Abstract:
The present invention provides a water-soluble or water-dispersible particulate pharmaceutical composition comprising, per one part by weight of glycyrrhetinic acid and/or glycyrrhetinic acid derivative (as hereinbefore defined), 10 to 100 parts by weight of lactose and/or sorbitol, 10 to 50 parts by weight of at least one buffer selected from sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium malate and potassium malate and 0.1 to 10 parts by weight of disodium edetate.

Description:
BACKGROUND OF THE INVENTION 
     It is well known that certain derivatives of glycyrrhetinic acid, such as the disodium salt of the hemisuccinate of glycyrrhetinic acid, have an excellent anti-inflammatory action and are useful for the treatment of gastric and duodenal ulcers, as well as for the treatment of reflux oesophagitis. 
     Non-liquid pharmaceutical compositions are also known which comprise at least one hydrophilic colloid and the disodium salt of the hemisuccinate of glycyrrhetinic acid. These compositions adhere well to moist mucous membranes and have been found to be useful for the treatment of ulcerations of the oral cavity. However, the use of these compositions is restricted to cases in which the degree of ulceration is limited and in which the ulcerations are readily accessible. Furthermore, these compositions cannot be used for the treatment of generalized inflammation of the oral cavity, such as stomatitis, which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth and gingivae. 
     Unfortunately, there are many common and widely spread inflammatory and ulcerative conditions of the oral cavity, including erosive lichen planus, recurrent ulceration of the aphtus and benign mucous membrane pemphigoid types and primary herpetic stomatitis, for which hitherto there has been no satisfactory treatment. Occasionally, in severe cases of primary herpetic stomatitis in immunologically suppressed patients, use has been made of a mouthwash containing idoxuridine but there is a natural reluctance to use this radiomimetic drug. 
     Consequently, it is an object of the present invention to provide a pharmaceutical composition which is to be used for making a mouthwash for the treatment of the above-mentioned diseases of the oral cavity and for prophylactic purposes in immunologically suppressed patients. 
     SUMMARY OF THE INVENTION 
     According to the present invention, there is provided a water-soluble or water-dispersible particulate and preferably granulated pharmaceutical composition comprising, per one part by weight of glycyrrhetinic acid and/or of a glycyrrhetinic acid derivative, as hereinafter defined, 10 to 100 and preferably 30 to 80 parts by weight of lactose and/or sorbitol, 10 to 50 and preferably 15 to 25 parts by weight of at least one buffer selected from sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium malate and potassium malate and 0.1 to 10 parts and preferably 0.3 to 1 part by weight of disodium edetate and optionally comprising a coloring and/or flavoring material. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The selection of the constituent components of the new pharmaceutical compositions of the present invention is of paramount importance. Bulking agents which are conventionally used in tablet manufacture, such as starch and the like, would clearly be unsuitable because they are insoluble or substantially insoluble in water and thus could not be used for making up an aqueous solution for use as a mouthwash. The use of mono- and disaccharides, such as glucose and sucrose, which are also commonly used in tablet manufacture, is also contraindicated because of the known cariogenic activity of such materials. Most of the other known water-soluble and low molecular weight saccharides which might, in principle, be considered cannot be used because they are not readily available and/or are too expensive. Consequently, sorbitol and lactose are the only materials which satisfy the essential criteria of being water-soluble, readily available at an economic price and having a very low cariogenic activity. 
     As is known, freshly secreted saliva is neutral or very nearly so and is also well buffered. It is also known that any marked shift from neutrality can result in the precipitation from solution of many potentially useful glycyrrhetinic acid derivatives, such as the disodium salt of the hemisuccinate thereof. Consequently, it is necessary to incorporate a buffer in the pharmaceutical composition of the present invention which not only ensures a substantially neutral pH but is also compatible with the other components, does not possess an unpleasant taste or leave an unpleasant aftertaste, has a very low toxicity and possesses a high degree of physiological and pharmacological compatibility. Of the large number of buffer substances which might be considered for this purpose, we have found that the only ones which optimally satisfy all the above-mentioned essential criteria are sodium and potassium citrate, sodium and potassium tartrate and sodium and potassium malate. 
     Glycyrrhetinic acid and many of its useful derivatives form insoluble or substantially insoluble magnesium and calcium salts. However, as is well known, tap water contains variable amounts of magnesium and/or calcium salts. Consequently, it is essential for the pharmaceutical composition of the present invention to contain a component which is not only capable of forming a water-soluble complex or chelate with magnesium and calcium ions but is also physiologically and pharmacologically compatible. We have found that only disodium edetate amply fulfils all these essential criteria. 
     Apart from glycyrrhetinic acid per se, the pharmaceutical composition of the present invention may also contain one or more derivatives thereof, such as the 3-0-acyl derivatives and especially those in which the acyl radical contains a carboxyl group (see our British Pat. Nos. 843,133 and 1,387,499), esters of glycyrrhetinic acid and of 3-0-acyl derivatives of glycyrrhetinic acid (see our British Pat. No. 1,255,672) and also 2-(ω-carboxyalkanoyl (and cycloalkanoyl)oxymethyl)-glycyrrhetinic acid derivatives (see our British Pat. No. 1,476,053). In those cases where use is made of a glycyrrhetinic acid derivative containing one or more free carboxyl groups, such groups are preferably salified and used, for example, in the form of alkali metal salts, the sodium salts being especially preferred. Of the large number of glycyrrhetinic acid derivatives which can be used, the preferred ones include the disodium salt of glycyrrhetinic acid hemisuccinate, the disodium salt of mono-(glycyrrhet-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid and cinnamyl glycyrrhetate. 
     Although the glycyrrhetinic acid derivatives used according to the present invention are known to possess anti-inflammatory properties, it is surprising that they also exert a dramatic healing action when used in a mouthwash, in which the contact time is very limited, for the treatment of hitherto intractable diseases, such as erosive lichen planus, pemphigoid types of ulceration, herpetic stomatitis and aphthous ulcers. 
     In order to improve the patient acceptability of the pharmaceutical compositions according to the present invention, it is desirable to add an appropriate coloring and/or flavoring material. We have found that peppermint is the most widely acceptable flavoring for the compositions according to the present invention but other flavorings may, of course, also be used. Furthermore, we have also found that the most widely acceptable coloring for the compositions according to the present invention is green. This can be obtained, for example, by admixing appropriate chlorophyllins or permicol lime green. However, it is to be understood that any pharmaceutically acceptable coloring material may be used. 
     We have found that 30 ml. is an adequate volume for a single mouthwash and that approximately 2 g. of the pharmaceutical composition of the present invention is sufficient to provide the desired effect. Consequently, for ease of use, the composition is preferably packed in individual sealed sachets, each of which contains 2 g. of composition, a plurality of such sachets being packed in a larger container in order to provide an adequate course of treatment for a patient. 
     In order to obtain the desired effect, it is recommended that the patient cleans the mouth after breakfast, luncheon and before retiring at night and then swishes the mouthwash around the mouth for about 30 seconds, after which the mouthwash is spat out. It is recommended that, in order to obtain the maximum beneficial effect, no food or drink is consumed for at least 30 minutes after using the mouthwash. 
    
