DENTIFRICE CONTAINING ALGINATE CALCIUM CHELATING AGENT

Abstract: A dentifrice composition effective to weaken the structure of dental plaque to permit easier removal comprises an effective amount of a water-soluble salt of alginic acid to produce a substantial reduction in the amount of dental plaque on teeth of a user, and a carrier acceptable for use in the oral cavity, said dentifrice being substantially devoid of a source of calcium ions.

Description: DENTIFRICE CONTAINING ALGINATE CALCIUM CHELATING AGENT BACKGROUND OF THE INVENTION Field of the Inventiont This invention relates to dentifrice compositions and more particularly to dentifrices containing a chelating agent which facilitates the removal of dental plaque. Description of the prior art: In recent years dental research has achieved a very good understanding of the overall mechanisms in¬ volved in tooth decay and has determined that it is the localized demineralization of tooth enamel, usually also of dentin, that leads eventually to the formation of a cavity. This demineralization is produced by organic acids that penetrate the surface of the enamel. The acids in turn are formed by the action of specific bacteria, especially Streptococcus mutans, on sugars and other fermentable carbohydrates present in plaque adhering to the teeth. Dental plaque consists of about 70% bacteria with the remainder being composed of bacterial products such as dextran-type polysaccharides, enzymes, acids and components of the saliva. It is a white or off-white substance of variable thickness and contains specific bacteria which form the polysaccharides that enable the micro-organisms to stick to the teeth and to each other. Consequently, plaque confines the acidic meta¬ bolic products of the bacteria, principally lactic acid, in close contact with the tooth surface where they decompose the hydroxyapatite in the enamel, and eventually form a cavity. The plaque also eventually becomes calcified to form calculus, a hard deposit which can irritate the gums and contribute to periodon- tal disease. The conventional method of combating plaque forma¬ tion on teeth is to mechanically remove it by brushing, usually employing a dentifrice which contains some detergent and a mild abrasive. This type of removal is not entirely effective, because the plaque is very adherent to the teeth and its removal requires careful and prolonged brushing in the proper manner. Such careful brushing is tedious, and neglected by people who eventually end up with tooth decay. A number of chemical anti-microbial materials have been added to dentifrice to aid in combating the forma¬ tion of plaque. Chlorhexidine, for example, has been incorporated in a dentifrice as an antimicrobial to kill the plaque-forming bacteria. Such techniques have achieved some success in preventing plaque but such anti-microbials have an offensive taste which cannot be masked in dentifrice- or other oral preparations. Also, certain questions have been raised about the long term toxicity of these agents. Certain other chemical substances which are chela- tors for calcium ions have been used in dentifrices to aid in removal of plaque. For example, British Patent 490,384 discloses the use of ethylenediamine-tetra- acetic acid (EDTA), nitrilotriacetic acid and their salts and related compounds as agents to prevent the formation of plaque and calculus. German Auslege- schrift 1,149,138, published May 22, 1963, discloses the use of certain water-soluble diglycolates to pre- vent calculus. U. S. Patent 1,516,206 discloses the use of certain sugar lactones in oral compositions for the prevention of calculus. McCune et al., U.S. Reis- sue Patent No. 29,182, discloses the use of certain polyphosphonic acids and their salts in oral prepara¬ tions for retarding the formation of dental calculus. These chemicals have certain drawbacks. Some of them, e.g., EDTA, have too strong a chelating power and may damage the tooth enamel. All of them are synthetic compounds which may have a certain toxicity or a sensi¬ tizing effect, especially when the user is exposed to their relatively frequent contact over a long period. SUMMARY OF THE INVENTION In accordance with the present invention, a denti¬ frice composition is provided which incorporates as an essential ingredient a water-soluble alginate or a mixture of water-soluble alginates which are effective in causing the removal of dental plaque. Such use of water-soluble alginates, and the discovery of their calcium chelating effect