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US2749274A - Stable aqueous procaine penicillin suspension - Google Patents

Stable aqueous procaine penicillin suspension Download PDF

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Publication number
US2749274A
US2749274A US286445A US28644552A US2749274A US 2749274 A US2749274 A US 2749274A US 286445 A US286445 A US 286445A US 28644552 A US28644552 A US 28644552A US 2749274 A US2749274 A US 2749274A
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procaine
penicillin
suspension
added
parts
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Frank H Buckwalter
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Bristol Laboratories Inc
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Bristol Laboratories 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • -It.-is an .object of the present invention to provides-a stableaaqueous"suspension of" procaine penicillinG. s It .isra furthenobject toprovide such a stable, aqueous sus- .pension :of, procaine penicillin G which contains an-nex- .cess-ofprocaine ions. It is a further object to provide :"SLlch" a"- stable; aqueous suspension of procaine: penicillin w G whichacontainsan excess of: procaine :ions,::a-. buffer, : ⁇ 3.l'1d-a suspending agent.
  • A-further object ofil-thetinvention. is..the,provision :ofaa sterile:- aqueousrsuspensiontof ,procainezpenicillin G- which, upon human-administration,
  • .'.. The. objects of the present invention have .-beenaccomplishedianda stable, aqueous suspension of iproc'aine .penicillinG, which is productive of longereffective blood levels :..upon administration than known saqueousacom- I positions, .has been.v obtained, byproviding an 'aqueous -suspension containing procainepenicillin G, a.suspend- 40 ing agent, an excess of procaine ions, and-water.
  • The. range for the procaine which-maybe in .thetorm of the. free base, the phosphate, the. acetate, thehydrochloride, or another water-soluble, ionized, .injectable procaine salt, is'between about 0.5 and 5.0 percent..by 5 weight of the total composition, and preferably. about 2.0
  • a buffering agent maybe adde'dpsuchas 0.25 to*5.0 percent by weight, and preferably -OLSPer- -:ent,-of'sodium citrate or 1.0 to"7.5'percent sodium phosphates and preferably 2.6 percent sodium dihydrogen phosphate .and.2.4 percent disodium' hydrogen phosphate .-to. makea-total-of five percentby'weight of the total composition.
  • a buffering agent maybe adde'dpsuchas 0.25 to*5.0 percent by weight, and preferably -OLSPer- -:ent,-of'sodium citrate or 1.0 to"7.5'percent sodium phosphates and preferably 2.6 percent sodium dihydrogen phosphate .and.2.4 percent disodium' hydrogen phosphate .-to. makea-total-of five percentby'weight of the total composition.
  • the bufieringagent is. not essential, however, to either. the stability or the therapeuticetfec- .tiveness of the compositions of the present invention.
  • the amount of suspending agent will vary to a certain extent, but usually from about 0.2 to' 5.0-percent, preferably from 0.5 to 2.5 percent, is employed and "variations 'within these ranges maybe made'by any-ex perienced chemist or pharmacist with regard-td-the in- 7 tendedause ofithe'composition. .Thus the concentration of polyvinylpyrrolidone may vary: from 0.1% :ito'. 25
  • the concentration of dextran may vary from 0.1% to 20%, with about 10% preferred.
  • the concentration of pectin may vary from 0.1% to 0.5%, with about 0.2% preferred.
  • the concentration of gum tragacanth may vary from 0.5% to 2%, with about 1% preferred; 5% sodium chloride may be added thereto.
  • suspending agent and dispersing agent are used interchangeably to describe the additives such as sodium carboxymethylcellulose, lecithin, Spans and Tweens which improve the pharmaceutical elegance of these preparations, as by increasing ease of injection and ease of resuspension upon settling.
  • Other suspending and dispersing agents include lecithin, Falba, cholesterol, Span 20, Span 40, Span 60, Span 80, the Tweens, Amerchols, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, alginic acid, propylene glycol alginate, polyoxyalkylene derivatives of sorbitol fatty acid esters, urea and sodium p-aminobenzoate.
  • the procaine penicillin G suspension may have a potency of anywhere from 10,000 to about 500,000 units per milliliter, preferably from about 100,000 to 400,000 units per milliliter. Ordinarily, a suspension of procaine penicillin G having a potency of about 300,000 units per milliliter is optimum, and found to be entirely satisfactory.
  • the potency of the procaine penicillin G is not to be construed as a limiting factor, and the various activities are merely mentioned to indicate that procaine penicillin G of various activities is suitable for incorporation into the composition of the present invention, again with regard for the intended application of the aqueous suspension.
  • composition is not limited to the exact ingredients previously described and to the exclusion of all others, since various other ingredients, while not necessary, may be added, if desired.
  • a small amount of preservative such as Phenol U. S. P., Cresol U. S. P., Methyl Paraben (methyl ester of p-hydroxybenzoic acid).
  • Ethyl Paraben ethyl ester of p-hydroxybenzoic acid
  • Butyl Paraben butyl ester of p-hydroxybenzoic acid
  • Propyl Paraben propyl ester of phydroxybenzoic acid
  • a small quantity of a vasoconstrictor may also be considered as advantageous addition, and, whatever additional ingredients are employed, the total amount should ordinarily not exceed more than about ten percent by weight, and preferably not more than five percent by weight, of the total composition.
  • Other ingredients which improve blood levels, handling properties and stability may be added. Examples of such ingredients are lecithin, Falba, cholesterol, Span 20, Span 40, Span 60, Span 80, Tween 20, Tween 40, Tween 60, Tween 80, Tween 85, Amerchols, urea, and sodium para-aminobenzoate.
  • the method of the present invention comprises dissolving the prescribed amount of procaine compound (from 0.5 to 5.0 percent, preferably about 2.0 percent of the total weight) and, if desired, a buifcr (e. g. sodium citrate, from about 0.25 to 5.0 percent, preferably about 0.5 percent, of the total weight) in sterile distilled water or physiological saline, adding suspending agent (0.2 to 5.0 percent, preferably 0.5 to 2.5 percent, of the total weight) thereto with stirring, and then mixing in the procaine penicillin G crystals. The volume is then adjusted by addition of the requisite amount of water to bring the concentration of ingredients within the required range. The pH of the final suspension is adjusted to 5.5 to 7.5 by adding citric acid or phosphoric acid.
