Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/282—Organic compounds, e.g. fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/282—Organic compounds, e.g. fats
  • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/2873—Proteins, e.g. gelatin

Definitions

• Tablet coating is a very old art, and up to a few years ago, most tablets for human consumption were coated with sugar solutions and the like.
• Sugar coating of tablets is a very slow process and usually involves one .or more sub-coatings and up to 100 individual, but extremely thin, sugar coatings.
• Various dyes that are physiologically acceptable may be incorporated into the sugar solution to give the finished tablet a pleasing appearance.
• One method of effectively protecting the coloring agent in tablets is by absorbing the ultra-violet portion of natural light by physical means.
• the color unstable tablets are I stored in containers that filter away the ultra-violet light; 1 e.g., brown containers which have found wide acceptance in the tableting industry.
• the use of such brown containers has serious disadvantages, i.e., the content of such a container cannot be ascertained by external observation, and the container has to be opened to determine the color, shape, and size of the tablet it contains as well as the size of the remaining stock.
• a further problem is connected with the inability of these tablets to be exhibited in displays and the like.
• compositions containing a water soluble or water dispersible, plastic coating material, one or more physiologically acceptable dyes, and a minor proportion of a complexing agent for these dyes.
• tannins and albumin severally or jointly are useful agents for this complexing action.
• compounds tried for this complexing action only the above type of materials were found to protect the dye permanently when mixed with a plastic coating material; and without incurring adverse effects on the coating formulation.
• the term tannin throughout this specification and the claims refers, as generally accepted to such materials as tannic acid (penta-digalloylglycose), Vietnamese or Chinese tannin, hamameltannin, and similar high molecular weight derivatives from glycose and digallic acid, and mixtures thereof.
• the plastic coating formulations are based on water soluble or water dispersible film-forming materials which are partially or completely synthetic. Some of these materials are described in US. 2,881,085 which refers to a combination of a water soluble wax-like material and cellulose esterified partially with lower aliphatic monocarboxylic acids and partially with a polycarboxylic acid. Such esters are described in US. 2,093,462, US. 2,093,464, and US. 2,126,460. An example of such an ester is cellulose acetate phthalate.
• Other film-forming materials use ful in coating formulations are: the combination of a copolymer of maleic anhydride/ ethylene and partial hydrolysis products thereof described in US.
• water soluble waxes and a cellulose ester of lower aliphatic carboxylic acids, such as cellulose acetate, acrylic polymers and copolymers such as meth acrylate, methylmethacrylate, methylmethacrylate/methacrylic acid, methacrylate/methacrylic acid, acrylate/ methylmethacrylate, methylacrylate/methylmethacrylate, etc.; or vinyl polymers such as polyvinylpyrrolidene/vinyl acetate with a water soluble wax, and similar polymers and copolymers.
• a cellulose ester of lower aliphatic carboxylic acids such as cellulose acetate
• acrylic polymers and copolymers such as meth acrylate, methylmethacrylate, methylmethacrylate/methacrylic acid, methacrylate/methacrylic acid, acrylate/ methylmethacrylate, methylacrylate/methylmethacrylate, etc.
• vinyl polymers such as polyvinylpyr
• the practice of coating tablets and the like with the foregoing plastics involves the steps of dispersing said plastics in a volatile slovent. To this liquid coating composition are added dyes and the complexing agent or agents. The resulting mixture is applied to the solid medicaments rotating in a coating pan. The coating composition is distributed evenly over the surface of the I solid medicament and additional portions of the coating compositions are added to the rotating pan as the solvent from the previous portion evaporates. Each of these coating steps results in a dry, hard film that forms on the medicament. The procedure is repeated until a film of desired thickness is obtained.
• the requirement for the film-forming plastic to be Water dispersible comes from the necessity for the plastic covered tablet to disintegrate after ingestion. If the plastic would not disperse, the ingredients inside this plastic coating would never be accessible by the body liquids.
• the volatile solvents can be selected from among those in which the foregoing plastics are soluble. This includes lower aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol and solvents of higher volatility such as acetone, methylene chloride, methylethyl-ketone, ethyl acetate and the like which are miscible with the alcohol solvents.
