CA1092028A

CA1092028A - Pharmaceutical compositions useful as bronchodilators

Info

Publication number: CA1092028A
Application number: CA284,372A
Authority: CA
Inventors: Norman E. Pitts
Original assignee: Pfizer Corp SRL
Current assignee: Pfizer Corp SRL
Priority date: 1976-08-26
Filing date: 1977-08-09
Publication date: 1980-12-23
Also published as: BE858094A; PT66866B; NL170367C; FR2362629B1; NL7708732A; AU2741277A; DE2737735B2; IL52588A0; IE45768L; AU503877B2; DE2737735C3; JPS5329935A; GB1541991A; DK354377A; IL52588A; MY8100263A; NZ184746A; FR2362629A1; PT66866A; HK30981A

Abstract

ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition in effective dosage unit form for enhancing pulmonary function in mammals comprising either (a) pirbuterol and hydroxyzine or (b) a pharmaceutically-acceptable acid addition salt of each of pirbuterol and hydroxy-zine, the said composition comprising pirbuterol and hydroxyzine in the weight ratio, calculated as the free base of each, of from 1:0.3 to 1:5; and the use of such composition for enhancing pulmonary function in a mammalian subject.

Description

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This invention relate6 to pharmaceutical composi-tions compri~ing pirbuterol and hydroxyzine, generally as th~ pharmaceutically-acceptable acid addition salts thereo~, and to their us~ as bronchodilators. More particularly the inventiQn is concerned with compositions of pirbuterol and hydroxyzin0, generally as the pharmaceutically-acceptable aaid addition salts thereof, in a mole ratio of ~rom 1:0.21 to 1:3.20 or alternatively i~ a weight ratio, calculAted as bas~ form o~ each of pirbuterol and hydroxyzine, of from 10 1:0.3 t~ 1:5, and their uee a~ b~onch~ailator~. .
Pirbut~rol, the g~neric name ~or 2-hydroxymethyl- :
3-hydroxy-6~ hydroxy-2-t-butylaminoethyl~ pyridine, and pharmaceutically-acceptable ~aIt~ thereof, are de~cribed in United State~ Patent~ 3,700,681 and 3,786,160 as bronchodi- ,,~'.J.. '' 15 lator~ having out~tanding potency and selectivity for pul-monary v~r~u~ cardiac tissue. Steen et al., Current Thera-, 16, 1077-1081 (1974) r~port pirbuterol dihydrochlorid~ to be an ef~ective, long-acting, oral bron-chodilator~
Hydroxyzine, the generic nam~ for l-(p-chloro-a-phenylbenzyl)-4-(2-hy~roxyethoxyethyl) piperazine, and acid addition ~alt~ thereof are described in United States Patent

2,899,436 a~ hiatamina antagonists or antihistamines, U8e-ful or ~h~ treatm~nt o~ allergy; f~r example, urticaria.
Kohn, ~ , 20, 252-256 ~1962) report-od the ben~fiaial eff~c~ o~ a combination of ephedrine, th~o-phylline and hydroxyzine for th~ 3ymptomatic and prophylactic tr~atmont of bronchial a3thma. The eficiency of the com-bination wa~ attribut2d to the tranqullizing and anti-sero-30 toni~, anti-ch~lin~rgic and anti-histamine properties ~f ., . . : : ' i)28 --2-- .
hydroxyzine Numerous othar investlgators have confirmed that thc addition of hydroxyzine to ephedrine/theophylline combinations results in an improvement in pulmonary functio~
It has now been found that compositions comprising fixed proportions of ~a) pirbuterol and h~droxyzine or (b) of pharmaceutiaally-acceptable acid addikion salts of each of pirbuterol and hydroxyzi~e, markedly enhance pulmonary unction of màmmals, including humans, and thus ~erve as more efficient bronchodilators than pirbuterol alo~c. The ~ree base forms of each of pirbuterol and hy~roxyzine may be used in the present invention and compositions containing pirbuterol and hydroxyzine a~ their free base forms are favored for aerosol use primarily because of the greater 301ubility o the free ba6eg in aero601 ~ormulations relative t~ that of the acid addition 8alt8. The present invention encompasse~ all compositions containing pharmaceutically-acceptable acid addition salt~ of each of pi~buterol and hydroxyzine. The salt~ may be administerad as such or in admixture with a pharmaceutical carrier selected on the ba~is of the chosen route of a*m~nistration and stand-ard pharmaceutical practice.
Pharmaceutical compo itions comprising pirbuterol and hydroxyzine or of pharmac~utically-acceptable acid addition ~alt~ of each of pirbuterol and hydroxyzine, effec-tive as bronchodilators for the preaent invention, are thosewh~rsin the mole ratio of pirbu~erol (or pirbuterol 6alt) to hydroxyzine (or hydroxyzine salt) i9 rom 1:0~21 to 1:3.2~. Alternatively, the effective compositions are those wherein the weight ratio of pir~uterol to hydroxy~
zi~e, each calculated as the frea base, is from 1:0~3 to 1:5. Particular interest resides in pharmaceutical compositions wherein ~he mole ratio of pirbuterol to h~drsxyzine (or acid addition salt6 of each) ls 1:0.64, 1:1.60 or 1:3,20. Alternatively, such ratio6 correspond, on a weight base of pirbuterol to hydrox~zin2, calcu-lated as their free ba~e forms, to 1:1, 1:2.5 or 1:5 The preferred composition i8 that containing the 1:0.64 : .

