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US3026248A - Thioglycerol and formaldehyde sulfoxylate stabilized tetracycline antibiotics in polyhydric alcohol solvents - Google Patents

Thioglycerol and formaldehyde sulfoxylate stabilized tetracycline antibiotics in polyhydric alcohol solvents Download PDF

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US3026248A
US3026248A US839281A US83928159A US3026248A US 3026248 A US3026248 A US 3026248A US 839281 A US839281 A US 839281A US 83928159 A US83928159 A US 83928159A US 3026248 A US3026248 A US 3026248A
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thioglycerol
formaldehyde sulfoxylate
tetracycline
polyhydric alcohol
stabilized
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US839281A
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Melvin M Noseworthy
Allen J Spiegel
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Pfizer Inc
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Pfizer Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S310/00—Electrical generator or motor structure
    • Y10S310/06—Printed-circuit motors and components

Definitions

  • the tetracycline antibiotics comprise a group of biologically active perhydronaphthacene-derivatives having the following essential structural features.
  • the numbering system indicated is that lemployed by fChemical Abstreets.”
  • magnesium, calcium, andfalum'inum ltetracyclines having a molar ratio of metal lion to tetracycline of about 3:1, and magnesium, calcium, and aluminum oxytetracyclines having amolarratio of metal ion to oxytetrasatisfactory are the glycols, preferably those ⁇ generally recognized as pharmaceutlcally acceptable, such as propylene glycol, polyethylene glycol, and mixtures thereof.
  • the chosen ymetal salt of the antibiotic is prepared in situ by dissolving the freeJbase form of a tetracycline antibiotic, or an acid salt thereof, in the selected pclyhydric alcohol and adding a solution of a salt of the desired metal in the polyol or in water.
  • a salt of a pharmaceutically acceptable anion be selected, that is, one which is free from obiectional side elfectsatthe 1leyels of ordinary use.
  • Ihe chloride and acetate salts, for example, are among those which 'f are suitable. 'Ihe retioi usually occurs readily at room temperature.
  • neutral to alkaline conditions are desirable, e.g.
  • solvents are the polyhydric aliphatic alcohols and thereof. Especially the potassium, lithium, calcium, magnesium and strontium salts.. Particularly preferred is the readily available sodium formaldehyde sulfoxylate.
  • 'Ihese new therapeutic combinations are particularly ⁇ suitable for parenteral administration and especially for intramuscular use.
  • a local anaesthetic such as those which are well known to those skilled inthe an.
  • lidocaine a-diethylamino2,6acetoxylidide, available from the Astra Chemical Co.
  • thepreparations will be formulated with pyrogen-free water and filtered aseptically before packaging.
  • Antibiotic concentrations which are particularly suitable for this mode of administration are those ranging from about S to about 125 nig/cc.
  • these stabilized solutions are also eminently suitable for oral and topical use, and may be employed, for example, in the treatment of bovine mastitis.
  • solutions A of tetracycline antibiotics are found to retain their voriginal color and potency substantially unimpaired over long periods of storagev at room temperature, and also in'ao celerated high-temperature experiments. Por optimum results it isv desirable to saturate the vehicle with nitrogen and to package these dosage forms under an inert atmosphere. However, single doses may be. withdrawn from multi-dose containers with attendant admission of air into the 'container without seriously impairing the stability of the remaining solution. vFor example, in accelerated tests at l50" C.
  • the antioxidant concentrations are as follows:
  • Example I A. 0.3% w./v. sodium formaldehyde sulfoxylate plus 1.0% w./v. thioglycerol v B. 0.5% w./v. sodium formaldehyde sulfoxylate C. 1.0% w./v. thiomalic acid EXAMPLE n f Samples of the solutions of Example I are subjected to a temperature of 75 C..for varying periods of time up to 24 hours. After heating, each sample is diluted. 1:1 with the aqueous glycol vehicle and the light absorbance is determined at 500 ma on a Beckman spectrophotometer with a tungsten light source and a slit width setting of 0.04, employing water as the blank. i' marized in the table below.
