CA1108622A - Metronidazole phosphate and salts - Google Patents
Metronidazole phosphate and saltsInfo
- Publication number
- CA1108622A CA1108622A CA319,763A CA319763A CA1108622A CA 1108622 A CA1108622 A CA 1108622A CA 319763 A CA319763 A CA 319763A CA 1108622 A CA1108622 A CA 1108622A
- Authority
- CA
- Canada
- Prior art keywords
- metronidazole
- phosphate
- agents
- water
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Abstract
METRONIDAZOLE PHOSPHATE AND SALTS
ABSTRACT OF THE DISCLOSURE
This invention relates to novel compounds of the formula:
wherein X ? is a pharmacologically acceptable cation.
The compounds are water soluble and are compounded with pharmaceutical carriers to form compositions which are useful as medical treatment for those conditions for which metronidazole is useful in treating.
The compounds of the Formula I are derivatives of the antibiotic compound metronidazole which is disclosed in U.S. Patent No. 2,944,061.
ABSTRACT OF THE DISCLOSURE
This invention relates to novel compounds of the formula:
wherein X ? is a pharmacologically acceptable cation.
The compounds are water soluble and are compounded with pharmaceutical carriers to form compositions which are useful as medical treatment for those conditions for which metronidazole is useful in treating.
The compounds of the Formula I are derivatives of the antibiotic compound metronidazole which is disclosed in U.S. Patent No. 2,944,061.
Description
11~8622 3633 BRIEF DESCRIPTION OF THE INVENTION
The compounds of the Formula are chemical derivatives of metronidazole which are useful for treating those diseases which metronidazole is useful in treating. The compounds are water soluble and can be prepared in dosage forms that the insoluble metronidazole could not. Addi~
tionaliy the compounds exhibit chemical stability in solutions.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention are represented by the formula:
H 3C ~ ~ NO2 Formula I
CH2-CH2-o-P-o(3 X (~) :
0~ X
X ~9 , a pharmacologically acceptable cation can be, for example H, Na, K, Li, 1/2 Ca, 1/2 Mg, 1/3 Al, 1/2 Fe, 1/3 Fe, NH4, organic amines such as long chain primary amines, e.g., decyl-, lauryl-, myristyl-, palmityl- or stearyl-amine, amines which yield crystalline salts with organic acid, e.g., dicyclohexylamine, piperazine, benzyl-hydrylamine, amantadine, or tris(hydroxymethyl)aminomethane.
Starting with metronidazole of the formula:
1 ~ ~
H 3C N NO~
, I
~ 30 ,,.~, 1~0862Z 3633 the compounds of the Formula I are prepared as follows:
A reaction mixture of metronidazole (l mole~, 2-cyano-ethyl phosphate (2 mole), and dicyclohexylcarbodiimide (5 mole) in anhydrous pyridine is left at room temperature for two days. A stock solution of dicyclohexylcarbodiimide in anhydrous pyridine is made from barium 2-cyanoethyl phosphate dihydrate by passing an aqueous suspension through a cationic exchange column (H+ resin) and subse-quent evaporation of water. After two days, dicyclohexyl-urea is precipitated out by adding water to the reactionmixture and filtered off. The filtrate is then concentrated and subject to silica gel 11quid chromatography. Diphos-phate ester thus obtained is hydrolyzed in KOH solution, carefully maintaining the pH of the reaction mixture at 10-ll. After neutralizing the mixture with hydrochloric acid solution, the solvent is completely evaporated. The methanol extract is then evaporated and the remaining solid ; is recrystallized twice with 95% ethanol to provide the potassium salt.
- 20 The potassium salt of metronidazole phosphate thus obtained is dissolved in distilled water and eluted through a cationic exchange column (H~ resin). Free phosphoric acid of metronldazole dihydrogen phosphate ester is resulted upon evaporation of water. For the salts of organic amines, the phosphoric acid in an organic solvent (e.g., ether) is titrated with calculated amount of the amines in ether.
The salts are obtained as precipitates. In case of the inorganic salts, the titration is carried out in distilled water and the water is evaporated. For both cases, the salts are recrystallized in a proper solvent system, if ~gD8622 ., necessary.
l'he sodium and ammonium salts can be prepared in the same manner as the potassium salt by substituting sodium hydroxide or ammonium hydroxide for the potassium hydroxide.
The Li, Ca, Mg, A1 and Fe salts are prepared from the potassium salt by adding the appropriate reagent to a solution of the potassium salt, i.e., addition of aluminum chloride or aluminum nitrate to a solution of potassium metronidazole phosphate will give aluminum metronidazole phosphate. The amine salts can be prepared from metronida-zole phosphate by adding one or two moles of the appro-priate amine to one mole of metronidazole phosphate and ! collecting the precipitated metronidazol,e phosphate amine salt. The free acid of metronidazole phosphate can be prepared from potassium metronidazole phosphate by passing the salt through a cationic exchange resin (H~,resin) and evaporating the water.
' The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.
Example 1 Metronidazole Phosphate Dipotassium Salt A stock solution of 1.0 M 2-cyanoethyl phosphate in anhydrous pyridine is prepared by suspending 16.16 gm. of
The compounds of the Formula are chemical derivatives of metronidazole which are useful for treating those diseases which metronidazole is useful in treating. The compounds are water soluble and can be prepared in dosage forms that the insoluble metronidazole could not. Addi~
tionaliy the compounds exhibit chemical stability in solutions.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of the present invention are represented by the formula:
H 3C ~ ~ NO2 Formula I
CH2-CH2-o-P-o(3 X (~) :
0~ X
X ~9 , a pharmacologically acceptable cation can be, for example H, Na, K, Li, 1/2 Ca, 1/2 Mg, 1/3 Al, 1/2 Fe, 1/3 Fe, NH4, organic amines such as long chain primary amines, e.g., decyl-, lauryl-, myristyl-, palmityl- or stearyl-amine, amines which yield crystalline salts with organic acid, e.g., dicyclohexylamine, piperazine, benzyl-hydrylamine, amantadine, or tris(hydroxymethyl)aminomethane.
Starting with metronidazole of the formula:
1 ~ ~
H 3C N NO~
, I
~ 30 ,,.~, 1~0862Z 3633 the compounds of the Formula I are prepared as follows:
A reaction mixture of metronidazole (l mole~, 2-cyano-ethyl phosphate (2 mole), and dicyclohexylcarbodiimide (5 mole) in anhydrous pyridine is left at room temperature for two days. A stock solution of dicyclohexylcarbodiimide in anhydrous pyridine is made from barium 2-cyanoethyl phosphate dihydrate by passing an aqueous suspension through a cationic exchange column (H+ resin) and subse-quent evaporation of water. After two days, dicyclohexyl-urea is precipitated out by adding water to the reactionmixture and filtered off. The filtrate is then concentrated and subject to silica gel 11quid chromatography. Diphos-phate ester thus obtained is hydrolyzed in KOH solution, carefully maintaining the pH of the reaction mixture at 10-ll. After neutralizing the mixture with hydrochloric acid solution, the solvent is completely evaporated. The methanol extract is then evaporated and the remaining solid ; is recrystallized twice with 95% ethanol to provide the potassium salt.
- 20 The potassium salt of metronidazole phosphate thus obtained is dissolved in distilled water and eluted through a cationic exchange column (H~ resin). Free phosphoric acid of metronldazole dihydrogen phosphate ester is resulted upon evaporation of water. For the salts of organic amines, the phosphoric acid in an organic solvent (e.g., ether) is titrated with calculated amount of the amines in ether.
The salts are obtained as precipitates. In case of the inorganic salts, the titration is carried out in distilled water and the water is evaporated. For both cases, the salts are recrystallized in a proper solvent system, if ~gD8622 ., necessary.
l'he sodium and ammonium salts can be prepared in the same manner as the potassium salt by substituting sodium hydroxide or ammonium hydroxide for the potassium hydroxide.
