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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• Such glycols include, inter alia, glycol; 1,2-propanediol; 1,2-butanediol, polyalkylene glycols having molecular weights between about 100 and about 20,000 including polyethylene glycols (i.e. Carbowaxes), such as Carbowax 300, Carbowax 1000, Carbowax 1500W, Carbowax 6000, etc. as well as the corresponding polypropylene glycols.
• polyethylene glycols i.e. Carbowaxes
• N-substituted amides which constitute an essential ingredient of the compositions of the invention are preferably N-substituted or N,N-disubstituted amides of lower aliphatic acids, such as formic, acetic, propionic, butyric, sec-butyric, pentanoic, Q-methyl butyric, trimethylacetic, hexanoic, heptanoic, etc., also, chloroacetic acid, chlorpropionic acid, dichloroacetic acid, B-hydroxy propionic acid, etc.
• lower aliphatic acids such as formic, acetic, propionic, butyric, sec-butyric, pentanoic, Q-methyl butyric, trimethylacetic, hexanoic, heptanoic, etc.
• the substituent on the amide nitrogen is preferably an alkyl substituent, especially a lower alkyl substituent, such as methyl, ethyl, isopropyl, propyl, butyl, hexyl, etc., but may be any other aliphatic substituent, such as ,B-hydroxyethyl, B-chlorethyl, etc., or an aromatic substituent, such as phenyl, tolyl, chlorophenyl, etc or an aralkyl substituent, such as benzyl, phenethyl, chlorbenzyl, etc. Where polycarboxylic acids are used, there may be additional N-substituents on the amide nitrogen atoms.
• dicarboxylic acids particularly lower alkylene dicarboxylic acids
• succinic acid such as succinic acid, adipic acid, etc.
• N-substituted and disubstituted ureas are included within the purview of the invention, as are the analogous trisubstituted and tetrasubstituted ureas, etc.
• ureas containing the same substituents as those mentioned above, may be employed in the invention.
• substituted amides which may be used in the invention are N- or N,N-lower alkyl subabout 5 to about 30% stituted lower fatty acid amides, such as N-methylacetamide; N,N dimethylacetamide; N,N diethylpropionamide; N,N-dibutylpropionamide; N-amylpropionamide; N,N-dimethylbutyrarnide; N-ethylbutyramide; ureas substituted on at least one nitrogen atom by a hydrocarbon substituent (particularly a lower alkyl substituent), such as N,N-dimethylurea; N,N'-dimethylurea; N,N,N',N'- tetramethylurea; N,N-diethylurea; N,N-diethyl thiourea; N,N,N',N'-tetraethylurea; N,N-dipropylurea, etc.
• N-mono or poly-substituted (especially lower alkyl substituted) amides of lower alkylene dicarboxylic acids such as N,N,N,N'-tetramethyl furnaramide; N,N- dimethyl fumaramide; N,N,N',N'-tetrarnethyl succinamide; N,N'-dimethyl succinamide; N,N'-diisopropyl succinamide; N,N,N',N'-tetramethyl glutaramide; N,N-diethyl adipamide, N-butyl adipamide, etc.
• Examples of such com pounds are N,N,N,N-tetramethylphthalamide; N,N'- dimethylphthalamide; N-methyl phthalamide; N,N-diethyl phthalamide; N,N,N'N-tetramethyl isophthalamide; N,N,N,N'-tetrabutyl isophthalamide; N,N,N,N'-tetramethyl terephthalarnide; N,N-dipropyl terephthalamide; etc.
• other amides such as N-lower alkylated xanthines, e.g.
• N-substituted amide polymers such as polyvinyl pyrrolidone, etc.
• non-toxic acids having a pK of about 3 to about 5 which are used in the inventive solutions are preferably alkane dicarboxylic acids, especially adipic but also in cluding other acids, such as malic, mandelic, tartaric,
• the reserpine (or equivalent Rauwolfia alkaloids) may be present in an amount ranging from about 1 to about 10 mg. (preferably about 1 to 5, especially about 2.5 mg), per milliliter of solution, theN-substituted amide may be present in an amount ranging from about 5 to about 30% (preferably about 10 to 20, especially about 10%) of solution, the glycol may be present in an amount ranging from (preferably about 5 to 15, especially about 5%) of solution, and the acid having a pK of about 3 to about 5 may be present in an amount ranging from about 0.5 to about 2%, (preferably 0.5 to 1.5%, especially about 1.0%) adjusted so that no acid precipitates from the solution.
• solution as used above refers, of course, to the final solution prepared for injection].
• antioxidants such as thiourea, sodium sulfite, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoxylate;
• Water for injection used is heated to a boil and then nitrogen gas passed through for 30 minutes.
• Example 2 Materials and formula ml 1000 Reserpine g 2.500 N,N-dimethylacetan1ide ml 100.000 Polyethylene glycol 300 ml 100.000 Adipic acid g 10.000 Water for injection, q.s .rnl 1000.000
• Example 3 Using the identical procedure and composition as that used in Example 1, except that deserpidine (or rescinnamine) is substituted for the reserpine, one may prepare the analogous composition.
• Example 4 Materials and formula ml 1000 Reserpine -g 2.500 N,N-dimethylacetamide ml 200.000 Adipic acid g 10.000 Water for injection, q.s ml 1000.000
• Pr0cedure Dissolve the reserpine in the N,N-dimethylacetamide. Then add the adipic acid and mix until a solution is obtained. Bring up to volume with water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 115 10 p.s.i. for 30 minutes.