• solvents of higher volatility can be used in conjunction with the alcohols to accelerate drying of the coating compositions after application to the tablets.
• An alternative procedure provides preparing the liquid composition in an anhydrous solvent medium; i.e., organic solvents without water.
• the present invention is particularly concerned with stabilization of the coloring agents incorporated in the coating formulation such as non-toxic dyes, lakes, and pigments certified for use in food, drug, and cosmetic industries.
• the coating composition may also include agents which provide gloss, such as silicone resins, long-chain fatty acids, long-chain metallic soaps, and long-chain alcohols.
• Opaquing agents may be added to overcome transparency of the film coating. Among them are titanium dioxide, calcium carbonate, dehydrated calcium sulfate, dicalcinm phosphate, and others known in the pharmaceutical art.
• Suspending agents such as Bentone 18C (alkyl ammonium montmorillonite) and Veegum (5% aqueous suspension of complex colloidal magnesium aluminum silicate) may be used to suspend the opaquing agents and other insoluble materials.
• Plasticizers are added to render the film coating more flexible, thereby overcoming any brittleness of the film coating.
• suitable and well known plasticizers are mineral oil, castor oil, polyhydroxy compounds such as polyethylene glycol 200, 300, or 400, propylene glycol, glycerine, and the like.
• sweetening agents customarily used are vanillin, saccharin, sucaryl (sodium cyclohexylsulfamate), coumarin, heliotropin, etc.
• the above complexing agents have a broad range of applicability, but work best when selected by the following simple method of determination.
• albumin is the indicated complexing agent.
• tannin is the preferred agent. This is true whether the basic nitrogen is in form of a quaternary ammonium configuration, in form of a primary, secondary or tertiary amine, or as a member of a heterocyclic ring.
• a dye contains both types of mentioned groups, either one or both of the mentioned complexing agents can be used.
• An operable liquid coating composition according to the v instant disclosure will contain at least a sufiicient amount of plastic to obtain a hard coat on the tablet after drying.
• the upper limit of plastic in the liquid composition will be determined by the practical consideration of retaining the facility of manipulation with a composition which is not too viscous.
• a preferred and easily manipulated composition contains about 180-250 grams of plastic in 1 liter of solvent.
• the amount of dye in said composition is about 0.05-4.0 grams/liter of solvent and the complexing agent which achieves the advantages of the invention is present in about 5-30 grams/liter of the solution.
• the solvent preferably is a mixture of acetone and alcohol in a ratio of about 2:1, but, of course, other low boiling solvents for the plastic or mixtures thereof may be used with equally good results.
• the composition of the film is about 88-97% plastic, about .05-l.5% coloring agent and about 2.5-10.5% of complexing agent.
• -a liquid coating composition will also contain excipients and adjuvants of the type previously enumerated.
• excipients and adjuvants of the type previously enumerated.
• a one liter mixture can contain from 15-25 g. plasticizer, 5-15 g. opaquing agents, 2-5 flavoring agents and 5-10 g. wetting agents. After evaporation of the solvents the composition of the dry film will be altered correspondingly by the presence of these excipients and adjuvants.
• hard plastic film will then comprise about 75-85% plastic, about .02-1% coloring agents, about 2-8% complexing agents, and about 13-16% of excipients and adjuvants.
• EXAMPLE 1 In a small amount of acetone, g. of polyethylene glycol of average molecular weight 6000 are dissolved. This solution is added to 600 cc. of a wt./vol. cellulose acetate phthalate solutionand acetone is added to this mixture with stirring to fill up to 1000 cc.
• the cellulose acetate phthalate solution contains 'per 1000 cc.: 100 g. of cellulose acetate phthalate, 316 g. of acetone, 32 g. of propylene glycol, 10 g. of a wetting agent and 386 g. of alcohol.
• the blue tablets are then dried in the usual manner on trays. They are pleasing in appearance and will disintegrate without delay either in water or in gastric secretions. They do not show any sign of fading after 4 /2 hours exposure in the fadometer. Tablets made in the identical manner but without the complexing agent fade in less than 22 /2 minutes.