The Li, Ca, Mg, A1 and Fe salts are prepared from the potassium salt by adding the appropriate reagent to a solution of the potassium salt, i.e., addition of aluminum chloride or aluminum nitrate to a solution of potassium metronidazole phosphate will give aluminum metronidazole phosphate. The amine salts can be prepared from metronida-zole phosphate by adding one or two moles of the appro-priate amine to one mole of metronidazole phosphate and ! collecting the precipitated metronidazol,e phosphate amine salt. The free acid of metronidazole phosphate can be prepared from potassium metronidazole phosphate by passing the salt through a cationic exchange resin (H~,resin) and evaporating the water.
' The following examples are illustrative of the process and products of the present invention but are not to be construed as limiting.
Example 1 Metronidazole Phosphate Dipotassium Salt A stock solution of 1.0 M 2-cyanoethyl phosphate in anhydrous pyridine is prepared by suspending 16.16 gm. of
2-cyanoethyl phosphate, barium salt dihydrate in 160 ml.
' 25 of water containing 70 ml. of Dowex 50W (20-50 mesh; H~
,, form) cationic exchanger. The suspension is stlrred to effect solution. The solution is poured lnto a glass column (3.0 cm lD x 50 cm length) containing another 50 ml.
of the same resin. The column is eluted with 300 ml. of water. The eluent plus 30 ml. of anhydrous pyridine is !
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' ~h ~
. . .
~1a!8622 evaporated at 40 C. under reduced pressure. The residue is further dried twice by the addition of 200 ml. of anhydrous pyridine. l'he residue is transferred to a 50 ml.
volumetric flask and anhydrous pyridine added to make 50 ml. 3.423 gm. of metronidazole (0.02 mole) and 40 ml. of the above stock solution of 2-cyanoethyl phosphate (0.04 mole) are mixed in a one liter round-bottom flask. The reaction mixture is concentrated at 40 C. under vacuum.
The mixture is dried two more times, each with 150 ml. of anhydrous pyridine.
20.6 Gm. of N,N'-dicyclohexylcarbodiimide (DCC;
Aldrich; MW-206'.33; 0.1 mole) dissolved in 180 ml. of anhydrous pyridine is added and the stopper of the flask is wrapped with PARAFILM and the reaction mixture kept in the dark at low humidity After 48 hours 50 ml. of water is added to the reac-tion mlxture and the pyridine evaporated under vacuum at 40 C. Another 300 ml. of water is added to the residue and let stand at room temperature for two hours. The r crystalline N,N'-dicyclohexylurea is filtered off. 60 Ml.
of Dowex 50W-X8 resin (H~ form) is suspended in the fil-trate. The suspension is stirred for 20 minutes at room temperature and the resin filtered off. The filtrate is concentrated to approximately 20 ml. under vacuum at 40.
The reaction mixture is injected into three consecu-' tive silica gel columns (Size C - Silica gel 60 prepacked columns by EM Regeants). The LC columns are el'uted with a mobile phase made of methanol (100 volume), water (2) and acetic acid (1). The eluent is monitored continuously by letting the flow pass through a flow cell of O.S cm.
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1~86~2 thickness in a spectrophotometer (Beckman DB-G) with the wavelength set at 390 nm. The fraction of the eluent between 1.30 and 2.00 1. is collected and the solvent evaporated.
To the oil obtained,20 ml. of water is added and the solution slowly titrated with 31.0 ml. of l.ON-KOH over a period of 30 min. at 45 maintaining the pH at 10-11. The solution is kept at 45 for 15 minutes. The solution is neutralized with lN-HCl. The water evaporated under vacuum at 45. The solid residue is extracted with 40 ml.
of methanol. After evaporating the methanol, the solid residue is twice recrystallized with 3A-alcohol.
Analysis:
Calc'd. for C6H aN 306K2P-1.35H20:
C, 20.50; H, 3.07; N, 11.95; O, 33.45;
K, 22.24; P, 8.81.
Found: C, 20.07; H, 3.14; N, 10.76i K, 23.04 Example 2 Metronidazole Phosphate Disodium Salt Following the procedure of Example 1 but substituting sodium hydroxide for the potassium hydroxide one can pre-pare metronidazole phosphate disodium salt.
Similarly by substituting ammonium hydroxide for potassium hydroxide in Example 1, one can prepare metro-nidazole phosphate ammonium salt.
Example 3 Metronidazole Phosphate Metronidazole phosphate potassium salt is dissolved in water and eluted through a cationic exchange column such as Dowex or Amberlite. The eluate is collected and evaporated to give metronidazole phosphate.
;; ' * Trademark ' ~1~8~2Z
Example 4 Metronidazole Phosphate Aluminum Salt Metronidazole phosphate potassium salt is dissolved in water. To this solution is added a solution of aluminum chloride in water. The solution is stirred and the water is evaporated to give metronidazole phosphate aluminum salt.
Example 5 Metronidazole Phosphate Amine Salts To a slurry of metronidazole phosphate in solvent is added the appropriate amine in an organic solvent and the mixture is triturated. The amine salts are obtained as precipitates.
The compounds of the Formula I have antibiotic activity and can be used for treating those conditions for which metronidazole is known to be useful.
The dosage of the compound of the Formula I for anti-biotic purposes is from about 0.5 to about 10.0 mg./kg.
body weight of the patient. The compounds of the Formula I are conveniently prepared in 10~ 50, 100, 250 and 500 mg.
dosage units for administration 1 to ~ times a day. Pre-~ 20 ferred dosages are from 1 to 5 mg./kg. body weight of the ; patient up to four doses per day.
The compounds are administered orally, parenterally, vaginally and rectally for systemic action.
The compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solu-tions or suspensions and oil-water emulsions containing suitable quantities of a compound of Formula I or its phar-macologically acceptable salts.
~8622 3633 Pharmaceutical dosage unit forms are prepared in accordance with the subsequent general specific descrip-tions to provide from about 10 mg. to about 500 mg. of the essential active ingredient per dosage unit form (pre-ferred 100-250 mg.).
Oral pharmaceutical dosage forms are either solid or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets are, for example, compressed (including chewable and lozenge), tablet triturates, enteric-coated, sugar-coated, film-coated, and multiple compressed. Capsules are either hard ~; or soft elastic gelatin. Granules and powders are either effervescent or non-effervescent.
Pharmaceutically acceptable substances utilized in compressed tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents, and wetting agents. Tablet triturates ~: (either molded or compressed) utilize diluents and binders.
Enteric-coated tablets, due to their enteric-coating, resist the action of stomach acid and dissolve or disin-tegrate in the alkaline intestine. Sugar-coated tablets are compressed tablets to which usually four different layers of pharmaceutically acceptable substances have been applied. Film-coated tablets are compressed tablets which have been coated with a water soluble cellulose polymer.
Multiple compressed tablets are compressed tablets made by ; more than one compression cycle utilizing the pharmaceuti-cally acceptable substances previously mentioned. Coloring agents are utilized in the above dosage forms. Flavoring and sweetening agents are utilized in compressed tablets, ~CJ 8622 tablet triturates, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
Examples of binders include glucose solution 125-50%), acacia mucilage (10-20%), gelatin solution (10-20~), sucrose and starch paste. Lubricants include, for example, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phos-phate. Disintegrating agents include, for example, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof, and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include, for example, sucrose, lactose, mannitol, and artificial sweetening agents such as sodium cyclamate and saccharine, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation. Flow inducing agents include, for example, silicon dioxide and talc. Wetting agents include, for example, propylene glycol monostearate, sorbitan mono-oleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Enteric-coatings include, for example, fatty dC~ ds, fats, waxes. sheliac, ammoniated shellac and cellu-lose acetate phthalates. Pharmaceutically acceptable sub-stances for the first layer, an undercoating, of sugar-coated tablets, include, for example, dextrin and gelatin.
