Patent Publication Number: US-4579846-A

Title: Antiinflammatory compositions and methods

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application is a continuation-in-part of co-pending application Ser. No. 659,602, filed Oct. 11, 1984, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention is concerned with an improved antiinflammatory composition and method of treating inflammation which employs antiinflammatory piroxicam, or a pharmaceutically acceptable salt thereof (particularly the ethanolamine salt) in combination with analgesic acetaminophen, antidepressant doxepin, bronchodilator pirbuterol, minor tranquilizer diazepam, or antihypertensive trimazosin or a related compound. The generic names used here and elsewhere herein are from the USAN and the USP Dictionary of Drug Names, 1961-1981, Griffiths et al., ed., U.S. Pharmacopeial Convention Inc., Rockville, Md., 1984, have subsequently been assigned and published as official USAN names, and/or appear in the Merck Index 10th Edition. 
     Gastrointestinal irritation, including ulcers, is a side effect commonly associated, to one degree or another, with antiinflammatory agents. In many cases, individuals requiring such antiinflammatory treatment are precluded from enjoying the benefits thereof because of their susceptibility to such side effects. The present combination of piroxicam with one or another of the medicinal agents defined above permits desirable antiinflammatory therapy while preventing or ameliorating said gastrointestinal irritation or ulcers. 
     Acetaminophen has been previously reported to reduce the ulcerogenicity of aspirin [Sugers et al., J. Pharm. Pharmacol. 30, 84 (1978); ibid. 31, 840 (1979); and Adv. Prost. Thromb. Res. 8, 1547 (1980)], or of acidifed aspirin [Konturek et al., Gut 23, 536 (1982)]. However, indomethacin reversed the protective effect of acetaminophen when given with acidified aspirin (loc. cit.). In later studies, it was reported that acetaminophen reduced the ulcerogenicity of indomethacin and aspirin, but not of phenylbutazone or glafenine, and of ibuprofen only at the highest dose (800 mg/kg) of the latter compound [van Kolfschoten et al., Agents Actions 12, 247 (1982); Toxicology Applied Pharm. 69, 37 (1983)]. Acetaminophen in combination with ketoprofen and other particular antiinflammatory agents has been reported to provide an analgesic effect which is greater than a simple additive effect (U.S. Pat. Nos. 4,233,313 to 4,233,317; 4,234,601; 4,207,340; and 4,242,353). While we are aware of no literature reports concerning the combination of acetaminophen with piroxicam or any other oxicam for any purpose, we have been advised that a piroxicam-acetaminophen combination has been recently marketed in Argentina. 
     Bronchodilators salbutamol (albuterol), phenylephrine and isoproterenol, but not propranolol, have been reported to inhibit formation of indomethacin-induced ulcers in animals [Fielding et al., Eur. Surg. Res. 9, 252 (1977); Kasuya et al., Japan J. Pharmacol. 29, 670 (1979)]. In another study, administration of isoproterenol to a chambered section of a dog&#39;s fundus reduced or prevented aspirin-induced tissue damage [McGreevy et al., Surg. Forum 28, 357 (1977)]. There are no known prior reports concerning the effect of bronchodilator pirbuterol on antiinflammatory agents. 
     Antidepressant doxepin has also been reported to have gastric antisecretory activity and to be as effective as cimetidine in the treatment of duodenal ulcers in humans [Hoff et al., Curr. Med. Res. Opin. vol. 6, supplement 9, page 36 (1980); Scand. J. Gastroent. 16, 1041 (1981)]. It has also been reported that doxepin shows antiulcer and antisecretory activity in rats and dogs; and that it significantly reduced the ulcerogenic potential of indomethacin, diclofenac and aspirin in water-immersion restraint-stressed rats f[Leitold el at. Arch. Pharmacol. 316 (supplement), R50 , abstract 199 (1981); Leitold el al., Advances in Experimental Ulcer, Umehara and Ito, editors, ICEU, Tokyo pp. 27-36 (1982); Arzneim-Forsch/Drug Res. 34, 468 (1984)]. 
     Major tranquilizer and antipsychotic chlorpromazine has been reported to reduce indomethacin-induced gastric ulcers in rats [Kasuya et al. loc. cit. (1979)]. However, there are no known prior reports concerning the use of an antihypertensive agent such as trimazosin or a minor tranquilizer such as diazepam in reducing gastric side-effects induced by nonsteroidal antiinflammatory agents. 
     Phospholipids have also been reported to reduce gastrointestinal distress (damage to the mucous membrane, gastric ulcer formation) when combined with nonsteroidal antiinflammatory agents, particularly phenylacetic or phenylpropionic acid derivatives such as ibuprofen, naproxen, diclofenac and fluribprofen [Ghyczy et al., U.S. Pat. No. 4,369,182 (1983)], as have antiulcer pirenzepine [Leitold et al., Therapiewoche 27, pp. 1532-1548 (1977); German Patent Application No. 2,708,520] and histamine-H 2  antagonist (gastric acid antisecretory, antiulcer) compounds such as ranitidine, cimetidine and 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]-propylamino]]-1H-1,2,4-triazole-3-methanol, which have been previously combined with indomethacin and other antiinflammatory agents for this purpose. See, for example, U.K. Patent Applications Nos. 2,105,193 and 2,105,588; and Lovelace, U.S. Pat. No. 4,230,717. 
     Co-pending U.S. patent application Ser. No. 659,733 by Lombardino, filed concurrently with the parent of the instant application, describes improved antiinflammatory salts of piroxicam, including those with trimazosin, doxepin, N-demethyldoxepin, isoproterenol and pirbuterol. 
