Patent Publication Number: US-2006013896-A1

Title: Methods of treating acute pain using diclofenac

Description:
RELATION TO PRIOR APPLICATIONS  
      The present application is a continuation-in-part of U.S. Ser. No. 09/524,747, filed Mar. 14, 2000 (pending), which is a continuation in part of U.S. Ser. No. 09/192,493, filed Nov. 17, 1998 (abandoned), which is a continuation of PCT/EP97/02709, filed May 15, 1997 with priority claimed to Italian App. No. MI96A000992, filed May 17, 1996. The contents of the foregoing applications are incorporated herein by reference as if fully set forth herein. 
    
    
     FIELD OF INVENTION  
      The present invention relates to new immediate release pharmaceutical compositions containing [(2,6-dichloro-anilino)-2-phenyl]-2-acetic acid (more commonly known as diclofenac) in acid and/or salt form, and therapeutic regimens involving same for the treatment of acute pain.  
     BACKGROUND OF INVENTION  
      Diclofenac is a non-steroidal drug which was invented at the end of the sixties by A. Sallmann and R. Pfister (NL-6,604,752 and U.S. Pat. No. 3,558,690 both to Ciba-Geigy) and whose structural formula is indicated below.  
                 
 
      Diclofenac is widely dispensed and used owing to its well-known analgesic, anti-pyretic, anti-arthritic, anti-phlogistic and anti-rheumatic properties. It is generally taken orally in the form of normal tablets or tablets covered with coatings resistant to gastric juices, or rectally, or by injection, or topically.  
      The possibility of taking it in the form of sweets, tablets dissolving in the mouth, drages, chewing gum or other similar pharmaceutical forms or in formulations for the extemporary preparation of diclofenac-based aqueous solutions and/or suspensions would represent a different mode of administration which is definitely more suitable, especially for children and elderly persons.  
      Owing to its poor solubility in water, diclofenac is normally used in salt form; the salts of diclofenac customarily used are those of sodium, potassium or other alkali and alkaline earth metals, together with salts of organic nature, such as the salts of basic amino acids, such as lysine, arginine and omithine, or other pharmacologically acceptable organic bases which have the ability to render the resulting salt soluble in water.  
      The pharmaceutical compositions of the diclofenac salts for oral use are generally accompanied by side effects of not inconsiderable consequence: Diclofenac salts are in fact characterised by a particularly unpleasant and bitter taste and by the fact that they produce a sensation of strong astringency and cause an especially intense form of irritation in the buccal cavity, especially in the area of the larynx.  
      Although the first problem has been partly solved by using flavorings which are able in some manner to mask the taste, satisfactory solutions have still not been proposed for the two remaining problems.  
      Therefore, the pharmaceutical compositions containing diclofenac salts still have a poor palatability which limits their adoption and possible fields of application, despite the excellent therapeutic effect with which they are associated.  
      A second problem connected to diclofenac is that, when it is orally administered by means of immediate release formulations, the corresponding T max  (the time to the maximum plasma concentration) is usually located at about 1 hour since administration, this being of course a not completely satisfactory result when a prompt and strong analgesic/anti-pyretic effect is sought for. Furthermore, the corresponding coefficient of variation is normally in the range of 70-90%, which means that the T max  is strongly variable and dependent on the physical characteristics of the patient (Physicians&#39; Desk Reference, 52 edition, 1998, page 1831). Attempts are therefore still being made in order to enhance the rate of absorption of diclofenac and to provide an earlier onset of the therapeutic effect (N. Davies, K. Anderson; Clinical Pharmacokinetics of Diclofenac, Clin. Pharmacokinet., 1997, September. 33(3)).  
      The object of the present invention is therefore that of providing a fully palatable formulation of diclofenac which is able to generate a more rapid, uniform and foreseeable release of the active principle if compared to the compositions known in the art and presently available on the market. For the purposes of the present invention T max  means the time to the maximum plasma concentration whereas C max  is the maximum plasma concentration of the active principle, namely diclofenac.  
     DISCUSSION  
      It has now been found that, by adding alkali metal bicarbonates or mixtures thereof to the diclofenac in its acid and/or salt form, preferably in amounts of from 20 to 80% by weight based on the acid-form of diclofenac, pharmaceutical compositions can be obtained which are substantially free from the side effects mentioned above. The first object of the present invention is therefore represented by a pharmaceutical formulation for oral use containing diclofenac in acid and/or salt form together with alkali metal bicarbonates or mixtures thereof and customary excipients and adjuvants, wherein said alkali metal bicarbonates are preferably present in amounts of from 20 to 80% by weight based on the weight of diclofenac.  
      It has in fact been surprisingly demonstrated that the use of alkali metal bicarbonates in the above-mentioned ratio permits to achieve constant, reproducible and foreseeable blood levels of the active ingredient, with the consequent indisputable advantages from the therapeutic point of view; furthermore, it has also been found that the combined use of diclofenac together with alkali metal bicarbonates yields diclofenac-based pharmaceutical compositions in which the active ingredient is released more rapidly compared with normal formulations, bringing about higher blood levels and therefore a more immediate therapeutic effect; finally the so-obtained immediate release formulations are substantially palatable and free from aftertaste.  
      According to the preferred embodiment of the present invention, the amount of alkali metal bicarbonates to be added is comprised between 40 and 80% by weight, based on the weight of the acid-form diclofenac, whereas the alkali metal bicarbonates are selected from sodium and/or potassium bicarbonates, diclofenac being normally present in the form of its sodium and/or potassium salts. In various further embodiments, alkali metal carbonates and bicarbonates are employed in a weight ratio relative to the diclofenac of greater than about 1:5, 2:5, 2:1, 3:1 or 5:1. If desired, an upper limit on the buffer:diclofenac ratio can be placed at about 20:1, 10:1, 5:1, 1:1, 4:5 or 3:5. Ranges can be selected from any two of the foregoing values that are mathematically possible. In a preferred embodiment, the buffer:diclofenac weight ratio ranges from about 1:5 to about 4:5.  
      Although the compositions of the present invention are useful in chronic pain conditions such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis; and periarticular disorders such as bursitis and tendonitis; they are particularly useful in the treatment of acute pain conditions, including soft tissue disorders such as sprains and strains, migraine attacks, and other painful conditions such as renal colic, acute gout, dysmenorrhoea, and following some surgical procedures.  
      It has also been found, and forms a second subject of the present invention, that the addition of flavoring substances selected from mint, aniseed, ammonium glycyrrhizinate and mixtures thereof to the compositions containing the diclofenac salts and alkali metal bicarbonates produces a synergistic effect which completely eliminates all the above-mentioned palatability/astringency effects, providing pharmaceutical compositions which are entirely palatable (and/or drinkable in the case of those used for the preparation of solutions and/or suspensions) and free from aftertaste.  
      The flavoring substances may be used as such or supported on inert materials, for example maltodextrin, in order to obtain a better distribution of the granulates and to facilitate excellent dispersibility of the flavoring in solution. Preferably, they are absorbed on maltodextrin with a power of 1 to 2000 and 1 to 1000.  
      The amount of flavoring substances in its pure form is also preferably from 1/5 to 3 times the weight of the acid-form diclofenac.  
      These flavoring substances are used in the implementation of the present invention without altering their organoleptic properties and without depriving them of their intrinsic qualities of flavorings which are liposoluble and generally oily in the pure state.  
      As it will be clear from the examples, the immediate release formulations for oral use of the present invention containing from 10 to 60 mg of diclofenac in acid and/or salt form together with alkali metal bicarbonates or mixtures thereof in amounts of from 20 to 80% by weight based on the weight of diclofenac permit to generate in human patients an average C max  of diclofenac comprised between 400 and 2500 ng/ml independently on the age, sex or weight of the patients themselves.  
      Secondly, the formulations according to the present invention permit to obtain in humans an average T max  of Diclofenac after 5-30 minutes since administration, generally 13-27, independently on the amount of diclofenac contained therein and also independently on the age, sex, weight of the patient.  
      Furthermore, the T max  of the formulations of the present invention show a coefficient of variation which is about 44-86% lower than the presently marketed formulations; this is evidently an extremely important result from the clinical point of view as it is now possible to have a therapeutic effect of diclofenac which is foreseeable, reproducible and independent of the sex, weight and health conditions of the patient.  
      Thus, the presently claimed diclofenac-based formulations permit to achieve a higher C max  in a shorter T max  and with a lower coefficient of variation if compared to the formulations available on the market, with therapeutic advantages which do not need to be commented.  
      Preferred Cmax and Tmax ranges for various formulations of the invention are set forth below in Table 1:  
                       TABLE 1                           Mean C max  (ng/ml)   Mean T max  (min)                    50 mg.   1500-2100; 1750-2000; 1600-1900   5-35; 10-30;       diclofenac       12-25; 15-20       tablet         25 mg.   700-1150; 750-950; 800-900;   5-35; 10-30;       diclofenac   850-1050; 900-1000   15-30; 15-25       tablet       12.5 mg.   350-650; 400-600; 450-550   5-35; 10-30; 15-25       diclofenac       tablet         50 mg.   1450-1850; 1500-2000; 1500-1750;   5-35; 8-20; 10-18       diclofenac   1900-2500; 2000-2400;       K powder   2100-2300       sachet                  
 