  • Light Absorbunoel Results are sumnour's'rit' iisi'fffi::1122212112111222112212 s1.. y s... .est
  • EXAMPLE IV A stabilized preparation containing approximately nig/cc. of oxytetracycline activity and suitable for intramuscular administration is prepared according to the following formulation and packaged under nitrogen:
  • Glycerine U.S.P., liter 1 Calcium ⁇ acetate monohydrate, gm 20.66 Oxytetr'acycline hydrochloride, gm. 60.2 Potassium formaldehyde sulfoxylate, gm. 2 Thioglycerol, gm. 4 10% sodium hydroxide in glycerine, to pH 9, cc.
  • Gylcerine U.S.P., cc. 500 Aluminum chloride hexahydrate, gm. 40.7 Tetracycline hydrochloride, gm. 27.55 Thioglycerol, gm. 20 Lithium formaldehyde sulfoxylate, gm. 5 10% sodium hydroxide in glycerine, to pH 9 Glycerine, U.S.P., to make 1 liter.
  • Glycerine U.S.P., cc. 500 Sorbitol, gm'. v 50 Zinc chloride, gm. 5.94
  • Glycerine U.S.P., cc. 500 Calcium acetate monohydrate, gm. 20.66
  • Oxytetracycline hydrochloride gm. 30.1 Thioglycerol, gm. 10 Magnesium formaldehyde sulfoxylate, gm 3 10% sodium hydroxide in glycerine, to pH 9 Glycerine, U.S.P., to make l liter.
  • a pharmaceutical composition comprising a tetracycline antibiotic dissolved in a pharmaceutically acceptable polyhydric alcohol solvent, and as stabilizer for said tetracycline antibiotic, a mixture of thioglycerol and a pharmaceutically acceptable formaldehyde sulfoxylate selected from the group consisting of the alkali-metal and alkaline-earth-metal salts, the weight ratio of sulfoxylate salt to thioglycerol being fromabout 5:2 to about 1:20.
  • a composition as in claim 1 wherein said antibiotic is selected from the group consisting of magnesium, calcium and aluminum tetracyclines having a molar ratio of metal ion to tetracycline of about 3:1 and magnesium, calcium, aluminum and zinc oxytetracyclines having a molar ratio of metal ion to oxytetracycline of from about 1:3 to about 3:1.
  • muscular administration comprising a solution containing magnesium oxytetracycline having a molar ratio of magnesium to oxytetracycline of about l, about 0.3% w./v. sodium formaldehyde sulfoxylate and about 1% w./v. thioglycerol in about 80% aqueous propylene glycol.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

\ been achieved in this direction by the addition of l (sr-monothioglyceml).
United States Patent Op lCe Patented Msi. zo, 1962 procedure with its obvious attendant disadvantages by `theiudicious addition of certain antioxidants and the careful packaging of the solution'insealed `ampoules undernitrogen gas. for example,somesuccess has formaldehyde sulfoxylate .tos the antibiotic' solution. However, even with this 4valuable additive it has lnot been practical to package these solutions in multi-dose containers but has rather been necessary to provide individual single-dosage ampoules. 'Ihis inconvenientgand expensive is required because the removal of individual dosages fromv a multi-'dose package (for example, by piercing a rubber bottle closure with a hypodermic needle, injecting and withdrawing an individual dosage intoa syringe) necessarily introduces air into the con- Now it has beenl discovered that these problema lare obviated by stabilizing solutions of the tetracycline antibioties with a combination of an alkali-metal or alkalineearth-metal formaldehydev sulfoxylate and thioglycerol With this antiodant combination it is now possi-ble for the tirst timeto package already constituted solutions of the tetracycline antibiotics in multi-dose containers with the assurance that even after a substantial proportionof air has been admitted to the container during partial withdrawal ofthe liquid contents, the residual solution will remain stable and light in color for long periods of storage. The savings in cost and space made possible by thisv development are obvious. The tetracycline antibiotics comprise a group of biologically active perhydronaphthacene-derivatives having the following essential structural features. The numbering system indicated is that lemployed by fChemical Abstreets."
' 1 Y, s s 4 fsw/ m/A\ 0H 65 i lma ua las -ooNm those containing following substituent tainer Abeyond the ability of thesulfoxylate to lstabilize the. residual solution, which soon darkensfand becomes anni for use.
t v3 v sbsurnum commun mocLYcnaoL msziihiimmanvnn sULr- 'f m giimcsrusrlgmvnglc ALcoiihL soLvnN'la 5 gt 8g; g; 318g; tj'gm-; Mm, 32mm 4Melvin M. Noseworthy Brooklyn, and Allen J. Spiegel, eN on. com con, 1-01, wou... v-eh orsrsoycnns.
