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Publication numberUS2741573 A
Publication typeGrant
Publication dateApr 10, 1956
Filing dateDec 28, 1953
Priority dateDec 28, 1953
Publication numberUS 2741573 A, US 2741573A, US-A-2741573, US2741573 A, US2741573A
InventorsKirchmeyer Frederick J, Vincent Hugh C
Original AssigneeAbbott Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Penicillin compositions for intramuscular injection
US 2741573 A
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Description  (OCR text may contain errors)

April 1956 F. J. KIRCHMEYER ETAL 2,741,573

PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION 7 Sheets-Sheet 1 Filed Dec. 28, 1955 gu p l Z I lff III/I II I III I!!! [I I I 1 11 1 7m 5 \C 15 ILF f U (v .i -4 i O O O O 0 0 0 O O m w w w w w m m .w w v Q Q 72 QWWQW Q Q Q FIG.I

8 7 W E m 0 J m w i W T O M c no W 1 20 T Y w a m K M m A d mmmM O C *Um e JM V10 0 W QM mfl W Fw F April 1956 F. J. KIRCHMEYER ETAL 2,741,573

PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION 7 Sheets-Sheet 3 Filed Dec.

W: oN-U- S- 7: OO-

IbmvzmJ mr mwurm .LNEVJdJd .ZHDIHM ZALLV'I'FH flu gk 0. Vincent April 10, 1956 F. J. KIRCHMEYER ETAL 2,741,573

PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION Filed Dec. 28, 1953 7 Sheets-Sheet 4 1N9083d 1149/5101 snuv'ua April 10, 1956 F. J. KIRCHMEYER ETAL 2,741,573

PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION Filed Dec. 28, 1953 7 Sheets-Sheet 5 w o w 5 w 3 qmmqh won KEY DYNE -CM Q avsues T5 312,000 R Invenzors Frederic/c cLIfir'cbme-ye C. Vincent T5 3 9,000 T 1 4ll,ooo T3 1 578,000

7 Sheets-Sheet 6 Inventors Frederick J. Kz'rcbmeyer jfl gk C. (/z'r2ceni' 6 MW (9W fiztorneg 2 3 4 5 6 7' 8 9 TOIFQUf IN w pms-cw April 10, 1956 F. J. KIRCHMEYER ETAL PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION Filed Dec. 28, 1953 \V O O O O O 0 O O O m M m w w w. w w w m I. -SQW t QMMQW mom M L W n V645 6 D2:: w BER I Y F m mu m m: uvw

April 10, 1956 PENICILLIN Filed Dec. 28, 3.953

KEY

DYNE-CM X""AVERAGE T3 |0z,000

F. J. KIRCHMEYER ETAL COMPOSITIONS FOR INTRAMUSCULAR INJECTION 7 Sheets- Sheet '7 -ao5 SPEED nv RPM 8 2 3 4 5 6 Y 8 TORQUE //v m DYA/E-CAI =29 wwzm United States Patent PENICILLIN COMPOSITIONS FOR INTRA- MUSCULAR INJECTION Frederick J. Kirchmeyer, Waukegan, and Hugh C. Vincent, Zion, Ill., assignors to Abbott Laboratories, North Chicago, 111., a corporation of Illinois Application December 28, 1953, Serial No. 400,529 Claims. (Cl. 1457-58) This invention relates to new penicillin compositions, and more particularly to an aqueous, injectable penicillin composition, capable of contributing a new and improved therapeutic eiiect in respect to the duration thereof.

The prior art compositions which have given prolonged therapeutic penicillin blood levels have been suspensions of penicillin in a non-aqueous menstruum, or in an aqueous menstruum containing a gelling agent, often with a retarding agent to help delay the absorption of the penicillin into the blood stream. Obviously, non-aqueous menstrua, many of which have gelling and retarding agents therein, introduced substances foreign to the human body and are generally not desirable because of possible side reactions, toxicity, sterile abcesses, and other untoward eiiects.

To avoid the foregoing untoward effects, the preferred practice in injectable penicillin therapy is to avoid as much as possible using ingredients other than penicillin. To achieve the desired high penicillin blood levels, however, it has heretofore been necessary to inject 2 cc. of the avail.- able aqueous penicillin preparations containing about 300,000 units of penicillin per cc. The blood levels attained therewith, however, are not prolonged for any appreciable time. Thus, with the prior art aqueous penicillin injectable preparations, additional injections must be given every 24 hours or less.