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-3-mol~ ratio sinc~ maximum ~nhancement of pulmonary func-tion; i.e., bronchodilator activity, is observed with this ratio.
The dosage unit compo~ition~ of this invention are those comprisi~g (a) at lea~t 5 mg. and not more than 15 mg. of pirbuterol and at least S mg. and net more than 25 mg. o~ hydroxyzine, or (b) euch compo6itions compriaing equivalent amounts of pharmaceutic~lly-acceptable acid addition salts of each of pirbut~rol and hydroxyzin~, such that ~he total weight of pirbuterol and hydroxy-zine, calculat~d as their free bas~ forms, is at l~aat 15 mg. and not more than 35 mg.
While th~ above weight ratios expr~ th~
w~$ght ratio o~ pirbutorol ~calculatad a~ ~r~ base) to hydroxyzine ~calculated as fr~ base) cp~ativ~ in ~hi~
invention, it i8 conv2nlent to ~xpr~9~ ~h2 operative com-posi~ions on a dosag~ unit basi~ slnco thi~ i~ kh~ manner in which ~uch cemposition6 are ua~d. On a do~age unit basis, the above w~ight ratio~ are intend~d to cov~r 2~ ~uch compos$tions a~ th~ followlng. In ~a~h in~tanca, the f~rst figur~ repreconts mg. of plr~uterol and th~
second figur~ mg. of hydroxyzin~: 10:5, 15:5, 10:10, 10:25, and 5:25. Th~ la~t th~2 ratio~ r~pr~ent th~
favor~d dosage unit composition6 ~inco t~y have bs~n obs2rved to enhance pulmonary functi~n in mammal~. Th~
preferred compo~it$~n, oxcept or aero~ol u~ 3 that comprising a pharmaceutically-aoc~ptabl~ ~id additi~n ~alt of oach of pirbuterol an~ hydroxyzino e~ulvalont - to 10 mgc of th~ reo base o~ ~ach of pirbuterol ~nd 30 hydroxyzino. `
~ of cours~, moro conveni~n~ t~ expre~s the rat$os of plrbut~rol ~or ~alt th~roof) to hydroxyzinQ
~or ~alt th~raof) as molo ratio~ ca th~ are in-~bp~n~ent of th~ form (ba~ or ~alt) o~ pirbuterol and hydro~yzin~ u~d. ~ho abova w~ight ratio~ o~ 10:5, 15:5, 10:10, 10:25 and 5:25 ~xpr~s~d as mol~ ratio~
ar~ 1:0.32, 1:~.21, 1:0,64, 1:1.60 and 1:3.20, r~sp~c-.