.
The second layer, an opaque zone, includes, for example,starch, talc, calcium carbonate, magnesium oxide and magnesium carbonate. The third layer, a translucent zone, includes, for example, sucrose. The fourth layer, a glaze, includes, for example, beeswax, carnauba wax, or a mixture of'these waxes. Film-coatings ;nclude, for example, hydroxyethylcellulose, sodium carboxymethylcellulose~ poly-ethylene glycol 4000 and cellulose acetate phthalate.
Hard gelatin capsules, sizes 5 through 1000, are made largely from gelatin and may be either clear or colored.
' These capsules may be filled with either a powder or coated pellets (sustained release).
The diluents utilized in powder filled capsules are the same as those illustrated above for tablets. Pharma-',~.9 '~' 15 ceutically acceptable substances utilized for coating ~ pellets include, for example, stearic acid, palmitic acid, .: .
glyceryl myristate, cetyl alcohol, fats, waxes, polymeric substances sensitive to small ch'ange's in pH of the gastro-intestinal tract, polyvinyl alcohol, ethyl cellulose and mixtures of beeswax, carnauba wax or bayberry wax with glyceryl monostearate. ~
Soft elastic gelatin capsules contain sufficient ;
glycerine so that they are permanently flexible. Pharma-'ceutically acceptable liquid diluents used in soft elastic 25 gelatin capsules are those which do not dissolve or harm ' the capsule and which are non-toxic, including, for example, corn oil, cottonseed oil, polysorbate 80, DMA and triacetin.
Pharmaceutically acceptable substances utilized in non-effervescent granules, for solution and/or suspension, include diluents, wetting agents, flavoring agents and . , ~S6ZZ
coloring agents. Examples of diluents, wetting agents, flavoring agents and coloring agents include those previously exemplified.
Pharmaceutically acceptable substances utilized in effervescent granules and powders include organic acids, a source of carbon dioxide, diluents, wetting agents, flavor-ing agents and coloring agents.
Examples of organic acids include, for example, citric acid and tartaric acid. Sources of carbon dioxide include, for example, sodium bicarbonate and sodium carbonate.
Examples of sweetening agents include, for example, sucrose, calcium cyclamate and saccharine. Examples of diluents, wetting agents and coloring agents include those previously exemplified.
Bulk powders have the compound of the Formula I uni-formly dispersed throughout a pharmaceutically acceptable powdered carrier diluent. Examples of the diluent include those previously exemplified.
The individual oral solid pharmaceutical dosage forms, tablets and capsules, are packaged individually, unit-dose, or in quantity, multiple-dose containers, for example, bottles of 50, 100, 500, 1000, or 5000.
The amount of compound of the Formula I analog per -dose unit is adjusted so that it provides the patient with an effective amount. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art. For example, tablets and capsules are given in sufficient number and frequency to obtain the desired pharmacological effect.
The sustained release tablets and capsules provide `
an effective amount upon ingestion and continue to release a sufficient amount of the active material to keep the con-centration at an effective level for increased periods of time, for example, 12 hours.
Non-effervescent granules and powders are packaged in ~ predetermined amounts, such that when reconstituted with a ; specified quantity of an appropr;ate l;quid vehîcle, usually distilled water, a solution and/or suspension results, pro-- viding a uniform concentration of the compound of the Formula I after shaking, if necessary. The concentration of the solution is such that a teaspoonful (5 ml.), a ~: tablespoonful (one-half ounce or 15 ml.) or a fraction or a multiple thereof will provide an effective amount to pro-duce the desired pharmacological effect. The exact dose 15 depends on the age, weight and condition of the patient or -animal, as is known in the art.
Effervescent granules and powders are packaged either in unit-dose. for example, tin foil packets, or in bulk, for example, in 4 oz. and 8 oz. amounts, such that a ;
,20 specific amount, either a unit-dose or, for example, a teaspoonful, tablespoonful, or a fract;on or a multiple thereof of bulk granules, when added to a specific amount of liquid vehicle, for example, water, yields a container of liquid dosage form to be ingested. The concentration of 25 the active material in the granules is adjusted so that a specified amount when mixed with a specific amount of water yields an effective amount of the active material and pro-duces the desired pharmacological effect. The exact amount of granules to be used depends on age, weight and condition of the patient as is known in the art.
.....
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1~8622 Liquid oral dosage forms include, for example, aqueous solutions, emulsions, suspensions, solutions and/or suspen-sions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent 5 granules. Aqueous solutions include, for example, elixirs -and syrups. Emulsions are either oil-in-water (o/w) or water-in-oil (w/o).
Elixirs are clear, sweetened, hydroalcoholic prepara-tions. Pharmaceutically acceptable substances utilized in elixirs include, for example, solvents. Syrups are concen-trated aqueous solutions of a sugar, for example, sucrose, - and may contain a preservative. An emulsion is a two-phase ~- system in which one liquid is dispersed in the form of small globules throughout another liquid. 0/w emulsions are much preferred for oral administrat;on over w/o emulsions. Phar-maceutically acceptable substances utilized in emulsions are non-aqueous liquids, emulsifying agents and preserva-tives. Suspensions utilize pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances utilized in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include, for example, diluents, sweeteners, and wetting agents.
Pharmaceutically acceptable substances utilized in effer-vescent granules, to be reconstituted into a liquid oral dosage form, include, for example~ organic acids and a source of carbon dioxide. Coloring and flavoring agents are utilized in all of the above dosage forms.
Solvents include, for example, glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium ~86ZZ 3633 benzoate and alcohol. Exampies of non-aqueous liquids utilized in emulsions include, for example, mineral oil and cottonseed oil. Examples of emulsifying agents include for example, gelatin, acacia, tragacanth, bentonite 9 and surfactants such as polyoxyethylene sorbitan monooleate.
S~spending agents include, for example, sodium carboxy-methylcellulose, pectin, tragacanth, Veegum and acacia.
Diluents include, for example, lactose and sucrose. Sweet- :
ening agents include, for examplej sucrose, syrups, glycer-in, and artificial sweetening agents such as sodium cyclamate and saccharin. Wetting agents include, for example, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and p-olyoxyethylene lauryl ether. Organic acids include, for example, citric and tartaric acid. Sources of carbon dioxide include, for example, sodium bicarbonate and sodium carbonate. Coloring agents include, for example, any of the approved, certified water soluble FD and C dyes, and mixtures thereof. Flav-oring agents include, for examplei natural flavors extracted from plants such as fruits, and synthetic blends of com-pounds which produce a pleasant taste sensation.
The concentration of the compound of the Formula I
throughout the solutions must be uniform. Upon shaking, - the concentration of the compound of the Formula I through-out the emulsions and suspensions must be uniform.
The concentration of the compound of the Formula I is adjusted so that a teaspoonful (5 ml.), a tablespoonful (one-half bunce or 15 ml.) or a fraction or multiple thereof, will provide an effective amount to produce the desired pharmacological effect. The exact dose depends on -i4-- . .
~8~Z~ 3633 the age, weight and condition of the patient or animal as is known in the art.
The liquid oral dosage forms may be packaged, for example, in unit-dose sizes of 5 rnl. (teaspoonful), 10 ml., 15 ml. (tablespoonful) and 30 ml. (one ounce), and multi-ple dose containers, including, for example, 2 oz., 3 oz., 4 oz., 6 oz., 8 oz., pint, quart, and gallon sizes.
Parenteral administration includes intravenous, sub-cutaneous, intramuscular, and the like.
Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or non-aqueous.
Pharmaceutically acceptable substances utilized in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutical necessities.
Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic (S percent) Dextrose Injection, Sterile Water for Injection, Dextrose and Sodium Chloride Injection and Lactated Ringers Injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin~ for example, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or 362~:
fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers (vials) `~-which include phenol or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid s esters, thimerosal, benzaTkonium chloride and benzethonium chloride. Isotonic agents include, for examplP, sodium chloride and dextrose. Buffers include, for example, phos-phate and citrate. Antioxidants include, for example, sodium bisulfite. Local anesthetics include, for example, procaine hydrochloride. Suspending and dispersing agents include, for example, sodium carboxymethylcellulose, hydroxy-propyl methylcellulose and polyvinylpyrrolidone. Emulsify-ing agents include, for example, Polysorbate 80 (Tween 80).
A sequestering or chelating agent of metal ions include, for example EDTA (ethylenediaminetetraacetic acid). Phar-maceutical necessities include, for example, ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
The concentration of the pharmaceutically active ingredient is adjusted so that an injection, for example, 0.5 ml., 1.0 ml., 2.0 ml., and 5.0 ml. or an intraarterial or intravenous infusion, for example, 0.5 ml./min., 1.0 ml.jmin., 1.0 ml./min., and 2.0 ml./min. provides an 25 effective amount to produce the desired pharmacological ;
effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
The unit-dose parenteral preparations are packaged, for example in an ampul or a syringe with a needle. The multiple-dose package, for exampl~, is a vial.
-~6-Trademark . . ., , . .. ; .
11~86Z2 All preparations for parenteral administration must be sterile, as is known and practiced in the art.
Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active material is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension con-taining an active material injected as necessary to produce the desired pharmacological effect.
Pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules, tablets for systemic effect.
Rectal suppositories as used herein mean solid bodies of insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or lS therapeutically active ingredients.
Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
Examples of bases or vehicles include, for example, cocoa butter (theobroma oil), glycerin gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include, for example, spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The usual weight of a rectal suppository is about 2.0 gm.
Tablets and capsules for rectal administration are manufactured utilizing the same pharmaceutically accept-able substance and by the same methods as for formulations 1~862Z
for oral administration.
Rectal suppositories, tablets or capsules are packaged either individually, in unit-dose, or in quantity, multiple dose, for example, 2, 6, or 12.
The pharmaceut~cally therapeutically active compounds of the Formula I are admin;stered ~rally, parenterally or rectally in unit-dosage forms or multiple dosage forms.
Unit-dose forms as used in the specification and cla;ms refers to physically discrete units suitable for human and animal subjects and packaged indiv;dually as is known in the art. Each unit-dose contains a predetermined quantity ; of the therapeutically active compound sufficient to pro-duce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
Examples of unit-dose forms ;nclude ampuls and syringes (parenteral), individually packaged tablet or capsule (oral-sol;d) or indiv;dually packaged teaspoonful or tablespoonful (oral-liquid). Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single conta;ner to be administered in segre-gated unit-dose form. Examples of multiple-dose forms include vials (parenteral), bottles of tablets or capsules (oral solid) or bottles of pints or gallons (oral-liquid).
Hence, multiple-dose form is a multiple of unit-doses which are not segregated in packaging. The specifications for the unit-dosage form and the multiple-dosage form are dictated by and directly dependent on (a) the unique char-acteristics of the therapeutically active compound and the particular therapeutic effect to be achieved and (b) the 8~ZZ
limitations inherent in the art of compounding such a therapeutically active compound for therapeutic or prophylactic.
In addition to the administration of a compound of Formula I as the principal active ingredient of composi-tions for the treatment of the conditions described herein, the said compound can be included with other types of com-pounds to obtain advantageous combinations of properties.
Such combinations include a compound of Formula I with other analgesics such as aspirin, phenacetin, acetaminophen, propoxyphen, pentazocine, codeine, meperidine, oxycodone, mefenamic acid, and ibuprofen; muscle relaxants such as methocarbamol, orphenadrine, carisoprodol, meprobamate, chlorphenesin carbamate, diazepam, chlordiazepoxide, and chlorzoxazone; analeptics such as caffeine, methylphenidate and pentylenetetrazol; corticosteroids such as methylpred-nisolone, prednisone, prednisolone and dexamethasone, antihistamines such as chlorpheniramine~ cyproheptadine, promethazine and pyrilamine.
Example 6 Tablets One thousand oral tablets, each containing 250 mg. of potassium metronidazole are prepared from the following types and amounts of materials: -- Potassium medronidazole250 g.
Lactose 50 9.
Corn starch 50 9.
Calcium stearate 2.5 g.
Light liquid petrolatum5 9.
The ingredients are thoroughly mixed and slugged.
The slugs are broken down by forcing through a number 11~)86Z2 sixteen screen. The resulting granules are then compressed into tablets, each containing 250 mg. of potassium metro-nidazole.
The foregoing tablets are useful for treatment of trichomoniasis by the oral administration of 1 tablet every six hours.
Example 7 Oral syrup One thousand ml. of an aqueous suspension for oral use, containing in each 5 ml. dose, 100 mg. of potassium metro-nidazole is prepared from the following types and amounts of ingredients:
Potassium metronidazole 20 g.
Citric acid 2 9.
Benzoic acid 1 9.
Sucrose 700 9.
Tragacanth 5 9.
Lemon oil 2 ml.
Deionized water q.s. 1000 ml.
The citric acid, benzoic acid, sucrose, tragacanth, and lemon oil are dispersed in sufficient water to make850 ml. of solution. The potassium metronidazole is stirred into the syrup until uniformly distributed. Suf-ficient water is added to make 1000 ml.
- The composition so prepared is useful in the treatment of amebiasis in adult humans at a dose of 1 teaspoonful 4 times a day.
Example 8 Parenteral solution A sterile aqueous solution for intramuscular use, containing in 1 ml. 400 mg. of potassium metronidazole is prepared from the following types and amounts of materials:
Potassium metronidazole400 9.
Lidocaine hydrochloride 4 g.
Methylparaben 2.5 g.
Propylparaben 0.17 g.
Water for injection q.s.1000 ml.
The ingredients are dissolved ;n the water and the solution sterilized by filtration. The sterile solution .
is filled into vials and the vials sealed.
The composition so prepared is useful in the treatment of trichomoniasis in adult humans at a dose of 1 cc injected I.M. every 8 hours.
Example 9 Suppository, rectal One thousand suppositoriesj each weighing 2.5 g. and containing 50 mg. of potassium metronidazole are prepared 5 from the following types and amounts of ingredients:
Potassium metronidazole 50 g.
Propylene glycol 162.5 g.
Polyethylene glycol 4000 q.s. 2300 g.
The potassium metronidazole is added to the propylene glycol and the mixture milled until the powders are finely divided and uniformly dispersed. The polyethylene glycol 4000 is melted and the propylene glycol dispersion added slowly with stirring. The suspension is poured into un-chilled molds at 40 C. The composition is allowed to cool and solidify and then removed from the mold and each suppository foil wrapped.
The suppositories are useful in the treatment of amebiasis in adult humans by the insertion rectally of 1 suppository every six hours.
Example 10 1~86Z2 3633 Compositions for similarly prepared following the procedure of the preceding Examples 6 through 9 substitut-ing an equimolar amount each of metronidazole phosphate, metronidazole phosphase sodium salt, metronidazole phos-phate amine salts, metronidazole phopshatP aluminum saltand the like for the potassium metronidazole of the Example.
' 25 of water containing 70 ml. of Dowex 50W (20-50 mesh; H~
,, form) cationic exchanger. The suspension is stlrred to effect solution. The solution is poured lnto a glass column (3.0 cm lD x 50 cm length) containing another 50 ml.
of the same resin. The column is eluted with 300 ml. of water. The eluent plus 30 ml. of anhydrous pyridine is !
~ -4-,j * Trademar~ .
' ~h ~
. . .
