Classifications

• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
  • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
  • A61L2/0023—Heat

Definitions

• This invention relates to solutions of the drugs heparin, dopamine, cimetidine and gentamicin, especially for parenteral administration.
• this invention relates to heat sterilizing solutions of these drugs while preserving their short and long term stability in dilute aqueous solution.
• Dopamine having the systematic name 4-(2-aminoethyl )-l , 2-benzenedioV, is commercially available as the hydrochloride salt. Its therapeutic utility is to correct he odynamic imbalances in the treatment of shock due to myocardial infarction, trauma, septicemia, open heart surgery, renal failure or congestive heart failure.
• Dopamine solutions are infused in accord with standard procedures and dosage rates, ordinarily intravenously at a rate of 1 to 5 mg/Kg body weight/ in. with increases in dosage until the desired elevation in venous pressure is achieved.
• Heparin is a naturally occurring, high molecular weight mucopolysaccharide with a high content of esterified sulfuric acid. It is commercially available as the sodium salt, although other pharmacologically acceptable salts are to be considered within the scope of the term heparin as used herein.
• 10,000 to 40,000 U.S. P. units are dissolved in one or two liters of diluent and administered intravenously or intramuscularly at varying dosages dependent upon the administration route and patient weight. Dosage will be titrated based on blood clotting time assays. The formulation and administration of therapeutic doses is well known in the art.
• Heparin has been reported to be "compatible" with infusion solutions containing dextrose, sodium chloride, invert sugar, Ringer's solution, lactated Ringers's and 1/6 M sodium lactate (American Hospital Formulary Service 20:12.04 [1976]).
• Gentamicin is a well known antibiotic. It is commercially available as the sulfate salt, although other pharmacologically acceptable organic or mineral salts shall fall within the meaning of gentamicin as used herein. Also, the various known gentamicin components, e.g. C, , C 2- C-, and A shall be construed as encompassed by the term gentamicin.
• Gentamicin has been dissolved in the following intravenous solutions at a potency of 0.2 to 2.5 mg/ml.: 10 per cent dextran 40 with 5 per cent dextrose; 5 per cent dextrose; 10 per cent dextrose; 5 per cent dextrose in Polysal® solution; 5 per cent dextrose in Polysal®-M solution; Isolyte® P solution with 5 per cent dextrose; Isolyte® M solution with 5 per cent dextrose; Isolyte® E solution with 5 percent dextrose; lactated Ringer's injection; Nor osol® M solution in
• Ci etidine is a histamine H 2 receptor antagonist having the systematic name N''-cyano-N-methyl-N'-[2-[[(5-methly-l H-imidazol-4-yl ) methyl] thio]-ethyl]-guanidine. It is used in the treatment or prophylaxis of duodenal ulcers and hypersecretory conditions. Recommended intravenous dosage is 300 mg. of cimetidine dissolved in dilute solutions haying concentrations from about 3 mg/ml to 12 mg/ml and delivered over a period of up to 6 hours.
• Terminal sterilization means heating the containers and their solutions until all adventitious microbes are killed.
• the sterilization conditions are harsh, ordinarily greater than 121 ⁇ C for about from 24 minutes to one hour depending upon the container size and characteristics.
• the manufactured drug solutions are to be suitable for parenteral administration they must contain an agent for osmotic control of the solution at the approximate isotonicity of blood.
• the drug itself will not be in a concentration suitable for this purpose, although it may make a modest contribution.
• the most commonly used osmotic agents have been sodium chloride and dextrose. While the aforementioned drugs can be terminally sterilized and stored for lengthy periods (1 week to two years) in saline, they are not stable in dextrose. Discoloration and activity losses will be encountered.
• the glycerol, mannitol or sorbitol may be employed in combination admixture or as the sole agent, either in combination with one another or with other known isotonicity agents such as sodium chloride, pharmacologically acceptable polymers and the like. It is preferred to use glycerol alone as the principal isotonic agent, although buffers, nutrients, the drug, salts, antioxidants or other solutes may make , a minor contribution. Mannitol and sorbitol are not the preferred agents.
• the glycerol, mannitol or sorbitol may be employed at concentrations ranging about from 0.5% to 5.0% by weight depending on the agent used.
• glycerol than 5.0% ordinarily would be used because its molecular weight is less than mannitol and sorbitol.