• the formulations given in the table tabulated below are made up in the same manner as the one described above; however, the albumin used in the above example is replaced in some formulations by tannin or a combination of albumin and tannin, as indicated in the table.
• the numbers given in the columns for albumin and tannin indicate these respective amounts in g./liter of coating formulation.
• the fadometer columns give the time elapsed before fading is noticeable and compares tablets not containing any complexing agent (control) with those being made as described in the respective examples. It should, however, be noted that the amounts of the complexing agent is not optimum in all examples and that in several instances longer ultra-violet stability can be achieved by increasing the amount of complexing agent.
• EXAMPLE 2 This example shows the procedure to make a large batch of colored coating solution with synthetic film-forming plastic coating materials. To 15 gallons of acetone is added 22.7 kg. of cellulose acetate phthalate. The mixture is agitated and then allowed to soak overnight. A second solution is prepared by mixing 7.05 kg. of propylene glycol, 2.2 kg. of Span (a wetting agent from sorbitol and common fatty acids), and 0.9 kg. of castor oil with a small amount of ethyl alcohol. The two solutions are then combined and mixed by agitation. Additional alcohol is added as necessary.
• Tablets coated With this formulation have an ultraviolet stability of more than 4 /2 hours in the fadometer.
• the same formulation without albumin and tannin will fade after less than 1 /2 hours in the fadometer.
• polymeric materials may replace cellulose acetate/polyethylene glycol, but for convenience, the above examples all refer to the same film coating formulation.
• This formulation may be a solution or dispersion, the complexing agents having the identical effect on light stability in both.
• other compounds may be mixed in with the above-mentioned ingredients, i.e., sweetening agents, flavoring agents, disintegrators, buffers, etc., as well as other dyes that may be suitable for tablet coloring.
• a mixture of dyes and lakes will give equally good results when used in combination with the complexing agents of the present invention.
• a liquid coating composition for applying a thin, color stable plastic film to solid medicaments which comprises a volatile organic solvent containing therein a water dispersible, non-toxic, film forming plastic, a physiologically acceptable coloring agent, and a complexing agent selected from the class consisting of albumin, tannin, and the combination of tannin and albumin, with the further provision that the complexing agent is at least in part '7 tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen and sulfonic acid groups.
• a liquid coating composition for applying a thin, color stable plastic film to solid medicaments which comprises a volatile organic solvent containing therein a waterdispersible, non-toxic, film forming plastic, a physiologically acceptable coloring agent, tannin, and albumin.
• a liquid coating composition for applying a thin, color stable plastic film to solid medicaments which comprises a volatile organic solvent containing therein a water dispersible, non-toxic, film forming plastic, tannin, and a physiologically acceptable coloring agent containing basic nitrogen.
• a liquid coating composition for applying a thin, color stable plastic film to solid medicaments which comprises a volatile organic solvent containing therein a water dispersible, non-toxic, film forming plastic, albumin, and a physiologically acceptable coloring agent containing sulfonic acid groups.
• a liquid coating composition for applying a thin, color stable film to solid medicaments which comprises a volatile, organic solvent containing therein about 180- 250 w./v. of a Water dispersible, non-toxic, film forming plastic, about 04-41) W./v. of a physiologically acceptable coloring agent, about 5-30 w./v. of a complexing agent selected from the class consisting of tannin, albumin, and a combination of tannin and albumin, with the further provision that the complexing agent is at least in part tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen and sulfonic acid groups.
• a liquid coating composition for applying a thin, color stable plastic film to solid medicaments which comprises a lower alkanol-acetone mixture containing therein about 180-250 'w./v. of cellulose acetate phthalate, about .044.0 w./v. of a coloring agent, and about 5-30 w./v. of a complexing agent selected from the class consisting of tannin, albumin, and a combination of tannin and albumin, with the further provision that the complexing agent is at least in part tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen and sulfonic acid groups.
• a coated, solid medicament having as the coating material a thin, color stable, plastic film comprising a water dispersible, non-toxic plastic, physiologically acceptable coloring agents and a complexing agent selected from the class consisting of albumin, tannin, and the combination of tannin and albumin, with the furtherprovision that the complexing agent is at least in part tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic .nitrogenand sulfonic acid groups.
