Note: Descriptions are shown in the official language in which they were submitted.
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I
A NASAL SPRAY CONTAINING AN INTRANASAL
STEROID AND AN ANTIHISTAMINE
TECHNICAL FIELD
The present invention relates to novel nasal spray compositions comprising a safe
and effective amount of a glucocorticosteroid and an ~ntihiet~mint~.
BACKGROUND OF THE INVENTION
Allergic disorders remain a leading cause of both acute and chronic illnessee the
world over. These illnPe~ec are often times present in the form of acute or chronic
rhinitie The symptoms of allergic rhinitis are nasal, ocular and palatial irritation,
me~7ing and hy~lsec.~lion. These symptoms occur following exposure to allergens.The main allergens are usually grass and/or tree pollens, hence, allergic rhinitis is
common during the spring and sl.mmer months.
The symptoms of allergic rhinitis are believed to be due to the stim~ tion of H-l
receptors by hist~min~ followed by reflexive activation of parasympathetic nerves
c~-~eing increases in nasal secretion and obstruction. E~iet~min~ is initially released from
the tissue mast cells upon s~ on of the mast cells. This sçn~iti7~tiQn results when
airborne allergens combine with specific IgE antibodies ~tt~rh~tl to mast cell membranes.
~ntihi~t~minPs and/or decongç~ have traditionally been the drugs of choice in
treating allergic rhiniti~ Other forms of therapy include the use of cromolyn sodium,
hypertonic salt solutions or immunotherapy.
Hagen et al., U.S. Patent 4~767 612. discloses nasal corticosteroid therapy as an
effective means of treating allergic rhinitic; and is herein incorporated by lc~.ence. The
effectiveness of these compounds is limited, however, by the slow onset of action
ch~-*-;~tis of nasal corticosteroids (activity generally occurring anywhere from 1-3
days) and, occasionally, the occurrence of "break-through" symptoms. For similarreasons, such products also tend to limit consumer comp!i~n~e
Notwith~t~ in~ the many disclosures in the area of allergic rhinitis, there is still a
need for additional forrn~ tions free of irritating powders or granules as well as hl;l~ g
drugs such as capsaicin which provide fast and improved symptomatic relief with
h~ ased user accc~ ce and compliance.
The present inventor has found that by combining a nasal corticosteroid with a
fast acting ~ntihi~minç, not only is the delay in onset considerably decreased, but the
rçs--ltin~ co",l,osilions of the present invention also provide improved relief of those
symptoms generally associated with either seasonal or perennial allergic rhinitis.
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Additionally, combining the ~ntihi~t~mine with the nasal steroid results in improved
symptom relief (e.g., improved nasal and ocular symptom relief). Furthermore, intranasal
~rlmini.ctration of ~ntihi~t~min~s requires dosage amounts less than those associated with
oral ~lmini.ctration, thereby reducing potentially annoying side effects (e.g., drowsiness).
By addressing such problems, the compositions of the present invention also help in
improving overall patient compliance.
It is, therefore, an object of the present invention to provide ph~rm~re~ltical
col,lyo~itions having improved effectiveness in the ~ rllL of ~yllly~llls generally
associated with either seasonal or perennial allergic rhinitis.
Another object of the present invention is to provide an irritant free
ph~rm~elltical composition for use in the ~ t of symptoms generally associated
with either seasonal or perennial allergic rhinitis.
A further object of the present invention is to provide a safe and effective method
for treating seasonal or perennial a}lergic rhinitic
These objects and other objects will becolllc more ayp~elll from the det~ilecl
description that follows.
SUMMARY OF TH~ INVENTION
The present invention relates to ~hA~ ccl~;c~l compositions for nasal
jq~lminictration comprising:
a) a safe and effective amount of a glucocorticoid selected from the group
concicting of beclomethasone, flunisolide, fluticasone, memet~conP
budesonide, ph~ cuLically acc~ ptable salts thereof and mixtures
thereof;
b) a safe and effective amount of a fast acting ~ntihi~t~min.o selected from
the group concicting of acrivastine, carbino~.. in~, .I;~.h.. h~dld,~ c,
chiolophc;~ e~ blOl~ph~P~ e, dexchlorol,hcllil~lline,
doxylamine, cl~ , promPth~7ine, lrllll~ l.la~llc, mPth~ 7inP,
hydroxyzine, pyril~mine~ roc~ctin~ tripclen~ , ...ec!;,;.-~,
triprolidine, ~7~t~ine~ cyproheptadine, phPnin-l~min~ l~h~ c~ cally
acceptable salts thereof and Ini~lules thereof; and
c.) an aqueous, irll~lasal carrier
wll~,.e,;ll the composition is free of capsaicin and, plc~elably, free of powders or granules.