New YorlnN Y I to Chas. Pllzes' l Co., Inc., t-N 0H: i. 2ait.. 1... s-dsmschylmrssysnns.
. N York NY" l um of www N OlIs s. 6-0H, 7-51. 12v-011m.; bglsliethylJ-bmmtstracy- No lklwilg'. Filed Sept. 1l, 1959, 8er. No. 839,281 .Ng n. WH. -OB: lss-deoxytetraorellne.
Il*This application relates to antibiotic solutions and more 4N 0H u H3 1 2a'0H......... s-dsoxytetrseyenns. particularly u stabilizes solutions or fue remt-.une gg mgm s IM-.- -Nmotlm swjsmwenl wn the tibi highly val ne s-Noniails-omaol.xhfolLmnm.. generan-maternos administration. Like many organic substances, however, sortons.. s-ou o-dsmszhyim -ssoxymthe tetracycline antibiotics vare particularly subject 1 0 Oli' mono s-on, 1-01, 12s-on s-vgunfi mamme. dative decomposition in solution with theformatlon of 20 l v enne. p highlycolored impurities which render them unsuitable y "mom," 7-'01' 2f`H"",""""""" gofsm* eurimyl'? for the desired applications. As a result it has usually s-Nogg.. com. 1Br. iza-oa......l..... s-asoxyn-bwmtemeynms. been necessary to prepare these dosage forms in a dry. "N c "7B"120H "r" "dbgge'fuffgl' 7 state for reconstitution with a solvent immediately before v t use. ln some cases it has been possible to eliminate this 25. some af thc aforementioned mrwycnne derivatives are well'known in the art, while others are described in copending applications Serial No. '773.172, tiled'November l2.v 1958, and Serial No. 802.655, led IMarch 30,1959. v, both 4assigned to the same al the preaen'tinven'- stione v Forms ofthe tetracycline antibiotics which are particuf larly suitable for. solution administration are the coordination complexes which are formed with metal salts. For example, in copending application Serial jNo. 669,460, flied July 2, 1957, and` to the same assignee as the present invention, there are described compounds of oxytetracycline lcontaining magnesium, calcium, zinc, aluminum, or combinations thereof, and compounds of tetracycline containing magnesium,v calcium, aluminum or combinations thereof. In particular there are disclosed magnesium, calcium, andfalum'inum ltetracyclines having a molar ratio of metal lion to tetracycline of about 3:1, and magnesium, calcium, and aluminum oxytetracyclines having amolarratio of metal ion to oxytetrasatisfactory are the glycols, preferably those` generally recognized as pharmaceutlcally acceptable, such as propylene glycol, polyethylene glycol, and mixtures thereof. v
solutions,v the chosen ymetal salt of the antibiotic is prepared in situ by dissolving the freeJbase form of a tetracycline antibiotic, or an acid salt thereof, in the selected pclyhydric alcohol and adding a solution of a salt of the desired metal in the polyol or in water. Of course it is necessary that a salt of a pharmaceutically acceptable anion be selected, that is, one which is free from obiectional side elfectsatthe 1leyels of ordinary use. Ihe chloride and acetate salts, for example, are among those which 'f are suitable. 'Ihe retioi usually occurs readily at room temperature. vGenerally neutral to alkaline conditions are desirable, e.g. a pH range of from about 5.0,to about 0 ion, preferably from s pH so te actor optimum stability.l pH may be by addition of base r sa cycline of'from about 1:3 to about 3:1. As disclosed in Y that copending application,'useful solvents are the polyhydric aliphatic alcohols and thereof. Especially the potassium, lithium, calcium, magnesium and strontium salts.. Particularly preferred is the readily available sodium formaldehyde sulfoxylate. (The barium derivative is toxic, and will, ofl course, notbe employed.) With as little as 0.05% (w./v.) or evenfless of these antioxidants useful stabilization is achieved,'but it is normally preferred to employ at least about 0.1% and ordinarily it will not be necessary y to employ more than about 0.5% to achieve the desired results. Similarly, concentrations of thioglycerol yof labout 0.1% (w./v.) or even less are beneficial but for optimum results at least about 0.2% willbe preferred and normally no more than about 2% will be required. l
'Ihese new therapeutic combinations are particularly `suitable for parenteral administration and especially for intramuscular use. For such application, it will often be desirable to-incorporate a local anaesthetic such as those which are well known to those skilled inthe an. For example, lidocaine (a-diethylamino2,6acetoxylidide, available from the Astra Chemical Co.), may be employed at a level of about 20 mg./cc. For intramuscular use thepreparations will be formulated with pyrogen-free water and filtered aseptically before packaging. Antibiotic concentrations which are particularly suitable for this mode of administration are those ranging from about S to about 125 nig/cc.