    
     The following Examples are given for the purpose of illustrating the present invention: 
     EXAMPLE 1 
     
         ______________________________________Components:______________________________________disodium salt of glycyrrhetinic acid hemisuccinate                     2.0     g.granulated sodium citrate 40.0    g.disodium edetate          1.0     g.spray-dried lactose       156.15  g.peppermint oil            0.8     g.sodium copper chlorophyllin                     0.05    g.purified water            20      ml.diethyl ether             4       ml.______________________________________ 
    
     The disodium salt of glycyrrhetinic acid hemisuccinate and the disodium edetate are thoroughly mixed, followed by admixing the sodium citrate and then the lactose. The sodium copper chlorophyllin is dissolved in the 20 ml. of purified water and added to the mixture which is then granulated in a pestle and passed through a 16 mesh sieve. After drying overnight at 50° C., the peppermint oil dissolved in the diethyl ether is added thereto and thoroughly mixed therewith, whereafter the diethyl ether is allowed to evaporate. 
     2 g. of the granules thus obtained, when dissolved in 30 ml. of water, give a clear blue-green solution with a pH of 7.4. 
     A similar product is obtained when an equivalent amount of the disodium salt of mono-(glycyrrhet-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid or of cinnamyl glycyrrhetate is used instead of the disodium salt of glycyrrhetinic acid hemisuccinate. 
     EXAMPLE 2 
     