• a coated, solid medicament having as the coating material a thin, color stable, plastic film comprising a non-toxic, water dispersible, plastic, physiologically acceptable coloring agents, tannin, and albumin.
• a coated, solid medicament having as the coating material a thin, color stable, plastic film comprising a non-toxic, Water dispersible, plastic, tannin, and a physiologically acceptable coloring agent containing basic nitrogen.
• a coated, solid medicament having as the coating material a thin, color stable, plastic film comprising a nontoxic, water dispersible plastic albumin, and a physiologically acceptable coloring agent having sulfonic acid groups.
• a coated, solid medicament having as the coating material a thin, color stable, plastic film comprising a nontoxic, water dispersible plastic, tannin, albumin, and a physiologically acceptable coloring agent having basic nitrogen and sulfonic acid groups.
• a coated, solid medicament having as the coating material a thin, color stable, plastic film comprising about 75-85 of non-toxic, water dispersible plastic, about .02- l% of a physiologically acceptable coloring agent, about 13-16% of tableting excipients and adjuvants, and about 2-8% of a complexing agent selected from the class consisting of albumin, tannin, and the combination of tannin and albumin, with the further provision that the complexing agent is at least in part tannin when the color-ing agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen'and sulfonic acid groups.
• a coated, solid medicament having as the coating material a'thin, hard, color stable, plastic film comprising about 75-85% of a mixture of cellulose acetate phthalate and polyethylene glycol, about .02-l% of physiologically acceptable coloring agents, about 'l-3-l6% of tableting excipients and adjuvants, and about 2-8% of a complexing agent selected from the class consisting of albumin, tannin, and the combination of tannin and albumin, with the further provision that the complexing agent is at least in part tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen and sulfonic acid groups.
• a coated, solid medicament having as the coating material a thin, plastic, color stable film comprising about 88-97% of a non-toxic, water dispersible plastic, about .05-l.5% of a physiologically acceptable coloring agent, and about 2.5-l0.5% of a complexing agent selected from the class consisting of albumin, tannin, and the combination of tannin and albumin, with the further provision that the complexing agent is at least in part tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen and sulfonic acid groups.
• the method of coating tablets and the like with a thin, color stable, plastic film which comprises the steps of applying to tablets a liquid composition having a volatile, organic solvent medium which contains therein a nontoxic, water dispersible, film forming plastic, a physiologically acceptable coloring agent, and a complexing agent selected from the class consisting of albumin, tannin, and the combination of tannin and albumin, with the further provision that the complexing agent is at least in part tannin when the coloring agent contains basic nitrogen, the complexing agent is at least in part albumin when the coloring agent contains sulfonic acid groups, and the complexing agent is a combination of tannin and albumin when the coloring agent contains basic nitrogen and sulfonic acid groups.
• liquid composition contains about -250 w./v. of a non-toxic, water dispersible, film forming plastic, about .04-4.0 w./v. of a physiologically acceptable coloring agent, and about 5-30 w./v.
• vent consists of a mixture of a lower alcohol and acetone Synthetic Dyes, Venkataraman, 1952, vol. 11, Academic and contains therein cellulose acetate phthalate, polyethylene glycol, a physiologically acceptable coloring agent, Press NY p 12124215 tannin and albumin. 10

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Cited By (15)

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Citations (1)

• 0
  • NL NL255509D patent/NL255509A/xx unknown
• 1959
  • 1959-09-02 US US837586A patent/US3030273A/en not_active Expired - Lifetime
• 1960
  • 1960-08-23 GB GB29148/60A patent/GB935386A/en not_active Expired
  • 1960-08-25 ES ES0260595A patent/ES260595A1/es not_active Expired
  • 1960-08-29 FR FR837055A patent/FR1266265A/fr not_active Expired
  • 1960-08-29 BE BE594492A patent/BE594492A/fr unknown
  • 1960-09-02 DE DEA35481A patent/DE1118932B/de active Pending

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