Abstract:
An aqueous acidic lubricating composition for use in the mucosal areas of the human body, that provides at least 30 ppm of available iodine. There is also provided a method of treating vaginitis preventing STD and group B streptococcus.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention relates to an antimicrobial lubricant which can be used in the mucosal areas of the human body. More particularly, there is provided an antimicrobial lubricating composition in gel form or as a liquid which can be utilized in the vaginal cavity.  
         BACKGROUND OF THE INVENTION  
         [0002]    One of the main disciplines of medicine is the treatment of the female reproductive system for the prevention, treatment, mitigation, diagnosis, and cure of diseases, and the prevention of conception. Usually, this involves the delivery of active agents to the vaginal cavity and its environs. Systems to affect the delivery of such agents are usually in the form of gels, foams, creams, or suppositories and quick dissolving tablets.  
           [0003]    The vaginal cavity is subject to conditions which render it as a target for disease and infection; however, it is extremely difficult to deliver an active agent to this area for an extended period of time. The vaginal cavity exhibits an aqueous environment containing secreting glands whose fluids create an acidic pH in the range of 3.5 to 5.5. The environment of the vagina is conducive to the growth of bacteria, fungi, yeast and other microorganisms since it is warm, moist, and dark. It is also the vestibule for menstrual debris and residual seminal fluid from sexual intercourse. The crevices of the vaginal cavity facilitate the retention of undesirable bacteria, fungi, yeast, and other microorganisms as well as the debris from menstruation and sexual intercourse. The vaginal cavity is also subject to considerable physical deformation, such as during sexual intercourse or the insertion of tampons.  
           [0004]    Infectious diseases and other inflammatory conditions affecting the vaginal mucosa and often secondarily involving the vulva are commonly referred to as vulvovaginitis. Physicians and investigators often believe that the normal vaginal flora has a nice role in protecting the vagina and contiguous tissues from various microorganisms that are causes of vulvovaginitis.  
           [0005]    Most vulvovaginitis and symptomatic vaginal discharges are caused by bacteria, usually Gardnerella vaginalis in combination with various anaerobes. Protozoa (Trichomonas vaginalis) cause one third of all cases. Candida is a frequent cause in pregnant women and diabetics, and occasionally oral contraceptives increase susceptibility. Candida also causes symptoms in women who do not have the risk factors of diabetes, pregnancy, and hormonal therapy.  
           [0006]    Another major cause of vaginal discharge is the human papillomavirus (HPV). The lesions from HPV are usually not described as volvovaginitis although they do cause vulvovaginal infection. The condition is not inflammatory (vaginitis) but rather wart-like outgrowths of the tissue of the vagina, vulva, and cervix and usually do not elicit any symptoms of pain or itching. But most importantly HPV is probably the most significant cause of cervical cancer in women.  
           [0007]    Other less common causes of vulvovaginitis are other bacteria (e.g.  Neisseria gonorrhoeae , members of the Chlamydia and Mycoplasma groups, streptococci,  Escherichia coli , and staphylococci), foreign bodies, viral infections (herpes simplex and HIV infections), pinworms ( Enterobius vermicularis ), fistulas, radiation, and tumors of the genital tract. Frequent douching, especially with chemicals, may disturb normal vaginal milieu. Deodorant sprays, laundry soaps and fabric softeners, and bath water additives may cause vulvar irritation. Tight, nonporous, nonabsorbent underclothing, as well as poor hygiene, may foster fungal and bacterial growth. Occasionally, sensitivity to spermicides, coital lubricants, or latex in a diaphragm or condom causes irritation.  
           [0008]    The pH of a healthy vagina is mildly acidic (pH 3.5-4.5) and this acidity is thought to be generated by the production of lactic acid by lactobacilli, which form a major component of the healthy vaginal flora. Together with other factors, this acid pH is widely recognized to prevent overgrowth of undesirable endogenous microbes (Candida, harmful anaerobes, and bacteria that may cause urinary tract infections) and encourages the continued dominance of lactobacilli which, in addition to mild acidity, provides other protective mechanisms such as production of hydrogen peroxide.  
