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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• compositions in the form of tablets suitable for sublingual administration, can be produced by wetting a substantially dry mixture of the nitroglycerin and the solid, water-soluble pharmaceutical carrier with a solvent mixture containing a non-volatile, water-soluble solvent and a volatile solvent, forming the wetted mixture into tablets, and removing the volatile solvent.
• the present invention relates to new and improved pharmaceutical compositions of nitroglycerin, and to methods for producing those compositions.
• Nitroglycerin (glyceryl trinitrate) is widely used in medical practice as a coronary vasodilator. It is normally used in the form of tablets for sublingual administration containing approximately 0.2 to 0.65 mg. of nitroglycerin per tablet. Nitroglycerin tablets are administered for the purpose of producing a rapid coronary vasodilator effect relieving acute attacks of angina pectoris, and thus it is important that they retain the correct potency in terms of the active ingredient and that the active ingredient be promptly released for absorption upon sublingual administration.
• nitroglycerin tablets that meet accepted standards of potency and uniformity at the time of manufacture may fail to meet those standards of potency and uniformity following storage over a period of only a few months or less.
• nitroglycerin tablets it has been found that the failure of nitroglycerin tablets to maintain satisfactory potency and uniformity upon storage can be attributed to a migration of nitroglycerin from tablet to tablet and from the tablets to the environment. It has been found that the migration of nitroglycerin from the tablets to the environment is especially significant when the container is not tightly sealed so that the nitroglycerin can volatilize from the tablets through the loose seal into the atmosphere. It has also been found that the migration of nitroglycerin from the tablets to the environment is especially significant when the container has rayon or cotton stuffing material whereby nitroglycerin is volatilized from the tablets and absorbed on the stuffing material.
• Another object of the invention is to provide pharmaceutical formulations of nitroglycerin in the form of sublingual tablets whichdo not undergo a significant degree of migration of nitroglycerin from tablet to tablet within the same container.
• a further object of the invention is to provide pharmaceutical formulations of nitroglycerin in the form of sublingual tablets which retain their original potency without significant deviation over a long period of storage.
• Still a further object of the invention is to provide pharmaceutical formulations of nitroglycerin in the form of sublingual tablets having the improved potency retention mentioned above and having in addition the cal compositions of nitroglycerin are prepared to contain in finished form (a) one part by weight of nitroglycerin, in combination with (b) 0.1 to 4 parts by weight of a non-volatile, water-soluble solvent, and (c) 20 to 200 parts by weight of a solid, water-soluble pharmaceutical carrier.
• non-volatile is used herein in a relative. sense to designate a solvent that when incorporated in the finished formulation volatilizes to no more than a minor extent over a period'of several months at ordinary temperatures and under ordinary conditions of storage.
• That solvent can be a high boiling liquid or a high boiling, low melting solid that exhibits the required solvent characteristics under the conditions of use. It should have a relatively high solubility for nitroglycerin.
• Some examples of such solvents are polyethylene glycols, tetramethylene glycol, and pentamethylene glycol.
• Preferred solvents are polyethylene glycols having an average molecular weight in the range of 300 to 7,500, especially 300 to 1,000.
• a preferred ratio of ingredients is one part by weight of nitroglycerin to 0.5 to 0.9 parts by weight of the nonvolatile, water-soluble solvent.
• the solid, water-soluble pharmaceutical carrier is a sugar or a sugar derivative such as lactose, glucose, sucrose, mannitol, or sorbitol.
• the solid, water-soluble pharmaceutical carrier is used in an amount, within the proportions indicated above, to impart to the finished formulation the desired solid state under normal as well as extreme temperature conditions of storage and use.
• the new pharmaceutical formulations of nitroglycerin, as described above, are desirably provided as tablets suitable for sublingual administration and containing 0.l to 1.0 mg, preferably 0.2 to 0.65 mg., of nitroglycerin per tablet. However, if desired, they can also be provided in other conventional pharmaceutical forms such as granules.
