US2476351A - Injectable penicillin compositions - Google Patents

Description

Patented July 19, 1949 UNITED STATES INJECTABLE PENICILLIN COMPOSITIONS Stephen B. Binkley, Detroit, Mich, assignor to Parke, Davis & Company,il)etroit, Mich., a corporation of Michigan No Drawing. Application June 7, 1945;

Serial No. 598,205

6 Claims.

This invention relates to repository products and to methods for Obtaining the same. More particularly, the invention relates to compositions containing the antibiotic known as penicillin.

At the present time it is the practice to admin-' inster salts of penicillin by intramuscular injection using saline solution as a, vehicle. When pen-cillin is administered in this manner it is quickly absorbed and large quantities appear in the blood stream soon after injection. These high blood levels of penicillinrapidly disappear due to the rapid excretion and destruction of the antibiotic. It is therefore necessary to reinject penicillin at twoor three-hour intervals if detectable amounts are-to be maintained in the blood stream. In an effort to overcome this rapid elimination of penicillin, diodrast (the chemical combination of 3,5-diiodo-4-pyridone- N-acetic acid and diethanolamine which contains about 50% iodine) or p-aminohippuric acid have been administered with penicillin to interfere with renal function and'thus depress the excretion of penicillin [PIOC. Soc. Exp. Biol. and Med, 53, 30 (1943) and Science, 100, 107 (1944) This unnatural physiological method has many obvious disadvantages in addition to the fact that it is not particularly efiective in accomplishing its purpose of maintaining high blood levels of penicillin over long periods of time.

Another method of maintaining blood levels of penicillin after intramuscular injection which hasbeen proposed in the retarding of the absorption of penicillin by placing an ice pack over the area of injection to limit the local circulation [(Science, 100,432 (1944) This method does not appreciably delay the absorption of penicillin and is'very cumbersome and extremely uncomfortable.

More recently the use-of vegetable oils and beeswax-peanut oil mixtures have been suggested as vehicles for penicillin because of theirslow rate of absorption [Science, 100, 412 94 and Science, 100, 196 (1944)]. Even when using these slowly absorbed vehicles for penicillin it is necessary to reinject penicillin every three or four hours to maintain adequate therapeutic blood levels of the antibiotic.

One of the objects of this invention is to con-' tinuously maintain therapeutic blood levels of 2 penicillin in humans and in animals for considerable periods of time.

Another object of the invention is to prevent the customary rapid elimination and destruction in vivo of penicillin. One of the objects of the invention is to obtain the maximum therapeutic eifect per unit of penicillin administered.

It is also an object of this invention to obtain more constant blood levels of penicillin.

A further object of the invention is to provide repository compositions containing penicillin which are stable and which are easy to administer.

Still another obj ect of this invention is to provide repository compositions containing pencillin which do not cause undesirable physiological reactions on administration to humans or animals.

I have found that by intramuscular injection of a suspension of a penicillin salt in a vehicle comprising a, natural oil containing a small amount of an organic compound possessing vasoconstrictor properties that it is possible to continuously maintain therapeutic blood levels of penicillin over a long period of time. I have also found that this period of time when using my new preparations is several times greater than obtained when one injects a saline solution of a vasoconstrictor and a penicillin salt or an oil or oil-wax suspension'of a penicillin salt not containing any vasoconstrictor. By the practice of my invention I have found that more constant blood levels of penicillin are obtainable. This insures the presence of adequate amounts of penicillin for the exercise of a continuous therapeutic eiiect between injections. The penicillin' compositions of the present invention are stable and do not cause undesirable physiological reactionson administration to humans or 40 zene and the like. I have found that only very small amounts of .the vasoconstrictor need be 3 used in my new preparations to accomplish the desired repository efiect. For example, in my oil suspension preparations, as little as 0.00005 g. of epinephrine per ml. of the preparation is sufficient to enhance the repository action to a very marked degree. However, as high as 0.002 g. of epinephrine per ml. may be used without causing significant rise in blood pressure, although for a margin of safety and to prevent a nervous or restless feeling, it is preferable to use less than about 0.001 g. per ml.