The present invention also relates to a method for the tre~tm~nt of symptoms
associated with seasonal or perennial allergic rhinitis colnp~;sillg the ~lmini-ctration of a
safe and effective amount of the i~ allasal pharmaceutical compositions of the present
Invention.
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By "symptoms associated with seasonal or perennial allergic rhinitis" is meant
ocular and palatial irritation, eneç7ing, mucoid hypersecretion, nasal congestion and
itching.
By "safe and effective amount," as used herein, is an amount that is effective to
mitigate and/or treat the symptoms for which the active ingredient is indicated in a human
without undue adverse side effects comm~nCl~rate with a reasonable risk/benefit ratio.
By "fast acting," as used herein, refers to an onset of action which occurs within
15-30 minlltes after ~lminictration.
The pH of the compositions is preferably from about S to about 9, more preferably
10 from about 5.5 to about 7.
All perce~ ges and ratios herein are by weight unless otherwise specified.
Additionally, all measurements are made at 25~C unless otherwise specified.
DETAILED DESCRIPTION OF THE INVENTION
The compositions of the present invention contain the eesenti~l components as well
15 as various optional components as indicated below.
More specifically, the compositions of the present invention are for nasal
~flminietration and contain a th.~dpe.llically safe and effective amount of the
ph~rm~t entic~l agents described herein. They are preferably provided as isotonic
aqueous solutions, suspensions or viscous compositions which may be buffered to a
20 selected pH.
Fesenti~l Ingredients
Glucocorticoid A~eents
Agents within this class have potent glucocorticoid activity and weak
mineralocorticoid activity. Glucocorticoid agents most useful to the present invention
25 include those selected from the group coneieting of beclometh~eon~ flunisolide,
fl~ltic~eorle~ m~m.ot~sQne, budesonide, ~ cc;~ltic~lly acceptable salts thereof and
nl~lures thereo~
When used in the compositions of the present invention, the glucocorticoid
colllponent is pl~feYably present at a concellL~ation of from about 0.001% to about 0.1%,
30 more prefe.ably from about 0.01% to about 0.1%.
~ntihiet~minic A~ents
~ntihi~ es most useful to the present invention are hi~ H-l receptor
antagonists which are fast acting. Such H-1 receptor ~ntihiet~min~e may be selçctecl from
among the following groups of antihist~min~s alkyl~mines, ethanol~min~s,
35 ethylen.o.1i~min~e, ~ip.,.d~ es, phenothi~7inçs, piperidines.
.
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Examples of useful fast acting antihistamines include acrivastine, carbinoxamine,
diphenhydramine, chloropheniramine, brompheniramine, dexchloropheniramine,
doxylamine, clemastine, promethazine, trimeprazine, meth~ 7ine, hydroxyzine,
pyrilamine, tripelenn~minç, meclizine, triprolidine, ~7~t~1inP, cyproheptadine, rocastine,
5 phenin~l~min~ or pharmaceutically acceptable salts and mixtures thereof. Without being
limited by theory, it is believed that the ~ntihi.st~min~ additionally improves the delivery
of the glucocorticoid, improving the glucocorticoid's onset of action. When used in the
compositions of the present invention, the ~ntihi~t~min~ component is preferably present
at a concentration of from about 0.01% to about 3.0%, more preferably from about 0.01%
10 to about 1%.
ph~rm~seutically-Acceptable Aqueous Nasal Carrier.
One other essenti~l component of the present invention is a ph~rm~celltic~lly-
acceptable intranasal carrier. Preferably, the nasal composition is isotonic, i.e., it has the
same osmotic plCS~ulc as blood and lacrimal fluid. The desired isotonicity of the
15 compositions of this invention may be accomplished using, for example, the sodium
chloride already present, or other ph~rm~rel1tically-acceptable agents such as dextrose,
boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosph~tç, propylene
glycol or other inorganic or organic solutes. Sodium chloride is p~fell~d particularly for
buffers co..~ g sodium ions. Further examples of sodium choride equivalents are
disclosed in Remington's Ph~rm~re~ltical Sciences pp. 1491-1497 (Alfonso Gennaro 18th
ed. 1990), which is herein incorporated by ref~.. nce.