      The amount of diclofenac used in the unit dosage forms of the present invention is preferably 12.5, 25, 50, 75 or 100 mg. According to the best mode for carrying out the present invention the pharmaceutical formulations will contain from 10 to 60 mg/dose of diclofenac in its potassium or sodium salt form together with 40 to 80% by weight of potassium or sodium bicarbonate based on the weight of diclofenac in its acid form, together with the usual excipients and adjuvants; even more preferably they will packaged as: 
          a sachet or tablet formulation containing 50 mg of diclofenac potassium salt and 22 mg of potassium bicarbonate, or a sachet or tablet containing 100 mg., 75 mg., 25 mg. or 12.5 mg of diclofenac potassium and potassium bicarbonate in an amount of 44 wt. % based on the weight of the diclofenac.     a sachet or tablet formulation containing 50 mg of diclofenac sodium salt and 19 mg of sodium bicarbonate, or a sachet or tablet containing 100 mg., 75 mg., 25 mg. or 12.5 mg of diclofenac sodium and sodium bicarbonate in an amount of 38 wt. % based on the weight of the diclofenac.        

      It will be by the way evident to any skilled in this art that the present formulations can also be used as immediate release layers of multilayered release pharmaceutical formulations containing diclofenac as one of the active ingredients; said formulations are therefore a further object of the present invention.  
    
    
     EXAMPLES  
      The following Examples are given purely by way of non-limiting illustration.  
     Example 1  
     Composition Dissolving Instantly in Water  
     
       
         
           
               
               
             
               
                   
               
               
                   
               
               
                 Active ingredients 
                   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 1) 
                 Diclofenac potassium salt*: 
                 50 
                 mg 
               
               
                 2) 
                 Potassium bicarbonate: 
                 22 
                 mg 
               
               
                 3) 
                 Mint flavoring on maltodextrin (1:2000)**: 
                 60 
                 mg 
               
               
                 4) 
                 Aniseed flavoring on maltodextrin (1:1000)***: 
                 104 
                 mg 
               
               
                   
                 Excipients and adjuvants 
               
               
                 5) 
                 Saccharin: 
                 4 
                 mg 
               
               
                 6) 
                 Aspartame: 
                 10 
                 mg 
               
               
                 7) 
                 Mannitol: 
                 50 
                 mg 
               
               
                 8} 
                 Saccharose****q.s.: 
                 2 
                 g 
               
               
                   
               
               
                   *If it is desired to prepare compositions based on diclofenac sodium salt, it is advantageous to use sodium bicarbonate in a quantity of approximately 38% by weight based on the weight of the diclofenac sodium salt present.    
               
               
                   Sodium carbonate may also be added to the sodium bicarbonate, maintaining the following optimum proportions: 27% of sodium bicarbonate and 4-5% of sodium carbonate, always based on the amount by weight of diclofenac sodium salt present.    
               
               
                   **The title of the pure mint essence, as obtained according to the Dean-Stark method, is of 18% by weight; the related amount is therefore in this case of 10.8 mg.    
               
               
                   ***The title of the pure anise essence, as obtained according to the Dean-Stark method, is of 14.5% by weight, the related amount is therefore in this case of 16 mg.    
               
               
                   ****The presence of saccharose is not strictly necessary; in its absence, a composition having a very limited granulate content is obtained which is perfectly 20 soluble in contact with water. In that case, nothing is changed from the point of view of tolerability in contact with the mucosa and. from the point of view of the palatability of the drinkable solution.    
               
            
           
         
       
     
      Preparation  
      Components 1, 2, 5, 6 and 7 are mixed in a suitable mixer, and the mixture so obtained is wetted with 95% ethanol. Granulation is carried out with a 66 mm mesh and the granulate is preferably dried in current of air.  
      Components 3, 4 and 8, which have already been granulated using a mesh of the same granulometry, are then added and the whole is mixed.  
      The mixture is then introduced into a metering machine for filling packets or similar containers.  
     Example 2  
     Tablet for Dissolving in the Mouth  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Active ingredients 
                   
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 1) 
                 Diclofenac potassium salt*: 
                  50 mg 
               
               
                   
                 2) 
                 Potassium bicarbonate: 
                  35 mg 
               
               
                   
                 3) 
                 Mint flavoring on maltodextrin** 
                  50 mg 
               
               
                   
                   
                 (1:2000) + gum arabic (E 414): 
               
               
                   
                 4) 
                 Aniseed flavoring (1:1000) 
                 120 mg 
               
               
                   
                   
                 on maltodextrin*** + silicon 
               
               
                   
                   
                 dioxide(E551): 
               
               
                   
                   
                 Excipients and adjuvants 
               
               
                   
                 5) 
                 Saccharin: 
                  50 mg 
               
               
                   
                 6) 
                 Aspartame: 
                  12 mg 
               
               
                   
                 7) 
                 Mannitol: 
                  20 mg 
               
               
                   
                 8) 
                 Saccharose****: 
                 300 mg 
               
               
                   
                   
               
               
                   
                   *to **** see Example 1    
               
            
           
         
       
     
     Example 3  
     Gum Tablet  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 Active ingredients 
                   
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 1) 
                 Diclofenac potassium salt*: 
                   50 mg 
               
               
                   
                 2) 
                 Potassium bicarbonate: 
                   35 mg 
               
               
                   
                 3) 
                 Mint flavoring on maltodextrin**: 
                   30 mg 
               
               
                   
                 4) 
                 Aniseed flavoring on maltodextrin***: 
                   80 mg 
               
               
                   
                   
                 Excipients and adjuvants 
               
               
                   
                 5) 
                 Mannitol: 
                   30 mg 
               
               
                   
                 6) 
                 Menthol: 
                 0.01 mg 
               
               
                   
                 7) 
                 Gum base: 
                  600 mg 
               
               
                   
                 8) 
                 Sorbitol: 
                  700 mg 
               
               
                   
                 9) 
                 Saccharin: 
                   3 mg 
               
               
                   
                 10) 
                 Hydroxypropylmethylcellulose: 
                   33 mg 
               
               
                   
                 11) 
                 Coloring agent: 
                   7 mg 
               
               
                   
                   
               
               
                   
                   *to *** see Example 1    
               
            
           
         
       