By small amounts of vasoconstrictors as used herein and in the appended claims. I intend to. include those proportions of vasoconstrictors which can be used with a therapeutic dosage of penicillin to produce effective prolonged vasoconstriction without the undesirable nervous reactions which result when too much of the. vaseconstrictor is used. The limits of these proportions will vary somewhat but are readily determined by simple experiment. v

In the preparation of my new products I may use any bland, non-irritating natural oil such as peanut oil, sesame oil, cottonseed oil, castor oil,

corn oil, olive oil, rape seed oil, coconut oil and the like. I have. found that particularly valuable products are obtained when such natural oils. also contain a small amount. of. dissolved wax such, as beeswax, spermaceti and similar waxes. These latter mixtures when incorporated with a. vaseconstrictor and. used as. vehicles ior penicillin salts prolong the action of. penicillin. considerably more than similar compositions not containing; wax.

The therapeutic blood level. of penicillin concentration in humans is between 0.02 and 0.03 Oxford units perml. or blood. serum. The main;

tenance of this therapeutic blood. level of.

cillin in humans is indicated by urinary excretion of over about 1000. Oxiord units. of penicillin per hour.

In accordance with the. present invention one to one and a half times the. therapeutic blood levels of penicillin may be maintained for at least twelvehours. by a single. intramuscular injectionof as little as 100,000- Oxford units at penicillin. The invention therefore makes it ssibl to, treat in.- fections and diseases which yield to penicillin therapy by not more than two intramuscular injections of penicillin per twenty-four hours in contrast to. the customary eight. to twelve intramuscular iniections. required. when penicillin salts in aqueous, or in saline solutions.

The invention is. illustrated by the following examples. EXAMPLE la 3 ml. of refined peanut oil and 215 mg. of epinephrine are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. Two or three sterile glass beads are added,

the mixture warmedto about C1, the bottlest-opperedand shaken for ten minutes to insure dispersion of the particles of penicillin. The mixture is then diluted to 5 ml. with refined peanut oil and shaken to insurehomogeneity.

This therapeutic preparation is uniform suspension of calcium penicillin which is stable and suitable for intramuscular injection into humans or animals. Injection of 1 ml. of this product furnishes 100,000 Oxford units of calcium penicillin the action of which is continuously: maintained above the therapeutic level for about 12 hours.

EXAMPLE. 2.

4.0 ml. of warm (about 40 C.) refined peanut 1 Oxford units of dry calcium penicillin contained in a small glass bottle. The bottle is stoppered and shaken to disperse the penicillin salt. The mixture is then diluted to 5 ml. with refined peanut oil.

This therapeutic preparation is stable and contains 200,000 Oxford units of calcium penicillin per ml. 0n intramuscular injection of this preparation into humans or animals the therapeutic blood level of penicillin is maintained for at least twelve hours.

Table I shows representative blood levels obtained following the intramuscular injection of the penicillin preparation prepared as described in, this Example.

Table I Penicillin blood concentration at the end of hours in Oxford Units per ml.

Patient No. serum 1 I 6 ours. 8.5 hours. labours. 12 hours Determined. by themediliedmethod ct Boseuhlati as. desc ibed in J". Beet, 48, 599 1944 Extracts 3 3 m1. of warm (about 35- C.) refined peanut oil and 0.5 mg. of epinephrine are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. The bottle is stoppered, shaken well to disperse the penicillin salt and then the mixture diluted to 5 ml. with refined peanut oil.

This therapeutic preparation is stable and contains 100,000 Oxford units of calcium penicillin per ml. When 1 ml. of this preparation is injected intramuscularly into humans the efiect of the penicillin maintained several times as long as in similar preparations not containing epinephrine.

' EXAMPLE 4 31111. of refined peanut oil and 2.5. mg. of neosynephrine are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. Two or three sterile lass beads are added, the mixture warmed to about. 40 (2., the bottle stoppered and shaken for ten minutes to insure dispersion of the particles of penicil in. The mixture is then. diluted to 5. ml. with refined peanut oil and shaken to insure homo enei y.

This. therapeutic preparation is a uniform suspension of. calcium penicillin which is stable and suitablev for intramuscular injection into humans or animals. Injection of 1 m1. of this product furnishes 100,000 Oxford units. of calcium penicillin the action of which is continuously maintained above the therapeutic level for about 12 hours.