~1a!8622 evaporated at 40 C. under reduced pressure. The residue is further dried twice by the addition of 200 ml. of anhydrous pyridine. l'he residue is transferred to a 50 ml.
volumetric flask and anhydrous pyridine added to make 50 ml. 3.423 gm. of metronidazole (0.02 mole) and 40 ml. of the above stock solution of 2-cyanoethyl phosphate (0.04 mole) are mixed in a one liter round-bottom flask. The reaction mixture is concentrated at 40 C. under vacuum.
The mixture is dried two more times, each with 150 ml. of anhydrous pyridine.
20.6 Gm. of N,N'-dicyclohexylcarbodiimide (DCC;
Aldrich; MW-206'.33; 0.1 mole) dissolved in 180 ml. of anhydrous pyridine is added and the stopper of the flask is wrapped with PARAFILM and the reaction mixture kept in the dark at low humidity After 48 hours 50 ml. of water is added to the reac-tion mlxture and the pyridine evaporated under vacuum at 40 C. Another 300 ml. of water is added to the residue and let stand at room temperature for two hours. The r crystalline N,N'-dicyclohexylurea is filtered off. 60 Ml.
of Dowex 50W-X8 resin (H~ form) is suspended in the fil-trate. The suspension is stirred for 20 minutes at room temperature and the resin filtered off. The filtrate is concentrated to approximately 20 ml. under vacuum at 40.
The reaction mixture is injected into three consecu-' tive silica gel columns (Size C - Silica gel 60 prepacked columns by EM Regeants). The LC columns are el'uted with a mobile phase made of methanol (100 volume), water (2) and acetic acid (1). The eluent is monitored continuously by letting the flow pass through a flow cell of O.S cm.
_5_ * Trademark . .
1~86~2 thickness in a spectrophotometer (Beckman DB-G) with the wavelength set at 390 nm. The fraction of the eluent between 1.30 and 2.00 1. is collected and the solvent evaporated.
To the oil obtained,20 ml. of water is added and the solution slowly titrated with 31.0 ml. of l.ON-KOH over a period of 30 min. at 45 maintaining the pH at 10-11. The solution is kept at 45 for 15 minutes. The solution is neutralized with lN-HCl. The water evaporated under vacuum at 45. The solid residue is extracted with 40 ml.
of methanol. After evaporating the methanol, the solid residue is twice recrystallized with 3A-alcohol.
Analysis:
Calc'd. for C6H aN 306K2P-1.35H20:
C, 20.50; H, 3.07; N, 11.95; O, 33.45;
K, 22.24; P, 8.81.
Found: C, 20.07; H, 3.14; N, 10.76i K, 23.04 Example 2 Metronidazole Phosphate Disodium Salt Following the procedure of Example 1 but substituting sodium hydroxide for the potassium hydroxide one can pre-pare metronidazole phosphate disodium salt.
Similarly by substituting ammonium hydroxide for potassium hydroxide in Example 1, one can prepare metro-nidazole phosphate ammonium salt.
Example 3 Metronidazole Phosphate Metronidazole phosphate potassium salt is dissolved in water and eluted through a cationic exchange column such as Dowex or Amberlite. The eluate is collected and evaporated to give metronidazole phosphate.
;; ' * Trademark ' ~1~8~2Z
Example 4 Metronidazole Phosphate Aluminum Salt Metronidazole phosphate potassium salt is dissolved in water. To this solution is added a solution of aluminum chloride in water. The solution is stirred and the water is evaporated to give metronidazole phosphate aluminum salt.
Example 5 Metronidazole Phosphate Amine Salts To a slurry of metronidazole phosphate in solvent is added the appropriate amine in an organic solvent and the mixture is triturated. The amine salts are obtained as precipitates.
The compounds of the Formula I have antibiotic activity and can be used for treating those conditions for which metronidazole is known to be useful.
The dosage of the compound of the Formula I for anti-biotic purposes is from about 0.5 to about 10.0 mg./kg.
body weight of the patient. The compounds of the Formula I are conveniently prepared in 10~ 50, 100, 250 and 500 mg.
dosage units for administration 1 to ~ times a day. Pre-~ 20 ferred dosages are from 1 to 5 mg./kg. body weight of the ; patient up to four doses per day.
The compounds are administered orally, parenterally, vaginally and rectally for systemic action.
The compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solu-tions or suspensions and oil-water emulsions containing suitable quantities of a compound of Formula I or its phar-macologically acceptable salts.
~8622 3633 Pharmaceutical dosage unit forms are prepared in accordance with the subsequent general specific descrip-tions to provide from about 10 mg. to about 500 mg. of the essential active ingredient per dosage unit form (pre-ferred 100-250 mg.).
Oral pharmaceutical dosage forms are either solid or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets are, for example, compressed (including chewable and lozenge), tablet triturates, enteric-coated, sugar-coated, film-coated, and multiple compressed. Capsules are either hard ~; or soft elastic gelatin. Granules and powders are either effervescent or non-effervescent.
Pharmaceutically acceptable substances utilized in compressed tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents, and wetting agents. Tablet triturates ~: (either molded or compressed) utilize diluents and binders.
Enteric-coated tablets, due to their enteric-coating, resist the action of stomach acid and dissolve or disin-tegrate in the alkaline intestine. Sugar-coated tablets are compressed tablets to which usually four different layers of pharmaceutically acceptable substances have been applied. Film-coated tablets are compressed tablets which have been coated with a water soluble cellulose polymer.
Multiple compressed tablets are compressed tablets made by ; more than one compression cycle utilizing the pharmaceuti-cally acceptable substances previously mentioned. Coloring agents are utilized in the above dosage forms. Flavoring and sweetening agents are utilized in compressed tablets, ~CJ 8622 tablet triturates, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
Examples of binders include glucose solution 125-50%), acacia mucilage (10-20%), gelatin solution (10-20~), sucrose and starch paste. Lubricants include, for example, talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phos-phate. Disintegrating agents include, for example, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof, and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include, for example, sucrose, lactose, mannitol, and artificial sweetening agents such as sodium cyclamate and saccharine, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation. Flow inducing agents include, for example, silicon dioxide and talc. Wetting agents include, for example, propylene glycol monostearate, sorbitan mono-oleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Enteric-coatings include, for example, fatty dC~ ds, fats, waxes. sheliac, ammoniated shellac and cellu-lose acetate phthalates. Pharmaceutically acceptable sub-stances for the first layer, an undercoating, of sugar-coated tablets, include, for example, dextrin and gelatin.
.
The second layer, an opaque zone, includes, for example,starch, talc, calcium carbonate, magnesium oxide and magnesium carbonate. The third layer, a translucent zone, includes, for example, sucrose. The fourth layer, a glaze, includes, for example, beeswax, carnauba wax, or a mixture of'these waxes. Film-coatings ;nclude, for example, hydroxyethylcellulose, sodium carboxymethylcellulose~ poly-ethylene glycol 4000 and cellulose acetate phthalate.
Hard gelatin capsules, sizes 5 through 1000, are made largely from gelatin and may be either clear or colored.
' These capsules may be filled with either a powder or coated pellets (sustained release).
The diluents utilized in powder filled capsules are the same as those illustrated above for tablets. Pharma-',~.9 '~' 15 ceutically acceptable substances utilized for coating ~ pellets include, for example, stearic acid, palmitic acid, .: .
glyceryl myristate, cetyl alcohol, fats, waxes, polymeric substances sensitive to small ch'ange's in pH of the gastro-intestinal tract, polyvinyl alcohol, ethyl cellulose and mixtures of beeswax, carnauba wax or bayberry wax with glyceryl monostearate. ~
Soft elastic gelatin capsules contain sufficient ;
glycerine so that they are permanently flexible. Pharma-'ceutically acceptable liquid diluents used in soft elastic 25 gelatin capsules are those which do not dissolve or harm ' the capsule and which are non-toxic, including, for example, corn oil, cottonseed oil, polysorbate 80, DMA and triacetin.