• the upper limit is critical since greater amounts will lead to side effects e.g. dehydration, that are undesirable in most patients, particularly if the drug solution also contains other components such as electrolytes and other solutes. Desirably, the upper limit is accommodated, i.e., reduced, by the osmotic contribution of other solutes. so that the solution is not other than substantially isotonic.
• the lower limit is not critical and only reflects the degree to which osmotic agents other than glycerol, mannitol or sorbitol can be employed in the solutions and the contribution by other solutes. The final solution, however, must not be hypotonic since this may result in hemolysis and • phlebitis.
• the solutions herein may contain buffers, antioxidants such as ascorbic acid, a bisulfite or metabisulfite, salts such as potassium or other electrolytes, other stabilizers and substances previously used in the formulation of sterile, dilute solutions of heparin, cimetidine, gentamicin and dopamine.
• the solutions also may contain amino acids for nutritional purposes.
• the pH of the solutions will be adjusted with a pharmacologically acceptable acid or base in order to provide the optimal pH for drug stability.
• the dilute solutions herein are not of general utility for enteral or intramuscular administration.
• a further advantage of glycerol, mannitol or sorbitol over dextrose is that dextrose is only optimally stable at pH 3.5, whereas glycerol, mannitol and sorbitol are stable throughout the range of pH 3 to 11.
• they offer an advantage when used with heparin, cimetidine and gentamicin, all of which have optimal stability at pH levels greater than 3.5.
• the above solutions typically are made by dissolving the glycerol, mannitol and/or sorbitol, drug and other desired solutes in water, filling them into containers, hermetically sealing the containers and heat sterilizing the contents.
• the containers may be any glass or flexible containers specially adapted for infusion into patients, i.e., containers including ports, caps or other means for communicating in sterile fashion with a conduit (administration set) for delivering the solution by infusion into a patient.
• Containers of this type are commercially available and well know, e.g. as disclosed in U.S. patents 4,046,276 and 4,393,909 and as constituted by the Viaflex® container sold by Travenol Laboratories, Inc.
• the sterile drug solutions may be placed into long term storage, i.e. greater than about one week and up to 2 or more years. They may be stored at room temperature, and need not be frozen.
• the drugs are administered to patients in exactly the same fashion as the dilute solutions of the aforementioned drugs have, been administered previously, primarily by intravenous infusion.
• the drug is continuously or intermittently infused by peripheral catheter at therapeutic dosages as discussed above.
• EXAMPLE 3 400 mg of dopamine hydrochloride is dissolved in 200 ml of a solution containing 2.5% wt/vol glycerol and 0.05% wt/vol sodium bisulphite, the pH adjusted with NaOH or HCl to pH 3.5, and q.s. to 250 ml with the same solution to produce a 250 ml final volume having an approximate dopamine concentration of 1.6 mg/ml.
• the solution is filled into an approximately 300 ml capacity Viaflex® bag and the bag sealed. The bag and contents are heated at 121°C for 24 min, cooled and stored for up to two years.
• EXAMPLE 4 Example 3 was repeated except that the concentration of dopamine is adjusted to approximately 0.4, 0.8 or 3. ' 2 mg/ml.
• EXAMPLE 5 100 mg of gentamicin sulfate U.S.P. is dissolved in 100 ml of an aqueous solution containing 2.5% wt/vol glycerol and the pH adjusted to 4.0 with NaOH or HCl. A Viaflex® container is filled with the solution, sealed, heat sterilized at 121°C for 30 min. and cooled. It may be stored for up to two years. The foregoing procedure is repeated with 40, 60, 80, 120, 200 or 240 mg of gentamicin sulfate U.S.P.
• Example 5 is repeated except that cimetidine hydrochloride (Tagamet® brand) in amounts of 300, 600 and 1200 mg was substituted for the gentamicin and the pH was adjusted to 6.0 rather than 4.0.
• cimetidine hydrochloride Tagamet® brand
• the sterilized solution could be stored in the Viaflex® bags for up to two years.

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Citations (7)

• 1985
  • 1985-01-15 WO PCT/US1985/000059 patent/WO1985003202A1/en not_active Application Discontinuation
  • 1985-01-15 JP JP50056485A patent/JPS61501148A/ja active Pending
  • 1985-01-15 EP EP19850900876 patent/EP0170680A4/de not_active Withdrawn
  • 1985-01-25 CA CA000472884A patent/CA1244771A/en not_active Expired

Patent Citations (7)

Non-Patent Citations (5)

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