     SUMMARY OF THE INVENTION 
     The present invention concerns an improved antiinflammatory composition which comprises an antiinflammatory amount of piroxicam, or a pharmaceutically acceptable salt thereof (particularly the ethanolamine salt), in combination with a piroxicam-induced gastric irritation and ulcer inhibiting amount of a compound selected from the group consisting of acetaminophen, doxepin, pirbuterol, diazepam, fanetizole, trimazosin and related compounds, and the pharmaceutically-acceptable salts thereof. 
     The present invention is also concerned with an improved method for the treatment of inflammation in a mammal, including man, which comprises, in addition to treatment with an antiinflammatory amount of piroxicam, treatment with a gastric antiirritation and ulcer inhibiting amount of acetaminophen, doxepin, pirbuterol, diazepam, fanetizole, trimazosin, or a pharmaceutically-acceptable salt thereof. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The antiinflammatory agent of the present invention, piroxicam, is known. For example, The Merck Index 10th Ed., 1983 contains a monograph concerning piroxicam (no. 7378), as does the Physicians&#39; Desk Reference (PDR), 38th Ed., pp. 1556-1557 (1984). The preferred ethanolamine salt of piroxicam is specifically disclosed in U.S. Pat. No. 4,434,164. 
     The compounds of the present invention which we have found to inhibit piroxicam-induced gastric irritation and ulcers are also known compounds. Acetaminophen is a proprietory analgesic (The Merck Index 10th Ed., monograph no. 39; see also the PDR, 38th Ed., p. 2096). Doxepin is an antidepressant, marketed in the form of its hydrochloride salt (The Merck Index 10th Ed., monograph no. 3434; PDR 38th Ed., pp. 1688-1689). Pirbuterol is a bronchodilator marketed or to be marketed around the world in the form of its dihydrochloride and monoacetate salts. See The Merck Index 10th Ed., monograph no. 7364. Its early synthesis and utility as a bronchodilator is disclosed in U.S. Pat. Nos. 3,700,681; 3,763,173; 3,772,314 and 3,786,160. Alternative and generally improved syntheses are found in U.S. Pat. Nos. 3,948,919; 4,011,231; and 4,031,108;  Luxembourg Pat. No. 79564; and European Patent Applications Nos. 58069, 58070, 58071 and 58072. More recently, pirbuterol has also found utility in the treatment of congestive heart failure (U.S. Pat. No.  4,175,128). Diazepam is a widely prescribed minor tranquilizer (The Merck Index 10th Ed., monograph no. 2967; PDR 38th Ed., pp. 1671-1674). Trimazosin (The Merck Index 10th Ed., monograph No. 9506) is an antihypertensive agent, marketed or to be marketed around the world as a hydrochloride salt, which is structurally related to prazosin. 
     The clinical value of the present improved formulation in inhibiting piroxicam-induced gastric irritation and ulcers is reflected by appropriate animal studies. Typical experimental protocols, in which the ability of the test compound to prevent or reduce piroxicam-induced gastric lesioning was determined, are found in the specific Examples below. 
     The present invention is readily carried out. The piroxicam or its salt is dosed in a mammal, particularly man, in the range of 0.1 to 1 mg/kg/day. The second medicinal agent can be dosed separately, in which case the latter will be employed in an amount within (but generally lower in) the dosage range and according to dosage regimens (frequency, routes and compositions) as specified for their alternative utility in the prior art, for example, in references cited above or futher cited in said references. 
     Preferably and conveniently, the piroxicam and a gastric irritation and ulcer inhibiting agent of the present invention are co-administered in a single, combined formulation. This can be in a form suitable for parenteral administration, but is preferably in a form suitable for oral administration. The proportion of each drug in the combined dosage form will be in the ratio of the total daily dosage of each drug when dosed alone. The combined drugs will be dosed in single or divided doses. Single daily dosage will be most preferred in those cases where the in vivo half-life of the second medicinal agent is (like that of piroxicam) relatively long, and where the daily dosage of the second agent for a typical adult patient is relatively small, e.g., less than 1-2 grams. 
     In the preferred oral route of dosage, the amount of piroxicam (or salt equivalent) for an average adult patient will generally be in the range of 5-50 mg/day in combination with: 
     200 to 4000 mg/day of acetaminophen, 
     4 to 200 mg/day of doxepin; 
     3 to 100 mg/day of pirbuterol; 
     2 to 40 mg/day of diazepam; or 
     4 to 500 mg/day of trimazosin; 
     an amount of the second medicinal agent generally sufficient to inhibit gastrointestinal irritation or ulcers which could otherwise be induced by the piroxicam in patients susceptible to this side effect. 
     The combined compounds are administered alone or inn further combination with pharmaceutically-acceptable carriers or diluents. For oral use, suitable pharmaceutical carriers include inert diluents or fillers, thereby forming dosage forms such as tablets, powders, capsules, and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. For example, tablets containing various excipients, such as sodium citrate, are employed, together with various disintegrants such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials therefor include lactose or milk sugar and high molecular weight polyethylene glycols. 
     The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. 
    
