Abstract:
Disclosed are water based, viscoelastic compositions comprising a mixture of high molecular weights hyaluronic salts and water soluble poly(ethylene oxides). Also disclosed are cosmetic formulations including said compositions.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to hyaluronate based compositions, and more particularly, to such compositions, including in addition to hyaluronate, a high molecular weight poly(ethylene oxide). The invention also relates to cosmetic formulations comprising such compositions. 
     2. The Prior Art 
     Hyaluronic acid (hereinafter referred to as &#34;HA&#34;) as well as its salts, such as sodium hyaluronate and other alkali metal and alkaline earth metal salts (hereinafter referred to as &#34;NaHA&#34;) is a known, naturally occurring high viscosity glycosaminoglycan having alternating β 1-3 glucuronidic and β 1-4 glucosaminidic bonds. The molecular weight of this material is generally within the range of 50,000 to 8,000,000 (although there are reports of HA having molecular weights as high as 13,000,000) depending on the source, method of isolation and method of determination. It is found in animal tissue, e.g., in umbilical cord, vitreous humor, synovial fluid, rooster combs, group A and C hemolytic streptococci and in skin. 
     The isolation and characterization of HA is described in Meyer et al, J. Biol. Chem. 107, 629 (1934); J. Biol. Chem. 114, 689 (1936); Balazs Fed. Proc. 17, 1086 (1958); Laurent et al; Biochim. Biophys. Acta 42, 476 (1960). The structure of HA was elucidated by Weissman et al, J. Am. Chem. Soc. 76, 1753 (1954) and Meyer, Fed. Proc. 17, 1075 (1958). 
     For certain uses, extremely pure HA preparations are required; see, for example Balazs U.S. Pat. No. 4,141,973, which describes the preparation and use of such an HA. 
     Poly(ethylene oxides) are known water soluble non-ionic homopolymers of ethylene oxide having molecular weights up to 5,000,000. Aqueous solutions of these polymers are highly viscoelastic and are known to be used in many areas including adhesives, lubricating agents, coatings, cosmetics, etc. 
     Poly(ethylene oxide) is also known to form strong association complexes with a large number of other materials, such as urea, phenolics, poly(acrylic acid), etc. The reaction products formed between poly(ethylene oxide) and polymeric polycarboxylic acids are insoluble in hot and cold water. (U.S. Pat. No. 3,387,061). 
     Poly(ethylene oxide) is known to be used in cosmetics. See, e.g., U.S. Pat. Nos. 2,991,229; 3,783,872; 3,811,349 and 4,192,862. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a graph showing the specific viscosity of various mixtures of a poly(ethylene oxide) and sodium hyaluronate described in examples 1-5; and 
     FIG. 2 is a graph showing the specific viscosity of an aqueous solution of 1:1 mixture of poly(ethylene oxide) and sodium hyaluronate at differing polymer concentrations (example 6). 
    