         ______________________________________Components:______________________________________disodium salt of glycyrrhetinic acid hemisuccinate                     0.150   kg.lactose                   11.707  kg.sodium citrate            3.000   kg.disodium edetate          0.075   kg.peppermint oil            0.060   kg.permicol lime green coloring                     0.0075  kg.purified water______________________________________ 
    
     The disodium salt of glycyrrhetinic acid hemisuccinate and the disodium edetate are mixed together and then the sodium citrate is admixed. The mixture thus obtained is transferred to a Hobart mixer and the lactose is added, followed by mixing for 30 minutes at a low speed. 
     The coloring material is dissolved in about 1 liter of purified water and added slowly to the mixture, followed by about 0.5 liters of purified water, a stiff, uniformly colored paste being obtained, which is granulated through a size 16 mesh sieve on an oscillating granulator, the granules obtained being dried overnight at 50° C. 
     The dried granules are then passed through a 16 mesh sieve and the peppermint oil slowly added, with stirring, until a uniform mixture is obtained. The final granulate thus obtained is then stored in an air-tight container. 
     EXAMPLE 3 
     
         ______________________________________Components:______________________________________disodium salt of mono-(glycyrrhet-3-yl)-                  2.2      g.cis-cyclohexane-1,2-dicarboxylic acidgranulated potassium citrate                  41.0     g.disodium edetate       1.0      g.sorbitol               83.1     g.peppermint oil         0.8      g.sodium copper chlorophyllin                  0.05     g.purified water         20       ml.diethyl ether          4        ml.______________________________________ 
    
     The components are worked up to give a granulate in the manner described in Example 1. 
     EXAMPLE 4 
     
         ______________________________________Components:______________________________________cinnamyl glycyrrhetate               2.2       g.sodium tartrate     40.0      g.disodium edetate    1.0       g.lactose             140.0     g.peppermint oil      0.8       g.permicol lime green coloring               0.08      g.purified water      20        ml.diethyl ether       4         ml.______________________________________ 
    
     The components are worked up to give a granulate in the manner described in Example 1. 
     EXAMPLE 5 
     
         ______________________________________Components:______________________________________disodium salt of glycyrrhetinic acid hemisuccinate                     2.0    g.potassium malate          32.0   g.disodium edetate          1.0    g.sorbitol                  92.0   g.peppermint oil            0.8    g.sodium copper chlorophyllin                     0.05   g.purified water            20     ml.diethyl ether             4      ml.______________________________________ 
    
     The components are worked up to give a granulate in the manner described in Example 1. 
     The following Table summarizes the results obtained in a limited clinical trial using two different glycyrrhetinic acid derivatives, namely, Viroxolone (the disodium salt of glycyrrhetinic acid hemisuccinate) and Biociclone (the disodium salt of mono-(glycyrrhet-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid). Other clinical trials which have been carried out clearly demonstrated that the mouthwash compositions according to the present invention bring about a dramatic healing and resolution of diseases of the oral cavity which have hitherto proved to be intractable. Thus, it has been demonstrated clinically that the pain and fever frequently associated with herpetic diseases of the oral cavity often disappear within the course of 24 to 48 hours, after which time visual manifestations of the diseases (lesions) are often no longer apparent. 
     
                       TABLE______________________________________               num-               ber               of               pa-preparation   clinical status               tients  results______________________________________Viroxolone   aphthous    12      10/12 pain reducedmouthwash   ulcer               1/12  no improvement                       1/12  complete                             recurrence                       1/12  coelic disease                             (recurred)                       4/12  ulcers healed                             completely                       1/12  pain-free but                             ulcers per-                             sistedBiociclone   aphthous    7       7/7   pain reducedmouthwash   ulcer               7/7   ulcers healed                       1/7   herpetic origin                       2/7   recurred                       1/7   coeliac disease                             (recurred)                       2/7   no recurrence                             with mainten-                             ance of treat-                             ment                       1/7   recurrence even                             with maintenance                             of treatmentViroxolone   chronic     7       1/7   less painfulmouthwash   erosive                   lesions, resol-   lichen                    ed on main-   planus                    tenance of                             therapy                       3/7   mouth more com-                             fortable, lesions                             unchanged                       1/7   pain-free in 1                             week, lesions                             improved                       1/7   mouth possibly                             less uncomfort-                             able, lesions                             unchanged                       1/7   pain became more                             severe, withdrewViroxolone   acute radiation               1             more comfortablemouthwash   mucositis                 in 48 hrs.,                             resolved pain-                             lessly in 3 weeks______________________________________