in combatting plaque, repre¬ sents a unique concept in dental hygiene. The alginates utilized in the invention are preferably low viscosity, water-soluble alkali metal salts of alginic acid or a mixture of low- and medium- viscosity water-soluble salts of such acid. Such algi¬ nates are utilized in an amount sufficient to weaken the structure of plaque by forming a complex with cal- cium ions contained in that structure, whereupon the complex is diffused out and washed away with water and saliva. Accordingly, it is an object of this invention to provide an improved dentifrice for combatting dental plaque. A further object is to provide a dentifrice which contains substances aiding in the removal of dental plaque. A still further object is to provide a dentifrice containing a calcium ion chelating agent. An additional object is to provide a dentifrice containing a calcium ion chelating agent which is essentially non-toxic. Another object is to provide a dentifrice contain- ing a water-soluble alginate or alginate composition in a sufficient amount for the effective removal of dental plaque. Further objects will become apparent from the description of the invention which follows. It should be apparent in view of the mechanism described above that it is important that the denti¬ frice not contain a significant amount of calcium ions, although it may contain conventional materials which are substantially devoid of such ions such as enzymes, sudsing agents, binders, humectants, flavoring and sweetening agents. The dentifrice of this invention will typically contain from about 1.5% to about 15% by weight (based on total weight) of a water-soluble algi¬ nate or mixture of such alginates. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Alginic acid is a polysaccharide made up of D- mannuronic acid and L-guluronic acid residues. It is produced from brown seaweeds (Phaeophycae) through an extraction process. Depending on the particular species of seaweed and the method used in extraction, alginates of various molecular weights can be prepared. The higher molecular weight alginates form viscous solutions in water at relatively low concentra- tions, e. g. , 1 % by weight, and hence have found utility as viscosity adjusting agents in foods and dentifrices. However, alginates have not been used previously in combatting dental plaque. It has now been found that water-soluble algi- nates, particularly water-soluble salts of alginic acid, are effective calcium ion chelating agents which can be incorporated into a dentifrice in amounts suffi¬ cient to remove a significant proportion of calcium ions from the plaque. It is believed that the calcium ions in the plaque contribute to its mechanical strength, and that their removal weakens the plaque so that it will dissolve, or at least can be more easily removed by brushing. The water-soluble alginates used in this invention are generally the alkali metal salts of alginic acid but sodium alginate is used in a preferred embodiment. The lower molecular weight algi¬ nates have a smaller viscosity-increasing effect in aqueous solutions and, accordingly, larger amounts of these alginates can be incorporated without excessive increase in viscosity. The term "dentifrice" as used herein is intended to include mouthwash, chewing tablets, lozenge tablets, and chewing gum as well as tooth-paste, -gel, -cream or -powder. The use of such alginates, when used in an effec- tive amount, will result in a substantial reduction in dental plaque. Any amount which is sufficient in achieving the desired substantial reduction in plaque is an effective amount. However, in general, the effective amount of water-soluble alginate used in this invention will be between about 1.5 percent to about 15 percent by weight, based on the total weight of the dentifrice. Alginates of relatively high molecular weight, the so-called medium-viscosity alginates, can be incorporated into a dentifrice formulation of this invention, but in amounts in excess of about 1.5 % by weight the viscosity becomes too great for practical utility. Accordingly, all, or a substantial propor¬ tion, of the water-soluble alginates should be low- viscosity alginates. Thus, up to 15 % by weight of the low-viscosity water-soluble alginates may be incorpo¬ rated into the dentifrice of this invention. While the alginates represent an essential ingred¬ ient of the desired formulation, various other materials may be incorporated in the dentifrice preparations of this invention which