  • a buifcr e. g. sodium citrate, from about 0.25 to 5.0 percent, preferably about 0.5 percent, of the total weight
  • suspending agent 0.2 to 5.0 percent, preferably 0.5 to 2.5 percent, of the total weight
  • the admixture is, of course, conducted under sterile conditions, and all solids introduced are in a finely-divided or powdered form, preferably below about eighty microns in diameter and usually below about fifty microns in diameter, e, g. micronized.
  • Example I Under sterile conditions, 5.0 parts of procaine hydrochloride and 2.5 parts of sodium citrate are dissolved in sterile distilled water in a glass flask, and about 2.0 parts of sodium carboxymethylcellulose added thereto with shaking, whereafter five parts of procaine penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make parts, the suspension bottled in sterile bottles, and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G.
  • Example II Under sterile conditions, 0.5 part of procaine hydrochloride and 5.0 parts of sodium citrate are dissolved in sterile distilled water. About 2.5 parts of sodium carboxymethylcellulose is added thereto with shaking, whereafter five parts of procaine penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procaine penicillin G.
  • Example III Under sterile conditions, 2.0 parts of procaine hydro chloride and 0.5 parts of sodium citrate are dissolved in sterile distilled water in a glass flask, about 0.5 parts of sodium carboxymethylcellulose added thereto with shaking, whereafter five parts of procaine penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles, and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procaine penicillin G.
  • Example IV 5.0 grams of anhydrous sodium citrate, 1 gram of procaine hydrochloride and 0.5 gram of sodium carboxymethylcellulose were added to 50 cc. of water and stirred with a laboratory agitator until solution was complete. 25 cc. of this solution were added to a 100 cc. beaker and 16.5 grams of procaine penicillin G (potency about 1000 units/milligramscreened through a 200 mesh screen) added. The volume was adjusted to 50 cc. with the citrate-CMC-procaine hydrochloride-water gel and the suspension thoroughly mixed. The pH of the suspension was adjusted to 6.5 with citric acid and the suspension thoroughly mixed. The suspension contains approximately 300,000 units of procaine penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G.
  • Example V 0.25 gram of anhydrous sodium citrate, 1 gram of procaine hydrochloride and 0.25 gram of sodium carboxymethylcellulose were added to 50 cc. of water and stirred with a laboratory stirrer until solution was complete. Twenty-five cc, of this solution were added to a 100 cc. beaker and 16.5 grams of procaine penicillin G (potency about 1000 units/milligram-screened through a 200 mesh screen) added. The volume was adjusted to 50 cc. with the citrate-sodium carboxymethylcellulose-procaine hydrochloride-water gel and the suspension thoroughly mixed.
  • the volume was adjusted to 50 cc. with-the aqueous carboxymethylcellulose procaine hydrochloride gel:and the suspension ineffectiveness over. knownaqueoussuspensions or procaine l uthoroughly mixed with a laboratory stirrer. This suspenrpeiiicillin G.
  • sion is vialed and tested.
  • the suspension containsapproximately 300,000..units of procaine penicillin G per cc., is stable for periods in excess of one year at room :temperature' (73 F.) andigives bloodglev'els oftincreased 4.0 grams procaine penicillin 'G (poten y about 10 i10-eifectiveness lover known .taqueous-t suspensions lei-pro- :units ;-per .milligram.screened ..through .a 250 mesh screen) 0:04gram sodium carboxymethylc'ellillose 0.2 gram'sodinm' citrate anhydrous 1.0 gram procaine carbonate 9.0 cc. distilled water
  • the vials were thoroughly shakento. givealhomogeneous suspension. Several of these were made. The vials were thoroughly shakento. givealhomogeneous suspension. Several of these were made. The vials were thoroughly shakento. givealhomogene
  • Example VIII Under sterile c0n'ditions,:5.0 parts of procaine hydrochloride .is dissolved in sterile distilled water in a glass fia'sk. About 2.5 parts of sodium carboxymethylcell'ulose ;:-is'.a'dded' theretoswith shaking, whereafter five parts of procaine-penicillin G, having an activity slightly in excess of 6,000,000 units per part, is'added-and shaking continued for a few minutes. Water is then added'to-make'100 parts,ithe suspension bottled in sterile bottles, andxistored.
  • the suspension contains approximately 300,000 units of ,.procaine .-p.enicillin .Gper milliliter, is stable for periods in*' .excess. of six-months, andgivesblood levels ofincreased .e'iiec'tiveness. over. known aqueous. suspensions of procaine- ,penicillinIG. upon administration.
  • Example IX procaine-peni'cillin'G'per milliliter is stable'for periods" "'in-excess-of six months, and gives blood levels of increased 'ffeotivenessover known aqueous suspensions-of procainepenicillin G.
  • Example X Oneagram ..er. procaine hydrochloride .and. 01375; gram of sodium carboxymethylcellulose were .dissolved. in. '50
  • Thesuspension contains approximately 300,000 units of procaine penicillin G per milliliter, .is' stable for periods in excess-of one year, and, upon administration, gives blood levels of increased eifectiveness over known aqueoussuspensions of procaine penicillin'jG;
  • disddium phosphate are .dissolvedin about 50 cc. of sterile distilled water in a glass flask. About 2.5 parts of sodium carboxymethylcelluloseis addedthereto with shaking,
  • procaine-penicillin G having an activity of about1;000,000 units per part, is added and 2;shaking OOIItlIlHGda-fOl .a.-few1minutes. '"Wa'teris then added: to .makei 100wparts. .iThe: pH; of thet'suspension is 16.5;grams ofprocainepenicillinfi..(potency about 1000. adjusted to pH;6:5 with:phosphorici:acidy'whereafter the suspension is bottled in sterile bottles and stored.
  • the suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of one year, and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G upon administration.
  • Example XV Under sterile conditions, 0.5 part of procaine hydrochloride, 0.25 part of sodium citrate, and 7.5 parts of disodium phosphate, are dissolved in about 50 cc. of sterile distilled water and about 1.5 parts of sodium carboxymethylcellulose added thereto with shaking, whereafter 30 parts of procaine penicillin G, having an activity of about 1,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the pH of the suspension is adjusted to pH 6.5 with phosphoric acid, the suspension bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of one year and gives blood levels of increased effectiveness over known aqueous suspensions of procaine penicillin G.
  • Example XVI pension contains approximately 300,000 units of procainepenicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increasing effectiveness over known aqueous suspensions of procainepenicillin G.
  • Example XVII Under sterile conditions, 5.0 parts of procaine hydrochloride and 0.25 part of disodium phosphate are dissolved in sterile distilled water. About 2.5 parts of sodium carboxymethylcellulose is added thereto with shaking, whereafter five parts of procaine-penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine-penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procaine-penicillin G.