     
     Example 4  
     Comparative Test  
      The packaged composition containing 50 mg of diclofenac potassium of Example 1 (formulation C) was subjected to a pharmacokinetic test for comparison with a similar composition not containing alkali metal carbonates and bicarbonates (formulation B), and with a second composition in tablet form (formulation A) produced by Ciba-Geigy (Voltaren Rapid®), also in this case not containing alkali metal carbonates and bicarbonates, both formulations A and B containing 50 mg of diclofenac potassium.  
      This comparative evaluation was carried out on the same 6 healthy volunteers in accordance with the experimental plan described hereinafter. 
          Experimental scheme: Single-dose study using three methods in randomized 15 cross-over with a wash-out of three days.     Sampling times: 0 h (before administration), 5 min, 10 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, after each administration.     Blood sample treatment: 8MI in heparinised test tubes, centrifugation for 15 min at 1500 rev/min, subdivided into two fractions and subsequently frozen at −200 C.     Times: wash-out of two days between treatments.     Determination method: HPLC, with internal standard, sensitivity 10 ng/ml        

      Analysis Method 
          Column: Nova Pak C18, 3.9×150 mm, 4 um Waters S.p.A.—Vimodrone, Italy.     Eluant: NaH2PO4 0.01 M+0.1% TEA, pH 3.0 (H3PO4)/acetonitrile, 60/40.     Flow: 1.2 ml/min     Detection: UV/275 nm     Temperature: 30° C.     Injection: 50 al     Analysis time: 16 min.        

      Sample Preparation  
      10 al of the internal standard methanolic solution, and flufenamic acid (corresponding to 1320 ng) are added to 1 ml of defrosted plasma in 10 ml glass test tubes. The tubes are agitated in a Vortex mixer for 1 minute. 0.5 ml of a 0.5N HCl/1N NaCl solution is added. The whole is agitated in a Vortex mixer for 1 minute. 6 ml of a 95/5 n-hexane/isopropanol solution are added.  
      The mixture is then agitated in the Vortex mixer for a further 15 minutes. Centrifugation is carried out at 3000 rev/min for 15 minutes and the organic phase is transferred to fresh 10 ml glass test tubes and evaporated to dryness in a centrifugal evaporator under vacuum at ambient temperature. The whole is taken up in 200 al of a 70/30 acetonitrile/water solution, and the precipitate is dissolved under ultrasound for 2 minutes.  
       FIGS. 1, 2  and  3  show the concentrations of diclofenac in the blood of the six volunteers as regards formulations A, B (Ciba-Geigy comparative formulations) and C (formulation corresponding to the composition of Example 1), respectively.  
      As will be appreciated, the blood concentration of the formulation of the present invention has, compared with the comparative formulations, a more constant and uniform pattern. This characteristic is also found in  FIGS. 4, 5  and  6  which show the average values corresponding to the blood levels of the six volunteers together with the corresponding standard deviation.  
      The result is clear and surprising: compared with the sample compositions, the compositions of the present invention permit constant, reproducible and foreseeable blood levels of the active ingredient, irrespective of the characteristics of the volunteer (weight, age, etc), with the consequent indisputable advantages from the therapeutic point of view.  
      Finally,  FIG. 7  shows, by comparison, the graphs relating to the average values of the six volunteers (that is to say, the preceding  FIGS. 4, 5  and  6 ); as will be noted, the formulation of the present invention permits, in addition to the advantages already mentioned, the attainment of a blood peak higher than that of the other formulations.  
     Example 5  
     Two Layered Tablet (Fast and Slow Release)  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                 Fast release layer 
                   
               
               
                   
                  1) Diclofenac potassium salt: 
                   15 mg 
               
               
                   
                  2) Potassium bicarbonate: 
                   30 mg 
               
               
                   
                  3) Lactose: 
                 13.2 mg 
               
               
                   
                  4) Maize starch (intragranular): 
                   6 mg 
               
               
                   
                  5) Methyl cellulose: 
                 0.12 mg 
               
               
                   
                  6) Sodium laurylsulfate: 
                 0.06 mg 
               
               
                   
                  7) Maize starch (extragranular): 
                   9 mg 
               
               
                   
                  8) Crospovidone: 
                  0.6 mg 
               
               
                   
                  9) Sodium carboxymethylstarch: 
                  1.5 mg 
               
               
                   
                 10) Magnesium stearate: 
                  2.7 mg 
               
               
                   
                 11) Colloidal silicon dioxide: 
                  0.6 mg 
               
               
                   
                 Slow release layer 
               
               
                   
                  1) Diclofenac potassium salt: 
                   70 mg 
               
               
                   
                  2) Potassium bicarbonate: 
                 30.8 mg 
               
               
                   
                  3) Lactose: 
                 32.2 mg 
               
               
                   
                  4) Polyvinylpyrrolidone: 
                 1.16 mg 
               
               
                   
                  5) Hydroxypropylmethylcellulose: 
                   70 mg 
               
               
                   
                  6) Magnesium stearate: 
                 0.84 mg 
               
               
                   
                  7) Colloidal silicon dioxide: 
                 0.21 mg 
               
               
                   
                  8) Talc: 
                 3.92 mg 
               
               
                   
                  9) Polyethylene glycol: 
                 0.56 mg 
               
               
                   
                   
               
            
           
         
       
     
     Example 6  
     Drops  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                 1) Diclofenac potassium salt: 
                   75 g 
               
               
                   
                 2) Methyl p-oxybenzoate: 
                  2.7 g 
               
               
                   
                 3) Propyl p-oxybenzoate: 
                  0.3 g 
               
               
                   
                 4) Aspartame: 
                  37.5 g 
               
               
                   
                 5) Potassium bicarbonate: 
                  37.5 g 
               
               
                   
                 6) Glycerol: 
                   300 g 
               
               
                   
                 7) Ethyl alcohol: 
                   450 g 
               
               
                   
                 8) Water q.s.: 
                  1500 g 
               
               
                   
                 Possible modifications: 
               
               
                   
                 a) Addition of sodium metabisulfite (0.06%) 
               
               
                   
                 b) Addition of sodium metabisulfite (0.06%) 
               
               
                   
                    Mint flavoring (1.25%) 
               
               
                   
                    Strawberry flavoring (0.75%) 
               
               
                   
                   
               
            
           
         
       
     
     Example 7  
     Drops  
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                 1) Diclofenac potassium salt: 
                  37.5 g 
               
               
                   
                 2) Methyl p-oxybenzoate: 
                  2.7 g 
               
               
                   
                 3) Propyl p-oxybenzoate: 
                  0.3 g 
               
               
                   
                 4) Aspartame: 
                  37.5 g 
               
               
                   
                 5) Potassium bicarbonate: 
                 18.75 g 
               
               
                   
                 6) Saccharin: 
                  6.0 g 
               
               
                   
                 7) Glycerol: 
                   300 g 
               
               
                   
                 8) Ethyl alcohol: 
                   450 g 
               
               
                   
                 9) Water q.s.: 
                  1500 g 
               
               
                   
                 Possible modifications: 
               
               
                   
                 a) Addition of sodium metabisulfite (0.03%) 
               
               
                   
                 b) Addition of sodium metabisulfite (0.03%) 
               
               
                   
                    Mint flavoring (1.25%) 
               
               
                   
                    Strawberry flavoring (0.75%) 
               
               
                   
                   
               
            
           
         
       
     
     Example 8  
     Mouthwash  
     
       
         
           
               
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                  1) Diclofenac potassium salt: 
                 0.75 
                 g 
               
               
                   
                  2) Glycerol: 
                 50 
                 g 
               
               
                   
                  3) Sorbitol: 
                 12 
                 g 
               
               
                   
                  4) Saccharin: 
                 0.5 
                 g 
               
               
                   
                  5) Aspartame: 
                 1.0 
                 g 
               
               
                   