    
     EXAMPLE 1 
     Protective Effect of Various Medicinal Agents on Piroxicam-Induced Gastric Lesions in Rats 
     Adult male &#34;specific pathogen free&#34; rats weighing 140-160 grams of the CD strain (Sprague-Dawley) were obtained from Charles River Breeding Laboratories (Kingston, N.Y.). The animals were acclimated for approximately one week and tested when they reached a body weight of 200-225 grams. The rats were fasted for 16 hours and randomized into groups consisting of 8 to 20 animals which were normalized with regard to their average body weight. 
     Gastric ulcers were induced in the animals by orally dosing them with a single 100 mg/kg dose of piroxicam in 2 ml. of aqueous 0.1% methylcellulose (pH=6.8). Those animals receiving a second medicinal agent separately received the second drug in an additional 2 ml. of the same medium at about the same time. Six and one-half hours later, the animals were sacrificed by cervical dislocation and autopsied. The stomachs were surgically removed, dissected along the greater curvature and rinsed with cold water. The stomachs were individually scored for both linear and punctate lesions. The total number of lesions was used for scoring purposes. The data obtained from each group of rats was analyzed after calculation of the mean number +/- the standard error of total gastric lesions. The values obtained were also compared to the controls which received only piroxicam by the two-tailed Student&#39;s T-Test for non-paired data. The protective effect of the second medicinal agent against piroxicam-induced ulcers is shown in Table I. These data show that pirbuterol, acetaminophen, doxepin and diazepam each significantly reduce piroxicam-induced gastric lesions in the healthy fasted rat. 
     