EXAMPLES 3 ml. of warm (about; 40 C.) refined peanut oil and 1.25 mg. of neosynephrine are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. The bottle is stoppered, the mixture agitated, to disperse the Denioil and 1 mg. of epinephrine are added to 1,000,000- cillin salt and the mixture diluted to a volume of 5 ml. with refined peanut oil and the mixture shaken to insure homogeneity.

This stable preparation contains 100,000 Oxford units of calcium penicillin per ml. and when injected into human subjects maintains therapeutic blood levels of penicillin over much longer periods of time than similar preparations not containing a vasoconstrictor drug.

EXAMPLE 6 3 ml. of warm (about 40 C.) peanut oil and 1.2 mg. of 2-naphthylmethylimidazoline are added to 300,000 Oxford units of calcium penicillin contained in a small glass bottle. The bottle is stoppered, shaken well to disperse the penicillin salt and diluted to a volume of 4 ml. with refined peanut oil.

This stable preparation contains 15,000 Oxford units of calcium penicillin and when administered by the intramuscular route to human subjects maintains a therapeutic blood level of penicillin for a much longer period of time than a similar preparation not containing the vasoconstrictor drug.

EXAMPLE 7 3 ml. of refined peanut oil and 2.5 mg. of epinephrine are added to 500,000 Oxford units of sodium penicillin contained in a small glass bottle. Two or three sterile glass beads are added, the mixture warmed to about 40 C., the bottle stoppered and shaken for ten minutes to insure dispersion of the particles of penicillin. The mixture is then diluted to 5 ml. with refined peanut oil and shaken to insure homogeneity.

This therapeutic preparation is uniform suspension of sodium penicillin which is stable and suitable for intramuscular injection into humans or animals. Injection of 1 ml. of this product furnishes 100,000 Oxford units of sodium penicillin the action of which is continuously maintained above the therapeutic level for about 12 hours.

EXAMPLE 8 3 ml. of refined peanut oil and 2.5 mg. of neosynephrine are added to 500,000 Oxford units of sodium penicillin contained in a small glass bottle. Two or three sterile glass beads areadded, the mixture warmed to about 40 C., the bottle stoppered and shaken for ten minutes to insure dispersion of the particles of penicillin. The mixture is then diluted to 5 ml. with refined peanut oil and shaken to insure homogeneity.

This therapeutic preparation is a uniform suspension of sodium penicillin which is stable and suitable for intramuscular injection into humans or animals. Injection of 1 ml. of this product furnishes 100,000 Oxford units of sodium penicillin the action of which is continuously maintained above the therapeutic level for about 12 hours.

EXAMPLE 9 2.5 mg. of epinephrine and 3 ml. of warm (about 40 C.) refined peanut oil containing 3% by weight of dissolved beeswax are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. The bottle is stoppered and shaken Well to disperse the penicillin salt. The mixture is diluted to a volume of 5 ml. with warm refined peanut oil containing 3% by weight of dissolved beeswax and shaken again to insure homogeneity.

This stable therapeutic preparation contains 100,000 Oxford units of calcium penicillin per ml. Therapeutic blood levels of penicillin are 1main- 2.5 mg. of 2-naphthylmethylimidazoline and 3 m1. of warm (about 45 C.) refined peanut oil containing 3% dissolved beeswax are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. Two or three sterile glass beads are added and the mixture shaken for five minutes. The mixture is made up to a volume of 5 ml. with warm refined peanut oil containing 3% beeswax.

When 1 ml. of this stable composition which contains 100,000 Oxford units of calcium penicillin per ml. is injected intramuscularly into human subjects therapeutic blood levels of penicillin are maintained for at least twelve hours.

EXAMPLE 1 l 3 ml. of warm cottonseed oil and 2.5 g. of l-ahydroxy-b-methylamino-4-hydroxyethylbenzene are added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. The bottle is stoppered and the mixture shaken to disperse the penicillin salt. The mixture is diluted to a volume of 5 ml. with cottonseed oil and mixed well.