It is therefore a primary object of the present invention to provide a novel aqueous penicillin composition which prolongs the therapeutically effective concentration of penicillin in the blood stream.

It is a further object of the present invention to provide a novel aqueous penicillin composition which maintains an unexpectedly high concentration of penicillin in the blood stream for a prolonged period.

It is also an object of the present invention to provide a novel aqueous penicillin composition which maintains an unexpectedly high concentration of penicillin in the blood stream for an unpredictably prolonged period without employing non-aqueous menstrua and retarding agents.

It is a still further object of the present invention to provide a novel aqueous penicillin composition which forms a compact depot of a relatively water insoluble penicillin salt upon injecting intramuscularly.

It is also an object of the present invention to provide an improved aqueous penicillin composition which forms a compact depot when injected intramuscularly Without presenting objectionable plugging characteristics when injected intramuscularly by means of a standard 20 gauge hypodermic needle.

Other objects of the present invention will be apparent from the detailed description and claims to follow.

It has been discovered that the foregoing and other objects of the invention are achieved by preparing a penicillin composition comprising an aqueous suspension of a relatively water insoluble penicillin salt or mixtures of relatively water insoluble penicillin salts which contains a proportion of relatively very finely divided particles of the said salt or salts admixed with a proportion of larger particles of the said salt or salts to form special thixotropic aqueous penicillin suspension characterized by its ability to form a compact depot when injected intramuscularly through a standard hypodermic needle without giving rise to objectionable resistance or plugging. It has been found that aqueous penicillin compositions of the above type can be prepared by incorporating a sutiicient proportion or weight per cent of ultra fine particles of a relatively water insoluble penicillin salt or salts with a proportion of larger particles of a relatively water insoluble penicillin salt or salts in a parenterally acceptable aqueous vehicle. It has been further discovered that the aqueous suspensions of relatively water insoluble penicillin salts exhibiting a type of thixotropy (i. e. the property of becoming or having characteristics of a fluid when subjected to mechanical disturbance and coagulating or reforming its original structure when the mechanical disturbance is removed and the materiai allowed to rest) which is characterized by having a rheological pattern with a. non-uniform rate of breakdown of the original structure with increasing rate of shear are particularly useful for providing a compact depot of the said penicillin salt when injected into muscular tissue without, however, causing plugging; thereby providing the desired prolonged high therapeutic concentration of penicillin in the blood stream.

While the thixotropic nature of the compositions of the present invention can be detected and measured by a number of devices, particularly reliable and reproducible measurements of the instant thixotropy of an aqueous suspension of relatively water insoluble penicillin salts and particularly of those exhibiting a discontinuous or nonuniform rate of breakdown are obtained with a Hercules high-shear viscometer, an instrument developed by the Hercules Powder Company. (See Smith et 211., Paper Trade Jour. 126, 60 (1940).) The commercial form of the viscometer is manufactured by the Martinson Machine Company of Kalamazoo, Michigan, and. is the instrument used to make the viscosity measurements recorded herein and referred to in the several figures of drawings.

The Hercules high-shear viscometer continuously records the torque or stress developed on a receiving chamber containing the penicillin suspension by a rotating bob which is revolved from a zero rate of rotation of the bob up to the maximum speed of rotation thereof and back to zero speed of rotation. The curve thus obtained which shows the rate of shear plotted against the shearing stress (torque) is called a rheogram. The rheological data and curves reported herein were obtained with the said Hercules viscometer using Bob B which has a radius of 1.90 cm. and a height of 2.50 cm.

The rheogram curve of a fluid (i. e. Newtonian materials) or of aqueous penicillin suspensions exhibiting properties of a fluid which fail to exhibit the properties of the compositions of the present invention is a linear or substantially linear curve with the upcurve and the downcurves either exactly coinciding or substantially coinciding (see Figure l for showing of rheogram curves of aqueous penicillin compositions which fail to provide prolonged penicillin blood levels). In contrast with the foregoing, the rheograms of the compositions of the present invention have the upcurves displaced laterally from the downcurves so that the rheograms define a characteristic loop (see Figure 2 for showing of rheogram curves of aqueous penicillin compositions which provide prolonged penicillin blood levels). The magnitude of the displacement is related to the extent and nature of thixotropic breakdown of the material.