Pharmaceutically acceptable substances utilized in non-effervescent granules, for solution and/or suspension, include diluents, wetting agents, flavoring agents and . , ~S6ZZ
coloring agents. Examples of diluents, wetting agents, flavoring agents and coloring agents include those previously exemplified.
Pharmaceutically acceptable substances utilized in effervescent granules and powders include organic acids, a source of carbon dioxide, diluents, wetting agents, flavor-ing agents and coloring agents.
Examples of organic acids include, for example, citric acid and tartaric acid. Sources of carbon dioxide include, for example, sodium bicarbonate and sodium carbonate.
Examples of sweetening agents include, for example, sucrose, calcium cyclamate and saccharine. Examples of diluents, wetting agents and coloring agents include those previously exemplified.
Bulk powders have the compound of the Formula I uni-formly dispersed throughout a pharmaceutically acceptable powdered carrier diluent. Examples of the diluent include those previously exemplified.
The individual oral solid pharmaceutical dosage forms, tablets and capsules, are packaged individually, unit-dose, or in quantity, multiple-dose containers, for example, bottles of 50, 100, 500, 1000, or 5000.
The amount of compound of the Formula I analog per -dose unit is adjusted so that it provides the patient with an effective amount. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art. For example, tablets and capsules are given in sufficient number and frequency to obtain the desired pharmacological effect.
The sustained release tablets and capsules provide `
an effective amount upon ingestion and continue to release a sufficient amount of the active material to keep the con-centration at an effective level for increased periods of time, for example, 12 hours.
Non-effervescent granules and powders are packaged in ~ predetermined amounts, such that when reconstituted with a ; specified quantity of an appropr;ate l;quid vehîcle, usually distilled water, a solution and/or suspension results, pro-- viding a uniform concentration of the compound of the Formula I after shaking, if necessary. The concentration of the solution is such that a teaspoonful (5 ml.), a ~: tablespoonful (one-half ounce or 15 ml.) or a fraction or a multiple thereof will provide an effective amount to pro-duce the desired pharmacological effect. The exact dose 15 depends on the age, weight and condition of the patient or -animal, as is known in the art.
Effervescent granules and powders are packaged either in unit-dose. for example, tin foil packets, or in bulk, for example, in 4 oz. and 8 oz. amounts, such that a ;
,20 specific amount, either a unit-dose or, for example, a teaspoonful, tablespoonful, or a fract;on or a multiple thereof of bulk granules, when added to a specific amount of liquid vehicle, for example, water, yields a container of liquid dosage form to be ingested. The concentration of 25 the active material in the granules is adjusted so that a specified amount when mixed with a specific amount of water yields an effective amount of the active material and pro-duces the desired pharmacological effect. The exact amount of granules to be used depends on age, weight and condition of the patient as is known in the art.
.....
:` : ,. ... .
1~8622 Liquid oral dosage forms include, for example, aqueous solutions, emulsions, suspensions, solutions and/or suspen-sions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent 5 granules. Aqueous solutions include, for example, elixirs -and syrups. Emulsions are either oil-in-water (o/w) or water-in-oil (w/o).
Elixirs are clear, sweetened, hydroalcoholic prepara-tions. Pharmaceutically acceptable substances utilized in elixirs include, for example, solvents. Syrups are concen-trated aqueous solutions of a sugar, for example, sucrose, - and may contain a preservative. An emulsion is a two-phase ~- system in which one liquid is dispersed in the form of small globules throughout another liquid. 0/w emulsions are much preferred for oral administrat;on over w/o emulsions. Phar-maceutically acceptable substances utilized in emulsions are non-aqueous liquids, emulsifying agents and preserva-tives. Suspensions utilize pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances utilized in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include, for example, diluents, sweeteners, and wetting agents.
Pharmaceutically acceptable substances utilized in effer-vescent granules, to be reconstituted into a liquid oral dosage form, include, for example~ organic acids and a source of carbon dioxide. Coloring and flavoring agents are utilized in all of the above dosage forms.
Solvents include, for example, glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium ~86ZZ 3633 benzoate and alcohol. Exampies of non-aqueous liquids utilized in emulsions include, for example, mineral oil and cottonseed oil. Examples of emulsifying agents include for example, gelatin, acacia, tragacanth, bentonite 9 and surfactants such as polyoxyethylene sorbitan monooleate.
S~spending agents include, for example, sodium carboxy-methylcellulose, pectin, tragacanth, Veegum and acacia.
Diluents include, for example, lactose and sucrose. Sweet- :
ening agents include, for examplej sucrose, syrups, glycer-in, and artificial sweetening agents such as sodium cyclamate and saccharin. Wetting agents include, for example, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and p-olyoxyethylene lauryl ether. Organic acids include, for example, citric and tartaric acid. Sources of carbon dioxide include, for example, sodium bicarbonate and sodium carbonate. Coloring agents include, for example, any of the approved, certified water soluble FD and C dyes, and mixtures thereof. Flav-oring agents include, for examplei natural flavors extracted from plants such as fruits, and synthetic blends of com-pounds which produce a pleasant taste sensation.
The concentration of the compound of the Formula I
throughout the solutions must be uniform. Upon shaking, - the concentration of the compound of the Formula I through-out the emulsions and suspensions must be uniform.
The concentration of the compound of the Formula I is adjusted so that a teaspoonful (5 ml.), a tablespoonful (one-half bunce or 15 ml.) or a fraction or multiple thereof, will provide an effective amount to produce the desired pharmacological effect. The exact dose depends on -i4-- . .
~8~Z~ 3633 the age, weight and condition of the patient or animal as is known in the art.
The liquid oral dosage forms may be packaged, for example, in unit-dose sizes of 5 rnl. (teaspoonful), 10 ml., 15 ml. (tablespoonful) and 30 ml. (one ounce), and multi-ple dose containers, including, for example, 2 oz., 3 oz., 4 oz., 6 oz., 8 oz., pint, quart, and gallon sizes.
Parenteral administration includes intravenous, sub-cutaneous, intramuscular, and the like.
Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or non-aqueous.
Pharmaceutically acceptable substances utilized in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutical necessities.
Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic (S percent) Dextrose Injection, Sterile Water for Injection, Dextrose and Sodium Chloride Injection and Lactated Ringers Injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin~ for example, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or 362~:
fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers (vials) `~-which include phenol or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid s esters, thimerosal, benzaTkonium chloride and benzethonium chloride. Isotonic agents include, for examplP, sodium chloride and dextrose. Buffers include, for example, phos-phate and citrate. Antioxidants include, for example, sodium bisulfite. Local anesthetics include, for example, procaine hydrochloride. Suspending and dispersing agents include, for example, sodium carboxymethylcellulose, hydroxy-propyl methylcellulose and polyvinylpyrrolidone. Emulsify-ing agents include, for example, Polysorbate 80 (Tween 80).
A sequestering or chelating agent of metal ions include, for example EDTA (ethylenediaminetetraacetic acid). Phar-maceutical necessities include, for example, ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
The concentration of the pharmaceutically active ingredient is adjusted so that an injection, for example, 0.5 ml., 1.0 ml., 2.0 ml., and 5.0 ml. or an intraarterial or intravenous infusion, for example, 0.5 ml./min., 1.0 ml.jmin., 1.0 ml./min., and 2.0 ml./min. provides an 25 effective amount to produce the desired pharmacological ;
effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
The unit-dose parenteral preparations are packaged, for example in an ampul or a syringe with a needle. The multiple-dose package, for exampl~, is a vial.
-~6-Trademark . . ., , . .. ; .
11~86Z2 All preparations for parenteral administration must be sterile, as is known and practiced in the art.
Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active material is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension con-taining an active material injected as necessary to produce the desired pharmacological effect.
Pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules, tablets for systemic effect.