                       TABLE I                                                     
______________________________________                                    
Protective Effect of Various Medicinal Agents                             
on Piroxicam-Induced Gastric Lesions in Rats.sup.a                        
          Oral                         Signifi-                           
Medicinal Dose     No. of Rats                                            
                             Lesions/Rat                                  
                                       cance                              
Agent.sup.a                                                               
          (mg/kg)  in Group  (--X+/- SE).sup.b                            
                                       p 0.05.sup.c                       
______________________________________                                    
(Control) --       20        10.1 (1.5)                                   
Pirbuterol                                                                
          3.3      10        2.8 (0.9) +                                  
          10       20        4.5 (1.1) +                                  
          33       20        2.6 (0.7) +                                  
(Control) --       10        4.1 (1.0)                                    
Acetaminophen                                                             
          100      10        4.6 (1.9) -                                  
          333      10        1 4 (0.7) +                                  
          1000     10        0.7 (0.5) +                                  
(Control) --       20        9.5 (1.1)                                    
Doxepin   3.3      10        4.4 (1.0) +                                  
          10       10        3.6 (1.0) +                                  
          33       20        4.2 (1.0) +                                  
(Control) --       20        9.3 (1.3)                                    
Diazepam  10       20        5.6 (1.1) +                                  
          33       20        4.2 (1.1) +                                  
______________________________________                                    
 .sup.a All animals, including controls, received 100 mg/kg of piroxicam. 
 .sup.b Represents the mean value --X+ /- the standard error (SE).        
 .sup.c As determined by the Student&#39;s two tailed Ttest for nonpaired data
                                                                          
 
    
     EXAMPLE 2 
     Protective Effect of Various Medicinal Agents on Gastric Lesions in Rats Induced by the Ethanolamine Salt of Piroxicam 
     According to the preceeding Example, gastric ulcers were induced by a single dose of 100 or 120 mg./kg. of the ethanolamine salt of piroxicam. Test groups received various doses of various medicinal agents as shown in Table II. These data show that the test compounds showed a significant reduction in gastric lesions induced by the ethanolamine salt of piroxicam in healthy, fasted rats. 
     
                       TABLE II                                                    
______________________________________                                    
Protective Effect of Various Medicinal Agents                             
on Gastric Lesions Induced by the Ethanolamine                            
Salt of Piroxicam                                                         
           Oral     No. of            Signifi-                            
Medicinal  Dose     Rats in Lesions/Rat                                   
                                      cance                               
Agent      (mg/kg)  Group   (--X+/-SE).sup.b                              
                                      p &lt; 0.05.sup.c                      
______________________________________                                    
(Control).sup.a                                                           
           --       20      6.5 (0.9)                                     
Acetaminophen.sup.a                                                       
           100      20      4.8 (1.0) -                                   
           333      20      0.9 (0.4) +                                   
           1000     20      2.0 (2.3) +                                   
(Control).sup.a                                                           
           --       30      7.7 (1.0)                                     
Doxepin.sup.a                                                             
           1.0      30      4.3 (0.7) +                                   
           3.3      30      3.4 (0.6) +                                   
           10       30      5.1 (0.8) -                                   
(Control).sup.a                                                           
           --       10      6.4 (1.1)                                     
Diazepam.sup.a                                                            
           10       10      5.1 (0.9) -                                   
           33       10      1.5 (0.7) +                                   
(Control).sup.d                                                           
           --       10      7.6 (0.7)                                     
Trimazosin.sup.d                                                          
           3.3      10      5.0 (1.6) -                                   
           10       10      3.9 (1.0) +                                   
           33       10      5.2 (1.3) -                                   
______________________________________                                    
 .sup.a All animals, including controls, received 100 mg/kg of the        
 ethanolamine salt of piroxicam.                                          
 .sup.b Represents the mean value --X +/- the standard error (SE).        
 .sup.c As determined by the Student&#39;s two tailed Ttest for nonpaired data
 .sup.d All animals, including controls, received 120 mg/kg of the        
 ethanolamine salt of piroxicam.                                          
 