                  6) Methyl p-oxybenzoate: 
                 0.5 
                 g 
               
               
                   
                  7) Propyl p-oxybenzoate: 
                 0.1 
                 g 
               
               
                   
                  8) Mint flavoring: 
                 1.0 
                 g 
               
               
                   
                  9) Ethyl alcohol: 
                 100 
                 g 
               
               
                   
                 10) Potassium bicarbonate: 
                 0.33 
                 g 
               
               
                   
                 11) Water q.s.: 
                 500 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
     Example 9  
     Gum-Paste  
     
       
         
           
               
               
               
             
               
                   
               
               
                   
               
             
            
               
                  1) Diclofenac potassium salt: 
                 5.0 
                 g 
               
               
                  2) Glycerol: 
                 630 
                 g 
               
               
                  3) Sodium benzoate: 
                 5.0 
                 g 
               
               
                  4) Silica (Wessalon S ® - Degussa): 
                 120 
                 g 
               
               
                  5) Silica (Siddent 9 ® - Degussa): 
                 80 
                 g 
               
               
                  6) Cellulose gum: 
                 3.0 
                 g 
               
               
                  7) Polyethyleneglycol 600: 
                 30 
                 g 
               
               
                  8) Sodium lauroyl sarcosinate (or sodium lauryl sulfate): 
                 60 
                 g 
               
               
                  9) Mint flavoring: 
                 10 
                 g 
               
               
                 10) Sodium saccharin: 
                 1.0 
                 g 
               
               
                 11) Aspartame: 
                 3.0 
                 g 
               
               
                 12) Potassium bicarbonate: 
                 2.2 
                 g 
               
               
                 13) Water q.s.: 
                 1 
                 kg 
               
               
                   
               
            
           
         
       
     
     Example 10  
     Tooth-Paste  
     
       
         
           
               
               
               
             
               
                   
               
               
                   
               
             
            
               
                  1) Diclofenac potassium salt: 
                 5.0 
                 g 
               
               
                  2) Glycerol: 
                 630 
                 g 
               
               
                  3) Sodium benzoate: 
                 5.0 
                 g 
               
               
                  4) Silica (Wessalon S ® - Degussa): 
                 20 
                 g 
               
               
                  5) Silica (Siddent 9 ® - Degussa): 
                 80 
                 g 
               
               
                  6) Cellulose gum: 
                 3.0 
                 g 
               
               
                  7) Polyethylenglycol 600: 
                 30 
                 g 
               
               
                  8) Sodium lauroyl sarcosinate (or sodium lauryl sulfate): 
                 60 
                 g 
               
               
                  9) Mint flavoring: 
                 10 
                 g 
               
               
                 10) Sodium saccharin: 
                 1.0 
                 g 
               
               
                 11) Aspartame: 
                 3.0 
                 g 
               
               
                 12) NaF: 
                 1.0 
                 g 
               
               
                 13) Na 2 FPO 3   
                 4.0 
                 g 
               
               
                 14) Potassium bicarbonate: 
                 2.2 
                 g 
               
               
                 15) Water q.s.: 
                 1 
                 kg 
               
               
                   
               
            
           
         
       
     
     Example 11  
     Tablet  
     
       
         
           
               
               
               
               
             
               
                   
                   
               
               
                   
                   
               
             
            
               
                   
                  1) Diclofenac potassium salt: 
                 50 
                 mg 
               
               
                   
                  2) Mannitol: 
                 50 
                 mg 
               
               
                   
                  3) Potassium bicarbonate: 
                 22 
                 mg 
               
               
                   
                  4) Maize starch (intragranular): 
                 10 
                 mg 
               
               
                   
                  5) Methyl cellulose: 
                 0.2 
                 mg 
               
               
                   
                  6) Sodium laurylsulfate: 
                 0.1 
                 mg 
               
               
                   
                  7) Maize starch (extragranular): 
                 15 
                 mg 
               
               
                   
                  8) Crospovidone: 
                 1.0 
                 mg 
               
               
                   
                  9) Sodium carboxymethylstarch: 
                 2.5 
                 mg 
               
               
                   
                 10) Magnesium stearate: 
                 4.5 
                 mg 
               
               
                   
                 11) Colloidal silicon dioxide: 
                 10 
                 mg 
               
               
                   
                   
               
            
           
         
       
     
     Example 12  
     Comparative Test  
      In the present experiment a sachet formulation containing 50 mg of diclofenac potassium was compared to a bioequivalent sugar coated fast release tablet also containing 50 mg of diclofenac potassium, produced and marketed in Italy by Novartis as Cataflam®.  
      The sachet formulation according to the present invention had the following composition:  
                                                          1) diclofenac potassium salt:   50   mg           2) Potassium bicarbonate:   22   mg           3) Mint flavor:   50   mg           4) Anice flavor:   100   mg           5) Saccharin sodium:   4   mg           6) Aspartame:   10   mg           7) Mannitol:   50   mg           8) Sucrose sugar crystals:   1714   g                      
 
      The above test formulation and the Cataflam® formulation were administered as a single dose to 24 healthy volunteers of both sexes. The pharmacokinetic parameters obtained with the two different formulations are reported in table 1 and in  FIG. 5 . As it will be easily appreciated, the rate of absorption was considerably faster with the sachet formulation of the present invention than with Cataflam®, the sachet formulation having a higher average C max  (2213 vs 1071 ng/ml) and a shorter average T max  (0.228 vs 0.885 hours); furthermore, the T max  of the sachet formulation shows a coefficient of variation lower than the reference formulation (16% vs 97%), this being an extremely important result from the clinical point of view regarding the healing of the pain in terms of quick time and repeatability inter-subjects in order to reach the C max .  
     Example 13  
     Comparative Test  
      Following to the excellent results obtained in example 12, two tablet formulations containing 12.5 or 25 mg. of diclofenac sodium salt and potassium bicarbonate (in the same weight ratio) have been prepared.  
      The tablet formulations had the following composition (in mg):  
                                                          Cores                   Diclofenac sodium   12.5   25           Mannitol   25   50           Lactose monohydrate   23.75   47.5           Potassium bicarbonate   5.5   11           Maize starch   22.5   45           Methylcellulose   0.075   0.15           Sodium laurylsulphate   0.125   0.25           Crospovidone   3   6           Ultramyl   5   10           Colloidal silica   0.55   1.1           Cellulose microcrystalline   0.5   1           Magnesium stearate   1.5   3           Purified water q.s.   100   200           Coating           Opadry OY-3 5009 red   2   4           Macrogol 400   0.25   0.5                      
 
      A four-way comparative bioavailability study was carried out on 18 healthy volinteers of both sexes in order to evaluate the in vivo results of the pharmacokinetic profiles of the present formulations if compared to those of bioequivalent fast release formulations such as Cataflam® (25 mg of diclofenac potassium) and Voltarol® (50 mg of diclofenac sodium), both by Novartis. The results, which are summarized in  FIG. 6 , indicate that T max  is prompter with the present formulations (T1=26 min, T2=24.6 min vs R1=71.4 min and R2=40.8 min) and that C max  is higher (T1=847 ng/ml and T2=861 ng/ml vs R1=452 ng/ml and R2=703 ng/ml); furthermore, the T max  of both present formulations shows a coefficient of variation lower than reference formulations (T1=46% and T2=49% vs R1=87% and R2=96%).  
     Example 14  
     Comparative Test  
      A further comparative test was carried out on immediate release formulations according to the present invention, containing 50 mg of diclofenac potassium and 22 mg of potassium bicarbonate, manufactured with different that is, respectively: T1=wet granulation using alcohol, T2=dry granulation by direct compression. The composition in mg of the two formulations is herebelow reported:  
                                                          Diclofenac potassium   50   50           Potassium bicarbonate   22   22           Mannitol/pearlitol 400 DC   119.9           Mannitol EP cf       50           Maize starch       25           Methocel A4C       0.2           Sodium laurylsulphate   0.1   0.1           Polyplasdone XL   6   1           Ultramyl       2.5           Magnesium stearate   2   4.5           Silicium aerosil       1           Core mass   200   156.3                      
 
