CA2187536A1 - Method of treating allergic rhinitis - Google Patents

Abstract

This invention relates to treating a disease caused by a type I immune response using a peptidoleukotriene antagonist and an antihistamine.

Description

WO 95/27487 218 7 ~ 3 ~9 r~l" c 1376 Method of Treating A11P.~ hiniti~
Scope of the I~. ' T~is invention tdatcs to treadn~ diseascs causct by a ~pe I tmmunc re~ponscs in rnammal, incluting aliergic nSinitis, using a S anugoni~ ant an - ' ~~ b ~ ' of the I~
'Slow Reacdng Substancc of .~ S~ ' " (SRS-A) h~s been ~Sowll to be -highly iotcn~ wbst~ncc which is rdeaset pri~y ~rom rnast cells ant b~hils on antigeDic chalicngc. SXS-A h~ oecn pr~posed s a primary 10 mediator in human aslhma SRS A, in ~didon to itsl ' effects on lung tissue, also p~tuccs I ~ chQnges ~ sl~in ant I~Qy be involvcd in Qcute cutanoous allergic reacdons fin~er, SRS-~ has bccn shown to cffect teplession ofvcnt~icular contraction Qnt 1 of the ~ v. ' effccts of hisla~ine.
Thc discovety o~the n~ally occuning I ' - and their ' to IS SRS-A has reinforced intest in SRS-A andother ~ ' ' n ' " SRS-A
denved fro~n mouse, ~ e~neapig cnd msn haw cll becn ' ~ as n~ixtu~es Of 1 ' C4 ~TC4), 1 ' D4 (LT~4) and I ' -E4 tL-T ' ' are a group of ~ fd ~om ' acit " via the ~ pthway. Thesc lipit daivadves ~iginate ~om 20 LTA~ snt sre of two types: tl) thoss containing a ' . A ' ' ~ site chQin (LTC4.
LTD4, and LTE4), ant (2) thosc tbal are . . " tLTB4). T ~ ' ' comprisc a g~up of na~ally o=ing substa~ces that have thc po~ential to contnbute ~ to tbe p ' _ of a vari ty of ~
disorte~ The 1 ~ - ' role of I ' has b~en tSe focus of recent 2S intens~re studies.
Ass b~,A.M.,~iQ~n;~lr ' ~v.~,2, 123-127 (1986) both ~he pep~de snd ..~, . ' 1 exc ~ ~ actions.
~modng lca~agc of f~uid actoss the alpillary cndothelial membrane in most rypes of ~scuiar bods. LIB4 has po~n~ :' aclior.s snt cont~ibu~es lo thc - snt atherence of rnolile scsYenger cells to the endotbelial rnernbrane.
LTC4, LTD4 ar t LrE4 stimula~ a va~ie~y of ypes of mDscles. LTC4 and LTD4 sre potent 1 - and effecti~e sti~nulstors of vsscular strooth muscle. Ti is ._ effecl has been shown to o~cur in puhronsry, coror~y, cereb~al, rensl, snt meseme~ic ~ ' 3S ~ ~ havc bcl imp}icatet in a number of I ~ diseases.
1 ~ ' are hlown to oe ~ent ~ ' in hmnans. LTC4 and LTD4 have been shown to be potent ant selectiw penpherai airway agonisrs, being rnorc sctiYc tban h~s~ne. [See Dr~zen, J.M. et al., E~, ~r~ S-~ USA.
77, 7, 43544358 (1980).] LTC4 and LTD4 have be~ shown ~o incruue tbe relesse of ~n~cus f~in~hu~nan sirways 1~ Y~s2; tsec ~ Z. et Dl., ~ p~v 12~n;r Oi~ ' , '126, 449-4S1 (1982).]
.
SUBSTITUTE SHEET (RULE 26) ~rB