    
     EXAMPLE 3 
     Protective Effect of Acetaminophen on Piroxicam-Induced Gastric Lesions in Rats 
     Male rats (Sprague-Dawley) having an average weight of 190 gms. were used in these studies. Animals were fasted overnight and then dosed with test compound suspended in 0.1% methylcellulose. Six and one-half hours after the administration of piroxicam or the combination, the rats were sacrificed in the same order as they were dosed. Their stomachs were excised, rinsed under running water and stored overnight between two saline soaked towels. The next morning the stomachs were evaluated and given an ulcer score. For each lesion a number was assigned according to size and another for intensity. The product of the two numbers is called the intensity factor, and the summation of the intensity factors represented the ulcer score for that stomach. Two separate (one was blind) runs were performed to obtain the data contained in Table III. The data show that acetaminophen attenuated the lesioning effect of 32 mg./kg. of piroxicam in healthy rats and that the protection is dose dependent. 
     Separate studies, in which piroxicam was dosed at 32 mg./kg., p.o. and acetaminophen at 250 mg./kg., p.o. or s.c., demonstrate that acetaminophen had no effect on the plasma levels of piroxicam. 
     Rats pre-dosed with acetaminophen (250 mg./kg., p.o.) at 16 and 3 hours before receiving piroxicam (32 mg./kg., p.o.), were not significantly protected from G.I. lesioning induced by the piroxicam under this protocol. 
     
                       TABLE III                                                   
______________________________________                                    
Dose Response of Acetaminophen With Piroxicam.sup.a                       
Dose of Drug (mg/kg, p.o.)  Mean Ulcer                                    
piroxicam                                                                 
        acetaminophen                                                     
                    Number of Rats                                        
                                Score + S.E.M.                            
______________________________________                                    
 0       0           4          0.0 ± 0.0                              
32       0          16          8.1 ± 0.8                              
                    10          (14.0 ± 1.7)                           
32       50         16          11.1 ± 1.6                             
32      100         16          10.2 ± 1.4                             
                    10          (10.8 ± 0.8)                           
32      200         16          2.7 ± 0.7                              
32      400         16          1.0 ± 0.4                              
 32.sup.b                                                                 
         800.sup.b  16          1.2 ± 0.8                              
0       100          8          0.3 ± 0.2                              
0       320         16          0.7 ± 0.2                              
______________________________________                                    
 .sup.a This study was run blindly, except bracketed data, which was from 
 preliminary, unblinded study.                                            
 .sup.b Several of the rats dosed with 32 mg/kg of piroxicam and 800 mg/kg
 of acetaminophen had stomachs that were slightly distended with gas.     
 
    
     EXAMPLE 4 
     Prophylactic and Therapeutic Effect of Doxepin and Acetaminophen on Gastric Lesions in Rats Induced by the Ethanolamine Salt of Piroxicam 
     Following the method of Examples 1 and 2, with sacrifice 6.5 hours post-dose of 100 mg/kg of the ethanolamine salt of piroxicam, the doxepin or acetaminophen were dosed prophylactically (8-24 hours prior to sacrifice) or therapeutically (1 to 4 hours prior to sacrifice). Results are shown in Table IV. Under this protocol, acetaminophen showed consistent protective activity when dosed 1.5 hours prior to piroxicam administration. 
     