In addition to the parenteral applications, these stabilized solutions are also eminently suitable for oral and topical use, and may be employed, for example, in the treatment of bovine mastitis.
With the newly discovered stabilizing system, solutions A of tetracycline antibiotics are found to retain their voriginal color and potency substantially unimpaired over long periods of storagev at room temperature, and also in'ao celerated high-temperature experiments. Por optimum results it isv desirable to saturate the vehicle with nitrogen and to package these dosage forms under an inert atmosphere. However, single doses may be. withdrawn from multi-dose containers with attendant admission of air into the 'container without seriously impairing the stability of the remaining solution. vFor example, in accelerated tests at l50" C. for 12 days containers from which 80% of the solution has been withdrawn by hypodermic syringe reyfor present initial Thesenew formulations are suitable for administration topman and animals` at conventional ,dosage levels for treatment of infections due to microorganisms sensitive to the contained antibiotic. For example, in the ease of oxytetracycline solutions, intramuscular administration of 200-300 mg. of antibiotic daily is usually satisfactory in the case of mild o r moderately severe infections. For more severe infections 300-500 mg. daily may be required. Administration individed doses 2-3 times daily is often desirable. It has been found that no luntoward side effects or impairment of potency attributable to the formaldehyde ysulfoxylate or the thioglycerol are encountered. 'l
The following examples are given byway of illustration and should not be interpreted as limiting the invention, the scope of which is deined by the appended claims.
EXAMPLE l Oxytetraeycline base (910 mcg/mg. potency),`
gm. 30.22 Magnesium chloride hexahydrate, gm. 12.36 Monoethanolamine, ce. 8.85
Propylene glycol, gm. 376 Water, cc. -94
The glycol is agitated for one hour while saturating with nitrogengas, and the antibiotic ls then addedand the mixture stirred for 30 minutes more. Next, a solu- Y ples are filled into ampoules under nitrogen and sealed. v
The antioxidant concentrations are as follows:
A. 0.3% w./v. sodium formaldehyde sulfoxylate plus 1.0% w./v. thioglycerol v B. 0.5% w./v. sodium formaldehyde sulfoxylate C. 1.0% w./v. thiomalic acid EXAMPLE n f Samples of the solutions of Example I are subjected to a temperature of 75 C..for varying periods of time up to 24 hours. After heating, each sample is diluted. 1:1 with the aqueous glycol vehicle and the light absorbance is determined at 500 ma on a Beckman spectrophotometer with a tungsten light source and a slit width setting of 0.04, employing water as the blank. i' marized in the table below.
Light Absorbunoel Results are sumnour's'rit' iisi'fffi::1122212112111222112212 s1.. y s... .est
The relatively high com stability of elution `A is apparent.
EXAMPLE m Solutions A and B whose preparation is described in solution A contained in the vial under a partial atmos phere of air darkens only slightly even after heating for 12 days at 50 C. In contrast, the residual solution Bv begins darkening within two days at room temperature, and after 12 days at room temperature is dark brown in color. y
EXAMPLE IV A stabilized preparation containing approximately nig/cc. of oxytetracycline activity and suitable for intramuscular administration is prepared according to the following formulation and packaged under nitrogen:
Propyleneglycol, gm. 275 Water, cc. 1 13 spasms Similar formulations are prepared substituting other tetracycline antibiotics, as hereinbefore described, in place of oxytetracycline, and enhanced stability attributable to the thioglycerol and sodium formaldehyde sulfoxylate EXAMPLE V 'Ihe followingpharmaceutical solutions are prepared and found to exhibit enhanced stability attributable to their content of thioglyce'rol and a formaldehyde sulfoxylate: y
yis observed.
