the method
`wherein said pH buffering agent comprises citric acid in
`an amount between about 0.001% and about 0.05%
`(w/v); and sodium citrate dihydrate in an amount be-
`tween about 0.001% and about 0.05% (w/v). A pre-
`ferred species of the invention is the method of treating
`inflammation of the nasal mucosa without
`inducing
`stinging, which method comprises intranasally adminis-
`tering to a subject in need thereof a substantially non-
`stinging aqueous anti-inflammatory steroid formulation
`comprising
`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 0.005% (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.
`DEFINITIONS
`
`As used herein, the term “anti-inflammatory steroid”
`refers to a steroid compound which is pharmaceutically
`acceptable, and which is known to be useful in reducing
`inflammation. Particularly suitable anti-inflammatory
`steroids are flunisolide and beclomethasone. Flunisolide
`is most advantageously used in the form of the hemihy-
`drate, as that form is non-hygroscopic and is thus easiest
`to handle curing formulation. Flunisolide is commer-
`cially available, and can be prepared as described in
`U.S. Pat. No. 4,273,710, incorporated herein by refer-
`ence. Beclomethasone is also commercially available,
`and can be prepared as described in G.B. Pat. No.
`912,378.
`Propylene glycol refers to 1,2-propanediol. Propy-
`lene glycol is available commercially.
`Polyethylene glycol 400 refers to commercially avail-
`able mixtures of polymers of the form H—(OCH2CH2.
`),,—OH, where the average value of n is between 8.2
`and 9.1. Polyethylene glycol 400 is abbreviated herein
`as “PEG 400.”
`Polysorbate 20 refers to commercially available po-
`lyoxyethylene-sorbitan monoesters,
`for
`example
`Tween ® 20.
`The term “BHT” refers to butylated hydroxytoluene,
`which is a commercially available preservative/antioxi-
`dant.
`The term “BHA” refers to butylated hydroxyanisole,
`which is a commercially available preservative/antioxi-
`dant.
`
`10
`
`20
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`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`The term “preservative” refers to a compound or
`mixture of compounds used in a formulation which is
`useful for reducing or eliminating microbial growth in a
`formulation. A preservative must be pharmaceutically
`acceptable at the concentrations used, and should not
`
`65
`
`4,782,047
`
`4
`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 of micro-
`organisms in the formulation. The effective amount
`may be determined using the USP-BP modified double
`blind assay. Exemplary preservatives include, without
`limitation, BHA, BHT, thimerosal, potassium sorbate,
`methylparaben, propylparaben, sodium benzoate and
`the like. Presently preferred preservatives are benzalko-
`nium chloride and thimerosal, particularly benzalko-
`nium chloride.
`‘
`The term “antioxidant” refers to a compound or mix-
`ture of compounds used in a formulation which is useful
`for preventing the oxidation of active compound(s) in a
`formulation. 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 “effective amount” of an antioxidant is
`that amount necessary to prevent undue oxidation of
`the active compound under normal storage conditions.
`Presently preferred antioxidants are BHA, and BHT,
`particularly BHT.
`The term “stabilizer” refers to a compound used in a
`formulation to prevent chemical degradation by means
`other than oxidation or microbial digestion. An “effec-
`tive amount” of an oxidant is that amount necessary to
`prevent unacceptable degradation of the active com-
`pound. The presently preferred stabilizer is disodium
`EDTA.
`The term “treatment” as used herein covers any treat-
`ment of a disease in a mammal, particularly a human,
`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 develop-
`ment; or
`(iii) relieving the disease, i.e., causing regression of
`the disease.
`
`ADMINISTRATION
`
`The compositions of the invention are advanta-
`geously administered intranasally by means of a “non-
`propellant” type aerosol or atomizer, especially using a
`pump-type dispenser. For example, the Calmar Mark II
`nasal pump (Calmar-Albert GmbH) and the Pfeiffer
`pump (lng.-erich Pfeiffer GmbH & Co. KG) are gener-
`ally useful.
`Preferably, the aerosol pump will deliver a spray in
`which less than 1% of the droplets are below 16 pm in
`diameter. This minimizes the amount of composition
`which reaches the lungs.