  • Example XVIII Under sterile conditions, 2.0 parts of procaine hydrochloride and 5.0 parts of disodium phosphate are dis solved in sterile distilled water in a glass fiask, about 1.5 part of sodium carboxymethylcellulose added thereto with shaking, whereafter five parts of procaine-penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles, and stored. The suspension contains approximately 300,000 units of procainepenicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procainepenicillin G.
  • Example XIX The following ingredients were added to a cc. vial:
  • procaine-penicillin G potency about 1000 units per mg.screened through a 200 mesh screen
  • sodium carboxymethylcellulose 8 8.5 cc. of an aqueous solution containing 5% NazHPOc and 2% procaine hydrochloride.
  • the vials were shaken thoroughly to give a homogenous uspension. Several vials were made.
  • the suspension contains approximately 300,000 units of procaine-penicillin G, per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine-penicillin G.
  • Example XX The following ingredients were added to a 15 cc. vial:
  • procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.04 gram sodium carboxymethylcellulose 0.6 gram Vietnamese-IP04 anhydrous 0.6 gram procaine carbonate 9.0 cc. distilled water.
  • the vials were shaken thoroughly to give a homogenous suspension. Several vials were made. The suspension contains approximately 300,000 units of procainepenicillin G per cc., is stable for periods in excess of one year, and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine-penicillin 6.
  • Example XXI The following ingredients were added to a 15 cc. vial:
  • procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.13 gram procaine base 0.04 gram sodium carboxymethylcellulose 0.6 gram Vietnamese-IP04 9.0 cc. distilled water
  • the vials were shaken thoroughly to give a homogenous suspension.
  • the suspension contains approximately 300,000 units of procaine penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G.
  • Example XXII The following ingredients were added to a 15 cc. vial:
  • procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.25 gram procaine phosphate 0.6 gram NazHPOs anhydrous 0.04 gram sodium carboxymethylcellulose (CMC) 9.0 cc. water
  • the vials were shaken thoroughly to give a homogenous suspension.
  • the suspension contains approximately 300,000 units of procaine-penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine-penicillin G.
  • Example XXIII Using sterile technique the following solution was made: In a 1 liter beaker was placed 400 cc. of distilled water, 25 grams of Na-2HPO4 anhydrous, 2.5 grams phenol U. S. P. and 5.0 grams of sodium carboxymethylcellulose. This was mixed with a laboratory stirrer until solution was complete. Then 10 grams of procaine base were added and sufficient distilled water to bring the volume to 500 cc. The pH of this suspension was then adjusted to 6.5 with 12 cc. of 42.5% H3PO4. This suspension was thoroughly mixed and then autoclaved for 30 minutes at 15 lbs. pressure. About cc. of the above suspension were placed in a 400 cc.
  • procaine-penicillin G potency about 1000 units per mg.-screened through a 200 mesh screen
  • the finished suspension was thoroughly mixed and passed through the Eppenbach colloid mill.
  • the suspension 9 contains approximately 300,000 units of procaine-penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing etfectiveness over known aqueous suspensions of procaine-penicillin G.
  • Example XXIV The following are mixed in filtered, pyrogen-free distilled Water (97.88 cc.): Lecithin (0.70 g.), Tween 40 (0.93 g.), Span 40 (0.33 g.), sodium citrate U. S. P. (0.57 g.), and Butyl Paraben (0.021 g.). There is throughly mixed into 69.40 cc. of this mixture under sterile conditions procaine hydrochloride U. S. P. (2.0 g.), micronized lecithin-coated procaine penicillin G (24.15 g.) and pulverized, 250 mesh, lecithin-coated procaine penicillin G (8.05 g.).
  • the product contains approximately 300,000 units of procaine penicillin G per cc. and is stable for periods in excess of one year.
  • the product is more stable and gives higher blood levels than previously known aqueous suspensions of procaine penicillin G which do not contain the added, excess procaine ion.
  • procaine penicillin G While the present invention has been described with particular reference to procaine penicillin G, it is to be understood that the procaine salts of other penicillins are also included within the scope of this invention.
  • the penicillins G, F, X, 0, dihydro F and K, and mixtures of two or more such penicillins, particularly mixtures containing at least 85% penicillin G, are included within the scope of this invention.
  • any injectable compound of procaine capable of yielding procaine ions such as procaine hydrochloride, procaine base or procaine phosphate, may be employed.
  • a sterile, aqueous suspension of procaine penicillin which is stable over long periods of time at room temperature and which is productive of highly etfective blood levels upon administration, including procaine penicillin, a suspending agent, and a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
  • a sterile, aqueous suspension of procaine penicillin which is stable over long periods of time at room temperature and which is productive of highly efiective blood levels upon administration, including procaine penicillin, a suspending agent, and from 0.5 to 5.0 percent of a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
  • a sterile, aqueous suspension of procaine penicillin which is stable over long periods of time at room temperature and which is productive of highly effective blood levels upon administration, including procaine penicillin, a suspending agent, and about two percent of a member selected from the group consisting of procaine base and Water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
  • a sterile, aqueous suspension of procaine penicillin G which is stable over long periods of time at room temperature and which is productive of highly efiective blood levels upon administration, including procaine penicillin G, a suspending agent, and a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
  • a sterile, aqueous suspension of procaine penicillin G which is stable over long periods of time at room temperature and which is productive of highly efiective blood levels upon administration, including procaine penicillin G, a suspending agent, and from 0.5 to 5.0 percent of a member selected from the group consisting of pro caine base and Water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
  • a sterile, aqueous suspension of procaine penicillin G which is stable over long periods of time at room temperature and which is productive of highly effective blood levels upon administration, including procaine penicillin G, a suspending agent, and about two percent of a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
  • a stabilized aqueous pharmaceutical preparation which comprises, in suspension in an aqueous medium, procaine penicillin, a water-soluble acid addition salt of procaine, and sodium carboxymethylcellulose.

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Description

; STABLE AQUEOUS "PROGAINE-PENICILLIN SUSPENSIQN Frai ik'. H. Buckwalter, Dewitt, N. Y.,' assignor to Bristol "Laboratories Inc.,-Syracuse,'N. Y., a corporation of NewYo'rk No.Drawing. Application May..6, 1952, i
. Serial No. 286,445
7 Claims. (Cl.:16765) penicillin G which contains anexcessofi procaineuions,
sand-tea method for the preparationxthereof.