    
     SUMMARY OF THE INVENTION 
     Water based, highly viscoelastic substances are very useful in cosmetic formulations because they impart to such formulations a smooth, silky texture which is desirable both in terms of the function and aesthetic appeal of cosmetics. One such substance is Hyladerm® (Biomatrix, Inc.) which is described in U.S. Pat. No. 4,303,676. These hyaluronate compositions are expensive and thus, the art has been seeking ways to easily provide such substances at relatively low cost. 
     While U.S. Pat. No. 3,387,061 suggests that the reaction products of a poly(ethylene oxide) and polymeric polycarboxylic acids are water insoluble, we have now found, quite unexpectedly, that when aqueous solutions of a hyaluronic acid salt and a high molecular weight poly(ethylene oxide) are mixed together, no water insoluble products are formed, even though hyaluronic acid is a polymeric polycarboxylic acid. Instead, what is observed is a highly viscoelastic substance in which the viscosity of the mixture is substantially in excess of the sum of the individual viscosities of the hyaluronate and the poly(ethylene oxide). This wholly unexpected property makes the resulting mixtures particularly well suited for use in cosmetic formulations both because of the desirability of the vastly increased viscosity and the reduced cost of the substance as compared with a like amount of a hyaluronate composition without the poly(ethylene oxide). 
     Accordingly, the invention provides, in one aspect thereof, water based, viscoelastic compositions comprising a mixture of a hyaluronate, preferably an alkali metal or alkaline earth metal hyaluronate, and most preferably, sodium hyaluronate and a poly(ethylene oxide). 
     In another aspect, the invention provides cosmetic formulations comprising the composition in admixture with other, conventional additives used in cosmetics, including surfactants, thickeners, moisturizing agents, fibers, pigments and dyes and fragrances. 
     DETAILED DESCRIPTION OF THE INVENTION 
     As noted above, the invention provides highly viscoelastic compositions comprising a mixture of a hyaluronate and a poly(ethylene oxide). Generally speaking, hyaluronates are more viscous than poly(ethylene oxides) and poly(ethylene oxides) are more elastic than hyaluronates. Moreover, suitable hyaluronates are quite expensive to produce. Notwithstanding the teaching in prior U.S. Pat. No. 3,387,061, we have found that when a composition according to the invention is produced, the result is a water soluble product having the desirable properties of both the hyaluronate and the poly(ethylene oxide) at a much reduced cost. 
     In accordance with the invention, as the hyaluronic acid salt there can be used a pure HA salt, for example, an alkali or alkaline earth metal salt; or a mixture of hyaluronates containing proteins and other naturally occurring substances, such as the product described in U.S. Pat. No. 4,303,676, the contents of which are incorporated herein by reference. Generally, the hyaluronate used in the invention will have a molecular weight in the range of about 1×10 6  -5×10 6 . 
     The poly(ethylene oxide) can be any water soluble linear homopolymer of ethylene oxide having a molecular weight of about 1×10 6  -5×10 6 . Such poly(ethylene oxides) are available from Union Carbide Corporation (Polyox® brand) and a particularly suitable grade of Polyox® is that which is identified as &#34;Polyox® Coagulant&#34; in the Union Carbide Corporation publication entitled &#34;Polyox®--Water Soluble Resins Are Unique&#34; © 1967, 1972, 1973, 1978, 1981 by Union Carbide Corporation. This poly(ethylene oxide) has an average molecular weight of 5×10 6  and a viscosity (1% solution) of 4,500-6,500 cps at 25° C. The relative concentration of each of the components in the mixture can be from 0.01 to 2%. The ratio: hyaluronate:poly(ethylene oxide) in the mixture can be from 1:50 to 100:1 by weight. 
     Cosmetic formulations according to the invention can be made containing widely varying amounts of the aforesaid mixtures, i.e., from 0.1 up to about 50% of a hyaluronate-poly(ethylene oxide) mixture depending on the nature of the cosmetic product and the performance characteristics desired by such formulation. Again, depending upon the type of formulation, it will contain various cosmetic ingredients such as emollients, sugar alcohols, neutral or anionic polysaccharides, preservatives (which do not react with or degrade the hyaluronate), fragrances, water and the like. These latter materials are all conventional in the art and well known to cosmetic chemists. Included among the cosmetic formulations are moisturizing creams and lotions, shampoos, liquid soaps, shaving cream, eye cream, lip protective creams and make-up, as well as eye drops. 
     The invention will now be described in greater detail in the following examples which are illustrative of the invention without, however, being a limitation thereof. 
     EXAMPLE 1 
     A 1% aqueous solution of Polyox® coagulant (molecular weight about 5,000,000, Union Carbide Corp.) was mixed with BIOMATRIX™ sodium hyaluronate (0.5% water solution of sodium hyaluronate, which includes large amounts of proteins, molecular weight about 2,000,000) and water in such proportions to obtain a mixture which contains 0.5% of poly(ethylene oxide) and 0.05% of sodium hyaluronate. The specific viscosity ηsp of the mixture was 451. The individual specific viscosities of an 0.5% solution of poly(ethylene oxide) and an 0.05% solution of sodium hyaluronate were 100 and 11, respectively. Thus, the additive value for the mixture of the two is 111, whereas the real or actual value of ηsp for the mixture is about four times greater than the additive value which would be expected. 
     EXAMPLE 2-5 
     The above example was repeated with different mixtures having different hyaluronate/poly(ethylene oxide) ratios. The specific viscosities of the mixtures of the solutions of poly(ethylene oxide) and sodium hyaluronate of the corresponding concentrations, and also, the calculated additive values are presented in FIG. 1. They are also set forth in Table I. 
     