wo 95/27487 218 rt ~ 3 6 r~ 376 T I ' have been identified in the Dasal secretions of allergic subjects who underwent M vivo challenge with specific antigen. The release of the r ' was correlated with typical allergic signs and symptoms. [See Creticos, P.S. et al., ~
r J. of ,U~A ~Q, 25, 16~1029 (1984).] This suggests that allergic rhinitis is 5 another area of utility for leukotriene: _ The " used in this invention are Hl receptor: ~ Other histamine receptors, namely H2 and H3 receptors, Ihave been identified and antagonists specific to these latter two receptors have been fouDd to have effects distinct from that of compounds which antagonize the Hl receptor. But the term " ' " still carriesthe ~ of an Hl antagonist. For sake of simplicity, the word ~ or ~L,.~,. AH will be used here to mean only Hl receptor ~
Histamine Hl-receptor antagonists have been and are used primarily for treating ~ , relief of h.~l v;l~ reactions such as urticaria and: - rhinitis, and, ~ and to control pruritis associated with skin disorders. Others are used to 15 control nausea and vomiting or to treat vertigo. That work is concerned with the use of ' for treating symptoms related to rhirdtis, ~ , allergic T~dnitis.
In so far as treating allergic rhinitis is concerned, ! '-' ' act by blocking the action of histamine which is released from the mast cells mainly in the early phase of an allergic reaction. They are useful for controlling nasal itching, sneezing, ' 20 and ocular symptoms such as ; .it;~ but are not optimally effective for controlling nasal congestion.
It has been found that ~ a I, ' ' such as LTC4, LTD4 and LTE4 while l~, r - ~ an non-sedadng - - provides a superior method of treating rhinids and associated I ' and particularly allergic rhinids. S ,~ of the I~.
This invention covers a method for treating dds~ase caused by a type I immune responses in a mammal, which method compris~s ~ ~ to a subject about to be exposed to or who is a]ready suffering from said disease an amount of a I . ' ' antagonist and an amourlt of an . ' which in ~
are sufflcient to treat.the disease.
In a second aspect this inventdon relates to the use of a l sntagonist and an ' in the ' of a ' for use in treating a disease caused by a type I immune response.
- Specific r '~his method can be used I , ~ as well as to treat an existing condition.
The scope of treatment . , treadng a type I immune response in a mammal. This type I immune response is related to or caused by the interaction of an ~r~

w095/27487 2187~ J~I s l376 antigen with IgE which results in an ~,v ' reaction to the antigen. This ~ ' immune response can be eaused by~ antigenic materials originate from manydifferent sources. For example plant and animal rnaterials, e.g., dander and pollen, or foods, dust, drugs, and chemicals are Imown to cause abnormal reactions in mammals.
5 Such reaction cause L~14 . ' _ ' changes which result in a number of disease states, aU
of which can be treated by the practice of this invention, including but not limited to, rhinids including allergic and perennial rhinitis, atopie clermatitis, exema, aUergic , urdcana, systemic . ' ~ , and hay fever. This list sets out only a few of the disease states which can a~ise from the T~P/ ~i_ interaction and is not intended to 10 limit the practice of this invention in any G.
An allergic response is initiated quite ;apicUy after an aUergen binds to IgE
andbc~oies on mast cells. This induces the ceU to release chernicals that generate symptoms lumped into the phrase aUergic rhinilis. Among the released chemicals are two symptom-causing groups referred to " .~,ly as allergic mediators, i.e., histamine and 15 L, - ' ' ' For example, where rhinitis is concerned, ' ' reheve the sneezing, rhinorreah, and itehing of the eyes, nose and throat. But they are not1~ effective against nasal congesdon or when aUergens are quite abundant or when there is long term exposure. In aUergie rhinidcs that are dual ~qlr- 1~ rg, the of histamine during the ~1~ 1 ' c,orrelates with the severity of sneezing 20 and itehing, whereas the of l , ' ' ' duling the late-phase correlates with the severity of nasal congestion, a symptom that is also indueed by the exogenous - ' of l The ~ . ' ' ' (PTL) antagonists ~TLA) wbich can be used in this invendon are drawn from those compounds which regulate the aelion, produedon or 25 release of ~ L ' . ~ that of LTC4 and LTD4. Included withirl this group of . ' are those compounds which antagonize the LTC4 and LTD4 receptor otherwise known as receptor ~ _ or . . ' which inhibit the l,iu~ ' of PLT, for example: i.) inhibidon of ~ ~,r substrate sueh as 1 ' . ' ~ A2 (PLA2 inhibitors) or CoA ' . ' i ~,~1~ (CoA-lT inhibitors); ii) direct 30 inhibidon of enzyme such as S-L0 inhibitors; or iii) inhibidon of h ' - ' ~liu . of enzyme sueh as 5-L0 aedyating protein (I;LAP inhibitors). C . ' whueh are ,~ irlhibitors or those wbieh bind "..,v. - '~ to areeeptor are ineluded in tius invendon. Of pardeular interest are the . . .., binciing LTC4 and LTDi reeeptor _ .
In so far a8 PTL antagonists are eoneerned, there are a number of eompounc1s ~ ~ elinieal .. i, - whieh are useful in tbis invendon. It is expeeted that some or all of these antagonists could be used in the treatment regime set forth herein.