;This application is a continuation-in-partof my; prior, uco-pending applications of Serial f'Numbers 130,592, HO-593,130,595 and 130,596, all of which-were-ifiled -.December 1, 1949 and all of whichare:nowabandoned.
:The. instability of penicillin compounds, includingin- -organic and organic salts,v is wellknown in the -pharmaceutical art. I For this reason, aqueous suspensions of such salts, and, in particular, stable aqueous suspensions of procaine penicillin G, have not been known, and have rpreviouslyrbeeu. considered an. impossibility. As a :con tsequence,.the-rnedical profession hastbeen limitedttolhe t'employmentoftprocaine penicillin Gpeanut o'il suspensions,:.and.aluminun1 monostearate-procaine penicillin .G ;suspensions,.-.and, when'such are notiindicatedfforitbe particular case, have been faced withrthe necessity::of preparing their own aqueous suspensions of procaine penicillin .G by mixing sterile water or saline solution "with drypreparations available from the pharmaceutical rtrade. "Thisrhas, of course,been aggreatzinconvenience "to .thezmedical profession, and, evencwhenz'preparedin thezofiice of thepractising-physician, such aqueous'suspensions are; of utility only forperiodsnotexceedingten days, according to recent Pure Food and Drug regulations. Although some aqueous suspensions of procaine penicillin G have been proposed-previously, 'thesehave all had theexpected disadvantage of an -inferior*shelflife. It is; obvious that a stable'suspensions of procainepenicillin G'retaining its original therapeutic activitypand therefore' having utility over prolonged periods; is highly .desirable from a commercial istandpoint, and much needed :by the medical profession.
It-isalso well-known in the .art that penicillin salts-are Aunfortunately. retained vby the human" body, after adrsministration, for. undesirably limitedyperiods, necessitatz-inga'repeated injections of the drug at 'intervals varying from several hours toone.day,.depending.upon the blood i=levels of the :drugdesired to be maintained. This physiological phenomenon,'.the rapid: absorption aridaexcretion of=penicillin drugs by the human body, is, of course, a limiting factor upon the "effectiveness of any pharmaceutical preparation employed, and it has been a con- 60 stant objective of researchers in the field to find a suitable penicillin composition, and in v particular, an' aqueous penicillin "G composition which, upon human' administration, would be productive of advantageous results, in .either of two ways:
. (ll-Production, oflonger effective blood level,.that is, .iretention of .a therapeutically. effective .quantity of ..-the :drug inthe blood stream over-an extended period.of-time, :say,forty-eighthours instead of twenty-four..hours which :istthex. present. maximum duration. ZIhis-wouldaallow 2: administration: of effective? procaine.- -penicillin' .G dosages {149,274 i'Patented June 5, 1956 .12 r-only once-every other day, instead of the requisite single day interval :which is now customary.
(2) Production of a higher effective blood level of .thezdrugat the end of any given period after administra- 5 '.tion,;that iZlS,'I6lZ6I1llOI1 of a higher percentage of the -;originally-.administered activity. This, too,:would'be an important-advance: in the art, inasmuch .as thextherapeutic ei-t'ectivenessof procaine peniciliinG, within. certain limits,;-app.ears: to be directly proportional tot-he'quantity -which :isipresent-in lihb100d stream. 'Ano'therutheory,
n lhichzhasrbeen advanced by way of explaining; the'sig- :nificance :of .the quantity of procaine penicillin. G in'the :blood,.places the'rate' at whichthequantityrof' .:drug.' in I the; blood stream diminishes, in an-inverse proportion -.to
the. curative; power of .thecomposition.
It is obvious that attainment of either.- advantagefwould be of considerable importance, especiallyirom' the-"standpoint-:oftthe patient undergoing such treatment, andithe r. medical profession administering the same.
-It.-is= an .object of the present invention to provides-a stableaaqueous"suspension of" procaine penicillinG. s It .isra furthenobject toprovide such a stable, aqueous sus- .pension :of, procaine penicillin G which contains an-nex- .cess-ofprocaine ions. It is a further object to provide :"SLlch" a"- stable; aqueous suspension of procaine: penicillin w G whichacontainsan excess of: procaine :ions,::a-. buffer, :\3.l'1d-a suspending agent. A-further object ofil-thetinvention. is..the,provision :ofaa sterile:- aqueousrsuspensiontof ,procainezpenicillin G- which, upon human-administration,
.produces longer-..effective blood devels than; previously -knowmcompositions; and istherefore of increased efiicacy -..and .importance. Other-objects of the invention will become apparent hereinafter.
.'..The. objects of the present invention have .-beenaccomplishedianda stable, aqueous suspension of iproc'aine .penicillinG, which is productive of longereffective blood levels :..upon administration than known saqueousacom- I positions, .has been.v obtained, byproviding an 'aqueous -suspension containing procainepenicillin G, a.suspend- 40 ing agent, an excess of procaine ions, and-water.
The. range for the procaine, which-maybe in .thetorm of the. free base, the phosphate, the. acetate, thehydrochloride, or another water-soluble, ionized, .injectable procaine salt, is'between about 0.5 and 5.0 percent..by 5 weight of the total composition, and preferably. about 2.0
percent is employed.
.i-If desired, a buffering agent maybe adde'dpsuchas 0.25 to*5.0 percent by weight, and preferably -OLSPer- -:ent,-of'sodium citrate or 1.0 to"7.5'percent sodium phosphates and preferably 2.6 percent sodium dihydrogen phosphate .and.2.4 percent disodium' hydrogen phosphate .-to. makea-total-of five percentby'weight of the total composition. When appropriate, as. in the; presence :of. excess, .zaddedprocaine: free base, the suspensionrnay;be'bufiered .by' the=addition of free acids, e. g.'citric acid,-phospho.ric
.acid. ..The,use of the bufieringagent is. not essential, however, to either. the stability or the therapeuticetfec- .tiveness of the compositions of the present invention.