A particularly significant and useful feature of the rheograms of the preferred compositions of the present invention, as will become evident hereinafter, is the occurrence of a marked change or discontinuity in the rate WWI-i of structural breakdown of the material being tested at a point between the zero and maximum value of the ap plied force (R. P. M.), as evidenced by the first marked change in the slope of the upcurve of the rheogram. The maximum torque value expressed in" dyne-centimeters at the instant of the said first marked change in the rate of breakdown of the structure has been arbitrarily designated herein as the T3 of a composition. It will be evident from the rheograms that the T3 value is peculiar to those thixotropic materials which exhibit a discontinuous or markedly non-uniform rate of breakdown of the initial structure as an increasing mechanical shearing force is applied. While the precise cause of the non-uniform rate of breakdown of the unique thixotropic compositions with increasing rate of shear has not been precisely established, it is possible that these compositions have both plastic and dilatant properties superimposed upon basic thixotropic characteristics. The T3 values arereadily reproducible with a given viscometer and are independent of the rate of application of the shear ing force, although the T3 absolute values may differ when a different type of viscometer is used. It has been found that compositions having T3 values as determined from rheograms of the Hercules viscometer between about 100,000 and 1,000,000 dyne-centimeters, and preferably compositions having T3 values between about 300,000 and 700,000 dyne-centimeters, have the desired attributes of the present invention and fulfill the objects thereof.

It has been observed that the principal factors which influence the rheological pattern and the T3 values of the aqueous penicillin salt compositions of the present invention wherein the compositions are comprised of a proportion of very finely divided relatively water insoluble penicillin salt or salts admixed with a proportion of larger sized particles of a relatively water insoluble penicillin salt or salts are the specific surface values and the particle size distribution of the materials making up the solid phase and, of course, the solids-water ratio used which, however, is largely predetermined by the desired unit concentration of penicillin per cc. in the final composition. The particle size distribution and the specific surface values of the solid components of compositions within the scope of the present invention are broadly limited by the necessity of the presence of a proportion of very finely divided material (i. e. particles between 0 and microns in size) admixed with a proportion of material having an average particle size substantially in excess of the range between 0 and 10 microns and preferably having an'average length of about 50 microns. Since the particle size distribution figures and specific surface values are either very difficult to obtain with a high degree of accuracy or of little significance without accurate corollary data, it has accordingly been considered particularly advisable and appropriate to define the compositions of the present invention in terms of their rheograms and T3 values which can be shown to, be directly correlated with the physical and therapeutic in vivo performance of the compositions of the present invention.

Particle size distribution studies of the solid components of the compositions of the present invention, however, are also helpful in characterizing compositions of the present invention and show that there is a significant range of distribution of the penicillin salt particles. Thus, in each of the compositions of the instant type which exhibit the desired physical and therapeutic properties of compositions of the present invention, it has been found that the solid component of thecomposition is comprised.

of particles having a maximum weight per cent in a size ranging between 0 and 10 microns in length admixed with particles ranging in length between about 20 and 100 microns with an average of around 50 microns. Figure 3 contains Several graphs in which the relative weight per cent of the penicillin salt particles is plotted against the average penicillin salt particle length in microns for a number of aqueous penicillin compositions embodying the present invention. Figure 4 contains several graphs in which the weight per cent is plotted against the particle length for a number of aqueous penicillin compositions which do not embody the present invention and with which the compositions embodying the present invention can be compared.

In each of the particle size distribution curves shown in Figure 3 illustrating the present invention, it will be evident that a first maximum in the distribution curves oc curs within the 0 to 10 micron range with a less pronounced concentration and wider distribution of particles having a size greater than 10 microns in length and between about 20 and microns with an average level of 50 microns or above which in combination with the particles between 0-10 microns in length provide the aqueous insoluble penicillin salt suspensions of the present invention with its improved injectable properties.

Another very significant property which can be used to characterize the compositions of the present invention and one which greatly influences therheogram 'of the compositions of the present invention is the specific surface value of the solid components thereof. For a given solidswater ratio, it has been found that the specific surface of the dry procaine penicillin powder together with the. particle size distribution largely determine the rheological b havior of the said compositions. The specific surface values of the solid components specified herein were measured with a precision Blaine air permeability fineness tester which is manufactured by the Precision Scientific Company, Chicago, Illinois (see A. S. T. M. Method C204- 51). i

The Blaine fineness tester consists essentially of a means of drawing a definite quantity of air through a prepared bed of sample of definite weight. The number andsize of the pores in this bed are related to the size of the particles and determines for a given instrument the rate of air fiow through the bed. The method of preparing the sample and measuring the air flow and the equation which is employed to obtain the specific surface values of the penicillin salt components of the present invention are described in A. S. T. M. Method C204- 51. In the said equation K4 for the specific instrument used in making the measurements herein, which is designated Model Serial #D-IZ, was determined from measurements made at a porosity of 0.500 on National Bureau of Standards Portland cement sample #114g having an established specific surface value of 3070 square crn./gm. The value of K4 for the said instrument determined under the foregoing conditions is 22.13.