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The compositions of the presen~ invention may be administered via the oral, parenteral or inhalation routes. The compositions may contain the stated active ingredients as such, as in the case of oral a*minis-tration of capsules, but generally include a pharmaceuti-cally-acceptable carrier or diluant ~elected on the basi~ of the chosen route of administration and stand-ard pharmaceutical practice. For example, the compo~i-tion may contain various pharmaceutically-acceptable inert carriers and be made up in the form of tablets, capsules, lozenges, troches, hard candies, powders, aerosol sprays, aqueous suspensions or solutions, in~ect~ble solutions, elixirs or syrups. Suitable carriers in-clude solid diluent~, or filler~, sterile a~ueous media and various non-toxic organic solvents. Moreover, the oral pharmaceutical compositions of thi3 inv~ntion may be ~uitably ~weetened a~d flavored by means of various agents of the type commonly used for this purpose.
For aero~ol use, the free base form of each of pirbuterol and hydroxyzine ig favored. However, the amount of the p~rbu~l-hydro~y~ine composition used is less vla the inhalation route than it is by other route~
as i8 discussed below. Nevertheless, the mole ratio o pixbuterol to hydroxyzine in aero~ol formulations is the same as that in formulations for other routes of~
administration; namely, from 1:0.21 to 1:3.20, correspond-ing to weight ratios of from 1:0.3 to 1:5.
The particular carrier select2d and the pro-portion of active ingredient to carrier are inEIuenced bythe solubility and chemical nature of the ~h~rapeutic compounds, the chosen route of administration and the needs of ~tandard pharmaceu~ical practice. For example, where those compounds are admini~tered orally in ta~let form, e ~ pients such as lactose, sodium citrate, ~ ciu~ carbcnats and dical-cium phosphabe may be used. Various dlsintegrants 8uch as starch, alginic acids, and oer~n o~lex ~ilioabesj ~x~ther wi~h lubricating ager.t~

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such as magnesium stearate, sodium lauryl sulphate and talc, may also be used in producing tablets for the oral administration of these compounds. For oral administration in capsule form, lacto~e and high mole-cular weight polyethylene glycols are among the pre-~erred materials for use a~ pharmaoeutically-acceptable carriers. ~here aqueous ~uspensions are to be used for oral administration, the compositions ~ this inven-tion may include emulsifying or suspending agents.
Diluents such as ethanol, propylene ~lycol, glycerine and mixtures th~reof may be employad as well as oth~r materials.
For purposes of parenteral admini~tratîon and inhalation, solutions or suspensions of the active in-gredients in sesame or peanut oil or in aqueou~ pro-pylene glycol solutions may be employed, as well as st~rile aqu~ous solutions of the ~oluble acid addition salts described hereinafter. These particular solutions are especially suited for intramuscular and subcutaneous injection purposes. Theaqueous solutlons, including those of the acid addition salts di~solved in pure distilled water, are also useful for intravenous inject-tion purposes provided that their pH i9 properly adjusted beforehand. Such solutions al~o should be suitably buffered, if necessary, and the liquid diluent first render2d isotonic with sufficient saline or glucose.
~ he compositions may be admini~tered to ~ub-jects suffering form broncho-constriction by mean~ o~
inhalators or other devices which permit the active compounds to come into direct contact with the ~on-stricted area6 of the tissues of the ~ubj2ct. When administered by inhalation, the compositions may com-prise (1) a solution or suspension of the active in-gredi~nt~ in a liquid medium of the type mentioned above for admini~tration via a nebulizer; ~2~ a sus-pension or ~olution of the active ingredient~ in a liquid ~ropellant such as dichloro-di1uoromethane or " ' ~ : . ' : ' , .
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chlorotrifluoroethane for administration from a pre -surized container; or (3) a mixture of the a~tive in-gredients and a solid diluen~ (e.g., lacto~) for ad-ministration from a powder inhalation device. Composi-