comprise the so- called carrier composition. Examples thereof are enzymes, sudsing agents, binders, humectants, coloring agents, preservatives, sweetening, and flavoring agents. These adjuvants are incorporated in amounts which do not substantially adversely affect the proper- ties and characteristics desired and are selected and used in proper amounts depending upon the particular type of preparation involved. Merely by way of example, a dentifrice according to this invention may incorporate a humectant in order to provide a means for preventing the formulation from drying out and becoming too hard, or to provide a moist feel to the mouth in the case of mouthwashes. Typical humectants include glycerol, sorbitol, maltitol, glu¬ cose, propylene glycol, polyethylene glycols of various molecular weights and the like. A preferred humectant is glycerol. The humectant can comprise up to 36% by weight of the dentifrice composition. The dentifrice of this invention must be devoid of substantial amounts of compounds which can supply cal- ciu ions or other divalent metal ions which can form chelates with alginates, since such materials would saturate the calcium chelating potential of the algi¬ nate and destroy its ability to remove calcium ions from the plaque. Accordingly, in toothpastes according to the invention, many conventional toothpaste abra¬ sives such as calcium phosphate, calcium carbonate and the like cannot be used in this invention. However, abrasives such as silica in its various forms, insolu¬ ble sodium metaphosphate, hydrated alumina,magnesium carbonate and the like can be effectively used in this invention. The abrasives may be incorporated in amounts up to about 35% by weight. In some embodiments of this invention, for example mouthwashes, toothpastes, and the like, a sudsing agent or surfactant will be included. Suitable surfactants include cationic, nonionic and amphoteric synthetic detergents. Useful cationic synthetic detergents can be broadly defined as quaternary ammonium compounds having 1 long alkyl chain containing from about 8 to about 18 carbon atoms such as lauryl trimethylammonium chloride; cetyl pyridinium chloride; cetyl trimethylam- monium bromide; di-isobutylphenoxyethoxyethyldimethyl- benzylammonium chloride; coconutalkyltrimethylammonium nitrite; cetyl pyridinium fluoride and the like. The amphoteric synthetic detergents useful in the present invention can be broadly described as deriva- tives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight chain or branched and wherein one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phospho- nate. Examples of compounds falling within this defi¬ nition are sodium 3-dodecylaminopropionate, sodium 3- dodecylaminopropane sulfonate, dodecyl-beta-alanine, N- alkyl-taurines all of which are well-known and prepared by conventional procedures. See, for example, U. S. Patent 2,658,072 to Kosmin. The sudsing agent can be present in the compositions of this invention in an amount from about 0.5% to about 5% by weight of the total composition. A water-soluble fluoride compound may also be present in an amount sufficient to give a fluoride concentration of from about 0.0025% to about 5.0% by weight, preferably from about 0.005% to about 2.0% by weight, to provide additional anticaries effec- tiveness. Suitable fluoride sources are well known in the art. Preferred fluorides are sodium fluoride, stannous fluoride, indium fluoride, and sodium mono- fluorophosphate. U. S. Patent 3,959,458 discloses dentifrice compositions containing such fluoride sources. In an important additional embodiment of the invention, the plaque combatting effect of the alginate ingredient in the dentifrice composition as previously described is supplemented with an effective amount of an enzyme material selected from any of the enzymes which are known to be useful in dental hygiene. Such enzymes are well known and comprise a broad spectrum including those which act according to hydrolysis, oxidation or reduction modes of action. Typical of such enzymes are proteases such as pepsin, pancreatin, trypsin and the like or amylases and glucose oxidase. The amount of such enzymes incorporated in dentifrices is rather widely known. A preferred enzyme is dextra- nase which in a typical dentifrice formulation will be present to the extent of 100-200,000 units (1 unit equals enzyme activity needed to produce one milligram equivalent of isomaltose monohydrate in one hour at 40 degrees C.) per gram of formulation. A typical