All specific surface measurementsreported herein for the penicillin samples were evaluated with the Blaine fineness tester Model Serial #D-12 and a modified form of Equation 10 of A. S. T. M. Method C204-51 wherein the expression 0.9-10 /e /(0.910e) was employed in place of /e (1e) in an efiort to make the equation less dependent upon porosity was employed. Assuming K4 is dependent only upon the instrument used and is independent of the specific surface of the sample being measured, its value was held at 22.13. The value of p for procaine penicillin employed was 1.247.

It has been found that the specific surface values of the dry sterile penicillin salt particles of the present invention which can be used in the preparation of the aqueous penicillin suspensions of the present invention are between about 7,500 and 60,000 square cm./ gm. of the saidpenicillin salt. For the preferred composition having a unit volume concentration of about 550,000 or 600,000 units penicillin per cc. of suspension the specific surface value of the dry penicillin salt particles are between about 14,000 and 35,000 square centimeters per gram.

It should also be understood that the compositions of the present invention which have specific surface values within the foregoing range do not necessarily have to be comprised of a mixture of two distinct and separately prepared components having the herein defined average particle size distribtuion provided a material having the above surface values can be produced directly by a single grinding operation. For example, where an aqueous suspension of a procaine penicillin composition having a penicillin potency of about 550,000 units per cc. is prepared by having the entire procaine penicillin G components thereof subdivided in special laboratory apparatus so as to produce a powder having a specific surface value of 24,000 cm. per gram, improved blood levels and compact depot formation are exhibited in contrast with those of compositions having a penicillin concentration of about 550,000 units per cc. which do not have specific surface values falling within the above specified broad range.

While aqueous penicillin suspensions of the type disclosed herein and having the herein disclosed properties can be prepared where the subdivided relatively insoluble penicillin salt component thereof is the product of a single specially controlled grinding operation, it is still preferable with the presently available commercial apparatus to prepare the compositions of the present invention by mixing definite proportions of two relatively water insoluble penicillin salts having relatively definite and distinct average particle sizes rather than attempt to obtain the desired particle size distribution by a single carefully controlled grinding operation. Thus, whereas it is possible to define the characteristics of a product made up of predetermined percentages of particles within certain size ranges and specific surface values, as herein described, in actual com mercial grinding practice with the type of grinding apparatus available the specific size grinding and grading so required is difiicult and inconvenient with ordinary production apparatus presently available. One difliculty encountered in this respect is connected with the particular shape of crystals dealt with, and also the small size of even the largest of them. Crystalline procaine penicillin upon grinding breaks up into particles having the approximate shape of an elongated parallelepiped or rod. On this account the best criterion to use in an assay of such a mixture is length, rather than volume, and the lengths that have to be dealt with according to the invention involve a maximum of about 100 mesh.

One of the features of the present invention, therefore is the discovery that among the grinding expedients known to the prior art it is possible by selecting the two different grinding processes known as milling and micronizing and compounding the natural assortments of relatively insoluble penicillin salt particles resulting from those processes in predetermined ratios in an aqueous medium, it is possible to secure the proper size assortment necessary to secure the unexpected results achieved by the present invention.

More specifically, the usual type of high speed hammer mill produces a pulverized or miller procaine penicillin which, while varying somewhat, will generally have a particle size distribution approximating that shown in the following table:

It is readily seen from Table I that the greatest percentage, by relative weight, of particles are above the 0-10 micron range, and approximately 50% of the particles fall within the size range of 20-60 microns. For convenience, this particular product is called 50 microns size procaine penicillin, or milled procaine penicillin. The number of particles above microns in length are relatively very few but because of their much greater weight mistakingly appear as comprising a more significant numerical proportion. The specific surface of the sterilized milled procaine penicillin G varies between about 4500 to 7000 cm. /grm., with a typical lot having a specific surface between about 5600 and 6000 crnF/grm.