It .desired,.suspending or dispersing agents .maybe added to increase pharmaceutical elegance. As .a.-suspending or dispersing agent,.sodiurn carboxymethylcel- 'lulose. has been found highly satisfactory but ca'rboxy- "methylcellulose, methylc'eilulose, polyvinyl. alcohol, polyvinylpyrrolidone, gum tragacanth, gelatin, pectin, sodium -alginates,*dextran, gum Karaya, and the like, are also useful. "-The amount of suspending agent will vary to a certain extent, but usually from about 0.2 to' 5.0-percent, preferably from 0.5 to 2.5 percent, is employed and "variations 'within these ranges maybe made'by any-ex perienced chemist or pharmacist with regard-td-the in- 7 tendedause ofithe'composition. .Thus the concentration of polyvinylpyrrolidone may vary: from 0.1% :ito'. 25
with about 10% preferred. The concentration of dextran may vary from 0.1% to 20%, with about 10% preferred. The concentration of pectin may vary from 0.1% to 0.5%, with about 0.2% preferred. The concentration of gum tragacanth may vary from 0.5% to 2%, with about 1% preferred; 5% sodium chloride may be added thereto.
It is to be understood that the words suspending agent and dispersing agent are used interchangeably to describe the additives such as sodium carboxymethylcellulose, lecithin, Spans and Tweens which improve the pharmaceutical elegance of these preparations, as by increasing ease of injection and ease of resuspension upon settling. Other suspending and dispersing agents include lecithin, Falba, cholesterol, Span 20, Span 40, Span 60, Span 80, the Tweens, Amerchols, sodium alginate, potassium alginate, ammonium alginate, calcium alginate, alginic acid, propylene glycol alginate, polyoxyalkylene derivatives of sorbitol fatty acid esters, urea and sodium p-aminobenzoate.
The procaine penicillin G suspension may have a potency of anywhere from 10,000 to about 500,000 units per milliliter, preferably from about 100,000 to 400,000 units per milliliter. Ordinarily, a suspension of procaine penicillin G having a potency of about 300,000 units per milliliter is optimum, and found to be entirely satisfactory. The potency of the procaine penicillin G is not to be construed as a limiting factor, and the various activities are merely mentioned to indicate that procaine penicillin G of various activities is suitable for incorporation into the composition of the present invention, again with regard for the intended application of the aqueous suspension.
The composition is not limited to the exact ingredients previously described and to the exclusion of all others, since various other ingredients, while not necessary, may be added, if desired. For instance, a small amount of preservative, such as Phenol U. S. P., Cresol U. S. P., Methyl Paraben (methyl ester of p-hydroxybenzoic acid). Ethyl Paraben (ethyl ester of p-hydroxybenzoic acid), Butyl Paraben (butyl ester of p-hydroxybenzoic acid) or Propyl Paraben (propyl ester of phydroxybenzoic acid) may be employed. A small quantity of a vasoconstrictor may also be considered as advantageous addition, and, whatever additional ingredients are employed, the total amount should ordinarily not exceed more than about ten percent by weight, and preferably not more than five percent by weight, of the total composition. Other ingredients which improve blood levels, handling properties and stability may be added. Examples of such ingredients are lecithin, Falba, cholesterol, Span 20, Span 40, Span 60, Span 80, Tween 20, Tween 40, Tween 60, Tween 80, Tween 85, Amerchols, urea, and sodium para-aminobenzoate.
The method of the present invention comprises dissolving the prescribed amount of procaine compound (from 0.5 to 5.0 percent, preferably about 2.0 percent of the total weight) and, if desired, a buifcr (e. g. sodium citrate, from about 0.25 to 5.0 percent, preferably about 0.5 percent, of the total weight) in sterile distilled water or physiological saline, adding suspending agent (0.2 to 5.0 percent, preferably 0.5 to 2.5 percent, of the total weight) thereto with stirring, and then mixing in the procaine penicillin G crystals. The volume is then adjusted by addition of the requisite amount of water to bring the concentration of ingredients within the required range. The pH of the final suspension is adjusted to 5.5 to 7.5 by adding citric acid or phosphoric acid. The admixture is, of course, conducted under sterile conditions, and all solids introduced are in a finely-divided or powdered form, preferably below about eighty microns in diameter and usually below about fifty microns in diameter, e, g. micronized.
The following examples are given for purposes of illustration only, and are not to be construed as limiting.
4 Example I Under sterile conditions, 5.0 parts of procaine hydrochloride and 2.5 parts of sodium citrate are dissolved in sterile distilled water in a glass flask, and about 2.0 parts of sodium carboxymethylcellulose added thereto with shaking, whereafter five parts of procaine penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make parts, the suspension bottled in sterile bottles, and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G.
Example II Under sterile conditions, 0.5 part of procaine hydrochloride and 5.0 parts of sodium citrate are dissolved in sterile distilled water. About 2.5 parts of sodium carboxymethylcellulose is added thereto with shaking, whereafter five parts of procaine penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procaine penicillin G.
Example III Under sterile conditions, 2.0 parts of procaine hydro chloride and 0.5 parts of sodium citrate are dissolved in sterile distilled water in a glass flask, about 0.5 parts of sodium carboxymethylcellulose added thereto with shaking, whereafter five parts of procaine penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles, and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procaine penicillin G.
Example IV 5.0 grams of anhydrous sodium citrate, 1 gram of procaine hydrochloride and 0.5 gram of sodium carboxymethylcellulose were added to 50 cc. of water and stirred with a laboratory agitator until solution was complete. 25 cc. of this solution were added to a 100 cc. beaker and 16.5 grams of procaine penicillin G (potency about 1000 units/milligramscreened through a 200 mesh screen) added. The volume was adjusted to 50 cc. with the citrate-CMC-procaine hydrochloride-water gel and the suspension thoroughly mixed. The pH of the suspension was adjusted to 6.5 with citric acid and the suspension thoroughly mixed. The suspension contains approximately 300,000 units of procaine penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G.
Example V 0.25 gram of anhydrous sodium citrate, 1 gram of procaine hydrochloride and 0.25 gram of sodium carboxymethylcellulose were added to 50 cc. of water and stirred with a laboratory stirrer until solution was complete. Twenty-five cc, of this solution were added to a 100 cc. beaker and 16.5 grams of procaine penicillin G (potency about 1000 units/milligram-screened through a 200 mesh screen) added. The volume was adjusted to 50 cc. with the citrate-sodium carboxymethylcellulose-procaine hydrochloride-water gel and the suspension thoroughly mixed. The pH of the suspension was adjusted i 3 -to= 6t5 withcitric izacid and the :suspension ihoroughly mixed. The suspensionucontainsapproximately:300,000 ..units .of procaine, penicillinfi per .cc.,iis.stable for periods ..inexcess of.=one yearanchgivesblood. levels of increasing nniiitsperimg=- screened through at200meshiscreenyadded wandtmixed: in'iwith a-laboratoryr stirrer. .The volume was adjusted to 50 cc. with-the aqueous carboxymethylcellulose procaine hydrochloride gel:and the suspension ineffectiveness over. knownaqueoussuspensions or procaine l uthoroughly mixed with a laboratory stirrer. This suspenrpeiiicillin G.