denti¬ frice of the invention will contain from about 0.005 % to about 0.05 % by weight of dextranase having an potency of 15,000 units per milligram. In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consis¬ tency. Preferred thickening agents are methyl cellu¬ lose, hydroxyethyl cellulose and water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can also be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used. A preferrred toothpaste of the invention includes from about 3% to about 15% by weight of polyvinylpyr- rolidone having a molecular weight from about 30,000 to about 90,000, which enhances the adhesion of the tooth- paste to the tooth surface. This adhesion brings the water-soluble alginate chelating agent into better contact with the plaque, thereby increasing its effect on weakening the mechanical structure of the plaque. Flavoring agents are also commonly added to dental compositions and may be added to this invention as well. Suitable flavoring agents include oil of winter- green, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents which can be used include saccharin, dextrose, levulose and sodium cycla ate. Flavoring agents are generally used in dentifrices at levels of from about 0.01% to 2% by weight and sweetening agents at levels of from about 0.05% to about 2% by weight. The dentifrice compositions of this invention may be prepared by any conventional means and with any of the commonly used ingredients, so long as they are substantially devoid of calcium or other divalent ions which form chelates with alginates. For example, mouthwash components can comprise the carrier for the alginate chelators of the present invention. Mouth¬ washes generally comprises a water/ethyl alcohol solu¬ tion and preferably other ingredients such as flavor, sweeteners, humectants and sudsing agents such as those mentioned above for dentifrices. The humectants, such as glycerine and sorbitol, give a moist feel to the mouth. Generally, on a weight basis the mouthwashes of the invention comprise 5% to 60% (preferably 10% to 25%) ethyl alcohol; 0% to 20% (preferably 5% to 20%) glycerine or other humectant; 0% to 2% (preferably 0.1% to 1.5%) sudsing agent; 0% to 0.5% (preferably 0.05% to 0.5%) sweetening agent such as saccarin; and 0% to 0.3% (preferably 0.05% to 0.3%) flavoring agent; and the balance water. The amount of bis-biguanide antibacte¬ rial agent in mouthwash is typically from about 0.01% to about 1.2% by weight. The invention will now be illustrated by the fol- lowing examples which are not intended to be limiting. All parts and percentages are by weight. EXAMPLE 1 This example depicts a mouthwash composition according to this invention. Ingredient % by weight sodium alginate (very low viscosity) 5.0 % aromatic substances 1.0 % p-amino benzoic acid (PAB)-esters 0.15 % disodium phosphate O aq. 1.5 % citric acid 1 aq. 1.0 % ethyl alcohol 10.0 % distilled water up to 100.0% EXAMPLE 2 This example depicts a chewing tablet composition according to this invention. Ingredient % by weight carbowax 6000 2.0 % aromatic substances (micro-capsules) 0.5 % coloring matter 0.1 % Na-fluoride 0.1 % sodium alginate 6.0 % mannitol up to 100.0 % EXAMPLE 3 This example depicts a chewing gum composition according to this invention. Ingredient % by we ight gum basis 14. .0 % sorbitol (70% solution) 25. , 0 % aromatic substances 0. .5 % sodium alginate 7. , 0 % sorbitol up to 100 , . 0 % EXAMPLE 4 This example depicts a lozenge tablet composition according to this invention. Ingredient % by we ight calcium gluconate 57. 0 % annitol 30.0 % aromatic substances 1. 0 % sodium carboxymethylcellulose 2. 0 % sodium alginate 10. 0 % EXAMPLE 5 This example illustrates the preparation of a toothpaste according to the invention. The following two solutions were prepared by thoroughly mixing the ingredients. The percentages given are based on the total weight of the final product. A. water 47.7 % sodium dodecyl sulfate 0.5 % benzalkonium chloride 0.1 % glycine 4.0 % trisodium citrate dihydrate 1.0 % blue food coloring 0.05 % sodium fluoride 0.1 % polyvinylpyrrolidone (MW 30,000) 10.0 % 5 B. glycerol 30.0 % sodium alginate (medium viscosity) 1.5 % sodium alginate (low viscosity) 5.0 % peppermint oil 0.05 % Solution B, which is a rather viscous compositin, 0 must be mixed thoroughly. Solution B is then added to solution A with vigorous stirring. The toothpaste preparation is complete when the two solutions have been uniformly blended. The effectiveness of this