           [0009]    It is also known that sperm are inactivated by the mild acidity of the healthy vagina, and acid substances have been used as home made vaginal contraceptives for centuries. More recently, it has been recognized that many sexually transmitted disease pathogens and most or all enveloped STD (sexually transmitted disease) viruses (Kempf 1001, Martin 1985) including herpes simplex virus, cytomegalovirus, and human immunodeficiency virus, are also inhibited or inactivated by mild acidic pH. However, semen contains a potent alkaline buffering capacity that neutralizes the vaginal acidity for a period of many hours after intercourse. The alkaline buffering capacity enables sperm to swim from the vagina into the cervix and upper reproductive tract.  
           [0010]    Unfortunately, STD pathogens in genital secretions can also exploit this period of neutral vaginal pH, since it allows time for them to reach and infect their target cells. If this semen-induced neutralization of vaginal acidity could be promptly and reliably overcome, both contraception and STD prevention could be achieved by a method that closely mimics the normal physiological state of the vagina.  
           [0011]    In addition, the elevated pH also allows certain strains of Staphylococcus aureus to produce shock toxin I, whereas production of this toxin is completely inhibited at acidic pH 5.0 (Schlievert 1983). Thus, loss of protective acidity may result in staphylococcal toxic shock syndrome, candida vaginitis, bacterial vaginosis, or urinary tract infection.  
         SUMMARY OF THE INVENTION  
         [0012]    The present invention relates to an antimicrobial lubricating composition having at least 30 ppm of available iodine preferably at least 125 ppm in liquid or gel form for topical use in mucosal areas, which can be used to treat or prevent the transmittal of sexually transmitted diseases (STD), prevention of group B streptococcus and possesses an antimicrobial activity against a variety of microorganisms responsible for vaginitis.  
           [0013]    The composition includes an effective amount of an aqueous acid solution containing a monobasic iodide salt, an organic acid having up to six carbon atoms, at least one oxidizing agent and an inorganic phosphate buffer.  
           [0014]    It is an object of the invention to provide an antimicrobial lubricating composition which can be used in connection with rectal thermometers, condoms, enemas, and in mucosal areas.  
           [0015]    It is another object of the invention to provide a lubricating composition that can be utilized with a condom.  
           [0016]    It is yet another object of the invention to provide an antimicrobial vaginal gel composition that is non-irritating and provides available iodine in an amount of 30-195 ppm.  
           [0017]    It is a further object of the invention to provide a method for preventing sexually transmitted diseases and still maintain and enhance the normal protection of vaginal flora.  
           [0018]    The compositions can be applied to external genitalia as well as internal mucosal surfaces to reduce microtrauma resulting from inadequate lubrication and will prevent transmission of viable STD pathogens as well as group B streptococcus to newborns.  
         DESCRIPTION OF THE PREFERRED EMBODIMENTS  
         [0019]    The acidic antimicrobial composition, according to the invention, may be presented in liquid and forms normally used for topical application, in particular in the form of aqueous, aqueous-alcoholic or, oil solutions, or anhydrous or lipophilic gels, or emulsions of liquid or semi-solid consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase (OW) or vice versa (W/O), or of suspensions or emulsions of soft, semi-solid consistency of the gel types. These compositions are prepared according to standard methods.  
           [0020]    They are preferanbly used in the form of aqueous, aqueous-alcoholic solutions, or in the form of gels, or foams.  
           [0021]    The amounts of the different constituents of the compositions according to the invention are those traditionally used in the pharmaceutical field.  
           [0022]    The aqueous antimicrobial composition used in the compositions of the invention comprises an aqueous acidic solution containing an effective amount of a monobasic iodide salt to provide between 30 to 195 ppm, preferably at least 125 ppm of available iodine, an effective amount of an organic acid, an effective amount of at least one oxidizing agent and an inorganic phosphate buffer. The composition has a pH of 3.2 to 5.5.  