5 tionS suitable for inhalation by msans of a conventionalnebulizer preferably comprise 0.1 to 015% by weight o~
active ingredients; and tho~e for use in pressurized containers preferably comprise ~orm 0.S to 5% by weight of active ingredients. Compositions for use as powder 10 inhalants may comprise ratios of active ingredients to dilu~nt oE from 1:0.5 to 1:1.5. When a~minister~d by means of a spray formulated a~ a 1% ~olutions in an aqueous or non-aqueous solvent, e.g., propellant~ such as fluorinat~d hydrQc~rbons, utiliza~ion several tim~s 15 a day is preferred. For such application, a halogenat~d hydrocarbon propellant of up to 2 carbon atom~ is em-ployed. The propellant may be any of the conventional propellants used in aerosol formulation , or example, halogenated hydrocarbons of the fluorohydrocarbon or 20 fluorohalohydrocar~on type such as trichloromonofluoro- -m~thane, dichlorodifluoromethane, dichlorotetrafluoroethane, m~nochlorotriflucromethan2, monochlorodifluoromethane and mixtures of any of these together or with oth0r pro--pellants. Typical of suitable propellant~ are those 25 disclosed in, for example United States Patent No.
2,868,691.
It is necessary that the a~tive ingredient form a proportion of the composition such that a ~uit-able dosage form will b~ obtained. Obviously, ~everal 30 dosage unit forms may be administered at about the same time~ Although compositions with less than 0.005 per oent by waight of active inyredi~nt migh~ be u~ed in oer4~n instanoe8, it i8 prefe ~ d to us~ o~it~o~ aon~ ng n~t less ~han 0.005 per ~ent of th~ active ihgr2dl3nt; oth~rwise ~h~ ~m~unt of carrier b~c~ms~ ~xoes-35 sively largo. Ac~ivit~ incr~ ~ ~ with the~-~c3jnpe~tration of ~hu activ~
ingre~nt;-tho o~ition may-co~tain ~ 7~ 95~or an ~ven higher Fero2ntage by weight of th2 acti~e ingr~t, ~, .

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~O9Z028 Although th~ use of the przsent in~ention i8 directed toward the treatment of mamrnals in gen~ral, the pr~ferred subject is humans. In determining an efficacious dose for human therapy, results of animal testing are frequently extrapolated and a correlation i~ a~sumed between animal test behavior and prQposed human dosage.
Whan a comrnercially employed standard is available, the dose level of the clinical candidate in humans is frequent-ly determined by comparison of its p~rfo~nance with the ~tandard in an animal test. For example, isoproterenol is employed as a standard bronchodilator and i8 administ-ered to hurnans at the rate of 0.1 to 0.4 mg. every 4 hours. It i~ assumed, then, that if cQmpositions of the present invention have activity comparable to isoproterenol in ~he test as~ay, that similar doses will provide comparable respon~es in humans.
Obviously, the physician will ultimately determine`the dosage which will be most suitable for a particular individual, and it will vary with the age, weight and rasponse of ths particular patient as well as with the nature and extent of the symptoms and the pharmacodynamic characteristics of the particular agent to be a~ninistered. Generally, small doses will be administered initially, with a gradual lncrease in the 2S dosage until the optimum level is determined~ It will often be found that when the composition i8 administered orally, larger quantities of the activo ingredie~ts will be requirod to produce the same level as i~ pro-duced by a smaller quantity administered parenterally.
An effec~ive daily dose of the composition of this invention in hurnans by the oral or parenteral routes of administratior~ is considered to be administra-tion, three to four times per day, of the herein des-cribed dosage unit forms. Of particular value are thoso compositions wherein the mole ratio of pirbuterol salt to hydroxyzine salt is from 1:0.64 to 1:3.20. The dosage unit ~orrnulations fulfilling this requir~ment .
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which are of particular interest are tho~e compri~ing weight ratios of an acid addition ~alt of each of pirbuterol and hydroxyzine BO as to provide weight ratios of pirbuterol base to hydroxyzine base of 10:10, 10:25, ~r 5:25, ~alent to mole ratiosof 1:0.64, 1:1.60 andl:3.20 respectively. The preferred dosage uni~ range is that comprising the base form or a pharmaceutically-acceptable acid addition salt of each of pirbuterol and hydroxyzine e~uivalent to 10 mg.of the base form of each component. E~pecially pr~f~rr~d, except for aerosol use, is a composition comprising pirbuterol dihydrochloride and hydroxyzine dihydrochloride which affords the equivalent of 10 mg, of each of pirbuterol and hydroxyzine.
Such compo~itions when administered by means of inhalators or ather de~ices which permit direct contact of the active compounds with the constricted areas of the tissues of the subject are de~irably administered in such manner that from 0.1 to 0.8 mg. of each of pirbuterol and hydroxyzine are administered to the 6ubjectl This dosage is repeated from three to four times per day.
For purposes of oral and parenteral administration, the dihydrochloride 6alts of each of pirbuterol and hydroxy-zine are favored because of their solubility and ease of handling. For aerosol administration, compositions com-prising the free base forms of each of pirbuterol andhydroxyzine are favored because of their relative ease of formulation.
Ten stable outpatients with chronic bronchospastic disease which is significantly reversed ~15% or more~ by ~o isoproterenol [1-(3,4-dihydroxyphenyl)-2-isopropylaminoetha-nol~ type of bronchodilator aerosol were admini~tered single doses of plac~bo and 5, ~0 and 15 mg. of pirbuterol dihydro-chloride alone, and ox~ition~ o~ri~ing pirbuterol dihydrodhloride , . . . , , .,.. . ~... . ...