wo ss/27487 2 t 8 7~ 36 r~ .1376 O
For example the following . . have been reported in the literature to be under as receptor ~ Zileuton (Abbott T ' ) Accolate, ZD 2138, and ZD 3523 (Zeneca); MK-476 (Merck); BAY x-1005, BAY y-1015, andBAY x-7195 tBayer); A78773 (AbbottT ' ); AS-35 tTaltabe); DS~IT574 tDiiachi); SK~zF
104353, SK~F 106203 and SB 205312 (~ - T~' Be~cham, plc), RG 12525 tRhone-Poulenc R~er); and CGP45715 and CGS 25019C (lCiba Geigy). These ~ , ' and their related analogs are available from the respective companies, or can be prepared via the chemistries set forth in the various published pafent ~ and issued patents disclosing and clauDing these , This is but a brief !ist and is set forth only to 10 exelttplify the compounds which can be used in fhis invention; this list is not intended to limit the scope of the invention is any manner.
PTL receptor antagonists are most preferred. The PTLA of greatest interest is 8- y)benzoyl]arnino-2-(tetr~zol-5'-yl) ~1-oxo-4H-I-b -rJ and its salts, isorners, ~1.~. Jl~h.. and the lilce. This compound and useful analogs are disclosed in U.S. patent 4,7~0,469 issued on 25 October 1988 which is . ' herein by reference.
Any ~ " '; ' can be used in this inveDtiOn so long as it retains its native H
receptor antagonist activity when used in j with a PTLA. The preferred AH
compounds are those which used in this invention a~e those which are non-sedating but 20 wbich retain their effect on the symptorns associated with rhinitis. CNS depression is a common effect of many ' While this .~ ; may have use in certain therapies, it is not viewed as a desirabb effect in the treatment of diseases where the purpose of treatment is to remove l - whicll interfere with normal activity path~rns. C' ~ , so caUed "l.. ' ~" ' have been developed.
25 The approach has been to rnake ~ , which i) have poor penetration across the blood/hrain barrier or ii) have a higher selectiviq for or a greater affinity for peripheral radter than CNS histarnine-H1 receptors. Exarnples of this group of ~ , includes acrivastine, aster~izole, cetrdizine, loratadine, terfenadine and its catboxylic acid metabolite. Loratadine is a preferred ' These exernplary, , are set 30 for~htogivedhel oftbisinvendonthec~ h--`1;- ~ofthe ' which are intended to be covered by the ter~n "non-sedating "
I~nown ' can be obtained from sources or rnade by published methods. The syntheses of ; approved for human , have been published either in the patent li_,rature or in, ' ' joumals. More : 35 ' on ~ ' which are approved for human use csn be such cornpendiaas The Mercl~ Index, 9th l~dition, Merck and Cor~p~tny, Rahway, New Jersey (1976), Cutting's Handb~olc of rl~ ,~, 6th Edition, Ed. T. Z Czacky, M.D., Appleton-WO 9sl27487 2 1 8 7 ~ 3 6 P~ 1376 Centu~y-Crofts, New Yorlc, 1979, Chapter 49:538-550, and Goodman and Gi~man, Th~Ph~., ' gic~l Basis of T~, _, 7th Ed. Editors A. G. Gilrnan, et al, 1985 Macmillan Publishing Co., New Yor~ All of tllese references also provide ' ' on the ~ of these: . ' or reference relevant research in thc areL As S regatds specific d~ugs, ac~ivastine is ' ' by Boroughs Wellcome. In the Chemical Abstracts System (CAS) it has been given number CAS-87848-99-5.
Astemizole is produced by Janssen and has the CAS number CAS-68844-77-9. Cetirizine is -available from Pfizer as the hJ ' ' ' ' ' salt; it has been assigned two CAS numbers:
CAS-83881-52-1 andCAS-83881-51-0. Loratadine~anothersr~ ~ I`lv_~product has been assigned the num~er CAS-79794-?5-5. Terfenadine (Seldane) and its carboxylic acid metabo]ite are available from Marion Mer~ll Dow. T~ CAS number is CAS-50679~8-8. T r " about all aspects of these several drugs can be had by searching the Chemical Abstracts System data base using the numbers indicated.