Most pl~felled for use herein are aqueous, isotonic saline solution carriers. These
solutions which generally contain sodium chloride as the salt are fully described in
Rel,li~ oll's Pll~...~ccl.~tir~l Sciences, 17th edition (1985) p. 835, which is herein
25 incorporated by l~r~,.ence. The salt is present in the solution at a level of about 0.01% to
about 2%, ple~.~biy from about 0.5% to about 1.0% and most preferably from about0.5% to about 0.75%.
The combination of any of the above described ~ntihi~t~minçs and glucocorticoidscan be conveniently ~lmini~t~red nasally to warm-blooded ~nim~lc to elicit the desired
30 thcldl)eu~ic le.,l,ollse by form~ ting it into a nasal dosage form, together with a nontoxic
ph~rm~seutically-acceptable nasal carrier. Suitable nontoxic ph~rm~reutically-acceptable
nasal carriers are known to those skilled in the art and are also fully disclosed in
Remington's Ph~ ical Sciences, 17th edition, 1985. Obviously, the choice of
suitable carrier forms will depend on the exact nature of the particular nasal dosage form
35 required, e.g., whether the drug is to be formulated into a nasal solution (for use as drops
or as a spray), a nasal suspension, a nasal ointm~nt, a nasal gel or another nasal form.
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Preferred nasal dosage forms are solutions, suspensions and gels, which normally contain
sodium chloride in a major amount of water (preferable purified water) in addition to the
Antihict~mine and glucocorticoid. Minor amounts of other ingredients such as pH
adjusters (e.g., a base such as NaOH), em-~lcifiers or dispersing agents, buffering agents,
preservatives, wetting agents and jelling agents (e.g., methylcellulose) may also be
present.
Preferably the composition is applied to the nasal mucosa via topical application of
a safe and effective amount of the composition to treat nasal symptoms. The amount of
the ~ntihictAmine and glucocorticoid combination and frequency of topical application to
10 the nacal mucosa may vary, depending upon personal needs, but it is suggested, as an
example, that topical application range from about once per day to about three times
daily, preferably twice daily, most preferably once daily. As a practical matter the
selected therapeutic compositions will normally be p~ d in unit dosage forms or
actuations to contain thc~al~è~ lly effective amounts of the selected ~ntihi~ e and
15 glucocorticoid combination. In specific inct~nces fractions of these dosage ur~its or
multiple dosage units will be employed. Typically dosage units may be plel,aled to
deliver from about 0.5 mcg to about 50 mcg of the glucocorticoid agent and from about 5
mg to about 75 mg of the ~ntihict~minic agent per dose (e.g., 50 mg to about 150 mg of
the spray composition). A typical dose co~ s one to three sprays per nostril.
20 Optional In~redients
An additional ~ntihict~mine may be optionally incol~olated into the compositionsof the present invention. Such ~ntihict~mines would preferably include those having a
durations of action greater than 6 hours. Examples of such ~ntihict~minPs include
terfçn~ttinP, ~7PI~ctint?~ cetirizine, ~ct~mi7nle~ ebastine, ketotifen, lo~ Y~mide7 lor~t~in~,
25 levoc~b~l;n~, meq~ " oy~tomirle, s~c~, tazifylline, t~m~ ctine or
ph~ cc.~l;cally ~ccept~ble salts and mixtures thereof. Active metabolites of the above
~ntihi~ s may also be used. Ex~lcs of such metabolites are disclosed in U.S.
Patents 3,878,217 and 4,254,129, issued April 15, 1975 and March 3, 1981, respectively,
to Carr et al.; U.S. Patent 5,375,693, issued Dec~mber 27, 1994, to Woosley et al.; and
30 European Patent 648759, each of which are herein incol~)olaled by lef~ence in their
entirety.
Optional ingredients useful in the present invention include deconges~
Deconge~ useful to the present invention may be selected from among the class ofsymp~thomimetic agents; examples of which include pseudoephedrine, desoxyephedrine,
35 propylhexedrine, phenylplo~ olamine, xylomPt~7oline, phenylephrine, tetrahydrozoline,
h~7Oline, oxymetazoline, tramazoline and ph~ eutic~lly acceptable salts thereof.
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Also useful as decongestants are the 5-(2-imidazolinylamino)benzimedazole compounds.
Mixtures of these decongestants can also be used.
When used in the compositions of the present invention, the sympathomimetic
agents may be incorporated at concentrations, preferably, of from about 0.01% to about
0.5%, more preferably from about 0.05% to about 0.1 %.