Glycerine, U.S.P., liter 1 Calcium `acetate monohydrate, gm 20.66 Oxytetr'acycline hydrochloride, gm. 60.2 Potassium formaldehyde sulfoxylate, gm. 2 Thioglycerol, gm. 4 10% sodium hydroxide in glycerine, to pH 9, cc.
approx. 150 Glycerine, U.S.P., to make 2 liters.
. Gylcerine, U.S.P., cc. 500 Aluminum chloride hexahydrate, gm. 40.7 Tetracycline hydrochloride, gm. 27.55 Thioglycerol, gm. 20 Lithium formaldehyde sulfoxylate, gm. 5 10% sodium hydroxide in glycerine, to pH 9 Glycerine, U.S.P., to make 1 liter.
Glycerine, U.S.P., cc. 500 Sorbitol, gm'. v 50 Zinc chloride, gm. 5.94
lOxytetracycline hydrochloride, gm. 33.5 Thioglycerol, gm. 10
Sodium formaldehyde sulfoxylate, gm. 3 10% sodium hydroxide in glycerine, to pH 8.5,
cc. approx. 72 Glycerine, U.S.P.to 'make l liter.
` `(D) jPolyethylene glycol 300, cc. 500 Magnesium chloride tetrahydrate, gm. 28.19 Tetracycline hydrochloride, gm. 27.55 Thioglycerol, gm. 10 Sodium formaldehyde sulfoxylate, gm. 3 Triethanolamine, cc. 25 10% sodium hydroxide in glycerine, to pH 8.5,
cc. approx. 125 Polyethylene glycol 300, to make 1 liter.
Propylene glycol, cc. 800 Benzocaine, gm. 51
Calcium chloride, anhydrous, gm. 3.46 Tetracycline hydrochloride, gm. 5.1 Thioglycerol, gm. 2
Calcium formaldehyde sulfoxylate, gm l 10% sodium hydroxide in propylene glycol, to pH 8.5, cc. approx. l5 Propylene glycol, to make l liter. 5 s (P) Glycerine, U.S.P., cc. 500 70% aqueous sorbitol, gm. 100 Aluminum chloride hexahydrate, gm. 24 Oxytetracycline base, gm. 46 Ethanol, cc. 80 Thioglycerol, gm. 5 Strontium formaldehyde sulfoxylate, gm. 2 10% sodium hydroxide in glycerine, to pHf8 Glycerine, U.S.P., to make 1 liter.
Glycerine, U.S.P., cc. 500 Calcium acetate monohydrate, gm. 20.66
Oxytetracycline hydrochloride, gm. 30.1 Thioglycerol, gm. 10 Magnesium formaldehyde sulfoxylate, gm 3 10% sodium hydroxide in glycerine, to pH 9 Glycerine, U.S.P., to make l liter.
What is claimed is:
1. A pharmaceutical composition comprising a tetracycline antibiotic dissolved in a pharmaceutically acceptable polyhydric alcohol solvent, and as stabilizer for said tetracycline antibiotic, a mixture of thioglycerol and a pharmaceutically acceptable formaldehyde sulfoxylate selected from the group consisting of the alkali-metal and alkaline-earth-metal salts, the weight ratio of sulfoxylate salt to thioglycerol being fromabout 5:2 to about 1:20.
`2. A composition as in claim 1 wherein said antibiotic is selected from the group consisting of magnesium, calcium and aluminum tetracyclines having a molar ratio of metal ion to tetracycline of about 3:1 and magnesium, calcium, aluminum and zinc oxytetracyclines having a molar ratio of metal ion to oxytetracycline of from about 1:3 to about 3:1.
3. A composition as in claim l wherein said solvent contains up to about by volume of water. v
4. A composition as in claim 1 wherein said formaldehyde sulfoxylate is present in a weight/volume concentration ranging from about 0.1 to about 0.5% and said thioglycerol is present in a weight/volume concentration ranging from about 0.2 to about 2%.
5. A pharmaceutical composition suitable for intra.-k
muscular administration comprising a solution containing magnesium oxytetracycline having a molar ratio of magnesium to oxytetracycline of about l, about 0.3% w./v. sodium formaldehyde sulfoxylate and about 1% w./v. thioglycerol in about 80% aqueous propylene glycol.
