Astringent gel composition and method for use
BACKGROUND OF THE INVENTION 
     1. Field of Invention 
     The present invention relates to aluminum containing astringent gel compositions and a method for their use. 
     2. Description of the Prior Art 
     Aluminum acetate solution, also referred to as Burow&#39;s solution, has long been known and used as an astringent when applied to the skin. It is approved for use by the US Food and Drug Administration dispensed as a 2.5 to 5% by weight clear solution of aluminum acetate (triacetate) for use as a wet dressing, compress or soak for relief of inflammatory conditions and minor skin irritations. Burow&#39;s solution may be prepared by reacting aluminum sulfate, calcium carbonate and 6 molar acetic acid to form aluminum subacetate topical solution (also referred to as monobasic aluminum diacetate) and a precipitate of calcium sulfate. The calcium salt precipitate is removed by filtration and the filtrate is converted to aluminum acetate solution (Burow&#39;s solution) by the addition of acetic acid. Other methods for the preparation of Burow&#39;s solution include treatment of dibasic aluminum monoacetate with glacial acetic acid and the methods disclosed in U.S. Pat. Nos. 2,824,042 and 2,827,420. 
     It is generally recommended that Burow&#39;s solution be freshly prepared before use because it tends to become unstable over prolonged periods of standing and tends to lose its potency. This loss in potency is due to the precipitation of the more basic aluminum salts. 
     It is also common in the prior art to prepare mediciment formulations in the form of a gel for application to the skin. For example, U.S. Pat. No. 3,856,941 discloses an astringent gel formulation based on a mixture of astringent salts such as aluminum and zinc, zirconium or magnesium salts, and further including a gelling agent and a glycol. The patent indicates that the stability of the formulation is enhanced by combining two or more such salts and formulating them into a gel at relatively high concentrations of about 13 to 18% by weight. 
     However, the requirement of the usage of such a mixture of salts at relatively high concentration in the gel formulation to achieve stability can give rise to other problems including tolerance or irritation of the skin to such preparations due to the high salt concentration. 
     Accordingly it is an object of this invention to provide a formulation of Burow&#39;s solution in gel form for convenient application to the skin. 
     Another object is to provide a formulation of Burow&#39;s solution as a gel which remains stable over extended periods of storage. 
     Yet another object of the invention is to provide an astringent formulation for application to the skin, particularly to the hands, for relief of inflammatory skin conditions, erythema. chapping and minor ulcerations of the skin. 
     SUMMARY OF THE INVENTION 
     The present invention provides a stable astringent gel composition containing pharmaceutically acceptable dosage levels of Burow&#39;s solution which remains stable over extended periods of storage and which can readily be applied to the skin to alleviate inflammatory conditions, erythema, chapping and minor skin irritations. The composition comprises a mixture of Burow&#39;s solution, a thickening or gelling agent, at least one glycol and/or polyglycol, dispersed in gypsum saturated purified water. The gel is adapted for application directly to affected areas of the skin to bind or tighten the soft tissue and also to tone and moisturize the skin. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The principal active ingredient in the gel composition of the present invention is Burow&#39;s solution. This aqueous solution of aluminum acetate may be prepared by any of the well known techniques as described hereinabove. Potent, freshly prepared Burow&#39;s solution comprises predominantly aluminum acetate present as the triacetate, most commonly present at a concentration of about 2.0 to about 7.0% by weight, more preferably from about 2.5 to about 5% by weight, the balance being water. 