Similarly a typical finely divided procaine penicillin product which is produced by a standard high velocity air mill and commonly designated as micronized has when classified in the following particle size groups a particle size distribution approximating that shown in Table II:

TABLE II Particle size, Relative weight length in microns percent 0-2 6 2-4 35 4-6 27 6-10 23 Over 10 9 The greatest percentage by relative weight of particles shown in Table 11 fall in the range of 2-6 microns, and for convenience the product is called 5 micron size procaine penicillin, or micronized procaine penicillin. The specific surface of the micronized procaine penicillin G varies generally between about 8,000 and 60,000 cn1. /grrn. with a preferred lot having a specific surface of about 31,000 cm. /grm.

It has been found that, for the preferred embodiment of this invention, a satisfactory 50 micron size grind or milled material is one that contains at least 50% by relative weight of particles in the 20-60 micron particle size range. The milled product should not have a great many particles substantially longer than about 100 microns in size. Similarly, the 5 micron grind or micronized material preferably has a substantial proportion of the particles less than 10 microns in length although this is not an important limitation provided the specific surface of the micronized relatively insoluble salt is within the broad range disclosed herein. The micronized product has been found satisfactory where at least 60% by relative weight is in the particle size range of less than 6 microns in length.

As a further embodiment of the present invention, milled and micronized procaine penicillin having the particle size distribution shown in following Table III and Table IV have been used with marked success:

It is readily seen from Table III that the greatest percentage, by relative weight, of particles are over 30 microns, and at least approximately 50% of the particles fall within the size range of 30-70 microns. For convenience, this particular product is called 50 micron size procaine penicillin, or milled procaine penicillin. Ideally, the milled product should have no particles greater than 100 microns in size.

, 7 "IABLlEiIV "Micronized procaine penicillin 'Particle size, length in microns Relative Weight percent The greatest percentage, by relative weight, of particles shown'in Table IV fall in the range of 2-6 microns and for convenience the product is called micron size procaine penicillin, or micronized procaine penicillin. Ideally, the micronized salt should have no particles greater than lOmicrons.

Specifically, the present invention is illustrated in detail in the following examples but it should be understood that the examples are only by way of illustration and the invention is not intended to be limited to the specific components disclosed nor to the precise proportions employe'd'therein.

EXA MPLE 1 Materials for 1000 cc. of suspension containing 600,000 units procaine penicillinper cc.:

Penicillin G procaine, crystalline, milled, 985

u./mg. (specific surface=5,600 cm. /gm.) gm 304.6

Penicillin G procaine, crystalline, mieronized, 985

u./mg (specific'surface=24,100 cmfi/gm.) gm 304.6

Sodium citrate grn 14.0 Wetting agent, Tween 80 "gm 1.0 Methyl Paraben gm 0.943 Propyl Paraben gm 0.105 Water, pure for injection cc 524.0

of'0.0l to 1.0%, however, 0.1% by weight of the wetting agent provides an elegant suspension without excessive amounts of the wetting agent.

A bacteriostatic may be employed as an added precaution to supply a sterile'product. In Example I the Methyl Paraben and Propyl Paraben are added as bacteriostatics. (Methyl Paraben is methyl para-hydroxybenzoate, and likewise Propyl Paraben is propyl para-hydroxybenzoate).

The procaine penicillin salt particles of the aqueous suspension prepared in the above manner have a specific surface value of 14,850 square centimeters per gram and the suspension exhibits the rheogram shown in curve R of Figure 5 and an average T3 value of 309,000 dynecentimeters. The particle size distribution curve of the penicillin salt components of the above aqueous suspension has one maximum at 7.5 microns and a second lessor maximum at 67 microns with the relative weight percent of the particles at the said peaks being 18 and 7 percent respectively (see curve vK, Figure 3). The above aqueous suspension is readily injected without objectionable plugging into muscle tissue or into a 2% aqueous gelatin gel forming a compact spherical depot and when injected into humans provides a high therapeutic penicillin blood level substantially in excess of 48 hours.

EXAMPLE l 11 Following the procedure of Example I, a suspension containing 600,000 units of penicillin per cc. is produced having ingredients according to the following table:

Materials for 1000 cc. of suspension containing 600,000 units procaine penicillin per cc.:

The aqueous suspension is filled into 1 cc. sterile Penicillin G procaine, crystalline, milled, 9 85 p u.'/mg g"rn -152:3 Penicillin G pr'oc'ain'e, crystalline, micronized,98'5

tn/mg gm 4569 Sodium citrate "gm "1410 Tween gm 1.0- Methyl Paraben 'gm 0.943- Propyl parab'en gm 0.105 Water for injection cc 524.0-

The aqueous suspension thus formed is readily-injected. in tra muscularly through a standard 20-gaugehypodermie needle and-maintains-a therapeutic penicillinblood levell fora prolonged period.