The compositions of the present invention may also contain a ~r~nthine derivative
such as caffeine and methylx~ h;l-e and the like. The ~nthine derivative may preferably
be incorporated at concc~ dlions of from about 0.01% to about 1%, most pief~.dbly from
about 0.1 % to about 0.5. Mixtures of x~nthine derivatives may also be incol~v,dled.
The compositions of the present invention may also contain antiallergics. Suitable
antiallergics include, but are not limited to, cromolyn, ketotifen, N-allyl-(dichloro-3, 4-
benzyl)-2-methylarnino-2-propanol-1, AP-582 (Pharmaprojects No. 3055-under
investigation by Ariad Ph~rrn~e~lticais)~ Andolast, o~t~mi-le and ph~rm~celltically-
acceptable salts thereof. Mixtures of these ~nti~llergics may also be used.
Similarly, mucolytics such as acetylcysteine and anticholinergics such as
ipl~llopiu~n bromide may also be used in the compositions of the present invention.
Also of optional use in the compositions of the present invention are nonopiate
analgesics such as ox~ . The hlLI~lasal use of ~A~iO~l1 is described in Namiki et
al., Studies on improvement of ph~rm~elltir~ ep~dlions prescribed in hospitals. VI.
20 oxapro~in nasal spray, Drug Design and Delivery 1988;2:pp. 311 -321, herein
incolpol~led by reference. Further ~A~lples of pl~ Ç~ d nonopiate analgèsics include,
but are not limited to, ~cel~ ophen~ acetylsalicylic acid, ibuprofen, etodolac, fen-
buprofen, f~noplofen, ketorolac, nulb;plofell, indom~th~in, ketoprofen, naproxen,
ph~rm~ el)tic~lly-acceptable salts thereof, optically active r~cçm~tec thereof and llliA~ s
25 thereof. Pl~f~ ,d for use herein are the S(+) isomers of the nonopiate analgesics. Still
further e,L _n~les of such drugs are disclosed in U.S. Patent No. 4,522,828, to Sunshine et
al., issued June 11, 1985; this patent being h~col~.olaled herein by refe.ence in its entirety.
Synthetic opiate ~n~lg~cics such as l~ul~ ol may also be il.coll.G~ated into thecompositions of the present invention. The ;~ nAC~1 use of bulol~hanol is described in
30 Baumel, Mi~raine: A pl~lllacolo~ic review with newer options and deliverY mo~liti,o~
Neurology 1994;44(supp):pp. s13-s17, herein incol~oldled by ler~.ence. Further
examples of ~)le~ d synthetic opioid analgesics include ~Ifent~nil, buprenorphine,
fentanyl, meperidine, meth~lone, nalbuphine, natrexone, propoxyphene, p- .~ Cil~,
sufenanil, ph~rm~eutically-acceptable salts thereof and mixtures thereof.
Leukotriene receptor antagonists may also be incorporated into the compositions of
the present invention. Suitable examples include, but are not limited to, ~,.l.-.;...~..l~l
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agents such as Zafirlukast (Accolate, Zeneca), MK-571 (Merck, Sharp and Dohme),
LY171883, Wy-45,911, LY163443, ONO-RS-411 and ONO-RS-347 and ICI 198,615. A
more detailed discussion of leukotriene receptor antagonists is found in Eu~peall Patent
Application 318093, and Fleisch, J. H., Development of Cysteinyl Leukotriene Receptor
~ S Anta~onists~ Vol. 12 Advances in Tnfl~mm~tion Research 173-189 (A. Lewis et al. ed.
1988), Both of which are herein incorporated by ~felence in their entirety.
Lipoxygenase inhibiting compounds may also be incol~oialed into the
compositions of the present invention. Suitable examples are ~ c~ ed in U.S. Patent
4,873,259, to Summers et al., issued October 10 1989 and U.S. Patent 5,037,853, to
Brooks et al., issued August 6, 1991, both of which are herein inco",olated by reference
in their entirety.
Various aromatic components (e.g., aldehydes and esters) may also be used. Thesearornatics include, for example, menthol, c~mph-r, eucalyptol, bPn7~lclehyde (cherry,
almond); citral (lemon, lime); neral; decanal (orange, lemon); aldehyde C-8, aldehyde C-9
and aldehyde C-12 (citrus fruits); tolyl aldehyde (cherry, ~lmon-l); 2,6-dimethyl-octanal
(green fruit); and 2--lodecPn~l (citrus, mandarin). ~ tion~l aromatic componentssuitable for use in the present invention include those described in U.S. Patent 4~136~163
to Watson et al., U.S. Patent 4~459.425 to Amano et al., and U.S. Patent 4~230~688 to
Rowsell et al.; all of which are herein incGI~oldt~d by ler~.~nce. Mixtures of these
aromatics can also be used.