Because the . ' ' ' of ~LA and " ' ' more effectively treats or 15 alleviates the symptoms caused by the IgE/antigen interaction than either compound ' ' ' alone, it is expected that a ~ ' ' product can or will contain less of each of the two actives than what would normally be ~ ' ' ' ' Thus a effective dose of the " ' ' can be lower than the dose which would be given if it was being: ' ' ' ' without a PTLA. It is expected that a low end dose 20 of the ' ' ' when combined with a PTLA will be about one-half of what it would be if ' ' ' ' alone. There will not necessarily be any need to reduce the dose at the high end of the range, but it is . ' ' dhat one will not need to use a dose equal to that of the highest dose currendy approved sale of the " ' alone. As a matter of.. ' , * is expected that one will use a dose of: " ' ' which has been 25 approved for sale by a regulatory agency or body which oversees the sale and matketing of " ' ' For example loratadine has been approved for sale in some countries as tablets containing lOmg, u.Ld.. Te~fenadine has been approved for a sale in tablets containing 60mg of drug b.ili An effective dose of the PTLA will be some dose between about io to 500 mg/l;g 30 body weight per day. It is expected that dhe PTLA wiU be ~ ' ' ' ' from one to four times a day. A preferred treatment regimen in~olving the PTLA will be a b.LL regimen involving an oral dose of 75 mg to 450 mg.
. - The foregoing active inf~ients may be combined in a single; . ' ' or provided as separate l"~ -- Any ~ acceptable vehicle can be used 35 in preparing ~ - contau~ing these two actives, so long as the preparation has dhe requisite stability and patient , ' " ' ~ . The ~ost preferred ' ' type is a solid or]iquid dosage form which is taken orally Wo95/27487 2187S36 P~ 1376 It is . . ' l, a preferred . ' " t, that both actives will be combined in one , for ~ and use. However, the actives can be separately formulated and separately ~ such as were one of the actives is ' fewer times per day than is the other. If the actives are ~ ' ' separately, it is: . ' ' that they will be ~ ' ' close in time, that is within acouple minutes of each other. In addition, the doses may be vaTied so that at one time point a higher dose of one ac~ive is being r ' ' ' For example it may be most efficacious to administer a higher dose of one active in the morning versus an evening dose of that ingredient, or some variation of this regimen. If one compound is normally ' fewer times per day, the treatment regimen must make ~ ' a split in the dositlg regimen. For example if an: ' is normally ' ' once a day, such as loratadine, but the PILA is ' ' ' twice daily! then two, or three, different wiU need to be prepared and pachged separately with specific for use.
These . may uke the form of u~lets, capsules (hard or soft), e]ixirs, syrups, . l . etc. consistent with ~ u~ du~ ' ' ' practices for treating cold or flu symptoms. For instance, for ~al ' in the form of tablets or capsules, the active drug , may be corlbined with any oral non-toxic accepuble inert ca~rier such as lactoæ, surch, sucrose, cellulose, ' stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (liquid forms) and the li~e. Moreov, when desired or necessary, suiuble binders, lub~icants, g, agents and colng agents can also be. , in the mixture. Suiuble binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium a~ginate, ~I,v~ ~,( - , POI~ glycol and waxes.
Among the lubricants there may be mentioned for use in these dosage fomls, boric acid, sodium benzoate, sodium acetate. sodium chloride, etc. r ~ include, without limitation, starch, - ~'( - agar, bentonite, ~uar gum, etc Sweetening and flavoring agents and ~ .w can also be included where , r.