                       TABLE IV                                                    
______________________________________                                    
Prophylactic and Therapeutic Properties of                                
Doxepin and Acetamincphen on Gastric Lesions                              
Induced by the Ethanolamine Salt of Piroxicam.sup.a                       
          Time(hours)                                                     
                     Oral              Signifi-                           
Compound  Prior to   Dose     Lesions/Rat                                 
                                       cance                              
Tested.sup.a                                                              
          Sacrifice  mg/kg    --X± (SE)                                
                                       p &lt; 0.05                           
______________________________________                                    
(Control) --         --       8.8 (2.2)                                   
Doxepin   24         1.0      4.9 (1.5)                                   
                                       -                                  
                     3.3      8.8 (1.6)                                   
                                       -                                  
(Prophylactic-       10.0     4.7 (2.2)                                   
                                       -                                  
prior to  20.5       1.0      7.0 (1.6)                                   
                                       -                                  
piroxicam            3.3      10.5 (2.5)                                  
                                       -                                  
administration)      10.0     7.3 (1.1)                                   
                                       -                                  
          8.0        1.0      4.6 (0.9)                                   
                                       -                                  
                     3.3      4.4 (1.6)                                   
                                       -                                  
                     10.0     5.2 (1.0)                                   
                                       -                                  
(Control) --         --       7.3 (1.2)                                   
Doxepin   4.0        1.0      3.0 (1.1)                                   
                                       +                                  
                     3.3      3.6 (1.1)                                   
                                       +                                  
(Therapeutic-        10.0     3.2 (1.3)                                   
                                       +                                  
after     2.5        1.0      2.2 (0.8)                                   
                                       +                                  
piroxicam            3.3      4.1 (1.3)                                   
                                       -                                  
administration)      10.0     3.1 (0.9)                                   
                                       +                                  
          1.0        1.0      3.5 (1.2)                                   
                                       +                                  
                     3.3      6.6 (1.2)                                   
                                       -                                  
                     10.0     7.0 (1.1)                                   
                                       -                                  
(Control) --         --       6.2 (0.9)                                   
Acetaminophen                                                             
          20.5       100      3.9 (1.1)                                   
                                       +                                  
                     333      9.8 (1.5)                                   
                                       -                                  
(Prophylactic)       1000     12.4 (2.0)                                  
                                       -                                  
          8.0        100      2.7 (1.0)                                   
                                       +                                  
                     333      2.2 (0.8)                                   
                                       +                                  
                     1000     2.9 (1.0)                                   
                                       +                                  
______________________________________                                    
 .sup.a All animals, including controls, received 100 mg/kg of the        
 ethanolamine salt of piroxicam 6.5 hours before sacrifice.               
 
    
     EXAMPLE 5 
     Capsules--Piroxicam (20 mg) and Acetaminophen (1000 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam (milled)   20                                                   
acetaminophen (milled)                                                    
                    1000                                                  
calcium carbonate   250                                                   
polyethylene glycol, average                                              
                    430                                                   
molecular weight, 4000                                                    
______________________________________                                    
 
    
     The mixture is thoroughly blended so as to obtain a uniform powder. Soft gelatin capsules containing 20 mg. of piroxicam and 1000 mg. of acetaminophen are prepared by filling suitably sized capsules with 1700 mg of the blend. 
     To make hard gelatin filled capsules, the amount of inert ingredients is adjusted so as to conveniently fill standard sized gelatin capsules containing the desired amount of each active component. 
     EXAMPLE 6 
     Capsules--Piroxicam (10mg) and Acetaminophen (500 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam ethanolamine salt (milled)                                      
                        11.84 (equiva-                                    
                        lent to                                           
                        10 as                                             
                        free                                              
                        acid)                                             
acetaminophen (milled)  500                                               
corn starch             485.16                                            
magnesium stearate      3                                                 
______________________________________                                    
 
    
     The mixture is thoroughly blended so as to form a uniform powder. The resultant mix is filled into appropriately sized hard gelatin capsules (fill weight 1000 mg) so as to obtain capsules containing the desired potency of each active ingredient. 
     EXAMPLE 7 
     Capsules--Piroxicam (20 mg) and Doxepin (15 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam (milled)   20                                                   
doxepin hydrochloride                                                     
                     16 (equivalent to                                    
                     15 of free base)                                     
polyethylene glycol, average                                              
                     664                                                  
molecular weight, 4000                                                    
______________________________________                                    
 
    
     The mixture is thoroughly blended so as to obtain a uniform powder. The resultant mix (700 mg fill weight) is filled into hard gelatin capsules of a suitable size so as to obtain capsules of the desired potency. 
     EXAMPLE 8 
     Capsules--Piroxicam (20 mg) and Doxepin (50 mg) 
     The following ingredient are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam (milled)    20                                                  
doxepin hydrochloride (milled)                                            
                      53.3 (equiva-                                       
                      lent to 50                                          
                      of free base)                                       
corn starch           633.7                                               
magnesium stearate    3                                                   
______________________________________                                    
 
    
     The mixture is thoroughly blended to form a uniform powder which is filled into size 0 hard gelatin capsules (fill weight 700 mg) to obtain capsules containing the desired potency of each ingredient. 
     EXAMPLE 9 
     Tablets--Piroxicam (20 mg) and Doxepin (20 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam (milled)   20                                                   
doxepin hydrochloride                                                     
                     21.3 (equivalent to                                  
(milled)             20 of free base)                                     
lactose              186.7                                                
hydroxypropyl methylcellulose                                             
                     3                                                    
sodium starch glycollate                                                  
                     15                                                   
magnesium stearate   4                                                    
______________________________________                                    
 