Viscosity of the compositions may be ...~ ed at the selected level using a
ph~ m~celltic~lly-accel)tdble thir~Pning agent. Methyl cellulose is pler~lled because it is
readily and ecollo"lically available and is easy to work with. Other suitable thir~ening
agents include, for eY~mple, ~nth~n gum, microcrystalline cellulose, carboxymethyl
25 cellulose, chito~n, h~dro~y~ro~yl cellulose, hyd~ y~yl methyl celllllose
hy~Lo"~/l"cll,yl celh-lose hydroxyethyl cellulose, carboxyvinyl polymer, C~bolllel, and
the like or ~h~....~c~ ;c~l salts thereof. Mixtures of such thi~ ~nin~ agents may also be
used. The pl~f .,.,d collce.,l~dlion of the thickener will depend upon the agent sçlected
The hnpol~lt point is to use an amount which will achieve the selected viscosity.
30 Viscous colllposilions are normally ~ pdled from solutions by the addition of such
thi~ ning agents.
~ lef. .,ed compositions within the scope of this invention will contain from about
0.01% to about 5% of a h-lmect~nt to inhibit drying of the mucous membrane and to
prevent irritation. Any of a variety of ph~ ce~tically-acceptable hllmect~nt~ can be
35 employed inrh~fling, for cAa.~l~,lc sorbitol, propylene glycol, polyethylene glycol, glycerol
or mixtures thereof. As with the thickeners, the concentration will vary with the selected
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agent, although the presence or absence of these agents, or their concentration is not an
essenti~1 feature of the invention.
Enhanced absorption across the nasal membrane can be accomplished employing a
therapeutically acceptable surfactant. Typical useful surf~ct~nt~ for these therapeutic
5 compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol
anhydrides such as Polysorbate 80, Polyoxyl 40 Stearate, Polyoxylethylene 50 Stearate
and Octoxynol, as well as Oxyethylated tertiary octyl phenol formaldehyde polymer
(available from Sterling Organics as tyloxapol) or ~ ,s thereof. The usual
concentration is from 0.5% to 10% based on the total weight.
A ph~ ce~1tically-acceptable preservative is generally employed to incre~e the
shelf life of the compositions of the present invention. Ben~yl alcohol is suitable,
although a variety of preservatives including, for example, parabens, phenylethyl alcohol,
thimerosal, chlorobutanol, phellyllllccuric acetate or ben7~1konium chloride may also be
employed. The most preferred preservative system for use herein co.ll~lises a
l 5 combination of benzalkonium chloride, chlorhexidine gluconate and disodium EDTA. A
suitable collc~ rdlion of the preservative will be from 0.001% to 2% based on the total
weight, although there may be appreciable variation depending upon the agent selected
Mixtures of these preservatives may also be used.
Combinations of any of the above optional cûlnponents may also be incol~uldled.
Other Optional Components. A variety of ~1iti~n~1 ingredients may be added to
the emulsion compositions of the present invention. These additional ingredients include
various polymers for aiding the film-forming prop~,llies and substantivity of the
formulation, pleS~ dLi~/es for ,..~ .;--g the antimicrobial hltegl;ly of the compositions,
antioxidants, and agents suitable for aesthetic purposes such as fragrances, pigmpnte~ and
25 colorings.
The con~osilions can also contain low levels of insoluble ingredients added, forexample fûr visual effect ~ oses, e.g. thermochromic liquid crystalline materials such
as the microenc~ps~ ted cholesteryl esters and chiral nPm~tic (nonsterol) based
chemicals such as the (2-methylbutyl) phenyl 4-alkyl(oxy)l,e.-7~1ee available from
30 Hallcrest, Glenview, Illinois 60025, U.S.A., Mixtures of these and the above ingredients
may also be used.
EXAMPLES
The following examples further describe and demon~lldle embo~lim~nt~ within the
scope of the present invention. The examples are given solely for the purpose of35 illustration and are not to be construed as limitations of the present invention, as many
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variations thereof are possible without departing from the spirit and scope of the
mventlon.
Example I
The intranasally a lrnini~tered ph~ ceutical composition of the present invention
5 is pl~,p~ed by combining the following components 1~tili7ing conventional mixing
techniques similar to that described below.