`PREPARATION
`
`Compositions of the invention may be prepared as
`follows:
`The desired amounts of propylene glycol, PEG 400,
`and polysorbate 20 are mixed well in an appropriate
`vessel. To this mixture is added the desired amount of
`flunisolide (preferably in the form of the hernihydrate),
`and BHT. The resulting mixture is heated to 50°—55° C.
`and mixed until the flunisolide and BHT dissolve.
`The desired amount of sorbitol (e.g., as a 70% solu-
`tion) is mixed with citric acid and sodium citrate (in the
`proper proportions for obtaining the desired buffer),
`benzalkonium chloride (e.g. as a 50% solution), edetate
`disodium, and water, to form a solution which is ap-
`proximately 90% water. This solution is then mixed
`
`

`
`4,782,047
`
`D
`0.0
`
`E
`0.0
`
`6 a
`
`mount % (w/v)
`C
`5.0
`
`A
`20.0
`
`B
`7.0
`
`
`
`Compound
`propylene
`glycol
`PEG 3350
`PEG 400
`po1ysor-
`bate 20
`benza1kon-
`ium C1
`disodium
`EDTA
`0.002
`0.002
`0.002
`0.002
`0.002
`BI-IA
`0.005
`0.005
`0.005
`0.005
`0.005
`citric acid
`0.0077
`0.0077
`0.0077
`0.0077
`0.0077
`Na citrate
`2.0
`2.0
`2.0
`3.0
`0.0
`sorbitol
`100.0
`100.0
`100.0
`100.0
`100.0
`water qs
`
`pH 5.3 5.3 5.3 5.3 5.3
`
`
`
`
`
`15.0
`0.0
`0.0
`
`0.02
`
`0.01
`
`0.0
`40.0
`0.0
`
`0.02
`
`0.01
`
`0.0
`20.0
`2.50
`
`0.02
`
`0.01
`
`0.0
`15.0
`3.5
`
`0.02
`
`0.01
`
`0.0
`0.0
`3.5
`
`0.02
`
`0.01
`
`The results indicated superior nasal acceptability for
`compositions C, D, and E.
`EXAMPLE 3
`
`(Accelerated Stability)
`
`The stability of formulations was investigated as fol-
`lows:
`
`Six formulations were prepared as set out below for
`testing. Ten mL of each formulation was filled and
`sealed in amber glass ampoules and stored at 30° C. (5
`month), 60° C. (1.5 months), and 15° C. for the period of
`time stated. In addition, 25 mL of each solution was
`filled in 1 oz round high density polyethylene bottles
`and screw capped. These bottles were stored at 50° C.
`(2, 3, 8, and 10 months), 40° C. (8 and 10 months), and
`room temperature (RT) (8 and 10 months). At the end
`of the appropriate time period, the steroid content was
`determined using HPLC, and the pH of the solution
`measured. The results are normalized against the 15° C.
`data for the appropriate time periods.
`
`
`amount % (w/v)
`Composition
`4
`5
`0.0
`5.0
`0.0
`0.0
`
`3
`5.0
`0.0
`
`2
`5.0
`0.0
`
` _
`
`6
`5.0
`0.0
`
`7
`0.0
`0.0
`
`1
`20.0
`PG
`PEG 15.0
`3350 ‘
`PEG
`400
`PS
`20
`BHA
`BHT
`cit-
`rate
`wa-
`ter
`qs
`
`0.0
`
`0.0
`
`0.01
`0.0
`0.01
`
`20.0
`
`20.0
`
`2.5
`
`0.01
`0.0
`0.01
`
`2.5
`
`0.01
`0.0
`0.02
`
`15.0
`
`3.5
`
`0.01
`0.0
`0.01
`
`20.0
`
`20.0
`
`2.5
`
`0.0
`0.01
`0.02
`
`2.5
`
`0.0
`0.01
`0.01
`
`15.0
`
`3.5
`
`0.0
`0.01
`0.02
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`100.0
`
`In addition, each formulation contained 0.025%
`flunisolide, 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 of Example 2. Com-
`positions 4 and 7 are equivalent to Composition D of
`Example 2.
`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.
`
`5
`
`10
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`5
`with the flunisolide solution and the pH measured and
`adjusted with HCl solution or NaOH solution as appro-
`priate.
`The resulting solution is brought to final volume with
`purified water, filtered through a 3 micron filter, and
`packaged.
