CA2256721A1 - A nasal spray containing an intranasal steroid and an antihistamine - Google Patents
A nasal spray containing an intranasal steroid and an antihistamine Download PDFInfo
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- CA2256721A1 CA2256721A1 CA002256721A CA2256721A CA2256721A1 CA 2256721 A1 CA2256721 A1 CA 2256721A1 CA 002256721 A CA002256721 A CA 002256721A CA 2256721 A CA2256721 A CA 2256721A CA 2256721 A1 CA2256721 A1 CA 2256721A1
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Abstract
The present invention relates to pharmaceutical compositions for nasal administration comprising: a) a safe and effective amount of a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, fluticasone, memetasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof; b) a safe and effective amount of a fast acting antihistamine selected from the group consisting of acrivastine, carbinoxamine, diphenhydramine, chloropheniramine, brompheniramine, dexchloropheniramine, doxylamine, clemastine, promethazine, trimeprazine, methdilazine, hydroxyzine, pyrilamine, rocastine, tripelennamine, meclizine, tripolidine, azatadine, cyproheptadine, phenindamine, pharmaceutically acceptable salts thereof and mixtures thereof; and c) an aqueous, intranasal carrier wherein the composition is free of capsaicin and, preferably, free of powders or granules. The present invention also relates to a method for the treatment of symptoms associated with seasonal or perennial allergic rhinitis comprising the administration of a safe and effective amount of the intranasal pharmaceutical compositions of the present invention.
Description
CA 022~6721 1998-11-30 W O 97146243 PCTrUS97109518 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.
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.
CA 022~6721 1998-11-30 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.
.
CA 022~6721 1998-ll-30 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.
CA 022~6721 1998-ll-30 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.
CA 022S672l l998-ll-30 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 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 CA 022~6721 1998-11-30 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 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 .. .. .
CA 02256721 1998-ll-30 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.
CA 02256721 1998-ll-30 WO 97/46243 PCTtUS97/09518 ---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.
. .
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.
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.
CA 022~6721 1998-11-30 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.
.
CA 022~6721 1998-ll-30 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.
CA 022~6721 1998-ll-30 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.
CA 022S672l l998-ll-30 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 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 CA 022~6721 1998-11-30 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 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 .. .. .
CA 02256721 1998-ll-30 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.
CA 02256721 1998-ll-30 WO 97/46243 PCTtUS97/09518 ---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.
. .
Claims (10)
1. A pharmaceutical composition comprising:
a) a safe and effective amount of a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, fluticasone, memetasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof;
b) a safe and effective amount of a fast acting antihistamine selected from the group consisting of acrivastine, carbinoxamine, diphenyldramine, chloropheniramine, brompheniramine, dexchloropheniramine, doxylamine, clemastine, promethazine, rocastine, trimeprazine, methdilazine, hydroxyzine, pyrilamine, tripelennamine, meclizine, triprolidine, azatadine, cyproheptadine, phenindamine, pharmaceutically acceptable salts thereof and mixtures thereof; and c) an aqueous, intranasal carrier wherein the composition is free of capsaicin.
a) a safe and effective amount of a glucocorticoid selected from the group consisting of beclomethasone, flunisolide, fluticasone, memetasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof;
b) a safe and effective amount of a fast acting antihistamine selected from the group consisting of acrivastine, carbinoxamine, diphenyldramine, chloropheniramine, brompheniramine, dexchloropheniramine, doxylamine, clemastine, promethazine, rocastine, trimeprazine, methdilazine, hydroxyzine, pyrilamine, tripelennamine, meclizine, triprolidine, azatadine, cyproheptadine, phenindamine, pharmaceutically acceptable salts thereof and mixtures thereof; and c) an aqueous, intranasal carrier wherein the composition is free of capsaicin.
2 A composition according to Claim 1 in the form of an isotinic aqueous solution.
3. A composition according to Claim 1 or 2 wherein the glucocorticoid is beclomethasone.
4. A pharmaceutical composition according to any one of the preceding Claims, which further comprises a sympathomimetic amine selected from the group consisting of pseudophedrine, phenylpropanolamine, phenylephrine, tetrahydrozoline, naphazoline, oxymetazoline, tramazoline, pharmaceutically acceptable salts thereof and mixtures thereof.
5 A pharmaceutical compositions according to any one of the preceding Claims, which further comprises an additional antihistamine selected from the group consisting of terfenadine, azelastine, cetirizine, astemizole, ebastine, ketotifen, lodozamide, loratadine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine or pharmaceutically acceptable salts and mixtures thereof.