      A comparative bioavailabilty study was carried out on 6 healthy volunteers of both sexes in order to evaluate the in vivo results of the pharmacokinetic profiles of the present formulations if compared to those of a bioequivalent fast release formulation such as Voltaren Rapid® (50 mg of diclofenac potassium), both by Novartis. The results, which are reported in  FIGS. 7-10  are also in this case excellent: the T max  is in fact prompter with the present formulations (T1=18.6 min, T2=16.8 min vs R1 40.8 min) and the C max  is higher (T1=1878.3 ng/ml and T2=1744.8 ng/ml vs R1 1307 ng/ml); furthermore, also in this case the T max  of both present formulations shows a coefficient of variation lower than reference formulation (T1=12.9% and T2=25% vs R1=95.6%).  
     Example 15  
     50 mg. Diclofenac K Tablet Comparison  
     
         
          Test Formulations: 
        T1: Diclofenac potassium 50 mg film-coated tablets, alcohol granulation     T2: Diclofenac potassium 50 mg film-coated tablets, dry granulation    
     
          Reference Formulation: Diclofenac potassium, 50 mg film-coated tablets, Voltarene® Rapid by Novartis Pharma  
          Study design: Single dose, 3-way, crossover randomised on 6 healthy volunteers  
          Blood samples drawn: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 8, 10, 12 h  
       
    
      Assay: LC-MS-MS //LOQ 5 ng/ml  
                                                          Reference, K salt, 50 mg,           T1, K salt, 50 mg, tablets   T2, K salt, 50 mg, tablets   Voltaren ® Rapid tablets               Description   Diclofenac potassium   Diclofenac potassium   Diclofenac potassium           50 mg film-coated tablets   50 mg film-coated tablets   50 mg film-coated tablets           (by alcoholic granulation)   (by direct compression)       Active   Diclofenac potassium mg 50   Diclofenac potassium mg 50   Diclofenac potassium mg 50       ingredient       Excipients   Potassium bicarbonate mg 22   Potassium bicarbonate mg 22   Calcium phosphate           Mannitol mg 50   Mannitol 400 mg 119.9   Saccharose           Maize starch mg 25   Sodium laurylsulfate mg 0.1   Maize starch           Hydroxypropylmethylcellulose mg 0.2   Polyvinylpyrrolidone mg 6   Talc           Sodium laurylsulfate mg 0.1   Magnesium stearate mg 2   Sodium carboxymethylcellulose           Polyvinylpyrrolidone mg 1   Film Coating Opadry Clear   Colloidal anhydrous silicium           Sodium starch glycollate mg 2.5   (HPMC 2910,   Polyvinylpyrrolidone           Magnesium stearate mg 4.5   polyethyleneglycol 400) mg 4   Microcrystalline cellulose           Silicium aerosil FK 160 mg 1       Magnesium stearate           Coating Opadry Clear (HPMC 2910       Polyethylenglycole           and polyethyleneglycol 400) mg 4       Titanidioxide (E171)                   Iron oxide red (E172)       Total weight   160.3 mg   204 mg                                 PK results                                                 Test 1 (K, tablets 50 mg)   Test 2 (K, tablets 50 mg)   Reference (K, tablets 50 mg)                       C max     Mean   1873.30   1744.8   1307.0               SD   553.80   572.3   558.4               CV %   29.5   32.8   42.7               Min   1228.9   1057.4   581.8               Max   2516.5   2468.9   1935.5           AUC   Mean   1219   1237   1168               SD   246   276   282               CV %   20.2   22.3   24.1               Min   874   848   913               Max   1615   1668   1642           t max     Mean   0.31 h (18.6 min)   0.28 h (16.8 min)   0.68 h (40.8 min)               SD   0.04   0.07   0.65               CV %   12.9   25.0   95.6               Min   0.25 h (15 min)     0.17 h (10.2 min)   0.25 h (15 min)                 Max   0.33 h (19.8 min)   0.33 h (19.8 min)   2.00 h (120 min)                       
 
     Example 16  
     50 and 25 mg. Diclofenac K Tablet Comparison  
     
         
          Test Formulations: 
        T1: Diclofenac potassium 25 mg film-coated tablets     T2: Diclofenac potassium 50 mg film-coated tablets    
     
          Reference Formulation: Diclofenac potassium, 50 mg film-coated tablets, Voltarene® Rapid by Novartis Pharma  
          Study design: Single dose, 3-way, crossover randomised on 24 healthy volunteers  
          Blood samples drawn: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 8, 10, 12 h  
       
    
      Assay: LC-MS-MS //LOQ 5 ng/ml  
                                                          Reference, K salt, 50 mg,           T1, K salt, 25 mg, tablets   T2, K salt, 50 mg, tablets   Voltaren ® Rapid tablets               Description   Diclofenac potassium 25 mg film-   Diclofenac potassium 50 mg   Diclofenac potassium 50 mg film-           coated tablets   film-coated tablets   coated tablets       Active   Diclofenac potassium mg 25   Diclofenac potassium mg 50   Diclofenac potassium mg 50       ingredient       Excipients   Potassium bicarbonate mg 11   Potassium bicarbonate mg 22   Calcium phosphate           Mannitol 400, mg 58.2   Mannitol 400, mg 116.4   Saccharose           Sodium laurylsulfate mg 0.05   Sodium laurylsulfate mg 0.1   Maize starch           Polyvinylpyrrolidone mg 3   Polyvinylpyrrolidone mg 6   Talc           Polyethylenglycole mg 0.75   Polyethylenglycole mg 1.5   Sodium carboxymethylcellulose           Magnesium stearate mg 2   Magnesium stearate mg 4   Colloidal anhydrous silicium           Film Coating Opadry Clear (HPMC   Film Coating Opadry Clear   Polyvinylpyrrolidone           2910, polyethyleneglycol 400) mg 2   (HPMC 2910,   Microcrystalline cellulose               polyethyleneglycol 400) mg 4   Magnesium stearate                   Polyethylenglycole                   Titanidioxide (E171)                   Iron oxide red (E172)       Total weight   102 mg   204 mg                                 PK results                                                     T2 (K, film-coated tablets                       T1 (K, tablets 25 mg)   50 mg)   Reference (K, tablets 50 mg)                       C max     Mean   940.2 (1880.4)*   1766.7   1339.6               SD   387.0   1020.2   627.5               CV %   41.2   57.7   46.8               Min   228.5   317.3   336.5               Max   1595.4   4516.9   2655.4           AUC   Mean   611.81 (1223.63)*   1267.67   1286.43               SD   144.76   356.46   351.22               CV %   23.7   28.1   27.3               Min   380.13   681.89   852.09               Max   919.81   2123.22   2185.01           t max     Mean   0.354 h (21.2 min)   0.489 h (29.8 min)   0.847 h (50.8 min)               SD   0.119   0.366   0.887               CV %   33.6   78.8   104.7               Min   0.250 h (15 min)     0.167 h (10 min)     0.333 h (20 min)                 Max   0.750 h (45 min)      1.5 h (90 min)      4 h (240 min)                         *values normalized to the dose of 50 mg             
 
     Example 17  
     25 mg. Diclofenac Na Tablet and Sachet Comparison  
     
         
          Test Formulations: 
        T1: Diclofenac sodium 25 mg sachets     T2: Diclofenac sodium 25 mg film-coated tablets    
     