           [0023]    More particularly, the aqueous antimicrobial composition comprises a monobasic iodide salt which is an alkali salt, preferably in an amount of about 0.01 to 2% of composition. The composition contains an organic acid containing up to three carboxylic acid groups having up to six carbon atoms, preferably selected from the group consisting of citric acid, ascorbic acid, and oxalic acid in an amount of about 0.1 to 2% by weight, preferably 0.1 to 2%.  
           [0024]    The oxidizing agent is an alkaline salt of a perborate or percarbonate or urea hydroxy peroxide which is present in an amount of at least about 0.001 to 1.0% by weight of a member, preferably selected from the group consisting of sodium percarbonate, sodium perborate and urea hydrogen peroxide and mixtures thereof.  
           [0025]    The inorganic phosphate buffer preferably comprises a mono or dibasic potassium hydrogen phosphate.  
           [0026]    A preferred antimicrobial composition consists essentially of about 0.01 to 0.25% by weight of sodium iodide, about 0.01 to 2.0 by weight of citric acid and about 0.005 to 2.0% by weight of a mono and/or dibasic alkali salt of hydrogen phosphate, preferably, potassium hydrogen phosphate and 0.01 to 0.06% by weight of sodium percarbonate. Most preferably in the form of a gel or foam.  
           [0027]    When the composition of the invention is an oil gel or solution, the fatty phase can represent more than 90% of the total weight of the composition.  
           [0028]    In a known manner, the composition of the invention may also contain adjuvants which are customary in the pharmaceutical field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes and fillers. The amounts of these different adjuvants are those traditionally used in the pharmaceutical or dermatological field, and are, for example, from 0.01% to 10% of the total weight of the composition. Those adjuvants, depending on their nature, may be introduced into the fatty phase or into the aqueous phase.  
           [0029]    As oils which can be used in the invention, mineral oils (liquid paraffin), vegetable oils (liquid fraction of sheat butter, sunflower oil), animal oils (perhydrosquatene), synthetic oils (Purcellin oil), silicone oils (cyclomethicone) and fluorinated oils (perfluoro polyethers) may be mentioned.  
           [0030]    As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, clays and natural gums may be mentioned.  
           [0031]    Natural gums which may be used includes carageenan gum, xantham gum, alginates and gelation. As hydrophilic active agents, proteins or protein hydrolysates, amino acids, polyols, urea, allantonin, sugars and sugar derivatives, water-soluble vitamins, starch and plant extracts, in particular those of the Aloe vera may be used.  
           [0032]    As lipophilic active agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides and essential oils may be used. These agents add extra moisturizing or skin softening features when utilized.  
           [0033]    The compositions of the invention may include plant or herbal extracts that reduce irritation. For example, there may be utilized extracts of Paraguay tea, Kola and Guarana, which provide a source of mathylxanthines, saponius, tannins, and glycosides that have been shown to be anti-inflammatory and can be used to treat irritations. The extract of Paraguay tea is known as “Mate extract” and is described in the “International Cosmetic Ingredient Dictionary”, 5 th  Edition. Mate extract is commercially available in combination with extracts of Kola and Guarana, which is sold by Cosmetic Ingredient Resources of Stamford, Conn. under the trademark “QUENCHT”.  
           [0034]    Each of mate extract, serine protease inhibitor and aloe vera extracts are known to provide anti-inflammatory activity. These components can be utilized to reduce irritation when an anti-viral is incorporated.  
           [0035]    A surfactant can be included in the composition so as to provide deeper penetration of the ingredients. Many surfactants are also antimicrobial agents, for example, nonoxynol-9 and octoxynol-p are used to prevent HIV. Generally, about 0.05 to 2.0% by weight surfactant can be used.  
           [0036]    An example of a lubricating base which can be used is HISPAGEL a glycol-free glycerine clarthrate which is generally described as glycerin polyacrylate which is sold by Centerchem Inc of Stamford, Conn. Generally, up to about 20% by weight of the composition comprises HISPAGEL. It can be used in combination with other gellants such as Cabopols, cellulose derivatives, clays and the like.  