This stable therapeutic product contains 100,- 000 Oxford units of calcium penicillin per ml. and

when administered to humans in dosages of 100,-

000 Oxford units gives therapeutic blood levels of penicillin for a period of about twelve hours.

EXAMPLE 12 2 ml. of Warm coconut oil and 0.9 mg. of epinephrine are added to 300,000 Oxford units of calmuch larger period of time than similar preparation not containing epinephrine.

EXAMPLE 13' A mixture consisting of 1 mg. of epinephrine and 8 ml. of warm refined corn oil is added to 500,000 Oxford units of calcium penicillin contained in a small glass bottle. The bottle is stoppered, the mixture shaken to disperse the penicilllin salt and the preparation diluted to a volume '7 of 10 ml. with refined corn oil.

This preparation is stable and contains 50,000 Oxford units of calcium penicillin per 1011.. When this product is administered intramuscularly to humans therapeutic blood levels of penicillin are maintained over a much longer period of time than by administration of the same quantity of similar preparation not containing epinephrine.

EXAMPLE 14 2.5 mg. of epinephrine and 4 ml. of warm sesame oil are added to 500,000 Oxford unitsof calcium penicillin contained in a small glass bottle. The bottle is stoppered, shaken to disperse the penicillin salt and the mixture diluted to a volume of 5 ml. with sesame oil.

This preparation which contains 100,000 Oxfor units of calcium penicillin is stable and when injected intramuscularly into humans results in therapeutic blood levels over much longer periods of time than corresponding preparation not containing epinephrine.

1 The great superiority of .the penicillin preparations of the present invention over the known penicillin preparations is readily apparent from examination of Table II which shows the rapid urinary excretion of penicillin in human patients prising a suspension of a penicillin salt in a nonaqueous vehicle comprising an injectable natural oil containing a small amount of an organic compound possessing vasoconstrictor properties, said composition, upon injection, providing prolonged tollowms intramuscular injec ions of 1 m of therapeutic blood levels of penicillin as comvarious control preparations of penicillin known pared with the blood levels attainable upon ino the prw a t as omp ed to the more p ojection of similar compositions containing no o ed urinary excretion of my ne preparations. vasoconstrictor and with the blood levels attain- Table II- Oxford Units oi.Penlcillin Excreted at Y r Total per- Patient Formula W m 2 0091 P9 11 W 1 cent. B No. cillin aliou'rs hours 7hours 0hours 2-ihours Excreted Control Prcpn. #L 4 50,000 Units of sodium penicillin in water 57,600 5,000 7 0 0 0 62 Control Prepn. #2. 2 50,000 linit s of sodium penicillin-{05 mg, epinephrine 36,400 5, 000 700 0 0 42 Cntrol Prepn. #3. 18 100,000 Units of calcium penicillin in peanut oil 32, 500 1,150 0 0 0 33.7 5 0 0 9 99. V. 9 4&5 Preps. described a 100,000 Units of calcium penicillin+0.5 mg. epi- 24,100 14,800 12,000 5,400 5,000 02 in Example 1. nephrine in peanut oil.

7 28, 500 18,000 13,000 5, 300 2,600 07 12 37, 240 24, 000 0, 300 7,000 1,700 77 p 1a V V V 22,750 29,300 6,000 315 58 Prepn. described 30 100,000 Units of calcium penicillin-P01 mg. epi- 21,000 5,500 1,000 500 0 27.5

in Example 3. nephrine lIl peanut 011. I

M V c. H @300 5,300 12,000 2,000 ,200 14 Control Prepn. #4- 14 100,000 gnilts of calcium penicillin+3% beeswax in 3, 500 5,200 1,250 250 250 Prepn. described 1 100,000 Units of calcium penicillin-+0.5 m em.- 1,030 0, 0 0,4 0 a 13,400

in Example 9. nephrine+3% beeswax in peanut oil.

1 Oxfordllnits of penicillin determined by the Oxford. Plate Test asdescrihcd by Fleming.

2 cc. of this preparation administered, a total of 100,000 Oxford Units 5 Samples not collected.

The penicillin products of the present invention when administered to humans or animals by the intramuscular route give blood levels which in duration, continuity and intensity are similar to those shown in Table I above for the specific preparation described in Example 2.