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g with hydroxyzine dihydrochloride in ratios of 5 mg.:10 mgG
and 10 mg.:10 mg. Each of the above doses is administered orally on six separate days with at least two days between dosings. The forced expiratory volume, one second (FEVl), which is closely related to the maximum breathing capacity and is useful in assessing the efficacy of bronchodilator therapy, is measured by means of a spircmeter. The FEVl is measured at 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0 and 7.0 hours post-dose. Results are reported as the geometric mean per cent change from the pre-dose (base line) value. In the accompanying drawing, the results are presented graphi-cally by plotting the geometric means FEVl versus time thours post dose~. For comparison, pirbuterol alone is administered to better asses the effect of pirbuterol-hydroxyzine c~mposi-tions as bronchodilatorsD
The data illustrated in the a~companying drawingshow that pirbuterol dihydrochloride:hydroxy~ine dihydro-chloride compositions containing 10 mg. of each provided better efficacy than did the 5 mg.:10 mg. compositions and much better efficacy than 15 mg. of pirbuterol dihydro-chloride alone~
A 5 mg.:50 mg. composition ~not shown in the drawing) of pirbuterol dihydrochloride:hydroxyzine dihydro-chloride afforded values close to those of the 10 mg.:10 mg.
composition but was accompanied by a relatively high incidence of drowsiness. A pirbuterol dihydrochloride:hydroxyzine dihydrochloride (10 mg.:50 mg.) composition gave somewhat better efficacy than did the 10 mg.:10 mg. composition but was accompanied by a relatively high incidence of drowsiness.
The 10 mg.:10 mg. (mole ratio of 1:0.54) composition illustrated in the drawing was found to be the preferred composition because of its superior bronchodilator acti~ity relative to that of other compositions or of pirbuterol alone and the relatively low incidence of drowsiness which it produces.
The following Examples illustrate the invention:

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E XaMPLE
~ ts The general procedure comprise~ adding pir~uterol in ethanol to a solution of an excess ~20%) of the 5 appropriate acid in a suitable solvent. The salts are precipitated by addition, if necessary, of a solvent in which the salt is insoluble ~non-solve~t~, and chilling of the mixture.

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~e~9;~0~15 EXaMPLE 2 ~ablets A tablet base is prepared by blending ~he following ingredients in the proportion b~ weight indicated below:
Sucrose, U.S.P. 80.3 Tapioca starch 13,2 Magne~ium stearate 6.5 Sufficient pirbuterol dihydrochloride and hydroxyzine dihydrochloride are blended into this tablet 10 base ~o provide tablets containing pirbuterol and hydroxyzine in the following proportions per tablet:
Pirbuterol~
mg. basemg. 2HClmillimoles ~ ~ m~ m~ll~le~
5.518 0.02081 1011~945 0.~2667 1510 13.035 0.04162 1011.945 0.02667

6,518 0,02081 2529.864 0.06668 13.035 0.04162 5059.768 0.13336 13.035 0.04162 5 5.973 0.0133.4 19.553 0.062~3 5 5.973 0.01334 The compositions ar~ compre~sed into tablets weighing 360 mg. by conve!ntional means.