6. A pharmaceutical composition according to any one of the preceding Claims, which further comprises a non-steroidal anti inflammatory agent.
7. A pharmaceutical composition according to any one of the preceding Claims, which further comprises a lipoxygenase inhibitor or antagonist.
8. A pharmaceutical composition according to any one of the preceding Claims, which further comprises a nonopiate analgesic.
9. A method for treatment of seasonal allergic rhinitis or using a safe and effective amount of the composition of any one of the preceding Claims.
10. A method for treatment of perennial allergic rhinitis using a safe and effective amount of the composition of any one of the preceding Claims.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65750696A | 1996-06-04 | 1996-06-04 | |
| US08/657,506 | 1996-06-04 | ||
| PCT/US1997/009518 WO1997046243A1 (en) | 1996-06-04 | 1997-06-03 | A nasal spray containing an intranasal steroid and an antihistamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2256721A1 true CA2256721A1 (en) | 1997-12-11 |
Family
ID=24637461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002256721A Abandoned CA2256721A1 (en) | 1996-06-04 | 1997-06-03 | A nasal spray containing an intranasal steroid and an antihistamine |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0954318A1 (en) |
| JP (1) | JPH11511758A (en) |
| AU (1) | AU3153797A (en) |
| BR (1) | BR9709650A (en) |
| CA (1) | CA2256721A1 (en) |
| WO (1) | WO1997046243A1 (en) |
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| US5976573A (en) * | 1996-07-03 | 1999-11-02 | Rorer Pharmaceutical Products Inc. | Aqueous-based pharmaceutical composition |
| FR2756739B1 (en) * | 1996-12-05 | 2000-04-28 | Astra Ab | NEW BUDESONIDE FORMULATION |
| MY121744A (en) * | 1997-12-23 | 2006-02-28 | Schering Corp | Composition for treating respiratory and skin dieseases, comprising at least one leukotriene antogonist and at least one antihistamine. |
| US6248308B1 (en) | 1998-04-14 | 2001-06-19 | Sepracor Inc. | Methods of using norastemizole in combination with leukotriene inhibitors to treat or prevent asthma |
| US6245785B1 (en) * | 1998-11-30 | 2001-06-12 | Warner Lambert Company | Dissolution of triprolidine hydrochloride |
| EP1020233A1 (en) | 1999-01-13 | 2000-07-19 | The Procter & Gamble Company | Dosing and delivering system |
| DE19924525A1 (en) * | 1999-05-28 | 2000-11-30 | Ruediger Scheunemann | Composition containing topical glucocorticoid and detumescent, useful for treating e.g. hayfever and sinusitis |
| IT1313567B1 (en) * | 1999-07-27 | 2002-09-09 | Zambon Spa | USE OF N-ACETYL-CISTEIN FOR THE PREPARATION OF TOPICAL PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF ALLERGIC PATHOLOGIES OF |
| GB9918559D0 (en) * | 1999-08-07 | 1999-10-06 | Glaxo Wellcome Kk | Novel pharmaceutical formulation |
| DE19947234A1 (en) * | 1999-09-30 | 2001-04-05 | Asta Medica Ag | New combination of loteprednol and antihistamines |
| ATE359784T1 (en) * | 1999-10-08 | 2007-05-15 | Schering Corp | TOPICAL NOSE TREATMENT WITH DESLORATADINE AND MOMETASONE FUROATE |
| CN1431919A (en) | 2000-04-03 | 2003-07-23 | 巴特勒记忆研究所 | Device and liquid formulations |
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| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
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| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| GB0021927D0 (en) * | 2000-09-07 | 2000-10-25 | Glaxo Group Ltd | Use of pharmaceutical combination |
| DE50115277D1 (en) * | 2000-10-31 | 2010-02-04 | Boehringer Ingelheim Pharma | DRUG COMPOSITIONS FROM TIOTROPIUM SALTS AND |
| US20020137764A1 (en) | 2000-10-31 | 2002-09-26 | Karin Drechsel | Inhalable formulation of a solution containing a tiotropium salt |
| US7776315B2 (en) | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
| EA009068B1 (en) * | 2000-10-31 | 2007-10-26 | Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг | Inhalative solution formulation containing a tiotropium salt |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| JP4320217B2 (en) * | 2002-07-10 | 2009-08-26 | 剤盛堂薬品株式会社 | Oral preparation for rhinitis |