                       TABLE I______________________________________   Specific ViscosityExample             additive value                           actual value______________________________________1     NaHA    11        111       451 Polyox  1002     NaHA    12.5      54.5      250 Polyox  423     NaHA    15        35        137.5 Polyox  204     NaHA    15        225       70 Polyox  7.55     NaHA    17.5      20        37.5 Polyox  2.5______________________________________ 
    
     From these data it can be seen that the real value for each mixture is substantially greater than the calculated or additive value. 
     EXAMPLE 6 
     Several mixtures were prepared from a 1% water solution of Polyox® coagulant and BIOMATRIX™ sodium hyaluronate with the ratio of two polymers being 1:1 and with different concentrations of polymers in the mixtures. The ηsp values are plotted in FIG. 2 against polymer concentrations. For these mixtures the measured values of ηsp are seen to be substantially greater than the additive values. 
     EXAMPLE 7 
     A 1% water solution of Polyox® coagulant and Hyladerm® (1% water solution of sodium hyaluronate, protein content 0.01%, molecular weight 4,000,000, Biomatrix, Inc.) were mixed with water in such a proportion that the resulting mixture contains 0.05% of each polymer. The ηsp of the mixture was 91. The specific viscosity of the poly(ethylene oxide) and sodium hyaluronate solutions of corresponding concentrations were, respectively, 1.8 and 39. The additive value thus is 40.8 is less than half of the actual value for the mixture. 
     The following examples (8 and 9) are directed respectively to a shaving cream and a moisturizing eye cream. 
     EXAMPLE 8 
     A shaving gel formulation as set forth below was prepared. 
     
         ______________________________________                 % by weight______________________________________Sodium hyaluronate, 1% solution                   2.56(Hyladerm ®, Biomatrix, Inc.)Poly(ethylene oxide), 1% solution                   0.36(Polyox ® coagulant)Polyacrylic acid (thickener)                   0.41(Carbopol 940 ®, B. F. Goodrich)Triethanolamine         0.41Hydroxyethylcellulose, 1% solution                   8.2(Cellosize ®, Union Carbide Corporation)Squalene                0.20Robane ®, Robeco Chemicals, Inc.)Coconut oil             0.31(Cochin ®, Acme-Hardesty Co., Inc.)Preservative            0.26Fragrance               0.26Water                   87.0______________________________________ 
    
     To prepare this formulation, the Carbopol resin was dispersed in water, after which all the other components but triethanolamine were added with stirring. Then the triethanolamine was stirred in. The formulation obtained is a translucent, viscous gel-like mixture. When tested as a shaving gel it gave very good results by providing a smooth and clean shave. Furthermore, this shaving gel provided moisturizing action and could be left on the skin after shaving. 
     EXAMPLE 9 
     This example illustrates a moisturizing eye gel. 
     
         ______________________________________                  % by weight______________________________________A.   Hyladerm ®          2.0Polyox ®, 1% water solution                        0.4Carbopol ® 940      0.4Water                   90.9B.   Liponic ® EG-1 (Lipo Chemicals, Inc.)                        0.55 (Croda, Inc.).1.0Solulan ® C-24 (Amerchol Co.)                        1.0Crodafos ® N3 neutral (Croda, Inc.)                        0.8Robane ®            1.0Crodamol ® PMP (Croda, Inc.)                        0.5Glucam ® E-10 (Amerchol Co.)                        0.7Preservative            0.3C.   Triethanolamine         0.4Fragrance               0.1______________________________________ 
    