          Reference Formulation: Diclofenac sodium, 25 mg film-coated tablets, Novapirina® by Novartis Consumer Health  
          Study design: Single dose, 3-way, crossover randomised on 24 healthy volunteers  
          Blood samples drawn: 0 (pre-dose), 10, 20, 30, 45, 60, 75, 90, 105 min, 2, 2.5, 3, 4, 6, 8, 10 h  
       
    
      Assay: LC-MS-MS //LOQ 0.5 ng/ml  
                                                          Reference, Na salt,           Na salt, 25 mg, sachets   Na salt, 25 mg, tablets   Novapirina ® tablets               Description   NA   Diclofenac sodium 25 mg   Diclofenac sodium 25 mg film-               film-coated tablets   coated tablets       Active   NA   Diclofenac sodium 25 mg       ingredient       Excipients   NA   Potassium bicarbonate mg 11   Colloidal silicium               Mannitol SD200, mg 58.25   Cellulose               Sodium laurylsulfate mg 0.25   Lactose               Polyvinylpyrrolidone mg 3   Magnesium stearate               Magnesium stearate mg 1   Polyvidone               Glyceryl Dibehenate mg 1.5   Sodium               Film Coating Opadry Clear   carboxymethylcellulose               (HPMC 2910,   Hydroxypropylmethylcellulose               polyethyleneglycol 400) mg 2   Polysorbate                   Talc                   Titanidioxide (E171)       Total weight   NA   102 mg                                 PK results                                         Test 1 (Na, sachets 25 mg)   Test 2 (Na, tablets 25 mg)   Reference (Na, tablets 25 mg)               C max     Mean   NA   863   554           SD   NA   373   255           CV %   NA   43.2   87           Min   NA   382   222           Max   NA   1620   1360       AUC   Mean   NA   632   581           SD   NA   175   151           CV %   NA   27.7   26           Min   NA   375   355           Max   NA   974   860       t max     Mean   NA   0.32 h (19.2 min)   0.67 h (40.2 min)           SD   NA   0.07   0.62           CV %   NA   21.9   92.5           Min   NA   0.17 h (10.2 min)   0.17 h (10.2 min)           Max   NA   0.50 h (30 min)     2.50 h (150 min)                   
 
     Example 18  
     50 mg. Diclofenac K Tablet Comparison  
     
         
          Test Formulation: Diclofenac potassium 50 mg film-coated tablets  
          Reference Formulation: Diclofenac potassium, 50 mg film-coated tablets, Voltfast® by Novartis Pharma  
          Study design: Single dose, 2-way, crossover randomised on 26 healthy volunteers  
          Blood samples drawn: 0 (pre-dose), 10, 20, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 8, 10, 12 h  
       
    
      Assay: LC-MS-MS //ILOQ 3.3 ng/ml  
                                                  Reference, K salt, 50 mg,           K salt, 50 mg, tablets   Voltfast ® tablets               Description   Diclofenac potassium   Diclofenac potassium 50 mg           50 mg film-coated tablets   film-coated tablets       Active   Diclofenac potassium   Diclofenac potassium mg 50       ingredient   mg 50       Excipients   Potassium bicarbonate   Calcium phosphate           mg 22   Saccharose           Mannitol 400, mg 116.4   Maize starch           Sodium laurylsulfate   Talc           mg 0.1   Sodium carboxymethylcellulose           Polyvinylpyrrolidone   Colloidal anhydrous silicium           mg 6   Polyvinylpyrrolidone           Polyethylenglycole   Microcrystalline cellulose           mg 1.5   Magnesium stearate           Magnesium stearate mg 4   Polyethylenglycole           Film Coating Opadry   Titanidioxide (E171)           Clear (HPMC 2910,   Iron oxide red (E172)           polyethyleneglycol 400)           mg 4       Total weight   204 mg                                 PK result                                     Test (K, tablets 50 mg)   Reference (K, tablets 50 mg)               C max     Mean   1768.6   1386.5           SD   771.6   693.3           CV %   43.6   50.0           Min   514.3   300.2           Max   3726.4   2744       AUC   Mean   1248   1220.2           SD   326   352.7           CV %   26.1   28.9           Min   661.8   609           Max   1918.4   1971.3       t max     Mean   0.455 h (27.3 min)   0.904 h (54.24 min)           SD   0.275   0.838           CV %   60.0   92.7           Min   0.166 h (10 min)     0.333 h (20 min)             Max    1.5 h (90 min)    4.00 h (240 min)                   
 
     Example 19  
     12.5 mg. Diclofenac K Tablet Comparison  
     
         
          Test Formulations: Diclofenac potassium 12.5 mg film-coated tablets  
          Reference Formulation: Diclofenac potassium, 12.5 mg immediate release film-coated tablets, Voltaren Dolo® by Novartis Consumer Health  
          Study design: Single dose, 2-way, crossover randomised on 24 healthy volunteers  
          Blood samples drawn: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 75, 90 min, 2, 3, 4, 5, 6, 8, 12 h  
       
    
      Assay: LC-MS-MS //LOQ 0.2 ng/ml  
                                                  Reference, K salt, 12.5 mg,           K salt, 12.5 mg, tablets   Voltaren Dolo ®               Description   Diclofenac potassium   Diclofenac potassium 12.5 mg           12.5 mg film-coated   film-coated tablets           tablets       Active   Diclofenac potassium   Diclofenac potassium mg 12.5       ingredient   mg 12.5       Excipients   Potassium hydrogen   Colloidal anhydrous silica           carbonate mg 5.50   Lactose           Mannitol mg 76.25   Maize starch           Sodium laurylsulfate   Sodium starch glycollate           mg 0.25   Polyvidone           Glycerol dibehenate   Magnesium stearate           mg 1.50   Microcrystalline cellulose           Crospovidone mg 3.00   Hydroxypropylmethylcellulose           Magnesium stearate   Titanidioxide (E171)           mg 1.00   Macrogol           Film Coating Opadry   Polysorbate 80           Clear (HPMC 2910 and   Maltodextrin           polyethyleneglycol 400)           mg 2.00       Total weight   102.00 mg                                 PK results                                     Test                   (K, tablets 12.5. mg)   Reference (K, tablets 12.5 mg)               C max     Mean   494.09   435.80           SD   223.36   228.92           CV %   45.21   52.53           Min   130.50   162.50           Max   909.10   959.00       AUC   Mean   331.19   330.14           SD   71.42   84.70           CV %   21.56   25.66           Min   172.54   171.38           Max   435.39   445.72       t max     Mean   0.35 h (21 min)     0.48 h (28.8 min)           SD   0.20   0.35           CV %   57.14   72.92           Min   0.17 h (10.2 min)   0.17 h (10.2 min)           Max   1.0 h (60 min)    1.50 h (90 min)                    
 
     Example 20  
     12.5, 25 and 50 mg. Diclofenac K and Diclofenac K Tablet Comparison  
     
         
          Test Formulations: 
        T1: Diclofenac sodium 12.5 mg tablets     T2: Diclofenac sodium 25 mg film-coated tablets    
     
          Reference Formulations:  
          R1: Diclofenac potassium, 25 mg film-coated tablets, Cataflam® by CIBA GEIGY  
          R2: Diclofenac 50 mg dispersible tablets, Voltarol® by CIBA GEIGY  
          Study design: Single dose, 4-way, crossover randomised on 24 healthy volunteers  
          Blood samples drawn: 0 (pre-dose), 5, 10, 15, 20, 30, 45, 60, 90 min, 2, 3, 4, 5, 6, 8, 10 h  
       