References cited in the me of this patent UNITED STATES PATENTS

Claims (1)

1. A PHARMACEUTICAL COMPOSITION COMPRISING A TAETRACYCLINE ANTIBIOTIC DISSOLVED IN A PHARMACEUTICALLY ACCEPTABLE POLYHYDRIC ALCOHOL SOLVENT, AND AS ATABILIZER FOR SAID TETRACYCLINE ANTIBIOTIC, A MIXTURE OF THIOGLYCEROL AND A PHARMACEUTICALLY ACCEPTABLE FORMALDEHYDE SULFOXYLATE SELECTED FROM THE GROUP CONSISTING OF THE ALKALI-METAL AND ALKALINE-EARATH-METAL SALTS, THE WEIGHT RATIO OF SULFOXYLATE SALT TO THIOGLYCEROL BEING FROM ABOUT 5:2 TO ABOUT 1:20.
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Cited By (35)

* Cited by examiner, † Cited by third party
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US3140232A (en) * 1962-12-19 1964-07-07 Pfizer & Co C Color stabilization of tetracycline compositions with polypropylene glycols
US3155586A (en) * 1963-01-23 1964-11-03 American Cyanamid Co Stable liquid preparations of 6-demethyltetracyclines
US3155587A (en) * 1963-01-23 1964-11-03 American Cyanamid Co Stable liquid preparations of 7-chlorotetracycline
US3159542A (en) * 1962-12-31 1964-12-01 American Cyanamid Co Stable aqueous glycol solution of tetracycline aluminum calcium gluconate complex having a ph of about 7. 5 to 9
US3232834A (en) * 1957-06-27 1966-02-01 Pfizer & Co C Antibiotic preparations
US3275513A (en) * 1963-05-29 1966-09-27 American Cyanamid Co Stable calcium tetracycline compositions
US3356571A (en) * 1964-11-25 1967-12-05 American Cyanamid Co Potentiation of tetracycline by polyacrylic acid or hydrolyzed polyacrylonitrile
US3517102A (en) * 1964-10-19 1970-06-23 Pierrel Spa Oxytetracycline antibiotic compositions employing n-(beta-oxyethyl) piperazine or n-n'bis - (beta - oxyethyl) piperazine and magnesium chloride
US4376118A (en) * 1980-10-06 1983-03-08 Miles Laboratories, Inc. Stable nonaqueous solution of tetracycline salt
US6638922B2 (en) 1998-11-18 2003-10-28 Collagenex Pharmaceuticals Incorporated 4-dedimethylaminotetracycline derivatives
US6946453B2 (en) 1998-11-18 2005-09-20 Collagenex Pharmaceuticals, Inc. 4-dedimethylaminotracycline derivatives
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US20070026080A1 (en) * 2005-06-16 2007-02-01 Wyeth Manufacturing process for tigecycline
US20070049560A1 (en) * 2005-05-27 2007-03-01 Lalitha Krishnan Tigecycline and methods of preparing 9-nitrominocycline
US20070049563A1 (en) * 2005-05-27 2007-03-01 Lalitha Krishnan Tigecycline and methods of preparing 9-aminominocycline
US20070049562A1 (en) * 2005-05-27 2007-03-01 Lalitha Krishnan Tigecycline and methods of preparation
US20070243244A1 (en) * 2005-12-22 2007-10-18 Shah Syed M Methods of treating gastrointestinal tract infections with tigecycline
US20070258938A1 (en) * 2006-05-03 2007-11-08 Josee Roy Compositions comprising biomembrane sealing agent for treatment of pain or inflammation, and methods of use
US20070259044A1 (en) * 2006-05-03 2007-11-08 Josee Roy Compositions comprising biomembrane sealing agent for treatment of neuronal injury, and methods of use
US20080014256A1 (en) * 2005-12-22 2008-01-17 Wyeth Oral formulations comprising tigecycline
USRE40086E1 (en) 1991-10-04 2008-02-19 Wyeth Holdings Corporation Method for treating bacterial infection with novel 7-substituted-9-substituted amino 6-demethyl-6-deoxytetracyclines
USRE40183E1 (en) 1991-10-04 2008-03-25 Wyeth Holdings Corporation 7-Substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
US20080112921A1 (en) * 2006-11-14 2008-05-15 Chamness Kathy L Method and use for increasing efficacy of anti-adhesive compositions in controlling inflammation and pain
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