| ES2393864T3 (en) | 2002-08-30 | 2012-12-28 | Nycomed Gmbh | The use of the association of ciclesonide and antihistamines for the treatment of allergic rhinitis |
| MXPA05002891A (en) | 2002-09-20 | 2005-06-22 | Fmc Corp | Cosmetic composition containing microcrystalline cellulose. |
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| TW200522932A (en) * | 2003-09-15 | 2005-07-16 | Combinatorx Inc | Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines |
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| US20070020299A1 (en) | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid |
| WO2005102287A2 (en) * | 2004-04-22 | 2005-11-03 | Duocort Ab | Pharmaceutical compositions for acute glucocorticoid therapy |
| US20050255154A1 (en) | 2004-05-11 | 2005-11-17 | Lena Pereswetoff-Morath | Method and composition for treating rhinitis |
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| SI2522365T1 (en) | 2004-11-24 | 2017-02-28 | Meda Pharmaceuticals Inc. | Compositions comprising azelastine and methods of use thereof |
| JP5393151B2 (en) * | 2005-09-01 | 2014-01-22 | メダ アーベー | Liposome compositions containing antihistamines and corticosteroids and their use for the manufacture of a medicament for the treatment of rhinitis and related diseases |
| CN101795565A (en) * | 2007-06-28 | 2010-08-04 | 锡德克斯药物公司 | Nasal and ophthalmic delivery of aqueous corticosteroid solutions |
| EP2408453B1 (en) | 2009-03-17 | 2022-01-05 | Nicox Ophthalmics, Inc. | Ophthalmic formulations of cetirizine and methods of use |
| US8569273B2 (en) | 2009-03-17 | 2013-10-29 | Aciex Therapeutics, Inc. | Ophthalmic formulations of cetirizine and methods of use |
| JP5683719B2 (en) | 2011-01-04 | 2015-03-11 | イスタ・ファーマシューティカルズ・インコーポレイテッドＩｓｔａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | Bepotastine composition |
| FR2970180B1 (en) * | 2011-01-06 | 2013-08-02 | Substipharm Dev | PROCESS FOR THE PREPARATION OF AQUEOUS PHARMACEUTICAL SUSPENSIONS COMPRISING AN EFFICIENT DRUG IN THE TREATMENT OF RHINITIS |
| WO2013017821A1 (en) | 2011-08-02 | 2013-02-07 | Cipla Limited | Pharmaceutical composition comprising ebastine and fluticasone |
| CN106074387B (en) * | 2016-08-15 | 2019-09-13 | 辽宁大学 | With thixotropic Triamcinolone acetonide nasal spray and preparation method thereof |
| US20200261433A1 (en) * | 2019-02-15 | 2020-08-20 | Ferrer Medical Innovations, LLC | Nasal spray compositions and related treatment methods |
| US11523986B2 (en) | 2019-03-22 | 2022-12-13 | Dbbh, Llc | Intranasally administered antihistamines and uses thereof |
| WO2021211504A1 (en) * | 2020-04-14 | 2021-10-21 | Glaxosmithkline Consumer Healthcare Holdings (Us) Llc | Nasal spray formulation with moisturizing benefits |
| US10874650B1 (en) * | 2020-04-24 | 2020-12-29 | Ferrer Medical Innovations, LLC | Antiviral and virucidal nasal spray compositions and related treatment methods |
| WO2023233570A1 (en) * | 2022-06-01 | 2023-12-07 | 佐藤製薬株式会社 | Nasal drip composition |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6392496A (en) * | 1995-06-29 | 1997-01-30 | Mcneil-Ppc, Inc. | The combination of topical nasal antihistamines and topical nasal steroids |
| WO1997001341A1 (en) * | 1995-06-29 | 1997-01-16 | Mcneil-Ppc, Inc. | The combination of topical nasal mast cell stabilizers and topical nasal steroids |
| EP0780127A1 (en) * | 1995-12-19 | 1997-06-25 | The Procter & Gamble Company | A nasal spray containing a steroid and a antihistamine |
-
1997
- 1997-06-03 WO PCT/US1997/009518 patent/WO1997046243A1/en not_active Application Discontinuation
- 1997-06-03 CA CA002256721A patent/CA2256721A1/en not_active Abandoned
- 1997-06-03 EP EP97926878A patent/EP0954318A1/en not_active Withdrawn
- 1997-06-03 JP JP10500771A patent/JPH11511758A/en active Pending
- 1997-06-03 BR BR9709650A patent/BR9709650A/en not_active Application Discontinuation
- 1997-06-03 AU AU31537/97A patent/AU3153797A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| BR9709650A (en) | 1999-08-10 |
| WO1997046243A1 (en) | 1997-12-11 |
| EP0954318A1 (en) | 1999-11-10 |
| JPH11511758A (en) | 1999-10-12 |
| AU3153797A (en) | 1998-01-05 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Dead |