Rectal suppositories as used herein mean solid bodies of insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or lS therapeutically active ingredients.
Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point.
Examples of bases or vehicles include, for example, cocoa butter (theobroma oil), glycerin gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include, for example, spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The usual weight of a rectal suppository is about 2.0 gm.
Tablets and capsules for rectal administration are manufactured utilizing the same pharmaceutically accept-able substance and by the same methods as for formulations 1~862Z
for oral administration.
Rectal suppositories, tablets or capsules are packaged either individually, in unit-dose, or in quantity, multiple dose, for example, 2, 6, or 12.
The pharmaceut~cally therapeutically active compounds of the Formula I are admin;stered ~rally, parenterally or rectally in unit-dosage forms or multiple dosage forms.
Unit-dose forms as used in the specification and cla;ms refers to physically discrete units suitable for human and animal subjects and packaged indiv;dually as is known in the art. Each unit-dose contains a predetermined quantity ; of the therapeutically active compound sufficient to pro-duce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
Examples of unit-dose forms ;nclude ampuls and syringes (parenteral), individually packaged tablet or capsule (oral-sol;d) or indiv;dually packaged teaspoonful or tablespoonful (oral-liquid). Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single conta;ner to be administered in segre-gated unit-dose form. Examples of multiple-dose forms include vials (parenteral), bottles of tablets or capsules (oral solid) or bottles of pints or gallons (oral-liquid).
Hence, multiple-dose form is a multiple of unit-doses which are not segregated in packaging. The specifications for the unit-dosage form and the multiple-dosage form are dictated by and directly dependent on (a) the unique char-acteristics of the therapeutically active compound and the particular therapeutic effect to be achieved and (b) the 8~ZZ
limitations inherent in the art of compounding such a therapeutically active compound for therapeutic or prophylactic.
In addition to the administration of a compound of Formula I as the principal active ingredient of composi-tions for the treatment of the conditions described herein, the said compound can be included with other types of com-pounds to obtain advantageous combinations of properties.
Such combinations include a compound of Formula I with other analgesics such as aspirin, phenacetin, acetaminophen, propoxyphen, pentazocine, codeine, meperidine, oxycodone, mefenamic acid, and ibuprofen; muscle relaxants such as methocarbamol, orphenadrine, carisoprodol, meprobamate, chlorphenesin carbamate, diazepam, chlordiazepoxide, and chlorzoxazone; analeptics such as caffeine, methylphenidate and pentylenetetrazol; corticosteroids such as methylpred-nisolone, prednisone, prednisolone and dexamethasone, antihistamines such as chlorpheniramine~ cyproheptadine, promethazine and pyrilamine.
Example 6 Tablets One thousand oral tablets, each containing 250 mg. of potassium metronidazole are prepared from the following types and amounts of materials: -- Potassium medronidazole250 g.
Lactose 50 9.
Corn starch 50 9.
Calcium stearate 2.5 g.
Light liquid petrolatum5 9.
The ingredients are thoroughly mixed and slugged.
The slugs are broken down by forcing through a number 11~)86Z2 sixteen screen. The resulting granules are then compressed into tablets, each containing 250 mg. of potassium metro-nidazole.
The foregoing tablets are useful for treatment of trichomoniasis by the oral administration of 1 tablet every six hours.
Example 7 Oral syrup One thousand ml. of an aqueous suspension for oral use, containing in each 5 ml. dose, 100 mg. of potassium metro-nidazole is prepared from the following types and amounts of ingredients:
Potassium metronidazole 20 g.
Citric acid 2 9.
Benzoic acid 1 9.
Sucrose 700 9.
Tragacanth 5 9.
Lemon oil 2 ml.
Deionized water q.s. 1000 ml.
The citric acid, benzoic acid, sucrose, tragacanth, and lemon oil are dispersed in sufficient water to make850 ml. of solution. The potassium metronidazole is stirred into the syrup until uniformly distributed. Suf-ficient water is added to make 1000 ml.
- The composition so prepared is useful in the treatment of amebiasis in adult humans at a dose of 1 teaspoonful 4 times a day.
Example 8 Parenteral solution A sterile aqueous solution for intramuscular use, containing in 1 ml. 400 mg. of potassium metronidazole is prepared from the following types and amounts of materials:
Potassium metronidazole400 9.
Lidocaine hydrochloride 4 g.
Methylparaben 2.5 g.
Propylparaben 0.17 g.
Water for injection q.s.1000 ml.
The ingredients are dissolved ;n the water and the solution sterilized by filtration. The sterile solution .
is filled into vials and the vials sealed.
The composition so prepared is useful in the treatment of trichomoniasis in adult humans at a dose of 1 cc injected I.M. every 8 hours.
Example 9 Suppository, rectal One thousand suppositoriesj each weighing 2.5 g. and containing 50 mg. of potassium metronidazole are prepared 5 from the following types and amounts of ingredients:
Potassium metronidazole 50 g.
Propylene glycol 162.5 g.
Polyethylene glycol 4000 q.s. 2300 g.
The potassium metronidazole is added to the propylene glycol and the mixture milled until the powders are finely divided and uniformly dispersed. The polyethylene glycol 4000 is melted and the propylene glycol dispersion added slowly with stirring. The suspension is poured into un-chilled molds at 40 C. The composition is allowed to cool and solidify and then removed from the mold and each suppository foil wrapped.
The suppositories are useful in the treatment of amebiasis in adult humans by the insertion rectally of 1 suppository every six hours.
Example 10 1~86Z2 3633 Compositions for similarly prepared following the procedure of the preceding Examples 6 through 9 substitut-ing an equimolar amount each of metronidazole phosphate, metronidazole phosphase sodium salt, metronidazole phos-phate amine salts, metronidazole phopshatP aluminum saltand the like for the potassium metronidazole of the Example.
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula:
and a pharmacologically acceptable salts thereof, which comprises reacting metronidazole with a phosphating agent.
and a pharmacologically acceptable salts thereof, which comprises reacting metronidazole with a phosphating agent.
2. The process defined in claim 1, including the step of preparing a pharmacologically acceptable salt of the product thus obtained.
3. The process of claim 1 wherein the phosphating agent is 2-cyano-ethyl phosphate.
4. The process of claim 1 wherein the phosphating agent is pyrophos-phoryltetrachloride.
5. The process defined in claim 2 wherein the salt is the dipotassium salt.
6. A compound of the formula:
and pharmacologically acceptable salts thereof, whenever prepared or produced by the process defined in claim 1, 2 or 3 or by the obvious chemical equivalent.
and pharmacologically acceptable salts thereof, whenever prepared or produced by the process defined in claim 1, 2 or 3 or by the obvious chemical equivalent.