The penicillin suspensions of the invention are more easily prepared by warming the vehicle to enhance its fluidity. However, I have found that in many cases it is not necessary to first warm the vehicle to obtain a homogeneous suspension of the penicillin salt. 7

While in the above examples I have used the free bases of the vasoconstrictors it should be understood that I may also use any non-toxic acid addition salt of these compounds in the preparation of my new therapeutic products. I have found that little or no reaction takes place between these acid addition salts of the vasoconstricter and the penicillin salts when they are suspended in the oil media of the present invention. Some specific examples of the nontoxic acid addition salts of the vasoconstrictors which I may use are the hydrochloride, sulfate, phosphate, nitrate, acetate, citrate and tartrate salts.

Any non-toxic salt of penicillin may be used in the preparation of the penicillin products herein described. For example, some of the penicillin salts which I may use instead of the calcium and sodium salts shown in the above examples are the ammonium, potassium, lithium and magnesium salts of penicillin.

While suspensions of the present invention slowly settle out, I have found that they do not pack and that they may be immediately and uniformly resuspendecl with ease.

What I claim is: I

1. An injectable therapeutic composition comable upon injection of similar compositions containing no oil.

2. An injectable therapeutic composition comprising a suspension of a penicillin salt in a nonaqueous vehicle comprising an injectable natural oil containing a small amount of epinephrine, said composition, upon injection, providing prolonged therapeutio blood levels of penicillin as compared with the blood levels attainable upon injection of similar compositions containing no vasoconstrictor and with the blood levels attainable upon injection of similar compositions containing no oil.

3. An lnjectable therapeutic composition consisting of a suspension of calcium penicillin in a non-aqueous vehicle comprising peanut oil containing a small amount of epinephrine, said composition, upon injection, providing prolonged therapeutic blood levels of penicillin as compared with the blood levels attainable upon injection of similar compositions containing no vasoconstrictor and with the blood levels attainable upon injection of similar compositions containing no oil.

4. An injectable therapeutic composition comprising a suspension of calcium penicillin in a non-aqueous vehicle comprising an injectable natural oil containing a small amount of an organic compound possessing vasoconstrictor properties, said composition, upon injection, providing prolonged therapeutic blood levels of penicillin as compared with the blood levels attainable upon injection of similar compositions containing no vasoconstrictor and with the blood levels attainable upon injection of similar compositions containing no oil.

5. An injectable therapeutic composition comprising a. suspension of sodium penicillin in a non-aqueous vehicle comprising an injectable natural oil containing a small amount of an organic compound possessing vasoconstrictor properties, said composition, upon injection, providing prolonged therapeutic blood levels of penicillin as compared with the blood levels attainable upon injection of similar compositions containing no vasoconstrictor and with the blood levels attainable upon injection of similar compositions containing no oil.

6. An injectable therapeutic composition comprising a suspension of sodium penicillin in a nonaqueous vehicle comprising peanut oil containing a small amount of epinephrine, said composition, upon injection, providing prolonged therapeutic blood levels of penicillin as compared with the blood levels attainable upon injection of similar compositions containing no vasoconstrictor and with the blood levels attainable upon injection of similar compositions containing no oil.

STEPHEN B. BINKLEY.

REFERENCES CITED Ihe following references are of record in the file of this patent:

10 UNITED STATES PATENTS Number Name Date 2,055,064 Bockmuhl et al Sept. 22, 1936 2,961,557 Bockmuhl et a1. Nov. 24, 1936 OTHER REFERENCES Article by Trumper et al. in Science, Sept. 1, 1944, pages 432-434,

J. A. M. A., Jan. 20, 1945, pages 161 and 162.

Article by Armstrong et al. in Proc. Soc. Exptl. Biol. 8: Med., Jan. 1945, pages 74 to 76.

Article by Fisk et al. in Science, Feb. 2, 1945, pages 124 and 125.

Article by Parkins et al. in Science, Feb. 23, 1945, pages 203 to 205.

Clinical Investigations into the Action of Protamine Insulinate" by Krarup (Copenhagen, 1935), page 21.

Article by Romasky et al. in Science, Sept. 1, 1944, pages 196 to 198.

Committee on Medical Research of the 0. S. R. D. Contract No. 0. E. M. cmr. 56Progress Report Nov. 15, 1944, 3 pages. (Copy in Division 43.)