Example VI The following ingredients were addedzto'a15rcc;"vial:
sion is vialed and tested. :The suspension containsapproximately 300,000..units of procaine penicillin G per cc., is stable for periods in excess of one year at room :temperature' (73 F.) andigives bloodglev'els oftincreased 4.0 grams procaine penicillin 'G (poten y about 10 i10-eifectiveness lover known .taqueous-t suspensions lei-pro- :units ;-per .milligram.screened ..through .a 250 mesh screen) 0:04gram sodium carboxymethylc'ellillose 0.2 gram'sodinm' citrate anhydrous 1.0 gram procaine carbonate 9.0 cc. distilled water The vials were thoroughly shakento. givealhomogeneous suspension. Several of these were made. The
suspension contains approximately3003000 units of *proeaine penicillin G'per cc.,* is stable-tor periods in excess *ot'one year' arid= gives-blood --levels "of increasingfiective- "-ness'over known'aqueous suspensions ofprocaine'penicillinG.
*Examp'leV-II Under sterile conditions,*'2.0* parts of procaine hydro- ;chloride is .idissolved in sterile distilled water; and about 2.0 parts of sodium carboxymethylcellulose added thereto with shaking;whereafterfive"parts'of'procaine penicillin Gj'having an activity slightly inexcess of6,000,000;;-3
units per part, is added and shaking continuedfor a few minutes. Water is'thenadded to make 100 parts, whereafter the suspension is bottled in sterile'bottles and stored. The suspension contains approximately300;000'units of :procainvpenicillinc G per'smilliliter, is stable for speriodsy 35 IZ'iIIxEXCBSS. of-"one year: at temperatures-below 30.C., and, -iuponaadministration,; gives .blood levels of increased "effectiveness: over known: aqueous 'suspensionssof procainez penicillinG.
"Example VIII Under sterile c0n'ditions,:5.0 parts of procaine hydrochloride .is dissolved in sterile distilled water in a glass fia'sk. About 2.5 parts of sodium carboxymethylcell'ulose ;:-is'.a'dded' theretoswith shaking, whereafter five parts of procaine-penicillin G, having an activity slightly in excess of 6,000,000 units per part, is'added-and shaking continued for a few minutes. Water is then added'to-make'100 parts,ithe suspension bottled in sterile bottles, andxistored.
The suspension contains approximately 300,000 units of ,.procaine .-p.enicillin .Gper milliliter, is stable for periods in*' .excess. of six-months, andgivesblood levels ofincreased .e'iiec'tiveness. over. known aqueous. suspensions of procaine- ,penicillinIG. upon administration.
Example IX procaine-peni'cillin'G'per milliliter, is stable'for periods" "'in-excess-of six months, and gives blood levels of increased 'ffeotivenessover known aqueous suspensions-of procainepenicillin G.
Example X Oneagram ..er. procaine hydrochloride .and. 01375; gram of sodium carboxymethylcellulose were .dissolved. in. '50
cc. of distilled water using .a laboratory. stirrer. About .cc. of ..this.. gelwere placed. ina. 100..cc..beaker.. and
.. caine penicillin .G.
.ExamplaXl .Under sterile-conditions, 52.0 parts of; procaine phos- 15-phateis dissolved in sterile distilled water, and.about-2.0
,parts: of sodium carboxymethylcellulose i added athereto with shaking; whereafter five :parts of procaine-penicillin G; having: anactivityslightly. in excess of.-,6,000,000; units -per; part, is added andnishaking. continued. for a. few 1minonnes. '-Water is 'then added to make 100 partsywhereafter tthes suspension '.-iS :bottled in. sterile? bottles and stored. :Thesuspension contains a approximately. 300,000. units-0f procaine-penicillin G per; milliliter, -iststab1etforperiods in excess of one yearattemperatures below C., and,
7,25 upon administration, gives blood levels of increased effe'ctivenesseoveriknown aqueous suspensions of procaineepenicillin G.
'.Example Xi! 0 .375. gram'of sodium ca-rboxymethylcellulose-weredis- ;zsolvedtinSO cc; of distilled water using a laboratory stirrer. To. this solutionwas added .one gram of procaine base awhich was suspended with-.a laboratory stirrer. "About: 25 cc. ofithis suspension were placed in a 100 cc. beaker'and to .it' were-added 16.5jgrams-of procaine-penicillinG (potency about v 1000..unitsper. mg'.). ".The procaine' base-- .CMC. suspension were added? tomake :the total volume -50 cc. Phosphoric acid was added until the-pH of .the suspension was 6.5. The suspension was thoroughly 40 mixed with a laboratory stirrer. The suspension contains approximately 300,000 units of procaine-penicillin G,per c.c.,- is st'ablefor periods in excess of. one yearat room temperature (about 73 F.) and givesblood levels of increased" iefiectiveness. over known aqueous suspensions of I p aine-penicillin G.
:Example;XlII
Under sterile conditions,' 2.0 parts or procaine 'hydrochloride,'0i5 part er sodium citrate, and'5'.0'parts"of di- "sodium phosphate, are dissolved'in about cc; of sterile distilled water, and" about 2.0- parts of sodium 'ca'rboxy- =ni'eth'ylcellulose 'added' thereto "with shaking; whereafter "30partsofprocaine penicillin.G,"having an activity'of about 1,000;000' units per part, is 'added and shaking continued for a few;minutes. Water is then added to make 100 parts. ThepHof thesuspension isadjusted to pH '6.5 wi th .pho spho'ric acid, whereafter 'the=su spen- -sion is bottled in sterile bottles,.and stored. Thesuspension contains approximately 300,000 units of procaine penicillin G per milliliter, .is' stable for periods in excess-of one year, and, upon administration, gives blood levels of increased eifectiveness over known aqueoussuspensions of procaine penicillin'jG;
disddium phosphate are .dissolvedin about 50 cc. of sterile distilled water in a glass flask. About 2.5 parts of sodium carboxymethylcelluloseis addedthereto with shaking,
whereafter 30 parts of procaine-penicillin G, having an activity of about1;000,000 units per part, is added and 2;shaking OOIItlIlHGda-fOl .a.-few1minutes. '"Wa'teris then added: to .makei 100wparts. .iThe: pH; of thet'suspension is 16.5;grams ofprocainepenicillinfi..(potency about 1000. adjusted to pH;6:5 with:phosphorici:acidy'whereafter the suspension is bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of one year, and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G upon administration.