    
     The mixture is thoroughly blended to form a uniform powder. Measured volumes of the powder, corresponding to 250 mg by weight, are compressed into tablets containing the desired potency of each active ingredient. 
     EXAMPLE 10 
     Tablets--Piroxicam (10 mg) and Pirbuterol (25 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam ethanolamine salt                                               
                      23.68 (equivalent                                   
(milled)              to 20 of free                                       
                      base)                                               
pirbuterol acetate    31.28 (equivalent                                   
                      to 25 of free                                       
                      base)                                               
lactose               220.04                                              
hydroxypropyl methylcellulose                                             
                      4                                                   
sodium starch glycollate                                                  
                      16                                                  
magnesium stearate    5                                                   
______________________________________                                    
 
    
     The mixture is thoroughly blended to form a uniform powder. The powder, in measured volumes corresponding to 300 mg. by weight, is compressed into tablets containing the desired potency of each active ingredient. 
     EXAMPLE 11 
     Capsules--Piroxicam (20 mg) and Pirbuterol (20 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam (milled)  20                                                    
pirbuterol dihydrochloride                                                
                    26.1 (equivalent to                                   
(milled)            20 of free base)                                      
cornstarch          652.9                                                 
magnesium stearate  3                                                     
______________________________________                                    
 
    
     The mixture is thoroughly blended so as to obtain a uniform powder. The resultant mix (700 mg fill weight) is filled into hard gelatin capsules of a suitable size so as to obtain capsules of the desired potency. 
     Equivalent proportions of piroxicam ethanolamine salt (23.7) and pirbuterol monoacetate (23.4) are combined with cornstarch and magnesium stearate and filled into hard gelatin capsules in like manner to obtain capsules containing the same potency of each active ingredient. 
     EXAMPLE 12 
     Capsules--Piroxicam (20 mg) and Diazepam (10 mg) 
     The following ingredients are combined in the following proportion by weight: 
     
         ______________________________________                                    
piroxicam ethanolamine salt                                               
                    23.68 equivalent to                                   
                    20 of free acid)                                      
diazepam            10                                                    
calcium carbonate   50                                                    
polyethylene glycol, average                                              
                    166.32                                                
molecular weight, 4000                                                    
______________________________________                                    
 
    
     The mixture is blended to a uniform powder and filled (250 mg fill weight) into hard gelatin capsules of a suitable size to obtain capsules of the desired potencies. 
     EXAMPLE 13 
     Tablets--Piroxicam (10 mg) and Diazepam (5 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
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piroxicam            10                                                   
diazepam             5                                                    
lactose              123                                                  
hydroxypropyl methylcellulose                                             
                     2                                                    
sodium starch glycollate                                                  
                     8                                                    
magnesium stearate   2                                                    
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     The mixture is thoroughly blended to form a uniform powder. Measure volumes of the powder, corresponding to 150 mg by weight, are compressed into tablets containing the desired potency of each active ingredient. 
     EXAMPLE 14 
     Tablets--Piroxicam (20 mg) and Acetaminophen (500 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam            20                                                   
acetaminophen        500                                                  
lactose              1035                                                 
hydroxypropyl methylcellulose                                             
                     10                                                   
sodium starch glycollate                                                  
                     25                                                   
magnesium stearate   10                                                   
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     The mixture is blended to a uniform powder and compressed into tablets in measured volumes corresponding to 1600 mg by weight to yield tablets of the desired potency in each drug. 
     EXAMPLE 15 
     Capsules--Piroxicam (20 mg) and Trimazosin (40 mg) 
     The following ingredients are combined in the following proportions by weight: 
     
         ______________________________________                                    
piroxicam            20                                                   
trimazosin hydrochloride                                                  
                     45 (equivalent to                                    
monohydrate          40 of free base)                                     
cornstarch           632                                                  
magnesium stearate   3                                                    
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     The mixture is thoroughly blended so as to obtain a uniform powder. The resultant mix (700 mg fill weight) is filled into hard gelatin capsules of a suitable size so as to obtain capsules of the desired potency in each drug.