• compositions of nitroglycerin in the form of tablets for sublingual administration are produced by the process which comprises (a) preparing a substantially dry mixture of one part by weight of nitroglycerin and 20 i to 200 parts by weight of a solid, water-soluble pharmaceutical carrier, (b) wetting that substantially dry mixture with a solvent mixture containing 0.1 to 4 parts by weight of a non-volatile, water-soluble solvent and a sufficient quantity of a volatile solvent to permit an even wetting of the substantially dry mixture by the solvent mixture, (c) forming the wetted mixture into tab-- lets, and (d) drying the tablets whereby substantially all of the volatile solvent is volatilized while substantially all of the non-volatile solvent remains unvolatilized.
• non-volatile is used herein in a relative sense to designate a solvent that when incorporated in the finished formulation volatilizes to no more than a minor extent over a period of several months at ordinary temperatures and under ordinary conditions of storage.
• That solvent can be a high boiling liquid or a high boiling, low melting solid that exhibits the required solvent characteristics under the conditions of use. It should have a relatively high solubility for nitroglycerin.
• Some examples of such solvents are polyethylene glycols, tetramethylene glycol, and pentamethylene glycol.
• Preferred solvents are polyethylene glycols having an average molecular weight in the range of 300 to 7,500, especially 300 to 1,000.
• a preferred ratio of ingredients is one part by weight of nitroglycerin to 0.5 to 0.9 parts by weight of the non-volatile, water-soluble solvent.
• volatile is used herein in a relative sense to designate a solvent that readily volatilizes under the conditions normally used in drying pharmaceutical tablets, for example drying in air at room temperature for 12 to 48 hours.
• solvents most suitably have a boiling point of about 100 C. or lower and a preferred solvent for this purpose is aqueous ethanol or water.
• the solid, water-soluble pharmaceutical carrier is a sugar or a sugar derivative such as lactose, glucose, sucrose, mannitol, or sorbitol.
• the solid, water-soluble pharmaceutical carrier is used in an amount, within the proportions indicated above, to impart to the finished tablets the desired solid state under normal as well as extreme temperature conditions of storage and use.
• the tablets, as prepared above, are desirably constituted to contain 0.1 to 1.0 mg., preferably 0.2 to 0.65 mg. of nitroglycerin per tablet.
• compositions described above can, if desired, also be formulated to contain other ingredients useful in pharmaceutical compounding.
• compositions of the invention exhibit the well-known activity of nitroglycerin in medical practice but show improved behavior on storage.
• the sublingual tablets give a rapid coronary vasodilator effect when dissolved under the tongue.
• they show improved retention of potency and uniformity when stored in either glass or plastic containers, with or without stuffing materials, at temperatures from room temperature to 45 C., when compared with the behavior of tablets prepared similarly but without the inclusion of a non-volatile, water soluble solvent.
• EXAMPLE 1 Ingredient Quantity N trqs ysstin m xtu e p 10% nitroglycerin Dilugent (lactose sucrose. 44- 7 kg. 95:5) Solvent mixture containing: Ethanol. 95% 3381 ml. Polyethylene glycol 400 520 ml. Purified Water 1302 ml.
• the nitroglycerin mixture soluble is a product containing 10% nitroglycerin on ,B-lactose and the quantity used is seven percent in excess of the calculated amount.
• the diluent contains 95% by weight of the usual lactose of pharmacy (at-lactose monohydrate) and 5% by weight of sucrose.
• the polyethylene glycol 400 is a polymer of ethylene oxide and water, represented by the formula H(OCH CH ),,OH, in which the average value ofn lies between 8.2 and 9.1.
• the nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture.
• the siftable mixture is passed through a number 80 mesh silk sieve.
• Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed. While the blender is operating the solvent mixture is then added and the ingredients are again blended.
• the wetted mixture is then formed into tablets, each weighing approximately 34 mg. after air drying, on a tablet molding machine.
• Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22 to 26 C. and a dew point temperature of 6 to 9 C.
• the molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg. and labeled to contain l/150 grain (approximately 0.43 mg.) of nitroglycerin per tablet; the acceptable variation is an average assay of percent to l 1 percent of the indicated potency.