Component Wgt ~/O
beclomethasone ~ o~l;onate, monohydrate 0.042
chlorphenirarnine 0.500
avicelRC-59ll l.200
dextrose 5. l 00
polysorbate 80 0.050
b~n7~1konium chloride 0.020
phenylethyl alcohol 0.025
l 5 ~ietilled water q.s. l OOml
lmicrocrystalline cellulose and sodium carboxymethyl cellulose, supplied FMC
Col~.olalion.
In an a~,opl;dlely sized vessel, the above listed ingredients are added one at atime to water with mixing, allowing each to dissolve before adding the next. After all the
ingredients have been added, purified water is used to bring the batch to the ;l~n~;ate
weight.
~mini~tration of ,l~lo~hl,alely 0.5 grams of the composition is used for topicalnasal application to provide relief from allergy or allergy-like syln~tu
Example II
The ;.,~ 11y ~ e~d ph~ ceutical colnposilion of the present invention
is lule~ed by combining the following colllpolle.lls ~lti1i~ing conventional mixing
techniques similar to that described in Example I.
Component Wgt %
flunisolide 0.025
chlorphe.lirdllline 0.350
levoç~b~stin~ 0.0125
propylene glycol 2.000
polyethylene glycol 1.000
ethyl~n~ mine tetraacetic acid 0.050
.. .. .
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benzalkonium chloride 0.010
distilled water q.s. 1 OOml
The above ingredients are combined
Administration of approximately 0.5 grams of the composition is used for topicalS nasal application to provide relief from allergy or allergy-like symptoms.
Example III
The intranasally ~llmini~tered ph~rm~ce~1tical composition of the present invention
is l,lepal~ed by combining the following components lltili7in~ conventional mixing
tech~iques similar to that described in Exarnple I.
Component Wgt ~/O
triamcinolone acetonide 0.050
acrivastine HCI 0. l 00
polysorbate 80 0.050
glycerin 2.000
lS hydroxypropyl methyl cellulose l.000
ethyl~n~ minç tetraacetic acid 0.050
ben7~1konium chloride 0.020
~lictilled water q.s. lOOml
A~lmini~tration of approximately 0.5 grams of the composition is used for topical~0 nasal application to provide relief from allergy or allergy-like symptoms.
Example IV
The int~ asally ~mini~t~red ph~rm~ce11tical composition of the present inventionis prepared by combining the following colllpollents ntili7inp conventional mixing
techniques similar to that described in F~mple I.
Component Wgt %
beclom~th~con~ dipro~l;onate, monohydrate 0.042
chlo~ lho~l.ine 0.500
oxymetazoline 0.050
avicel RC - 591 l 1.200
dextrose 5.100
polysorbate 80 0.050
ben7~1konium chloride 0.020
phenylethyl alcohol 0.025
distilledwater q.s. lOOml
35 lmicrocrystalline cellulose and sodium carboxymethyl cellulose, supplied FMC
corporation.
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11
Administration of approximately 0.5 grams of the composition is used for topicalnasal application to provide relief from allergy or allergy-like symptoms. Additionally,
subst~nti~lly similar results are also obtained using, in whole or in part, equivalent
amounts of other glucocorticoid agents such as fluticasone, mometasone, budesonide,
5 ph~rrn~ceutically acceptable salts thereof and mixtures thereof or by using, in whole or in
part, equivalent amounts of other fast acting ~nfihict~mines such as carbinoxamine,
Ai~henhydramine, brompheniramine, dexchloruphe.~ ine, doxylamine, clem~tinP,
promf~th~7ine, rocastine, Il;~llepl~ine, methflil~7inf7 hydroxyzine, pyril~minf,tripelenn~minf~, meclizine, triprolidine, ~7~t~Aine, cyproheptadine, pheninA~minf,
10 ph~rm~ceutically acceptable salts thereof and mixtures thereof. Furthermore, the above
described compositions may also contain a sy~ olnimf tic amine such as
pseudoephf Arinf, phenylpropallolamine, phenylephrine, tetrahydrozoline, n~ph~7O1ine,
oxymetazoline, ll~~ n~oline, 5-(2-imid~olinylamino)b~ .PA~701es, ph~ eutically
acceptable salts thereof and Ini~lw~s thereof. Those skilled in the art will quickly realize
15 other suitable ingredients, diluents and dosage forms (or readily asc.,.lain such using
routine ~,.;...f .~l;on) which may further be incorporated into the above compositions
without departing from the scope and spirit of the present invention.
. .