           [0037]    The preferred natural gums that can be used in amounts up to about 5% by weight include carageenan gum, xantham gum, alginates, and gelatin.  
           [0038]    The preferred synthetic polymers that can be used include Carbopol, polyacrylic acid, polymethacrylis acid, hydroxyalkyl cellulose, methacrylate, polyacrylamide, polyvinyl pyrrolidone and polyvinyl alcohol. They may also be used in the form of aqueous, aqueous-alcoholic solutions, or in the form of gels or foams.  
           [0039]    The amounts of the different constituents of the compositions according ro the invention are those traditionally used in the pharmaceutical field.  
           [0040]    The following examples illustrating the compositions of the invention are not intended to limit the scope of the invention. The amounts are by weight percent unless otherwise noted. 
       
    
    
     EXAMPLE 1  
       [0041]    A. Preparation of an Antimicrobial Composition.  
         [0042]    The following ingredients are admixed.  
                                                                 Ingredients   % W/W                                        Potassium Phosphate Monobasic   1.000           Sodium Iodide   0.024           Citric Acid   0.157           Sodium Perborate Monohydrate   0.033           Purified Water   q.s.               100.00                                  
 
         [0043]    B. Preparation of a Gel.  
         [0044]    To the mixture of part A is added 1.500% hydroxypropyl cellulose and 0.500% of liquid GERMALPLUS (Diazolindmyl urea and iodopropynyl butylcarbonate).  
         [0045]    In lieu of the hydroxypropyl cellulose and GERMAPLUS, there may be used carageenan gum.  
         [0046]    C. Primary Dermal Irritation  
         [0047]    The procedure was adapted from Draize, J. H., “The Appraisal of Chemicals in Food, Drugs, and Cosmetics.” Dermal Toxicity, pp. 45-49. Association of Food and Drug Officials of the United States, Topeka, Kansas (1965).  
         [0048]    The backs of six Albino rabbits were clipped free of hair and examined for healthy, intact skin within 24 hours prior to testing. One intact and one abraded site (prepared by disrupting the stratum corneum) was dosed with 0.5 ml of the composition of Example 1B, covered with 1-in gauze patched and wrapped with impervious material. Test sites were uncovered after 24 hours, examined and scored (0 for no erythemaledema to 4 for severe erythema/edema). Sites were also scored at 72 hours after application. Based on the score, a Mean Primary Irritation Index was calculated and any reaction is assigned a descriptive rating, from the index, for degree of irritation (0 for non-irritating to AE6 for severely irritating; see 16 CFR Part 1500.41).  
         [0049]    Results  
         [0050]    All test sites scored 0 for all times points and thus, the composition of Example 1B was assigned a Mean Primary Irritation Score of 0.  
         [0051]    Conclusion  
         [0052]    The composition was classified as non-irritating to the skin.  
       Example 2  
       [0053]    A. Preparation of a Liquid Antimicrobial Composition.  
         [0054]    0.245 g of a sodium iodide, 1.57 g of citric acid, 0.7939 g of urea hydrogen peroxide, 0.5 g of sodium hydrogenphosphate, and 0.03297 g of sodium percarbonate are mixed in one liter of water. The pH was 3.5. The composition can be used as a vaginal douche to kill S. enterditis. The composition had 120 ppm of available iodine.  
         [0055]    B. Preparation of a Gel.  
         [0056]    To the composition of part A was added 2.0 g of hydroxyethylcellulose to produce a gel.  
         [0057]    In lieu of hydroxyethylcellulose there may be used carageenen gum to enhance the spectrum of antimicrobial effect and prevent the transmission of STD.  