Example XV Under sterile conditions, 0.5 part of procaine hydrochloride, 0.25 part of sodium citrate, and 7.5 parts of disodium phosphate, are dissolved in about 50 cc. of sterile distilled water and about 1.5 parts of sodium carboxymethylcellulose added thereto with shaking, whereafter 30 parts of procaine penicillin G, having an activity of about 1,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the pH of the suspension is adjusted to pH 6.5 with phosphoric acid, the suspension bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine penicillin G per milliliter, is stable for periods in excess of one year and gives blood levels of increased effectiveness over known aqueous suspensions of procaine penicillin G.
Example XVI pension contains approximately 300,000 units of procainepenicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increasing effectiveness over known aqueous suspensions of procainepenicillin G.
Example XVII Under sterile conditions, 5.0 parts of procaine hydrochloride and 0.25 part of disodium phosphate are dissolved in sterile distilled water. About 2.5 parts of sodium carboxymethylcellulose is added thereto with shaking, whereafter five parts of procaine-penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles and stored. The suspension contains approximately 300,000 units of procaine-penicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procaine-penicillin G.
Example XVIII Under sterile conditions, 2.0 parts of procaine hydrochloride and 5.0 parts of disodium phosphate are dis solved in sterile distilled water in a glass fiask, about 1.5 part of sodium carboxymethylcellulose added thereto with shaking, whereafter five parts of procaine-penicillin G, having an activity slightly in excess of 6,000,000 units per part, is added and shaking continued for a few minutes. Water is then added to make 100 parts, the suspension bottled in sterile bottles, and stored. The suspension contains approximately 300,000 units of procainepenicillin G per milliliter, is stable for periods in excess of six months, and gives blood levels of increased effectiveness over known aqueous suspensions of procainepenicillin G.
Example XIX The following ingredients were added to a cc. vial:
4.0 grams procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.04 gram sodium carboxymethylcellulose 8 8.5 cc. of an aqueous solution containing 5% NazHPOc and 2% procaine hydrochloride.
The vials were shaken thoroughly to give a homogenous uspension. Several vials were made. The suspension contains approximately 300,000 units of procaine-penicillin G, per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine-penicillin G.
Example XX The following ingredients were added to a 15 cc. vial:
4.0 grams procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.04 gram sodium carboxymethylcellulose 0.6 gram Nazi-IP04 anhydrous 0.6 gram procaine carbonate 9.0 cc. distilled water.
The vials were shaken thoroughly to give a homogenous suspension. Several vials were made. The suspension contains approximately 300,000 units of procainepenicillin G per cc., is stable for periods in excess of one year, and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine-penicillin 6.
Example XXI The following ingredients were added to a 15 cc. vial:
4.0 grams procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.13 gram procaine base 0.04 gram sodium carboxymethylcellulose 0.6 gram Nazi-IP04 9.0 cc. distilled water The vials were shaken thoroughly to give a homogenous suspension. Several vials were made. The suspension contains approximately 300,000 units of procaine penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine penicillin G.
Example XXII The following ingredients were added to a 15 cc. vial:
4.0 grams procaine-penicillin G (potency about 1000 units per mg.screened through a 200 mesh screen) 0.25 gram procaine phosphate 0.6 gram NazHPOs anhydrous 0.04 gram sodium carboxymethylcellulose (CMC) 9.0 cc. water The vials were shaken thoroughly to give a homogenous suspension. Several vials were made. The suspension contains approximately 300,000 units of procaine-penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing effectiveness over known aqueous suspensions of procaine-penicillin G.
Example XXIII Using sterile technique the following solution was made: In a 1 liter beaker was placed 400 cc. of distilled water, 25 grams of Na-2HPO4 anhydrous, 2.5 grams phenol U. S. P. and 5.0 grams of sodium carboxymethylcellulose. This was mixed with a laboratory stirrer until solution was complete. Then 10 grams of procaine base were added and sufficient distilled water to bring the volume to 500 cc. The pH of this suspension was then adjusted to 6.5 with 12 cc. of 42.5% H3PO4. This suspension was thoroughly mixed and then autoclaved for 30 minutes at 15 lbs. pressure. About cc. of the above suspension were placed in a 400 cc. beaker and to it were added 66 grams of procaine-penicillin G (potency about 1000 units per mg.-screened through a 200 mesh screen) and the volume adjusted to 200 cc. with the above suspension. The finished suspension was thoroughly mixed and passed through the Eppenbach colloid mill. The suspension 9 contains approximately 300,000 units of procaine-penicillin G per cc., is stable for periods in excess of one year and gives blood levels of increasing etfectiveness over known aqueous suspensions of procaine-penicillin G.
Example XXIV The following are mixed in filtered, pyrogen-free distilled Water (97.88 cc.): Lecithin (0.70 g.), Tween 40 (0.93 g.), Span 40 (0.33 g.), sodium citrate U. S. P. (0.57 g.), and Butyl Paraben (0.021 g.). There is throughly mixed into 69.40 cc. of this mixture under sterile conditions procaine hydrochloride U. S. P. (2.0 g.), micronized lecithin-coated procaine penicillin G (24.15 g.) and pulverized, 250 mesh, lecithin-coated procaine penicillin G (8.05 g.). The product contains approximately 300,000 units of procaine penicillin G per cc. and is stable for periods in excess of one year. The product is more stable and gives higher blood levels than previously known aqueous suspensions of procaine penicillin G which do not contain the added, excess procaine ion.
While the present invention has been described with particular reference to procaine penicillin G, it is to be understood that the procaine salts of other penicillins are also included within the scope of this invention. For instance, the penicillins G, F, X, 0, dihydro F and K, and mixtures of two or more such penicillins, particularly mixtures containing at least 85% penicillin G, are included within the scope of this invention.
It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims. For example, any injectable compound of procaine capable of yielding procaine ions, such as procaine hydrochloride, procaine base or procaine phosphate, may be employed.