     This formulation is prepared in separate stages as follows: Part A of the mixture was prepared by dispersing the Carbopol in water and then stirring in the other components. All the Part B components were mixed together and heated to 70° C. Parts A and B were then combined and the triethanolamine and fragrance were added. The resulting cream was stable and smooth and had good moisturizing qualities and an excellent feel on the skin. 
     The following examples 10-11 illustrate, respectively, formulations for a moisturizing hand lotion and an emollient moisturizing cream. 
     EXAMPLE 10 
     
         ______________________________________               parts by weight______________________________________Hyladerm ®        2.5Polyox ®, 1% water solution                 0.3Glycerine             5.0Ethyl alcohol         15.0Oleth-5               2.0(Lipocol ® 0-5. Lipo Chemicals, Inc.)Glucam ® E-10     0.7Preservative          0.3Fragrance             0.15Water up to           100.00______________________________________ 
    
     The formulation was prepared by mixing all the components together. 
     EXAMPLE 11 
     
         ______________________________________             parts by weight______________________________________A.    Hyladerm ®    2.5 Polyox ®, 1% water solution                   1.5 Carbopol ® 940                   0.5 Water             83.5B.    Petrolatum        5.0 Robane ®      2.0 Lanoxide ® 59 2.5 Silicone Copolymer ® F-754                   1.5 Preservative      0.3C.    Triethanolamine   0.5 Fragrance         0.1______________________________________ 
    
     This formulation was prepared in separate stages as described in example 9. The resulting cream was rich with excellent moisturizing qualities and did not give a greasy feeling on the skin. 
     The invention also includes within its scope eye drop formulations, including both eye drop formulations containing one or more preservatives to ensure stability of the formulation in an already opened container of the product as well as eye drop formulations in single dose forms without preservative. Such non-preservative containing formulations are desirable because certain users have eyes that are sensitive to the commonly used preservatives. Such formulations according to the invention are feasible because as a result of the very low protein content of the hyaluronate used, the formulation will not support the growth of most microorganisms and, therefore, the need for preservatives is avoided. 
     The following examples 12 and 13 illustrate, respectively, eye drop formulations with and without preservatives. 
     EXAMPLE 12 
     
         ______________________________________            parts by weight______________________________________Hyladerm ®     2.00Polyox ®, 1% water solution              2.20Benzalkonium chloride              0.01Disodium edetate   0.05Water up to        100.00______________________________________ 
    
     The formulation, when applied into an eye, gives a very comfortable feeling. 
     EXAMPLE 13 
     
         ______________________________________            parts by weight______________________________________Hyladerm ®     0.45Polyox ®, 1% water solution              0.20Water up to        100.00______________________________________ 
    
     EXAMPLE 14 
     Single Dose Non-Preserved Eye Drop 
     The formulation of example 13 which does not contain a preservative was packed in 0.2 ml sterile plastic containers and used as eye drops for a single application. The amount can vary from about 0.1-0.5 ml, but 0.2 ml is the preferred amount. 
     Certain ingredients set forth in the formulations of examples 8-13 are identified by trademarks. The following is a list of the chemical names of these ingredients. 
     
         ______________________________________Liponic ® Eg-1           Glycereth-26 (polyethylene           ether of glycerin)Volpo-5 ®   Oleth-5 (polyethylene glycol           ether of oleyl alcohol)Solulan ® C-24           Choleth-24 (polyethylene glycol           ether of Cholesterol)Crodafos ® N3 neutral           DEA-Oleth-3 Phosphate (die-           thanolamine salt of a com-           plex mixture of esters of           phosphoric acid and Oleth-3)Crodamol ® PMP           (propoxylated myrisryl pro-           pionate) PPG-3 Myristyl           Ether Propionate)Glucam ® E-10           Methyl gluceth-10 (poly-           ethyene glycol ether of           methyl glycose)Lanoxide ®  Polyoxyethylene glycol ether           of stearic acid, Lanaetex           Products, Inc.______________________________________ 
    
     Variations and modifications can, of course, be made without departing from the spirit and scope of the invention.