    
      Assay: HPLC-UV //LOQ 10 ng/ml  
                                                                  Reference, acid as such,                   Reference, K salt, 50 mg,   50 mg, Voltarol ®           Na salt, 2 × 12.5 mg, tablets   Na salt, 25 mg, tablets   Cataflam ® tablets   dispersible tablets               Description   Diclofenac sodium 12.5 mg   Diclofenac sodium 25 mg   Diclofenac potassium 50 mg   Diclofenac free acid 46.5 mg           film-coated tablets   film-coated tablets   film-coated tablets   dispersible tablets       Active   Diclofenac sodium 12.5 mg   Diclofenac sodium 25 mg   Diclofenac potassium 50 mg   Diclofenac acid 46.5 mg       ingredient               (equivalent to 50 mg as                       sodium salt)       Excipients   Potassium bicarbonate mg 5.5   Potassium bicarbonate   Calcium phosphate   Microcrystalline cellulose           Mannitol mg 25   mg 11   Saccharose   Croscarmellose sodium           Lactose mg 23.75   Mannitol mg 50   Maize starch   Sodium starch glycollate           Maize starch mg 22.5   Lactose mg 47.5   Talc   Sodium saccharin           Cellulose methylether mg   Maize starch mg 45   Sodium   Cellulose           0.075   Cellulose methylether   carboxymethylcellulose   Hydrogenated castor oil           Sodium laurylsulfate mg   mg 0.15   Colloidal anhydrous   Talc           0.125   Sodium laurylsulfate mg   silicium   Silicion dioxide           Polyvinylpyrrolidone mg 3   0.25   Polyvinylpyrrolidone   Erythrosine           Sodium starch glycollate mg 5   Polyvinylpyrrolidone mg 6   Microcrystalline cellulose   Aluminium oxide           Magnesium stearate mg 1.5   Sodium starch glycollate   Magnesium stearate   Blackcurrant flavour           Colloidal hydrated silicium   mg 10   Polyethylenglycole           mg 0.55   Magnesium stearate mg 3   Titanidioxide (E171)           Microcrystalline cellulose mg   Colloidal hydrated   Iron oxide red (E172)           0.5   silicium mg 1.1           Film Coating Opadry Red   Microcrystalline           (HPMC 2910,   cellulose mg 1           polyethyleneglycol 400) mg   Film Coating Opadry           2.25   Red (HPMC 2910,               polyethyleneglycol 400)               mg 4.5       Total weight   102.25   204.5 mg                                 PK results                                                                 Reference 2                       Test 2 (Na, tablets   Reference 1 (K,   (dispersible tablets                   Test 1 (Na, tablets 2 × 12.5 mg)   25 mg)   tablets 25 mg)   50 mg)*                       C max     Mean   847.0   861.3   453.4   351.4               SD   440.7   395.1   265.49   179.4               CV %   0.52   0.46   0.59   0.51               Min   314.4   221.2   1799.9   108.9               Max   1700.9   1569.3   992.3   635.2           AUC   Mean   570.50   565.59   518.46   506.26               SD   126.23   159.77   154.54   161.92               CV %   22   26   30   32               Min   346.13   304.44   322.04   322.71               Max   859.60   911.34   836.58   858.59           t max     Mean   0.44 h (26.4 min)   0.41 h (24.6 min)   1.19 h (71.4 min)   0.68 h (40.8 min)               SD   0.20   0.20   1.03   0.66               CV %   46   49   87   96               Min   0.17 h (10.2 min)   0.17 h (10.2 min)   0.25 h (15 min)     0.17 h (10.2 min)               Max   1.0 h (60 min)    1.00 h (60 min)     4.00 h (360 min)    2.00 h (120 min)                       
 
     
       
         
           
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
               
               
                 Pharmacokinetic parameters for two different diclofenac formulations: test (Diclofenac 
               
               
                 potassium salt sachets) and reference (Diclofenac potassium salt sugar coated tablets) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 t max   
                 C max   
                 t 1/2   
                 AUC 0-1   
               
               
                   
                 (h) 
                 (ng/mL) 
                 (h) 
                 (ng · mL −1 -h) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Vol. No. 
                 Test 
                 Ref. 
                 Test 
                 Ref. 
                 Test 
                 Ref. 
                 Test 
                 Ref. 
               
               
                   
               
               
                 Vol. 1 
                 0.250 
                 0.500 
                 1573.000 
                 1186.211 
                 1.505 
                 0.939 
                 1024.511 
                 885.549 
               
               
                 Vol. 2 
                 0.250 
                 4.000 
                 2382.368 
                 965.100 
                 0.875 
                 1.358 
                 1653.124 
                 2092.036 
               
               
                 Vol. 3 
                 0.184 
                 1.000 
                 2614.655 
                 1352.400 
                 0.796 
                 1.610 
                 1687.529 
                 1763.484 
               
               
                 Vol. 4 
                 0.250 
                 3.000 
                 2404.848 
                 735.454 
                 0.996 
                 1.132 
                 1881.944 
                 1834.958 
               
               
                 Vol. 5 
                 0.250 
                 0.500 
                 2971.457 
                 1405.000 
                 1.667 
                 1.903 
                 1819.756 
                 1687.075 
               
               
                 Vol. 6 
                 0.250 
                 0.750 
                 2158.700 
                 1351.500 
                 0.843 
                 0.650 
                 1197.716 
                 1091.996 
               
               
                 Vol. 7 
                 0.250 
                 0.750 
                 1739.200 
                 1741.717 
                 0.596 
                 0.658 
                 1448.713 
                 1301.887 
               
               
                 Vol. 8 
                 0.250 
                 0.500 
                 1715.350 
                 543.300 
                 0.818 
                 1.111 
                 991.864 
                 1126.414 
               
               
                 Vol. 9 
                 0.250 
                 0.750 
                 444.112 
                 747.800 
                 0.787 
                 1.188 
                 669.084 
                 886.300 
               
               
                 Vol. 10 
                 0.267 
                 0.750 
                 2350.100 
                 1110.400 
                 .0960 
                 1.070 
                 1327.808 
                 1020.286 
               
               
                 Vol. 11 
                 0.167 
                 0.500 
                 1867.200 
                 1465.502 
                 1.141 
                 0.762 
                 1337.821 
                 892.870 
               
               
                 Vol. 12 
                 0.167 
                 0.500 
                 4273.026 
                 1432.200 
                 1.052 
                 0.697 
                 1703.655 
                 1139.003 
               
               
                 Vol. 13 
                 0.250 
                 0.500 
                 2097.089 
                 1155.371 
                 1.313 
                 1.198 
                 1486.526 
                 1233.531 
               
               
                 Vol. 14 
                 0.167 
                 0.250 
                 2242.684 
                 967.795 
                 0.997 
                 0.837 
                 987.522 
                 927.726 
               
               
                 Vol. 15 
                 0.184 
                 0.500 
                 2040.247 
                 1129.957 
                 0.724 
                 0.804 
                 1213.725 
                 1040.424 
               
               
                 Vol. 16 
                 0.250 
                 0.750 
                 2143.692 
                 818.200 
                 0.560 
                 1.199 
                 1186.603 
                 1250.221 
               
               
                 Vol. 17 
                 0.250 
                 1.500 
                 1527.845 
                 480.900 
                 2.752 
                 1.309 
                 958.821 
                 987.797 
               
               
                 Vol. 18 
                 0.250 
                 1.000 
                 1859.608 
                 666.500 
                 1.630 
                 1.383 
                 1131.413 
                 933.008 
               
               
                 Vol. 19 
                 0.250 
                 0.750 
                 1537.508 
                 770.100 
                 1.726 
                 1.137 
                 980.348 
                 906.275 
               
               
                 Vol. 20 
                 0.250 
                 0.250 
                 1956.004 
                 655.100 
                 0.853 
                 0.883 
                 1309.289 
                 1036.836 
               
               
                 Vol. 21 
                 0.250 
                 0.500 
                 3551.360 
                 2421.060 
                 1.322 
                 1.233 
                 2147.217 
                 1639.619 
               