                                                                                           C. Summary of Preliminary Toxicity Studies of Example 1A Liquid.            Study/                           Route of Administration   Dose   Species   Frequency   Duration   Notes                    1. Irritation/Intravagnial   2   mL   Rabbit   Daily   5   Days   Non-irritating to                                   mucus membrane       2. Acute/Intraperitoneal   20   mL/kg   Mice   Once   &gt;7   Days   No adverse effects       3. Acute/Oral   5000   mg/kg   Rats   Once   14   Days   No adverse effects       4. Acute/Dermal   2000   mg/kg   Rabbit   Once   14   Days   No adverse effects       5. Primary Eye Irritation   0.1   mL   Rabbit   Once   3   Days   Non-initating to eye       6. Primary Dermal Irritation   0.5   mL   Rabbit   Once   3   Days   Non-irritating to skin       7. Dermal Sensitization   0.3   mL   Guinea Pig   3(@ 6 hr)   5   Weeks   No potential for       (Buehler patch method)                           contact sensitization                  
 
         [0058]    [0058]                                             D. Liquid of Example 1A has activity against all of the following:                                  Streptococcus agalactiae *     Myobacterium bovis  BCG     Psuedomonas aeruginosa         HIV     Mycobacteriium abscessus       Burkholder cepacia         Endotoxin     Brevundimonas diminuta       Salmonella enteriditis         Herpes Simplex Virus Type 1     Salmonella typhimurium       Salmonella choleraesuis         Poliovirus Type 1     Actinomyces naeslundii       Staphylococcus aureus           Porphyromonas intermedia       Lactobacillus paracasei       Serratia marcescens           Treponema denticola       Porphyromonas gingivalis       Candida albicans           Trichtophyton mentagrophytes       Streptococcus mutans       Streptococcus mitis           Streptococcus oralis                              
       Example 3  
       [0059]    Preparation of a Gel.  
                                                                 Ingredients   % W/W                                        Sodium Iodide   0.25           Phytosphingosine   5.0           Citric Acid   1.6           Sodium Percarbonate   0.03           Carbopol 940   0.4           Butylene glycol   6.5           Quench T   3.0           Chamomile glycolic extract   3.0           Sodium hydrogenphosphate   0.5           Preservative   0.1           Fragrance   0.1           Deionized Water   q.s.               100%                      
 
         [0060]    To 20 ml of water with stirring, is added the Carbopol 940. The mixture is stirred until hydration is complete and then butylene glycol is added. The remaining ingredients are mixed together and added to the first mixture, The mixing is continued until uniform. Optionally, 0.16 g of sodium perborate can be added.  
         [0061]    The gel can be used to prevent the transmission of group B streptococcus to newborns or the transmission of STD.  
       Example 4  
       [0062]    A lubricant is prepared by admixing the following ingredients.  
                                                                 Ingredients   % W/W                                        Hispagel   20.0           Sodium Iodide   0.2           Flax Oil   1.0           Carbolpol 940   0.4           Butylene Glycol   6.0           Potassium hydrogen phosphate   0.1           Citric Acid   0.5           Saffron   0.2           Urea hydrogen peroxide   0.1           Deionized Water   q.s.               100%                      
 
       Example 5  
       [0063]    A lubricating gel, which can be used with a condom, prepared by admixing the following ingredients:  
                                                 Ingredients   % W/W                                1.   Propylene Glycol   43.00       2.   Polyacrylic acid   2.10       3.   Dipropylene Glycol   16.00       4.   Xantham Gum   0.15       5.   Ethoxydiglycol   15.00       6.   Dimethylisosorbide   10.00       7.   Ascorbic Acid   2.00       8.   Chloroxylenol   0.20       9.   Linoleamidopropyl PG-diammonium   1.50           chloride phosphate       10.    Glycereth 4.5 Lactate   2.00       11.    Sodium iodide   1.00       12.    Sodium hydrogen phosphate   1.00       13.    Octoxynol-9   0.50       14.    Sodium Perborate   1.00       15.    Cocamidopropyl PG-dimon           chloride phosphate   1.00       16.    Water   q.s.               100%                  
 
         [0064]    Ingredients 1 and 2 are mixed to disperse and form a gel. About 80% of ingredient 3 is mixed with ingredient 4, added to the gel and slightly heated with admixture. The balance of 3 is mixed with ingredients 5-16 and added to the gel at 38 degrees C. After mixing, the pH is adjusted to about 4 and then the gel is brought to room temperature.