toothpaste in removing 5 plaque was evaluated by the following experiment. Extracted teeth having plaque thereon were paired as closely as possible, then treated for 60 seconds with a commercially available plaque disclosing dye solution to dye the plaque and make it readily 20 . visible. The teeth were then rinsed for 60 seconds to remove excess disclosing solution, leaving the teeth with the dyed plaque clearly disclosed. The teeth were then brushed for 60 seconds, one tooth of each pair being brushed using the toothpaste of this invention 25 and the other being brushed using a commercially available gel toothpaste that contained no chelating agent. Conventional soft toothbruses (Oral B β ) were used. The teeth were then evaluated by estimating the amount of dyed plaque remaining on the teeth. It was 30 found that the teeth brushed using the toothpaste of this invention had much less plaque remaining than the teeth brushed with the commercial gel toothpaste. The plaque remaining on the teeth brushed with the tooth¬ paste of this invention was mostly confined to the pits 35 and fissures where the brush bristles did not reach it. As a control, the teeth of each pair were then switched, and the tooth initially brushed with the commercial gel toothpasete was brushed with the tooth¬ paste of this invention, and vice versa. It was found that the plaque remaining on the tooth initially brushed with the commercial toothpaste was almost com¬ pletely removed by the toothpaste of this invention and the appearance was similar to that of the tooth initially brushed with the toothpaste of this inven¬ tion. This establishes that the difference in plaque removal on the initial brushing was not due to syste¬ matic differences in the durability of the plaque on the teeth. EXAMPLE 6 This example illustrates a further embodiment of the present invention. A toothpaste having the following composition was prepared by the process of Example 1: A. glycine 4. 0 % trisodiu citrate 1. 0 % sodium dodecyl sulfate 0. 5 % water q. s. p. 100. 0 % B. glycerol 30. 0 % sodium alginate (low viscosity) 7 . 0 % EXAMPLE 7 This example illustrates another toothpase accord¬ ing to the invention. A toothpaste having the following composition was prepared by the procedure of Example 1: A. glycine 4. 0 % trisodium citrate 1. 0 % sodium dodecyl sulfate 0. 5 % polyethylene glycol (M. W. 8000) 7. 5 % water q. s. p. 100.0 % B. glycerol 30. 0 % sodium alginate (low viscosity) 7 .0 % EXAMPLE 8 This example illustrates an additional embodiment of the invention. A toothpaste having the following composition was prepared by the procedure of Example 1: A. glycine 4. 0 % trisodium citrate 1 . 0 % sodium dodecyl sulfate 0. 5 % benzalkonium chloride 0.1 % water q. s. p. 00. 0 % B. glycerol 30. 0 % sodium alginate (low viscosity) 5. 0 % methyl cellulose 2.0 % EXAMPLE 9 This example illustrates a tooth-gel of the inven- tion containing a magnesium compound. water 64.05 % trisodium citrate 1.0 % sodium lauryl sulphate .5 % sorbitol powder 10.5 % FDC blue 1 (1% solution) 0.05 % FDC yellow (1% solution) 0.15 % glycerine 15.0 % sodium alginate TCU/53 6.5 % methyl paraben 0.2 % protenal MgF 10/60 2.0 % flavour 0.05 % Thus a preferred toothpaste of the invention includes a quantity of a magnesium conpound, e.g., MgF2, which may be present in amounts from about 0.2 % to about 3 % by weight. The invention having now been fully described, it should be understood that it may be embodied in other specific forms or variations without departing from its spirit or essential characteristics. Accordingly, the embodiments described above are to be considered in all respects as illustrative and not restrictive; the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims: WHAT IS CLAIMED IS: 1. A dentifrice composition comprising an effective amount of a water-soluble salt of alginic acid to pro¬ duce a substantial reduction in the amount of dental plaque on teeth of a user, and a carrier acceptable for use in the oral cavity said dentifrice being substan¬ tially devoid of a source of calcium ions. 2. The dentifrice of Claim 1 wherein said water solu¬ ble salt of alginic acid is present in an amount of from about 1.5 percent to about 15 percent by weight. 3. The dentifrice of Claim 1 wherein said water-solu¬ ble salt of alginic acid is an alkali metal alginate. 4. The dentifrice of Claim 3 wherein said water-solu¬ ble salt of alginic acid is sodium alginate. 