US3509256A - Lincomycin-2-phosphate antibiotic compositions and process of treatment - Google Patents

Lincomycin-2-phosphate antibiotic compositions and process of treatment Download PDF

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Publication number
US3509256A
US3509256A US789915A US3509256DA US3509256A US 3509256 A US3509256 A US 3509256A US 789915 A US789915 A US 789915A US 3509256D A US3509256D A US 3509256DA US 3509256 A US3509256 A US 3509256A
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phosphate
lincomycin
prepared
treatment
amounts
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Walter Morozowich
Donald J Lamb
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Pharmacia and Upjohn Co
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Upjohn Co
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    • 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

Definitions

  • compositions comprising, in unit dosage form, a compound of the formula R l l' CH3 ill a? R OH SCHa 0-P-OH OH Formula 1 wherein X is hydroxy, chlorine, or bromine, R is alkyl of from 1 to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms or aralkyl of from 7 to 12 carbon atoms and R is hydrogen, alkyl of from 1 to 8 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms or aralkyl of from 7 to 12 carbon atoms; and including the pharrnaceutically acceptable salts thereof in combination with a pharmaceutical carrier.
  • Typical, but not all, therapeutic compounds of this invention include the following as referred to the above Formula 1:
  • the vertical wavy line I is used to indicate that the group R can be in position cis (below the plane of the ring) or trans (above the plane of the ring), with respect to the carbonyl group.
  • the horizontal wavy line is used to indicate that both epirners are to be included, i.e., the D-erythro configuration and L- threo configuration are intended.
  • alkyl examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl and isomeric forms thereof.
  • cycloalkyl examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Z-methylcyclopentyl, 2,3-dimethylcyclobutyl, 4-methylcyclobutyl, and 3-cyclopentylpropyl.
  • aralkyl examples include benzyl, phenethyl, a-phenylpropyl, and a-naphthylmethyl.
  • the compounds of the Formula 1 can be prepared by the methods disclosed in copending application Ser. No. 602,116 filed Dec. 16, 1966.
  • the invention relates to a process for therapeutic treatment of humans and animals hosting bacterial and other microparasites and the prophylactic treatment of a disease-susceptible host comprising the administration of a compound of the formula 1 or a pharmaceutically acceptable salt thereof to the host.
  • the compounds of the invention have essentially the same antibacterial spectrum in vivo as the antibiotic lincomycin and can be used for the same purposes as lincomycin.
  • the compounds of the invention are particularly useful for oral administration to animals, including birds, because they lack the bitter taste of lincomycin.
  • 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 parenternal solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of a compound of Formula 1 or its pharmacologically acceptable salts.
  • either solid or fiuid unit dosage forms can be prepared.
  • the principal active ingredient is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • the tablets can be laminated or ng the advantage of prolonged or delayed action or pre-. letermined successive action of the enclosed medication. or example, the tablet can comprise an inner dosage lIld an outer dosage component, the latter being in the mm of an envelope over the former.
  • the two component system can be utiized, for preparing tablets containing two or more incomiatible active ingredients.
  • Wafers are prepared in the ame manner as tablets, differing only in shape and the nclusion of sucrose or other sweetener and flavor.
  • capsules like tablets, are prepared )y mixing the antibiotic with an inert pharmaceutical liluent and filling the mixture into a hard gelatin capsule of appropriate'size.
  • capsules tre prepared by filling hard gelatin capsules with polyneric acid coated beads containing the antibiotic.
  • Soft elatin capsules are prepared by machine encapsulation f a slurry of the antibiotic with an acceptable vegetable il, light liquid petrolatum or other inert oil.
  • Fluid unit dosage forms for oral administration such s syrups, elixirs, and suspensions can be prepared.
  • the later-soluble forms can be dissolved in an aqueous vehicle agether with sugar, aromatic flavoring agents and preervatives to form a syrup.
  • An elixir is prepared by using hydro-alcoholic (ethanol) vehicle with suitable sweetners such as sugar and saccharin, together with an aronatic flavoring agent.
  • Suspensions can be prepared of the insoluble forms /ith a syrup vehicle with the aid of a suspending agent uch as acacia, tragacanth, methylcellulose and the like.
  • Topical ointments can be prepared by dispersing the ntibiotic in a suitable ointment base such as petrolatum, illOliI'l, polyethylene glycols, mixtures thereof, and the ike.
  • a suitable ointment base such as petrolatum, illOliI'l, polyethylene glycols, mixtures thereof, and the ike.
  • the antibiotic is finely divided by leans of a colloid mill utilizing light liquid petrolatum s a levigating agent prior to dispersing in the ointment Iase.
  • Topical creams and lotions are prepared by disersing the antibiotic in the oil phase prior to the emulsi- :cation of the oil phase in Water.
  • fluid unit dosage forms re prepared utilizing the antibiotic and a sterile vehicle, ater being preferred.
  • the antibiotic depending on the arm and concentration used, can be either suspended or issolved in the vehicle.
  • the wateroluble antibiotic can be dissolved in water for injection nd filter sterilized before filling into a suitable vial or mpule and sealing.