`
`EXAMPLE 1
`
`(Example Formulations)
`
`The following are representative compositions of the
`invention. The compositions are prepared as described
`in the Preparation above.
`
`Compound
`Q).
`flunisolide hemihydrate
`propylene glycol
`PEG 400
`polysorbate 20
`benzalkonium chloride
`disodium EDTA
`BHT
`citric acid
`sodium citrate.2I-I20
`sorbitol
`water qs
`pH
`GEL
`flunisolide hemihydrate
`propylene glycol
`PEG 400
`polysorbate 20
`benzalkoniurn chloride
`disodium EDTA
`BHT
`citric acid
`sodium citrate.2I-120
`sorbitol
`water qs
`pH
`
`~
`
`amount % (w/v)
`
`0.025
`5.0
`20.0
`2.50
`0.035
`0.01
`0.01
`0.005
`0.00765
`2.00
`100.0
`5.2
`
`0.01
`2.0
`10.0
`1.0
`0.03
`0.01
`0.01
`0.005
`0.00765
`2.00
`100.0
`5.3
`
`Qb
`
`0.05
`eclomethasone
`10.0
`propylene glycol
`25.0
`PEG 4-00
`4.0
`polysorbate 20
`0.03
`benzalkonium chloride
`0.01
`disodium EDTA
`0.01
`BI-IT
`.
`0.005
`citric acid
`0.00765
`sodium citrate.21-I20
`5.00
`sorbitol
`100.0
`water qs
`
`pH 5.2
`
`EXAMPLE 2
`
`(Nasal Acceptability)
`The following example illustrates a procedure for 55
`assaying the nasal acceptability of various compositions.
`Eighteen volunteers were randomly divided into two
`groups. Group 1 received formulations A, B, and D.
`Group 2 received formulations A, C, and E. The tests
`were performed by applying one spray to each nostril,
`with a rest period of 4 hours between administrations of
`different formulations.
`
`60
`
`The following parameters were recorded, both im-
`mediately and 15 minutes after administration: nasal
`stinging, taste, other sensations, and willingness to use
`the spray three times daily. The formulations tested
`were as follows:
`
`65
`
`

`
`4,782,047
`
` 8
`
`-continued
`0.005% (w/v)
`Citric Acid (Anhydrous)
`0.00765% (w/v)
`Trisodium Citrate Dihydrate
`2.86% (w/v)
`Sorbitol (70%)
`100.0 and
`Purified Water, q.s. to
`
`adjust pH to 5.3.
`
`7
`EXAMPLE 4
`
`(Preservative Efficacy)
`
`3. The formulation of claim 1 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); and
`stabilizer in an amount between about 0.005% and
`about 0.05% (w/v).
`4. The formulation of claim 3 wherein said anti-in- .
`flammatory steroid is flunisolide in an amount of about
`0.025% (w/v).
`5. The formulation of claim 4 wherein:
`said preservative is benzalkonium chloride;
`said stabilizer is disodium EDTA; and
`said antioxidant is BHT.
`6. The formulation of claim 5 which further com-
`
`prises sorbitol in an amount between about 0.001% and
`about 5% (w/v).
`7. The formulation of claim 6 wherein said pH buffer-
`ing agent comprises:
`citric acid in an amount between about 0.001% and
`about 0.05% (w/v); and
`sodium citrate dihydrate in an amount between about
`0.001% and about 0.05% (w/v).
`8. A stable, effectively preservable, substantially non-
`stinging aqueous anti-inflammatory steroid formulation
`suitable for intranasal administration, which formula-
`tion 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 0.005% (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.
`9. A method of treating inflammation of the nasal
`mucosa without inducing stinging, which method com-
`prises intranasally administering to a subject in need
`thereof a substantially non-stinging aqueous anti-inflam-
`matory steroid formulation comprising
`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
`
`»
`
`The compositions listed below are tested for preser-
`vative effieacy using the USP-BP modified double chal-
`lenge test.