• Example 5 Using the identical procedure and composition as that used in Example 4, except that deserpidine (or rescinnamine) is substituted for the reserpine, one may prepare the analogous composition.
• Example 6 Materials and formula ml 1000 Reserpine g 2.500 N,N-dimethylacetamide rnl 100.000 Polyethylene glycol 300 ml 50.000 Benzyl alcohol rnl 10.000 Adipic acid g 10.000 Water for injection, q.s ml 1000.000
• Procedure-Dissolve the reserpine in the N,N-dimethylacetamide Add the adipic acid and mix until a solution is obtained. Then add the polyethylene glycol 300 and benzyl alcohol and stir, until a clear solution results. Bring up to volume with water for injection. Pass nitrogen gas through finished solution for 30 minutes. Filter solution through a medium porosity filter. Fill into ampuls (or vials) that have been previously flushed with nitrogen gas. Sterilize at 10 p.s.i. for 30 minutes.
• Example 8 Materials and formula ml 1000 Reserpine g 2.500 N,N,N,N'-tetramethyl urea g 100.000 Polyethylene glycol 300 m 200.000 Benzyl alcohol ml.. 10.000 Adipic acid g 10.000 Water for injection, q.s ml 1000.000
• Example 9 Materials and formula ml 1000 Reserpine ..g 2.500 Adipic acid g 10.000 N,N-dimethylacetamide ml 100.000 N,N,N,N'-tetramethyl urea g 50.000 Benzyl alcohol ml 10.000 Water for injection, q.s ml 1000.000
• An injectable aqueous solution consisting essentially of an efiective amount up to about 10 mg. of a member selected from the group consisting of reserpine, rescinnamine and deserpidine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halolower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl and about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5, per millimeter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.
• composition of claim 1 wherein an N-substituted amide is an amide containing two to four substituents on amino nitrogen atoms.
• composition of claim 1 wherein an N-substituted amide is an amide containing two substituents on amino nitrogen atoms.
• composition of claim 1 wherein an N-substituted amide is an amide containing three substituents on amino nitrogen atoms.
• composition of claim 5, wherein the soluble, nontoxic acid is adipic acid.
• An injectable aqueous solution consisting essentially of an elfective amount up to about 10 mg. of reserpine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl and about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.
• An injectable aqueous solution consisting essentially of about 1 to about 5 mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxylower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl and about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.
• An injectable aqueous solution consisting essentially of an elfective amount up to about 10 mg. of a member selected from the group consisting of reserpine, deserpidine and rescinnamine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halolower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5 and about '5 to about 30 percent by weight of a poly-lower alkylene glycol having a molecular weight about 300 to about 20,000, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic
• An injectable aqueous solution consisting essentially of an eifective amount up to about 10 mg. of reserpine, about 5 to about 30 percent by weight of at least one N-substituted amide, each of said N-sub'stituents being members selected from the group consisting of lower alkyl, hydroXy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 2.0 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5 and about 5 to about 30 percent by weight of a poly-lower alkylene glycol having a molecular weight about 300 to about 20,000 per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-car
• An injectable aqueous solution consisting essentially of about 1 to about 5 mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3 to about 5 and about '5 to about 30 percent by weight of a polyethylene glycol having a molecular weight about 300 to about 20,000, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thio urea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.
• composition of claim 11 wherein the N-substituted amide is N,N-dimethylacetamide.
• a composition of claim 12, wherein the soluble, non-toxic acid is adipic acid.
• An injectable aqueous solution consisting essentially of about 1 to about 10' mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3.5 to about 4.5, per milliliter of solution, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a saturated lower aliphatic di-carboxylic acid amide.
• An injectable aqueous solution consisting essentially of about 1 to about 10 mg. of reserpine, about 10 to about 20 percent by weight of at least one N-substituted amide, each of said N-substituents being members selected from the group consisting of lower alkyl, hydroXy-lower alkyl, halo-lower alkyl, phenyl, lower alkyl-phenyl and halo-phenyl, about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3.5 to about 4.5 and about 15 percent by weight of a polyethylene glycol having a molecular weight about 300, said N-substituted amide being derived from those selected from the group consisting of urea, thiourea, a saturated lower aliphatic mono-carboxylic acid amide and a lower aliphatic di-carboxylic acid amide.
• An injectable aqueous solution consisting essentially of about 2.5 mg. of reserpine, about 10 to about 20 percent by weight of N,N-dimethylacetamide and about 0.5 to about 1.5 percent by weight of a soluble, non-toxic acid of pK about 3.5 to about 4.5, per milliliter of solution.
• An injectable aqueous solution consisting essentially of about 2.5 mg. of reserpine, about 10 percent 7 by weight N,N-dimethylacetamide and. about 1 percent by weight of adipic acid.
• An injectable aqueous solution consisting essentially of about 2.5 mg. of reserpine, about 10 percent by weight N,N-dimethylacetamide, about 5 percent by weight polyethylene glycol having a molecular Weight about 300 and about 1 percent by weight of adipic acid, per milliliter of solution.

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• 1959
  • 1959-07-15 US US827146A patent/US3142617A/en not_active Expired - Lifetime
• 1960
  • 1960-07-11 DE DEC21889A patent/DE1248233B/de active Pending
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