     Gelling agents which are useful in the preparation of the astringent gel in accordance with the present invention include those agents known in the art and used in gels to be applied to the skin. Preferably the gelling agent used in the present invention is a non-ionic gelling agent and therefore exhibits none or only slight sensitivity to multivalent cations such as aluminum. Ionic gelling agents can lead to crosslinking of aluminum and consequent precipitation of ionic hydrocolloids. The most preferred gelling agents are cellulose ethers or esters having a molecular weight within the range of about 10,000 to about 30,000, most preferably methyl cellulose ethers. Also suitable as a gelling agent are polyvinyl alcohols having an average molecular weight within the range of about 15,000 to about 90,000 and containing up to about 15% acetate groups. 
     Non-ionic gelling agents such as described above can lead to an undesirable foaming or whitening of the gel composition after application to the skin due to their tendency to reduce surface tension. It has been found that the inclusion of minor amounts of a lower poly alkylene glycol into the formulation will eliminate this foaming or whitening before it can occur by replacing the gelling agent at the air/water interface after application to the skin. Preferred polyols are polyethylene glycol, polypropylene glycol and polybutylene glycol, and mixtures thereof. 
     The preferred composition of this invention also includes a C 2  to C 4  alkylene glycol such as ethylene glycol, propylene glycol, 1,3 butylene glycol, glycerol, or mixtures thereof. It has been found that the presence of the lower alkylene glycol serves a two fold purpose: to impart a moisturizing effect to the skin after application of the gel thereby extending the time that the skin remains wet, and to act as a solvent for the polyol thereby enhancing its anti-foaming and anti-whitening effect. 
     The balance of the aqueous component of the gel formulation is a solution of gypsum saturated water, preferably purified distilled water. This saturated solution imparts stability to the aluminum acetate active ingredient present in the gel and tends to prevent a loss in potency of the astringent gel over prolonged periods of storage. Preferably, the gypsum is used in the form of calcium sulfate, NF grade. The saturated solution may be prepared by boiling a 5% dispersion of gypsum (or calcium sulfate) in purified water (USP) for a period of at least about 10 minutes. The solution/dispersion is then cooled to room temperature and filtered to remove the non-dissolved salt. The resultant saturated solution assays at about 0.2% by weight dissolved calcium sulfate. 
     It has also been found that the presence of the purified water saturated with calcium sulfate in the gel also imparts a cooling effect when the gel is applied to the skin. 
     Preferably, the astringent gel composition of the present invention consists essentially of the above named ingredients, but it may also contain other ingredients which do not detract from either the astringent effect or the stability of the gel. 
     Examples of such ingredients include dyes, perfumes, non-ionic emulsifiers, healing agents, antiseptic, antibacterial, antibiotic and/or germicidal substances, and keratolytic agents. 
     The gel composition is formulated to have a pH in the range of about 3.5 to about 5.5, preferably from 4.0 to 4.5. 
     The preferred proportion of the ingredients present in the gel may range generally from about 40 to about 80% by weight of aluminum acetate solution, from about 0.5 to about 4.0% by weight of gelling agent, from about 0.05 to about 2.0% by weight of lower polyalkylene glycol, from about 5 to about 25% by weight of C 2  to C 4  alkylene glycol, and the balance of gypsum saturated water is generally present in the range of about 15 to about 40% by weight. The concentration of aluminum acetate present in the aluminum acetate solution (Burow&#39;s solution) may generally range between about 2 to about 7% by weight, more preferably about 4.5% by weight. 
     The following example is illustrative of the invention. 
    