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A): A blend is prepared containing the following 25 ingredients in the proportion by weight indicated below:
Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesium trisilicate, U.S.P. 5.2 Lactose, U.S.P. 5.2 30 Potato starch 5.2 Magnesi~n stearate A 0.8 Magnesium stearate B 0.35 To this blend i9 add~3d sufficient pirbuterol .
dihydrochloride and hydroxyzine dihydrochlorid~ to pro~
35 vide capsules containing pirbuterol bas~ ~P) and hydroxy-z~ne base (H) in the following proportionB by we~ight:

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--~3--p m~ millimol~e m~ ~ mil1imoles - 10 0.04162 10 0.02667 0002081 10 0.02667 515 0.06243 5 0.01334 0.02081 25 0.06668 B) A second batch of capsules is prepared con-talning only the above proportions of pirbuterol dihydrochloride and hydroxyzine dihydroc~loride.
ExaMpLE 4 Susp~nsion A suspension of pirbuterol dihydrochloride (P) and hydroxyzine dihydrochloride ~H) is pr2pared having the following composition:
P dihy~rochloride 13.035 g. ~0.04162 milLim~le~) H dihydrochloride 11.945 g. ~0.02667millimoles) 70~ aqueous sorbitol 741.290 g.
Glycerine, U.S.P. 185.350 g.
Gum acacia ~10% soluti~) 100.000 ml.
Polyvinylpyrrolidone 0.500 g.
Distill~d water to make one liter Various sweeteners and ~lavorant~ are added to this suspension to irnprove its palatability. The suspension contains approximately 10 mg. of each o~
25 pirbuterol (base) and hydroxyzine (base) per milliliter.
E X~4PLE 5 SolutiGn A ~olution of pirbuterol ~ihydrochloride and hydroxyzine dihydrochloride is prepared with the 30 following composition:
pirbuterol dihydrochloride 3.26 mg. ~0.01~4 mill3~i~le~) hydroxyzine dihydrochlorid~ 2.99 m~. ~0.0067 mill~mol2~) water, distilled 498~00 ml.
The resulting ~olution has a concentration of 35 approximately 6.25 mg./ml. of pirbuterol dihydrochloride and hydroxyzine dihydrochloride mixture, equivalent to 2.52 mg. of each of pirbuterol and hydroxyzine per ml.
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(mole ratio = 1:0.64).
EX~UPLE 6 Aerosol An aerosol composition o~ pirbuterol a~d hydroxyzine i8 prepared containing:
pirbuterol 0.2 g. ~1.041 millimoles~
hydroxyzine 0.2 g. (0.667 millimoles) Freon* 115/Freon* 114(40/60 w/w) 65.5 g.
Ethyl alcohol 33. g.
~ra~rk 10 The pirbuter~l and hydroxyzine ara added to the ethyl alcohol and the mixture placed into a plastic coated aerosol bottle. The bottle is charged with the propellant and then sealed with a metering device designed to meter 0.2 gram per dose, equivalent to 0.5 mg. of each of pirbutiarol and hydroxyzine~
Similar compositions are prepared comprising the following amounts of pirbuterol and hydrox~zine:

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,, '~ ' ' ~ ' ~ ' ' , EX~MPLE 7 The procedures of Examp~es 1 to 6 are repeatedbut using the following compositions o~ pirbu~erol acid addition salt-hydroxyzine acid addi~ion ~alt in thesame ratios as are exemplified in these Exampl~s:
Pirbuterol H droxyzine dihydrochloride acetate acetate dihydrochloride dihydrobromide dihydrobromide citrate citrate dihydrochloride ~uccinat~
laatate propionat~
sulfate dihydroch~oride phenylacetate dihydroiodide decanoate dihydrochloride palmitate citrate .
stearate dihydrochloride succinate sulfate gluconate dihydrochloride maleate dihydrobromide glutarate dihydrochloride ;;. ' ,.
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Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A pharmaceutical composition in effective dosage unit form for enhancing pulmonary function in mammals which comprises a mixture of either (a) pirbuterol with hydroxyzine or (b) a pharmaceutically-acceptable acid addition salt of each of pirbuterol and hydroxyzine with each other, in a weight ratio of pirbuterol and hydroxyzine, calculated as the free base of each, of from 1:0.3 to 1:5.

2. A composition according to claim 1, which includes a pharmaceutically-acceptable carrier or diluent.

3. A composition according to claim 1, which com-prises a mixture of the pharmaceutically-acceptable dihydrochloride salts of each of pirbuterol and hydroxyzine.

4. A composition according to claim 3, which comprises a mixture of pirbuterol dihydrochloride and hydroxyzine dihydrochloride in amounts equivalent to 10 mg. of the free base form of each of pirbuterol and hydroxyzine.