I claim:
1. A sterile, aqueous suspension of procaine penicillin which is stable over long periods of time at room temperature and which is productive of highly etfective blood levels upon administration, including procaine penicillin, a suspending agent, and a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
2. A sterile, aqueous suspension of procaine penicillin which is stable over long periods of time at room temperature and which is productive of highly efiective blood levels upon administration, including procaine penicillin, a suspending agent, and from 0.5 to 5.0 percent of a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
3. A sterile, aqueous suspension of procaine penicillin which is stable over long periods of time at room temperature and which is productive of highly effective blood levels upon administration, including procaine penicillin, a suspending agent, and about two percent of a member selected from the group consisting of procaine base and Water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
4. A sterile, aqueous suspension of procaine penicillin G which is stable over long periods of time at room temperature and which is productive of highly efiective blood levels upon administration, including procaine penicillin G, a suspending agent, and a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
5. A sterile, aqueous suspension of procaine penicillin G which is stable over long periods of time at room temperature and which is productive of highly efiective blood levels upon administration, including procaine penicillin G, a suspending agent, and from 0.5 to 5.0 percent of a member selected from the group consisting of pro caine base and Water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
6. A sterile, aqueous suspension of procaine penicillin G which is stable over long periods of time at room temperature and which is productive of highly effective blood levels upon administration, including procaine penicillin G, a suspending agent, and about two percent of a member selected from the group consisting of procaine base and water-soluble, ionized, injectable salts of procaine other than procaine penicillin.
7. A stabilized aqueous pharmaceutical preparation which comprises, in suspension in an aqueous medium, procaine penicillin, a water-soluble acid addition salt of procaine, and sodium carboxymethylcellulose.
References Cited in the file of this patent UNITED STATES PATENTS 2,515,898 Rhodehamel July 18, 1950 FOREIGN PATENTS 658,467 Great Britain Oct. 10, 1951 OTHER REFERENCES Chem. Engineering, National Edition, April 1951, pages 174 to 177, Penicillin.
Noguer-More, VII Congres dermatologistes syphiligraphes lange franc, meet. 4/ 21-23/49, Delayed action penicillin in aqueous solution. Through Presse m., Volume 57, page 748, August 13, 1949; Through Squibbs Abstract Bulletin, September 7, 1949, page 1034.

Claims (1)

1. A STERILE, AQUEOUS SUSPENSION OF PROCAINE PENICILLIN WHICH IS STABLE OVER LONG PERIODS OF TIME AT ROOM TEMPERATURE AND WHICH IS PRODUCTIVE OF HIGHLY EFFECTIVE BLOOD LEVELS UPON ADMINISTRATION, INCLUDING PROCAINE PENICILLIN, A SUSPENDING AGENT, AND A MEMBER SELECTED FROM THE GROUP CONSISTING OF PROCAINE BASE AND WATER-SOLUBLE, IONIZED, INJECTABLE SALTS OF PROCAINE OTHER THAN PROCAINE PENICILLIN.
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US6818229B1 (en) 1993-09-20 2004-11-16 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia
US20050222472A1 (en) * 2004-04-01 2005-10-06 Honeywell International Inc. Method of making difluoromethane, 1,1,1-trifluoroethane and 1,1-difluoroethane
US20080045573A1 (en) * 1993-09-20 2008-02-21 Bova David J Methods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia
CN103301059A (en) * 2012-03-16 2013-09-18 重庆方通动物药业有限公司 Procaine benzylpenicillin suspension injection and preparation method thereof
CN103301140A (en) * 2012-03-16 2013-09-18 重庆方通动物药业有限公司 Veterinary procaine penicillin-dihydrostreptomycin sulfate suspension injection and preparation method thereof

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Cited By (24)

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Publication number Priority date Publication date Assignee Title
US2975102A (en) * 1956-03-01 1961-03-14 Raion Hamigaki Kabushiki Kaish Transparent jelly-type tooth-paste
US2973300A (en) * 1956-05-07 1961-02-28 American Home Prod Process for making antibiotic-enzyme topical film-forming compositions
US2939818A (en) * 1957-04-09 1960-06-07 Pfizer & Co C Aqueous therapeutic compositions
US2951015A (en) * 1957-07-02 1960-08-30 Pfizer & Co C Aqueous readily injectable therapeutic compositions containing water-insoluble penicillin and sucrose dilaurate
US2985559A (en) * 1958-01-27 1961-05-23 Glaxo Lab Ltd Stabilized therapeutic ferrous fumarate aqueous suspensions
US3063905A (en) * 1959-08-21 1962-11-13 Central Pharmacal Company Carboxy methyl benzyl dextran dextro-amphetamine
US3065138A (en) * 1959-10-09 1962-11-20 Warren Teed Products Company Therapeutic preparations of elemental iron
US3065143A (en) * 1960-04-19 1962-11-20 Richardson Merrell Inc Sustained release tablet
US3063906A (en) * 1960-09-13 1962-11-13 Central Pharmacal Company Benzyl dextran-amphetamine and method of making same
US3312594A (en) * 1963-06-21 1967-04-04 Squibb & Sons Inc Longlasting troche
US4344934A (en) * 1978-11-20 1982-08-17 American Home Products Corporation Therapeutic compositions with enhanced bioavailability
US6129930A (en) * 1993-09-20 2000-10-10 Bova; David J. Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night
US6080428A (en) * 1993-09-20 2000-06-27 Bova; David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US6676967B1 (en) 1993-09-20 2004-01-13 Kos Pharmaceuticals, Inc. Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia
US6746691B2 (en) 1993-09-20 2004-06-08 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics
US6818229B1 (en) 1993-09-20 2004-11-16 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia
US20050118257A1 (en) * 1993-09-20 2005-06-02 Bova David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US20070225342A1 (en) * 1993-09-20 2007-09-27 Bova David J Nicotinic Acid Compositions For Treating Hyperlipidemia and Related Methods Therefor
US20080045573A1 (en) * 1993-09-20 2008-02-21 Bova David J Methods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia
US7998506B2 (en) 1993-09-20 2011-08-16 Kos Life Sciences, Inc. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US20050222472A1 (en) * 2004-04-01 2005-10-06 Honeywell International Inc. Method of making difluoromethane, 1,1,1-trifluoroethane and 1,1-difluoroethane
US7112708B2 (en) 2004-04-01 2006-09-26 Honeywell International Inc. Method of making difluoromethane, 1,1,1-trifluoroethane and 1,1-difluoroethane
CN103301059A (en) * 2012-03-16 2013-09-18 重庆方通动物药业有限公司 Procaine benzylpenicillin suspension injection and preparation method thereof
CN103301140A (en) * 2012-03-16 2013-09-18 重庆方通动物药业有限公司 Veterinary procaine penicillin-dihydrostreptomycin sulfate suspension injection and preparation method thereof

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