    
     EXAMPLE 1 
     An astringent gel composition having the following composition was prepared: 
     
         ______________________________________                                    
INGREDIENT % BY WEIGHT                                                    
______________________________________                                    
propylene glycol                                                          
           20.0         Sold as Methocel K-100M                           
hydroxypropyl           by Dow Chemical Corp.                             
methylcellulose                                                           
           1.3                                                            
2208                                                                      
polypropylene                                                             
           0.20         Sold as Polyglycol P-1200                         
glycol                  by Dow Chemical Corp.                             
aluminum acetate                                                          
           60.00        Containing about 4.5% by                          
solution                weight aluminum                                   
                        triacetate.                                       
purified water                                                            
           18.00        Containing about 0.2% by                          
(gypsum                 weight dissolved calcium                          
extracted)              sulfate.                                          
FDC Blue #1                                                               
           0.50                                                           
(0.1% aqueous                                                             
soln)                                                                     
Total      100.00                                                         
______________________________________                                    
 
    
     The aluminum acetate solution was prepared by dissolving dibasic aluminum acetate in distilled water and adding sufficient glacial acetic acid to form aluminum triacetate at about a 4.5% by weight concentration. The resulting solution is then filtered to remove insolubles. The purified gypsum extracted water was prepared by dispersing about 5% by weight of calcium sulfate (NF grade) in purified water, boiling for about 10 minutes, cooling and filtering to remove insolubles. The resulting saturated solution of calcium sulfate had a content of calcium sulfate of about 0.2% by weight. 
     The gel containing the aforementioned ingredients was prepared by first dissolving the polypropylene glycol in the propylene glycol and mixing until uniform. Next the methyl cellulose gelling agent is added slowly to this mixture with adequate stirring until a uniform dispersion is obtained. This dispersion is then added to a blend of aluminum acetate solution, dye and gypsum extracted water and mixed until the dispersion is uniform and gelatinization is complete. 
     The gel is then ready for packaging and for use. 
     CLINICAL TRIAL 
     Procedure 
     A group of 30 female subjects between the ages of 18 and 65 having erythema and dryness/chapping of both hands was selected for evaluation. 
     The subjects were provided with the gel of the present invention for application twice daily to a single hand, in the evening and in the morning, over a period of 5 days for a total of nine applications. The panelists were issued nine capped 1 ml syringes each containing about 0.5 grams of the gel, and a supply of rubber gloves. The panelists were instructed to place the plastic glove on the hand opposite the hand to be treated, to empty the entire contents of the syringe on the back of the hand to be treated and to gently spread and to gently massage the gel into the skin of the back of the hand to be treated, between the distal knuckles and wrist crease, and into the interdigital spaces, until the gel was absorbed. 
     The panelists were also instructed to bath once per day and to wash both the hands with IVORY® soap four times per day at selected intervals. 
     Both prior to and subsequent to the clinical evaluation, the degree of erythema and dryness/chapping of the back of the panelists hands were evaluated according to the following five point scoring scales: 
     
         ______________________________________                                    
(a)   Erythema                 Score                                      
      None                     0                                          
      Pink                     1                                          
      Red                      2                                          
      Fiery red                3                                          
      Fiery red and raw; hemorrhagic areas                                
                               4                                          
(b)   Dryness/Chapping                                                    
      Smooth, soft, good turgor (and/or slight                            
                               0                                          
      drying but no scaling)                                              
      Definite dryness with slight scaling                                
                               l                                          
      Definite dryness and chapping with                                  
                               2                                          
      scaling and some flaking                                            
      Severe dryness and chapping with definite                           
                               3                                          
      scaling and flaking, and some                                       
      rigidity and cracking                                               
      Very severe dryness with roughness,                                 
                               4                                          
      severe scaling and wide cracking,                                   
      rigidity and eczematous appearance                                  
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     Each of the selected 30 panelists had a rating in each category of at least 2 prior to being selected for the clinical treatment. 
     Clinical evaluation scores for erythema and dryness/chapping are summarized in Table 1. For both the untreated and treated hands there are reductions (improvements) in the scores for erythema and dryness/chapping over the course of the test period. These improvements for the treated hand are approximately four times greater than those for the untreated hand, and are satistically significant at the 99% confidence level. The relatively small score changes for the untreated hand are not statistically significant. Even after correction of the changes in treated hand scores by the corresponding changes in untreated hand scores, the improvement in treated hand scores is still of statistical significance at the same confidence level. 
     
                                           TABLE l                                 
__________________________________________________________________________
CLINICAL EVALUATION SCORES                                                
Time        Untreated                                                     
                   Treated                                                
                          Treated                                         
                                 Corrected.sup.1                          
__________________________________________________________________________
            M ± SD.sup.b                                               
                   M ± SD                                              
                          Δ                                         
                                 t.sup.c                                  
A.                                                                        
  Erythema                                                                
  Initial   2.57 ± 0.63                                                
                   2.57 ± 0.68                                         
  (Baseline)                                                              
  Final     2.43 ± 0.68                                                
                   2.00 ± 0.64                                         
  (End Study)                                                             
  Δ   0.13 ± 0.57                                                
                   0.57 ± 0.68                                         
                          0.43 ± 0.57                                  
                                 4.18**                                   
  t         1.28   4.57**                                                 
B.                                                                        
  Dryness/Chapping                                                        
  Initial   2.63 ± 0.72                                                
                   2.63 ± 0.67                                         
  (Baseline)                                                              
  Final     2.37 ± 0.85                                                
                   1.60 ± 0.77                                         
  (End Study)                                                             
  Δ   0.27 ± 0.69                                                
                   1.03 ± 0.7                                          
                          0.77 ± 0.82                                  
                                 5.14**                                   
  t         2.11                                                          
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 FOOTNOTES:                                                               
 .sup.a The difference (Δ) between initial and final mean values of 
 the treated hand corrected for the difference (Δ) between the      
 initial and final mean values of the untreated hand.                     
 .sup.b Mean ± standard deviation.                                     
 .sup.c Student&#39;s t test value with the statistical significance of the   
 difference (Δ) between mean values at the 95% confidence level     
 indicated by *, and at the 99% confidence level by **.                   
 
    
     It is to be understood that the above described embodiments of the invention are illustrative only and that modifications throughout may occur to those skilled in the art.