               
                 Vol. 22 
                 0.167 
                 0.500 
                 2464.978 
                 1274.648 
                 0.611 
                 0.624 
                 1038.817 
                 816.924 
               
               
                 Vol. 23 
                 0.167 
                 0.750 
                 2304.351 
                 453.500 
                 2.066 
                 0.862 
                 1161.414 
                 1049.327 
               
               
                 Vol. 24 
                 0.250 
                 0.500 
                 2901.504 
                 894.337 
                 0.970 
                 1.279 
                 1645.384 
                 1086.512 
               
               
                 Mean 
                 0.228 
                 0.885 
                 2213.370 
                 1071.461 
                 1.148 
                 1.076 
                 1332.942 
                 1192.544 
               
               
                 SD 
                 0.038 
                 0.860 
                 743.099 
                 450.780 
                 0.523 
                 0.320 
                 358.048 
                 350.116 
               
               
                 CV % 
                 16.300 
                 97.091 
                 33.573 
                 42.072 
                 45.557 
                 29.700 
                 26.862 
                 29.359 
               
               
                 Min. 
                 0.167 
                 0.250 
                 444.112 
                 453.500 
                 0.560 
                 0.624 
                 669.084 
                 816.924 
               
               
                 Max. 
                 0.267 
                 4.000 
                 4273.026 
                 2421.060 
                 2.752 
                 1.903 
                 2147.217 
                 2092.036 
               
               
                 Geom.Mean 
                 0.225 
                 0.692 
                 2070.719 
                 987.480 
                 1.056 
                 1.032 
                 1287.195 
                 1150.713 
               
               
                 Median 
                 0.250 
                 0.625 
                 2151.196 
                 1039.098 
                 0.983 
                 1.122 
                 1261.507 
                 1067.920 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 AUC 
               
               
                   
                 AUC 0-0   
                   
                 C max /AUC U-o   
                 extrapolated 
               
               
                   
                 (ng · mL −1 -h) 
                 C 1   
                 (h 1 ) 
                 (%) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Vol. No. 
                 Test 
                 Ref. 
                 Test 
                 Ref. 
                 Test 
                 Ref. 
                 Test 
                 Ref. 
               
               
                   
                   
               
               
                   
                 Vol. 1 
                 1050.137 
                 910.868 
                 11.800 
                 18.700 
                 1.498 
                 1.302 
                 2.37 
                 0.00 
               
               
                   
                 Vol. 2 
                 1693.172 
                 2092.036 
                 31.700 
                 13.500 
                 1.407 
                 0.461 
                 1.82 
                 1.38 
               
               
                   
                 Vol. 3 
                 1718.755 
                 1788.111 
                 27.200 
                 10.600 
                 1.521 
                 0.756 
                 0.83 
                 1.15 
               
               
                   
                 Vol. 4 
                 1897.754 
                 1856.346 
                 11.000 
                 13.100 
                 1.267 
                 0.396 
                 1.39 
                 1.88 
               
               
                   
                 Vol. 5 
                 1845.486 
                 1719.478 
                 10.700 
                 11.800 
                 1.610 
                 0.817 
                 1.56 
                 1.90 
               
               
                   
                 Vol. 6 
                 1216.693 
                 1113.146 
                 15.600 
                 22.500 
                 1.774 
                 1.214 
                 2.50 
                 1.79 
               
               
                   
                 Vol. 7 
                 1485.867 
                 1325.661 
                 43.200 
                 25.500 
                 1.170 
                 1.314 
                 1.46 
                 1.78 
               
               
                   
                 Vol. 8 
                 1006.522 
                 1146.775 
                 12.400 
                 12.700 
                 1.704 
                 0.466 
                 3.08 
                 2.75 
               
               
                   
                 Vol. 9 
                 690.354 
                 911.329 
                 18.700 
                 14.600 
                 0.643 
                 0.821 
                 1.74 
                 1.80 
               
               
                   
                 Vol. 10 
                 1351.357 
                 1038.971 
                 17.000 
                 12.100 
                 1.739 
                 1.069 
                 3.01 
                 3.01 
               
               
                   
                 Vol. 11 
                 1379.311 
                 920.579 
                 25.200 
                 25.200 
                 1.354 
                 1.592 
                 1.62 
                 2.03 
               
               
                   
                 Vol. 12 
                 1731.709 
                 1162.638 
                 18.500 
                 23.500 
                 2.468 
                 1.232 
                 1.26 
                 1.56 
               
               
                   
                 Vol. 13 
                 1505.454 
                 1253.088 
                 10.000 
                 11.300 
                 1.393 
                 0.922 
                 2.58 
                 2.26 
               
               
                   
                 Vol. 14 
                 1013.665 
                 949.163 
                 18.200 
                 17.700 
                 2.212 
                 1.020 
                 1.91 
                 2.86 
               
               
                   
                 Vol. 15 
                 1237.399 
                 1071.029 
                 22.700 
                 126.400 
                 1.649 
                 1.055 
                 1.33 
                 1.58 
               
               
                   
                 Vol. 16 
                 1202.653 
                 1270.280 
                 19.900 
                 11.600 
                 1.782 
                 0.644 
                 4.16 
                 2.80 
               
               
                   
                 Vol. 17 
                 100.433 
                 1006.986 
                 10.500 
                 14.900 
                 1.527 
                 0.478 
                 5.51 
                 2.26 
               
               
                   
                 Vol. 18 
                 1197.411 
                 954.597 
                 28.100 
                 10.800 
                 1.553 
                 0.698 
                 2.57 
                 2.11 
               
               
                   
                 Vol. 19 
                 1006.229 
                 925.835 
                 10.400 
                 11.900 
                 1.528 
                 0.832 
                 2.03 
                 2.02 
               
               
                   
                 Vol. 20 
                 1336.472 
                 1058.242 
                 22.400 
                 16.800 
                 1.464 
                 0.619 
                 1.19 
                 1.07 
               
               
                   
                 Vol. 21 
                 2173.030 
                 1657.372 
                 13.500 
                 10.000 
                 1.634 
                 1.461 
                 1.75 
                 1.68 
               
               
                   
                 Vol. 22 
                 1057.293 
                 830.908 
                 21.000 
                 15.500 
                 2.331 
                 1.534 
                 3.13 
                 1.80 
               
               
                   
                 Vol. 23 
                 1198.950 
                 1068.588 
                 12.600 
                 15.500 
                 1.922 
                 0.424 
                 2.19 
                 1.94 
               
               
                   
                 Vol. 24 
                 1682.290 
                 1108.024 
                 26.400 
                 11.700 
                 1.725 
                 0.807 
                 2.10 
                 1.78 
               
               
                   
                 Mean 
                 1361.600 
                 1214.169 
                 19.113 
                 15.725 
                 1.620 
                 0.914 
                 2.213 
                 1.883 
               
               
                   
                 SD 
                 358.359 
                 348.108 
                 8.244 
                 5.160 
                 0.377 
                 0.365 
                 1.035 
                 0.641 
               
               
                   
                 CV % 
                 26.319 
                 28.671 
                 43.134 
                 32.812 
                 23.277 
                 39.991 
                 46.795 
                 34.056 
               
               
                   
                 Min. 
                 690.354 
                 830.908 
                 10.000 
                 10.000 
                 0.643 
                 0.396 
                 0.833 
                 0.000 
               
               
                   
                 Max. 
                 2173.030 
                 2092.036 
                 43.200 
                 26.400 
                 2.468 
                 1.592 
                 5.512 
                 3.010 
               
               
                   
                 Geom.Mean 
                 1316.580 
                 1173.325 
                 17.609 
                 15.011 
                 1.573 
                 0.841 
                 2.023 
                 // 
               
               
                   
                 Median 
                 1286.936 
                 1089.527 
                 18.350 
                 14.050 
                 1.582 
                 0.827 
                 1.974 
                 1.843