  • adjuvants such as local anesthetic, preservative and buffering agents can e dissolved in the vehicle.
  • the omposition can be frozen after filling into the vial and he Water removed under vacuum.
  • the dry lyophilized owder is then sealed in the vial and an accompanying ial of water for injection is supplied to reconstitute the quid prior to use.
  • Parenteral suspensions are prepared 1 substantially thesame manner except that the antiiotic is suspended in the vehicle instead of being disalved and sterilization cannot be accomplished by filtraion.
  • the antibiotic can be .sterilized by exposure to thylene oxide before suspending in the sterile vehicle.
  • novel unit I .osage forms of this invention are dictated by and diectly dependent on (a) the unique characteristics of be active material and the particular therapeutic effect a be achieved, and (b) the limitations inherent inthe .rt of compounding such an active material for therape'iitic use in'hur'n aiis'and anlmals, as disclosed in detail inthisspecification, these beingfeatures of the present invention.
  • suitable unit dosage forms in accord with this invention are tablets, capsules, pills, troches, suppositories, powder packets, granules, wafers, cachets, teaspoonfuls,tablespoonfuls, dropperfuls, am-
  • Such combinations include -a compound of Formula 1 with antibiotics such as spectiriomycin, .clilorarnphenicol, tetracyclines( e.g., tetracycline, oxytetracycline and chlortetrachcline), penicillin, erythromyin, novobiocin, kahamycin, streptomycin, neom'ycim: polymyxin, bacitracin, nystatin, and endomycin to broaden the *bacterial spectrum of the composition and for synergistic action against particular bacteria; steroids having antiinflammatory activity such as hydrocortisone, prednisolone, methylprednisolone, fluprednisolone and "the like; analgesics such as aspirin, sodium salicylate, (acetylsalicylic acid) anhydride, acetaminophen and salicylamide; antihistamines, such as chloropheniramine maleate, diphenhydramine, promethaz
  • the dosage of a compound of Formula 1 for treatment depends on route of administration; the age, weight, and
  • the antibiotic is compounded with a suitable pharmaceutical carrier in unit dosage form for convenient and effective administration.
  • the dosage units contain a compound of Formula 1 in: 50,100, 200 and 500 mg. amounts for systemic treatment; in 0.25, 0.5, 1 2 and 5% amounts for topical or localized treatment; and 5 to 25% w./v. for'parenteral treatment.
  • the dosage ofcompositions containing a compound of Formula 1 andone or more other active ingredients is tobe determined with reference to the usual dosage of each such ingredient.
  • One thousand two-piece hard gelatin capsules for oral use, each containing 200 mg. of lincomycin-2-phosphate are prepared from the following types and amounts of materials:
  • 500 mg. amounts by substituting 50, 100 and 500 gm. of lincomycin-Z-phosphate for the 200 gm. used above.
  • EXAMPLE 2 Capsules One thousand two-piece hard gelatin capsules for oral use, each containing 200 mg. of lincomycin-Z-phosphate and 250 mg. of tetracycline hydrochloride, are prepared from the following types and amounts of ingredients:
  • the ingredients are thoroughly mixed and then encapsulated in the usual manner.
  • capsules are similarly prepared containing lincomycin-Z-phosphate and each of the following antibiotics in place of tetracycline by substituting 250 gm. of such other antibiotic for tetracycline: chloramphenicol, oxytetracycline, chlortetracycline, fumagillin, erythromycin, streptomycin, dihydrostreptomycin and novobiocin.
  • a penicillin such as potassium penicillin G
  • 250,000 units per capsule is employed.
  • Such combination products are useful for the systemic treatment of mixed infections in adult humans by the oral administration of 1 capsule every 6 hours.
  • EXAMPLE 3 Tablets One thousand tablets for oral use, each containing 500 mg. of lincomycin-Z-phosphate are prepared from the following types and amounts of materials:
  • One thousand oral tablets, each containing 200 mg. of lincomycin-Z-phosphate and a total of 250 mg. (83.3 mg. each) of sulfadiazine, sulfamerazine, and sulfamethazine, are prepared from the following types and amounts of materials:
  • slugs are broken down by forcing through a number sixte'en screen.
  • the resulting granules are then compressed into tablets, each containing 200 mg. of lincomycin-Z- phosphate and a total of 250 mg. (83.3 mg. each) of sulfadiazine, sulfamerazine, and sulfamethazine.
  • the foregoing tablets are useful for systemic treatment of infections by the oral administration of 4 tablets first and then 1 every six hours.
  • the triple sulfas in the above formulation is advantageously replaced by 250 gm. of sulfamethylthiadiazole or 250 gm. of sulfacetamide.
  • EXAMPLE 5 Granules 2367 gm. of a granulation suitable for reconstitution with water prior to use is prepared from the following types and amounts of ingredients:
  • Lincomycin-Z-phosphate 150 Tetracycline hydrochloride 150 Lecithin 5 Sucrose, powdered 2000 Flavor Sodium metabisulfite 2
  • the tetracycline is finely divided and coated with the lecithin.
  • the coated tetracycline, lincomycin-Z-phosphate, sugar, flavor, and sodium metabisulfite are mixed together until thoroughly blended.
  • the powder mixture is wetted with water and forced through a screen to form granules.
  • the granules are dried and 23.67 gm. filled into 60 cc. bottles. Prior to use sufficient water is added to the granules to make 60 cc. of composition.
  • composition is useful for systemic treatment of infection, particularly in children at a dose of one teaspoonful 4 times daily.
  • EXAMPLE 6 Oral syrup One thousand cc. of an aqueous suspension for oral use, containing in each 5 cc. dose, one-half gram of total sulfas and 200 mg. of lincomycin-Z-phosphate is prepared from the following types and amounts of ingredients:
  • Citric acid2 gm Citric acid2 gm.
  • the citric acid, benzoic acid, sucrose, tragacanth, and lemon oil are dispersed in sufficient water to make 850 cc. of solution.
  • the lincomycin-Z-phosphate and finely EXAMPLE 7 Parenteral solution A sterile aqueous solution for intramuscular use, containing in 1 cc. 75 mg. of lincomycin-Z-phosphate is prepared from the following types and amounts of materials:
  • Parerifeml solution w ,..A; sterile aqueous solution forintramuscula'r use, .conaimingin 1 cc. .250 mg. of lincomycin-Z-phos'phate, as he Na salt is prepared fromthe following types and mountsof-ingredientsfi .inco'myc in-2-phosphate 250 gal; lodium hydroxide 10% solution, q.s. Vater for injection, q.s..1000 cc.
  • the lincomycin-Z-phosphate is added to the water and ufficient sodium hydroxide added to form a solution nd the solution sterilized by filtration.
  • the sterile soluion,v in the amount of 2 cc. is aseptically filled into terile vials and frozen.
  • the Water is removed under igh vacuum and the vials containing the lyophilized owder are sealed.
  • sufiicient sterile later for injection to make 2 cc. of solution is added a the vial.
  • the foregoing ointment is usefully applied topically the skin of mammals for the treatment of infection.
  • the foregoing composition can be prepared by omitting 1e zinc oxide and calamine.
  • EXAMPLE Cream One thousand gm. of a vaginal cream are prepared tom the following types and amounts of ingredients:
  • the antibiotics are finely divided by means of an air micronizer and added to the light liquid 'petrolatum.
  • the mixture is passed through a colloid mill to uniformly distribute the antibiotics.
  • the wool fat and white petrolatum are melted together, strained, and the temperature adjused to 4550 C.
  • the liquid petrolatum slurry is added and the ointment stirred until congealed.
  • the ointment is packaged in one dram ophthalmic tubes.
  • the foregoing ointment is usefully applied'to the eye for treatment of localized infection in humans and other animals.
  • the foregoing composition can contain 5 gm. (0.5%) of methylprednisolone for the treat- 'ment of inflammation,- and, alternatively, the bacitracin and polymyxin B sulfate can be omitted.
  • EXAMPLE 12 Eye-ear drops One thousand cc. of 'a' sterile aqueous solution for eye or ear use containing 10 mg. of lincomycine2-phosphate and 10 mg. of prenisolone succin'ate sodium in each cc. is prepared fromthe following types and amounts'of ingredients: 7
  • EXAMPLE 13 Track es en thousand troches are prepared from the following types and amounts of ingredients: 1 v
  • Lincornyclin-Z-phosphate Neomycin sulfate I 50 The powdered materials are mixed thoroughly and then compressed into half gram troches following the usual techniques for the preparation of compressed tablets.
  • the troches are held in the mouth and allowed to dissolve slowly to provide treatment for the mouth and throat.
  • EXAMPLE 14 Suppository, rectal One thousand suppositories, each weighing 2.5 'gm. and containing 100 mg. of lincomycin-Z-phosphate are prepared from the following types and amounts of ingredients:
  • the foregoing suppositories are inserted rectally for local treatment of inflammation and infection.
  • the foregoing composition can be prepared omitting the steroid.
  • Lincomycin-Z-phosphate 50 Prednisolone acetate 0.5 Light liquid petrolatum 300 Chlorobutanol, anhydrous Polysorbate 80 5 2% aluminum monostearate-peanut oil gel 400 White petrolatum, q.s. 1000 Animal feed One thousand gm. of a feedmix is prepared from the following types and amounts of ingredients:
  • composition can be fed to laboratory animals, i.e., mice, rats, mice, etc.
  • the composition can be added to the animals regular feed in an amount calculated to give 'the desired dose of lincomycin-2-phosphate.
  • each member selected from the group consisting of sodium novobiocin, calcium novobiocin, chlortetracyline hydrochloride, oxytetrac'ycline hydrochloride, tetracycline, tetracycline hydrochloride, and tetracycline phosphate complex is added "in 50, 100, and 250 gm. amounts to provide a combination having a wider spectrum of therapeutic effectiveness in the treatment of infectious diseases resulting frornfimixed organisms susceptible to lincomycin-Z-phosphate as indicated in the present specification and the above indicated antibiotics as already well known to the medical art.
  • EXAMPLE 18 Following the procedure of the preceding Examples 1 through 5, '9 through 11, and 13 through 16, inclusive, each member selected from the group consisting of 7 (S) -chloro-7-deoxylincomycin-Z-phosphate, calcium salt, 7 (S )-chloro-7-deoxylincomycin-2-phosphate, magnesium salt, 7(S)-chloro 7 deoxy-1'-demethyllincornycin-2-phosphate, calcium salt, or 7 (S)-chloro 7 deoxy-1'-demethyllincomycin-Z-phosphate, magnesium salt is substituted in an equivalent amount for the lincomycin-Z-phosphate shown in the example and provides similar therapeutic properties.
  • An antibacterial composition comprising, in unit dosage form, from about 50 to 500 mg. of a compound of the formula:
  • X is hydroxy, chlorine or bromine
  • R is alkyl of C cycloalkyl or C or aralkyl of C and R ion of the compoundof ,t a is from about 0.25% v./w. to about 25% wjw. -j3, ; ⁇ A ⁇ :-eornposition iiOfiLiClfliIIl: Lwherein: zth edleoncentraion of thel-lcompoundwfr therformula is from about;
  • vherein" X is'hydro'xy, 'chlorineor bromine, R is alkyl )1?
  • C cycloalkyl of C or aralkyl of C R is lydrogen', alkyl of C cycloalkyl of C or ar'alkyl )f C5 or'pharmaceutically acceptable salts thereof in :ombination with a pharmaceutical carrier.
  • aa diseasevsusceptiblejhuman for animal host a prophylactic 5; antibacterial; amountof a compound 0f:the iormulaz 1 pound of the formula is adtr'rinistered in unitdosage form in an amount of from about. to about 500 mg; of said "compound in association with a pharmaceutical carrier;