`
`amount % (w/v)
`Comysition
`A
`B
`C
`D
`E
`
`flunisolide
`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
`
`5
`
`10
`
`0.0
`15.0
`20.0
`40.0
`0.0
`PEG 400
`3.5
`3.5
`2.50
`0.0
`0.0
`polysorbate 20
`0.01
`0.01
`0.01
`0.01
`0.01
`disodium EDTA
`0.002
`0.002
`0.002
`0.002
`0.002
`BHA
`0.01
`0.01
`0.01
`0.01
`0.01
`citrate buffer
`2.0
`2.0
`2.0
`3.0
`0.0
`sorbitol
`100.0
`100.0
`100.0
`100.0
`l(X).0
`water qs
`
`pH 20 5.3 5.3 5.3 5.3 5.3
`
`
`
`
`
`
`15
`
`In addition, each composition is prepared with 0.01,
`0.02, 0.025, 0.03, 0.035, or 0.04% (w/v) benzalkonium
`chloride. These compositions correspond to composi- 25
`tions A—E of Example 2.
`Compositions A—E are prepared, added to culture
`media, and the resulting test media directly inoculated
`with challenge organisms. After incubation for 14 days,
`the test media are inoculated again. The number of 30
`colony forming units is recorded over the remaining 14
`days of the test.
`The results indicated that Compositions A and B
`were effectively preserved with 0.01% benzalkonium
`chloride and Composition C was effectively preserved 35
`with 0.03% benzalkonium chloride, whereas Composi-
`tion D required more than 0.04% benzalkonium chlo-
`ride, and Composition E was not effectively preserved
`with any concentration of benzalkonium chloride
`tested.
`What is claimed:
`1. A stable, effectively preservable, substantially non-
`stinging aqueous anti-inflammatory steroid formulation
`suitable for intranasal administration, which formula-
`tion 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.
`2. The formulation of claim 1 which comprises:
`
`55
`
`50
`
`45
`
`50
`
`Flunisolide (hemihydrate)
`Propylene Glycol
`PEG 400
`Polysorbate 20
`Benzalkonium Chloride (50%)
`Edetate Disodium
`Butylated Hydroxyanisole
`Butylated I-Iydroxytoluene
`
`0.0255% (w/v)
`5.0% (w/v)
`20.0% (w/v)
`2.50% (w/v)
`0.07% (w/v)
`0.01% (w/v)
`0.01% (w/v)
`0.01% (w/v)
`
`55
`
`

`
`4,782,047
`
`9
`pH buffering agent sufficiem to adjust the pH of the
`resulting solution to between about 3.5 and about 7.
`-
`-
`-
`-
`10. The method of claim 9 wherein said formulation
`compnses:
`preservative in an amount between about 0-02% and
`3b°11t0-03% (W/V);
`antioxidant in an amount between about 0.001% and
`about 005% (w/v); and
`stabilizer in an amount between about 0.005% and 1°
`11815:; meth<)od(c‘:;'/ellgzim 10 wherein said anti-inflam-
`‘
`_
`_
`_
`_
`,
`matory steroid is flumsolide in an amount of about
`0-025% (W/V)
`12. The method of claim 11 wherein:
`said preservative comprises benzalkonium chloride;
`said stabilizer comprises disodium EDTA; and
`said antioxidant comprises BHT.
`13. The method of claim 12 which further comprises
`sorbitol in an amount between about 0.001% and about
`5% (W/V)
`14. The method of claim 13 wherein said pH buffer-
`ing agent comprises:
`
`10
`citric acid in an amount between about 0.001% and
`SP0‘-“ (_3t°05t%d(_;"/3’); tan_d
`t b t
`b
`t
`so ium Cl ra e 1 y ra e in an amoun
`e ween a on
`0.001% and about 0.05% (w/v)-
`15. A method of treating inflammation of the nasal
`mucosa without inducing stinging, which method com-
`prises intranasally administering to a subject in need
`thereof a substantially non-stinging aqueous anti-inflam-
`matory steroid formulation comprising
`fl“‘“5°hde hemlhydrate 1“ 3“ 3m°“'“ °f ab°“t
`P’°PY1°“e.8‘V°°1 “1 an amount of about 5% (w/v);
`PEG 400 in an amount of about 20% (w/v);
`polysorbatp 20 in at.‘ aqlount of about 250% (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 °f about 0-0170 (W/V);
`citric acid in an amount of about 0.005% (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_
`*
`*
`
`*
`
`*
`
`*
`
`5
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65