" thewe ~ . may be formulated in sustained release form to provide the rate controlled release of any one or more of the ~ A ' to opdmize the therapeudc effects while munimizing undwirable side effects. Suitable dosage forms for wstained reiease include layered tablets contair~ing layers of ~,u~ ., - - " rates or controlled release polymeric matrices , O ' with the acdve L _--r ' and shaped in tablet form or capsules containing such , O or; A ' porous . . 3S polymeric matrices.
One example of a sustained release preparadon is a pardally or wholly transparent soft gelatin capsule preparadon wherein the internal rûlume is filled with a WO 95127487 218 7 tri 3 6 r~ 76 acceptable liquid and beadlets i~ an arnount which comprise apar~al fill of the soEt capsule void, or in which the oeadlets fill all the capsule and the interstices between she beads are filled with said liquid~ Such a preparation can be found in co-t pending U.S. ~ - - USSN 08/080851 filed 18 J 1993 and USSN 08/089361 filed 09 July 1993, which are , ' herein by reference. The tcchnology for making beadlets was pioneered by R H. Blythe as per U.S. patent 2,738,303. He descnbes there a therapeudc preparation in unit dosage form prepared from noQ-parid seeds (sugar peUets), screehed, placed in a coating pan, wetted with syrup, then treated with a 80:20 mixture of dextro . ' ~ sulfate and calcium sulfate dihydrate, then dried. This process wasrepeated several times to build up drug on the non-pariel seedt it is treated with talc to create the core pellet. These pellets were then treated with a wax-fat coating solution one or rnore times to cr~ate pellets with one or more fatty layers " ~ the core pellet.
Later d~,. . ', include placing an osmotic wall around the core pellet, and where the drug dissolves in the wall-fonning malerial of tne particle and passes through it to the exterior on exposure to water. Reference to such particles can be found in the literature, for exaunple in U.S. patent 4,434,153; the relevant parts are ' herein by reference. See also U.S. patent 4,961,932 which contains a substantial }ist of patents said to relate to tiny or slmall piDs, and dosage forms comprising same.
~ these I , -' can be presellted in the form of tr~che_, lozenges and the lilce where the acdve ingredients are either dissolves or suspended in the matrix or are presented in a beadlet form. These I , - may be opaque or c. n: . or A prefelred ' ' ' is one where beadlets are entrapped in a solid matrix-forming materiaL
In yet another . ' " ~ beadlets may be filled into a hard-shelled gelatin skin.
of the ' ' described in the two prece~dng paragraphs can be found in co-pending U.S. pater~t appdcadon serial number 08/090387 filed ~l~uly ~993, =e con_ of c~ =o , ' here~ I~y ~.
' ' ' ' ''' ,' ' ' ~ ' ' ' - . .

Claims (3)

What is claimed is:

1. A method for treating a disease caused by a type I immune response in a mammal, which method comprises administering to a subject about to be exposed to or who is already suffering from said disease an amount of a peptidoleukotriene antagonist and an amount of an antihistamine which in combination are sufficient to treat the disease.

2. The use of a peptidoleukotriene antagonist and an antihistamine in the manufacture of a medicament for the treatment of type I immune response in a mammal.

3. A pharmaceutical composition for use in treating type I immune response in a mammal, which comprises an effective amount of a peptidoleukotriene antagonist and an antihistamine and a pharmaceutically acceptable excipient.