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US789915A 1969-01-08 1969-01-08 Lincomycin-2-phosphate antibiotic compositions and process of treatment Expired - Lifetime US3509256A (en)

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DE (1) DE2000349A1 (fr)
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MY (1) MY7400119A (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2392666A1 (fr) * 1977-01-21 1978-12-29 Meiji Seika Kaisha Procede de production de suppositoires d'antibiotiques a base d'aminoglucosides et nouveaux produits ainsi obtenus
US4208648A (en) * 1977-08-18 1980-06-17 Fichtel & Sachs Ag Sensor panel for locating a load
EP0183322A3 (fr) * 1984-11-28 1987-07-22 The Procter & Gamble Company Compositions antibiotiques sous forme de gel pour application topique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002238063A1 (en) * 2002-02-05 2004-02-25 Pharmacia And Upjohn Company Composition and method for rectal delivery of a lincosamide antibacterial drug

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3150042A (en) * 1963-03-15 1964-09-22 Upjohn Co Treating coccidiosis with lincomycin
US3268556A (en) * 1964-04-13 1966-08-23 Upjohn Co Novel lincomycin derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3150042A (en) * 1963-03-15 1964-09-22 Upjohn Co Treating coccidiosis with lincomycin
US3268556A (en) * 1964-04-13 1966-08-23 Upjohn Co Novel lincomycin derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2392666A1 (fr) * 1977-01-21 1978-12-29 Meiji Seika Kaisha Procede de production de suppositoires d'antibiotiques a base d'aminoglucosides et nouveaux produits ainsi obtenus
US4208648A (en) * 1977-08-18 1980-06-17 Fichtel & Sachs Ag Sensor panel for locating a load
EP0183322A3 (fr) * 1984-11-28 1987-07-22 The Procter & Gamble Company Compositions antibiotiques sous forme de gel pour application topique

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BE744167A (fr) 1970-07-08
GB1219700A (en) 1971-01-20
MY7400119A (en) 1974-12-31
DE2000349A1 (de) 1970-09-24

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