7. Metronidazole phosphate dipotassium salt, whenever prepared or produced by the process defined in claim 5 or by the obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/875,393 US4160827A (en) | 1978-02-06 | 1978-02-06 | Metronidazole phosphate and salts |
| US875,393 | 1978-02-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1108622A true CA1108622A (en) | 1981-09-08 |
Family
ID=25365724
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA319,763A Expired CA1108622A (en) | 1978-02-06 | 1979-01-17 | Metronidazole phosphate and salts |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4160827A (en) |
| JP (1) | JPS54115375A (en) |
| AU (1) | AU523423B2 (en) |
| BE (1) | BE873973A (en) |
| CA (1) | CA1108622A (en) |
| CH (1) | CH638535A5 (en) |
| DE (1) | DE2903269A1 (en) |
| ES (1) | ES477265A1 (en) |
| FR (1) | FR2416234A1 (en) |
| GB (1) | GB2013683B (en) |
| GR (1) | GR67623B (en) |
| IT (1) | IT1116516B (en) |
| NL (1) | NL7900858A (en) |
| PH (1) | PH14464A (en) |
| SE (1) | SE445221B (en) |
| ZA (1) | ZA79282B (en) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4531004A (en) * | 1981-11-23 | 1985-07-23 | The Upjohn Company | Dimetronidazole phosphates |
| US4386079A (en) * | 1981-11-23 | 1983-05-31 | The Upjohn Company | Method of treating depression |
| CA1237670A (en) * | 1983-05-26 | 1988-06-07 | Andrew S. Janoff | Drug preparations of reduced toxicity |
| US5059591B1 (en) * | 1983-05-26 | 2000-04-25 | Liposome Co Inc | Drug preparations of reduced toxicity |
| PT78628B (en) * | 1984-05-02 | 1986-06-18 | Liposome Co Inc | Pharmaceutical composition with reduced toxicity |
| US4943579A (en) * | 1987-10-06 | 1990-07-24 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Water soluble prodrugs of camptothecin |
| US7223421B2 (en) * | 2000-06-30 | 2007-05-29 | Mcneil-Ppc, Inc. | Teste masked pharmaceutical particles |
| US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
| US6423707B1 (en) | 2000-08-28 | 2002-07-23 | California Pacific Medical Center | Nitroimidazole ester analogues and therapeutic applications |
| EP1305008A4 (en) * | 2001-03-27 | 2005-02-09 | R P Scherer Technologies Inc A | Improved forms of pharmaceutically active agents and method for manufacture thereof |
| IL152486A0 (en) | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
| US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
| US8486376B2 (en) | 2002-10-25 | 2013-07-16 | Foamix Ltd. | Moisturizing foam containing lanolin |
| US10117812B2 (en) | 2002-10-25 | 2018-11-06 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
| US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
| US7700076B2 (en) | 2002-10-25 | 2010-04-20 | Foamix, Ltd. | Penetrating pharmaceutical foam |
| US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
| EP1556009B2 (en) | 2002-10-25 | 2021-07-21 | Foamix Pharmaceuticals Ltd. | Cosmetic and pharmaceutical foam |
| US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
| US8119150B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Non-flammable insecticide composition and uses thereof |
| US8900554B2 (en) | 2002-10-25 | 2014-12-02 | Foamix Pharmaceuticals Ltd. | Foamable composition and uses thereof |
| US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
| US20080138296A1 (en) | 2002-10-25 | 2008-06-12 | Foamix Ltd. | Foam prepared from nanoemulsions and uses |
| US9265725B2 (en) | 2002-10-25 | 2016-02-23 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
| US7575739B2 (en) | 2003-04-28 | 2009-08-18 | Foamix Ltd. | Foamable iodine composition |
| GB0315671D0 (en) * | 2003-07-04 | 2003-08-13 | Chelsea And Westminster Nhs Tr | Improvements in or relating to organic compounds |
| US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
| US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
| US7608724B2 (en) * | 2003-10-28 | 2009-10-27 | Ems S.A. | Antibacterial and/or antiprotozoal nitromidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines |
| CA2610662A1 (en) | 2005-05-09 | 2007-05-18 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
| US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
| US8636982B2 (en) | 2007-08-07 | 2014-01-28 | Foamix Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
| US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
| WO2009072007A2 (en) | 2007-12-07 | 2009-06-11 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
| WO2010041141A2 (en) | 2008-10-07 | 2010-04-15 | Foamix Ltd. | Oil-based foamable carriers and formulations |
| CA2712120A1 (en) | 2008-01-14 | 2009-07-23 | Foamix Ltd. | Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses |
| CA2760186C (en) | 2009-04-28 | 2019-10-29 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
| WO2011013008A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
| WO2011013009A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
| US8871184B2 (en) | 2009-10-02 | 2014-10-28 | Foamix Ltd. | Topical tetracycline compositions |
| US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
| CN102516298A (en) * | 2011-12-09 | 2012-06-27 | 陕西合成药业有限公司 | Stable pharmaceutical salt of L-aonitrate phosphate ester, its preparation method and application |
| CN102516299A (en) * | 2011-12-09 | 2012-06-27 | 陕西合成药业有限公司 | S-Ornidazole phosphate amino acid salt, its preparation method and application |
| MX2020012139A (en) | 2016-09-08 | 2021-01-29 | Vyne Pharmaceuticals Inc | Compositions and methods for treating rosacea and acne. |
| CN108295039A (en) * | 2018-02-28 | 2018-07-20 | 重庆希尔安药业有限公司 | Metronidazole vagina effervescent tablet and preparation method thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE571291A (en) * | 1957-09-20 | 1962-01-12 | Rhone Poulenc Sa | NEW DERIVATIVES OF IMIDAZOLE AND THEIR PREPARATION. |
| US2944061A (en) * | 1957-09-20 | 1960-07-05 | Acyl derivatives and process | |
| GB1280355A (en) * | 1969-06-20 | 1972-07-05 | Rech S Et D Applic Scient Et M | Substituted 5-nitro-imidazoles and their preparation |
| FR2054504B1 (en) * | 1969-07-18 | 1973-06-08 | Rhone Poulenc Sa | |
| US3910945A (en) * | 1972-10-04 | 1975-10-07 | Searle & Co | 2-(2-Methyl-5-nitro-1-imidazolyl)ethyl-N-arylalkyldithiocarbamates |
| US3882136A (en) * | 1973-11-16 | 1975-05-06 | Searle & Co | S-{8 omega-(1-imidazolyl) alkyl{9 hydrogen monothiosulfates and salts thereof |
-
1978
- 1978-02-06 US US05/875,393 patent/US4160827A/en not_active Expired - Lifetime
-
1979
- 1979-01-17 CA CA319,763A patent/CA1108622A/en not_active Expired
- 1979-01-23 ZA ZA79282A patent/ZA79282B/en unknown
- 1979-01-26 AU AU43705/79A patent/AU523423B2/en not_active Ceased
- 1979-01-29 GR GR58208A patent/GR67623B/el unknown
- 1979-01-29 DE DE2903269A patent/DE2903269A1/en not_active Ceased
- 1979-01-30 ES ES477265A patent/ES477265A1/en not_active Expired
- 1979-02-02 NL NL7900858A patent/NL7900858A/en not_active Application Discontinuation
- 1979-02-02 IT IT47874/79A patent/IT1116516B/en active
- 1979-02-02 SE SE7900952A patent/SE445221B/en not_active IP Right Cessation
- 1979-02-05 PH PH22156A patent/PH14464A/en unknown
- 1979-02-05 FR FR7902950A patent/FR2416234A1/en active Granted
- 1979-02-05 GB GB7903940A patent/GB2013683B/en not_active Expired
- 1979-02-06 JP JP1275979A patent/JPS54115375A/en active Pending
- 1979-02-06 CH CH116479A patent/CH638535A5/en not_active IP Right Cessation
- 1979-02-06 BE BE0/193304A patent/BE873973A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2416234A1 (en) | 1979-08-31 |
| PH14464A (en) | 1981-07-29 |
| GR67623B (en) | 1981-09-01 |
| ES477265A1 (en) | 1980-10-01 |
| ZA79282B (en) | 1980-01-30 |
| FR2416234B1 (en) | 1983-02-04 |
| GB2013683A (en) | 1979-08-15 |
| US4160827A (en) | 1979-07-10 |
| BE873973A (en) | 1979-08-06 |
| AU523423B2 (en) | 1982-07-29 |
| AU4370579A (en) | 1979-08-16 |
| CH638535A5 (en) | 1983-09-30 |
| SE7900952L (en) | 1979-08-07 |
| GB2013683B (en) | 1982-06-30 |
| NL7900858A (en) | 1979-08-08 |
| IT7947874A0 (en) | 1979-02-02 |
| IT1116516B (en) | 1986-02-10 |
| DE2903269A1 (en) | 1979-08-09 |
| JPS54115375A (en) | 1979-09-07 |
| SE445221B (en) | 1986-06-09 |
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| MKEX | Expiry |