• the tablets prepared as described above are suitable for sublingual administration and exhibit improved behavior on storage when compared with tablets prepared similarly but without the use of polyethylene glycol. They maintain acceptable standards of potency and uniformity upon prolonged storage at room temperature, at 37 C., and at 45 C.
• the improved behav ior on storage is observed in closed containers as well as in containers that are opened periodically to simulate conditions of use. i
• EXAMPLE 2 Ingredient Quantity l lit 'oglycerin mixture soluble, 10.2 kg. 10% nitroglycerin Diluent (lactose sucrose. 40.8 k :5)
• the nitroglycerin mixture soluble is a product containing 10% nitroglycerin on B-lactose and the quantity used is five percent in excess of the calculated amount.
• the diluent contains 95% by weight of the usual lactose of pharmacy (ct-lactose monohydrate) and 5% by weight of sucrose.
• the polyethylene glycol 400 is a polymer of ethylene oxide and water, represented by the formula H(OCH CH ),,OH, in which the average value of n lies between 8.2 and 9.1.
• the nitroglycerin mixture soluble is blended with a sufficient quantity of diluent to produce a siftable mixture.
• the siftable mixture is passed through a number 80 mesh silk sieve.
• Approximately one-half of the diluent, then the sifted nitroglycerin and diluent mixture, and then the remainder of the diluent are added to a blender and thoroughly mixed; While the blender is operating the solvent mixture is then added and the ingredients are again blended.
• the wetted mixture is then formed into tablets, each weighing approxi mately 34 mg. after air drying, on a tablet molding machine.
• Optimum temperature and humidity conditions for this operation are a dry bulb-temperature of 22 to 26 C.
• the nitroglycerin mixture soluble is a product containing 10% nitroglycerin on B-lactose and the quantity used is nine percent in excess of the calculated amount.
• the diluent contains 95% by weight of the usual lactose of pharmacy (oz-lactose monohydrate) and 5% by weight of sucrose.
• the polyethylene glycol 400 is a polymer of ethylene and water, represented by the formula H(OCH CH ),,OH, in which the average value of n lies bemately 34 mg. after air drying, on a tablet molding machine.
• Optimum temperature and humidity conditions for this operation are a dry bulb temperature of 22 to 26 C. and a dew point temperature of 6 to 9 C.
• the molded tablets are collected into trays and air dried at room temperature. Yield equals 1,400,000 to 1,500,000 tablets, each weighing approximately 34 mg.
• the tablets prepared as described above are suitable for sublingual administration and exhibit improved behavior on storage as described in Example 1.
• a pharmaceutical molded tablet composition for sublingual administration consisting essentially of a. one part by weight of nitroglycerin,
• a non-volatile, watersoluble solvent selected from the group consisting of polyethylene glycols having an average molecular weight in the range of 300 to 7,500, tetramethylene glycol, and pentamethylene glycol, and
• said molded sublingual tablet composition being capable of giving a rapid release of nitroglycerin upon sublingual administration, and being thereby stabilized against the tendency of nitroglycerin to otherwise migrate significantly from tablet to tablet, from tablet to environment, and from tablet 'to container stuffing capable of absorbing nitroglycerin in sealed or imperfectly sealed containers with resulting loss of original potency during storage.
• non-volatile, water-soluble solvent is a polyethylene glycol having an average molecular weight of 300 to 1,000.
• a pharmaceutical composition according to claim 1 wherein the solid, water-soluble pharmaceutical carrier is substantially a mixture of lactose and sucrose.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Emergency Medicine (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

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Cited By (23)

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Citations (4)

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• 1971
  • 1971-06-01 US US00149072A patent/US3789119A/en not_active Expired - Lifetime
• 1972
  • 1972-05-10 CA CA141,800A patent/CA983854A/en not_active Expired
  • 1972-05-17 GB GB2327472A patent/GB1343374A/en not_active Expired
  • 1972-05-29 FR FR7219103A patent/FR2140028B1/fr not_active Expired
  • 1972-05-29 BE BE784136A patent/BE784136A/xx not_active IP Right Cessation

Patent Citations (4)

Non-Patent Citations (1)

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