5. The dentifrice of Claim 1 wherein said water-solu¬ ble salt of alginic acid is low viscosity sodium algi¬ nate. 6. The dentifrice of Claim 1 wherein said water-solu¬ ble salt of alginic acid is a mixture of low viscosity sodium alginate and medium viscosity sodium alginate. 7. The dentifrice of Claim 6 wherein said medium vis¬ cosity sodium alginate is present in an amount of from about 0.5 percent to about 1.5 percent by weight and said low viscosity sodium alginate is present in an amount of from about 2 percent to about 15 percent by weight. 8. The dentifrice of Claim 1 wherein said water-solu¬ ble salt of alginic acid is a very low viscosity sodium alginate. 9. The dentifrice of any one of claims 1 through 8 wherein said carrier includes an enzyme. 10. The dentifrice of Claim 9 wherein said enzyme is dextranase. 11. The dentifrice of Claim 10 wherein said dextranase is present in amount of about 100 to about 200,000 units per gram. 12. The dentifrice of Claim 10 wherein said dextranase is present in an amount of from about 0.005 % to about 0.05 % by weight of dextranase having a potency of about 18,000 units per milligram. 13. The dentrifice of Claim 1 wherein said dentrifice is a toothpaste. 14. The dentrifice of claim 1 additionally comprising a magnesium compound. 15. A mouthwash composition comprising Ingredient % by weight sodium alginate (very low viscosity) 1.5 - 15 ethyl alcohol 5 - 60 humectant 0 - 20 sudsing agent 0 - 1.5 sweetener 0 - 0.5 flavoring agent 0 - 0.3 water balance 16. A tooth gel composition comprising Ingredient % by weight water 64.05 % trisodiumcitrate 1.0 % sodium lauryl sulphate 0.5 % sorbitol powder 10.5 % FDC blue 1 (1% solution) 0.05 % FDC yellow 5 (1% solution) 0.15 % glycerine 15.0 % sodium alginate TCU/53 6.5 % methyl paraben 0.2 % protenal MgF 10/60 2.0 % flavour 0.05 % 17. A process for removing plaque from plaque-contain¬ ing teeth comprising applying to said plaque a dentifrice comprising an effective amount of a water-soluble salt of alginic acid to produce a substantial reduction in the amount of dental plaque on teeth of a user, and a carrier acceptable for use in the oral cavity, said dentifrice being substantially devoid of a source of calcium ions. maintaining said dentifrice in contact with said plaque for a sufficient period of time to weaken the structure of the plaque, and removing the weakened plaque from the teeth. 18. The process of Claim 17 wherein said weakened plaque is removed by rinsing 19. The process of Claim 17 wherein said water soluble salt of alginic acid is present in an amount of from about 1.5 percent to about 15 percent by weight. 20. The process of Claim 17 wherein said water-soluble salt of alginic acid is an alkali metal alginate. 21. The process of Claim 20 wherein said water-soluble salt of alginic acid is sodium alginate. 22. The process of Claim 17 wherein said water-soluble salt of alginic acid is low viscosity sodium alginate. 23. ' The process of Claim 17 wherein said water-soluble salt of alginic acid is a mixture of low viscosity sodium alginate and medium viscosity sodium alginate. 24. The process of Claim 23 wherein said medium visco- sity sodium alginate is present in an amount of from about 0.5 percent to about 1.5 percent by weight and said low viscosity sodium alginate is present in an amount of from about 2 percent to about 15 percent by weight. 25. The process of Claim 17 wherein said water-soluble salt of alginic acid is a very low viscosity sodium alginate. 26. The process of any one of Claims 17 through 25 wherein said carrier includes an enzyme. 27. The process of Claim 26 wherein said enzyme is dextranase. 28. The process of Claim 27 wherein said dextranase is present in amount of about 100 to about 200,000 units per gram. 29. The process of Claim 28 wherein said dextranase is present in an amount of from about 0.005 % to about 0.05 % by weight of dextranase having a potency of about 18,000 units per milligram. 30. A toothpaste composition comprising Ingredient % by weight water 47. . 7 % sodium dodecyl sulfate 0. . 5 % benzalkonium chloride 0. . 1 % glycine 4. , 0 % trisodium citrate dihydrate 1. , 0 % blue food coloring 0. , 05 % sodium fluoride 0. . 1 % polyvinylpyrrolidone (MW 30,000) 10. , 0 % glycerol 30. , 0 % sodium alginate (medium viscosity) 1. , 5 % sodium alginate (low viscosity) 5. , 0 % peppermint oil 0. , 05 %

Inventors: KEITH ALEC D, USHER THOMAS C, KEITH, ALEC, D., USHER, THOMAS, C.
Applicants: ZETACHRON INC, ZETACHRON, INC.
Application year: 1985
Main classification: A61K7
IPC codes: A61K8, A61Q11