EXAMPLE in Materials for a suspen'si'onc'ontaining 700,000 units of.'

procaine penicillin percc. areas follows:

Penicillin G procaine, crystalline, milled, 985

u./mg gm 8391' Penicillin G procaine, crystalline, micronized, 985

u./mg -gm 2.797 Tween 80 -gm 0.0157 Distilled water cc 7.0

The procaine penicillin mixture prepared by thoroughly premixing the two dificrent procaine penicillin ground products is admixed with the water having the Tween 80 dissolved therein. The'suspen'sion is thoroughly mixed and filled into 1 cc.-ampoules as in Example I.

The-aqueous suspension thus formed is readily injected intramuscularly through a standard ZO-g'au'ge hypodermic needle and maintains a therapeuticpenicillin blood level for a prolongedperiod.

EXAMPLE IV Materials-for 1000 cc. of suspension containing 552,000 units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

The above ingredients are combined precisely as described in Example I to provide 1000 cc. of an aqueous procaine penicillin G suspension containing 552,000 units of penicillin per cc.

The aqueous penicillin suspension prepared in the above manner exhibits the rheogram shown in curve Q ofFigure 5 and an averageT value of 312,000 dyne-centimeters. The specific surface of the dry finely divided sterile procaine penicillin G powder mixture is 15,620 square centimeters per gram. The said penicillin suspension' is readily injectable into muscle tissue through a standard ZO-gauge hypodermic needle and forms a com pact spherical depot characteristic of the preferred compositions of the present invention and produces prolonged therapeutic blood levels in excess of 48 hours.

EXAMPLE V Materials for 1000 cc. of suspension containing 552,000 units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

9 V The foregoing ingredients are combined in accordance with the procedure described in Example I to provide an aqueous penicillin G suspension having a concentration of 552,000 units penicillin per cc. The said suspension exhibits a rheogram as shown by curve S of Figure and an average T3 value of 411,000 dyne-centimeters. The sterilized finely divided procaine penicillin G has a specific surface of 20,200 square centimeters per gram. Upon injecting into muscle tissue through a standard 20-gauge hypodermic needle the said suspension forms a compact spherical depot which exhibits an unexpectedly prolonged and high blood level as will be shown by subsequent data (Table V).

EXAMPLE VI Materials for 1000 cc. of suspension containing 552,000 units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

u./mg. (specific surface=6,000 cm. /gm.) gm..- 139.4 Penicillin G procaine, crystalline, micronized, 990

Following the procedure for Example I, the foregoing ingredients are combined to provide an aqueous suspension of procaine penicillin G containing 552,000 units of penicillin per cc.

The penicillin suspension prepared in the above manner exhibits the rheogram shown by curve T of Figure 5 of the drawing and an average Ts value of 578,000 dynecentimeters. The finely divided procaine penicillin G powder after sterilization has a specific surface of 24,000 square centimeters per gram and has 23% by weight of the particles Within the range of 05 microns. The particle size distribution curve of the finely divided material of the aqueous suspension exhibits one maximum at 7.5 microns and a second maximum at 55 microns, with a relative weight per cent of 40 and 2 respectively at the foregoing maximums (see curve I of Figure 3). Upon injection into muscle tissue through a standard ZO-gauge hypodermic needle the foregoing aqueous penicillin suspension forms a compact spherical depot which maintains a remarkably high penicillin blood level for a prolonged period (see Table V).

EXAMPLE VII Materials for 1000 cc. of suspension containing 552,000 units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

u./mg. (specific surface=6,000 cm. /gm.) gm 139.4 Penicillin G procaine, crystalline, micronized, 990

u./mg. (specific surface=33,700 cmF/gm.) gm 418.2 Sodium citrate gm 15.0 Tween 80, wetting agent gm 1.10 Methyl Paraben gm 1.00 Propyl Paraben gm .112 Water, pure for injection cc 545.4

EXAMPLE VIII Materials for 1000 cc. of suspension containing 450,000 units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

u./mg. (specific surface=6,000 cm. /gm.) gm 113.6

Penicillin G procaine, crystalline, micronized, 990

u./mg. (specific surface=31,300 cm. gm.) gm 340.9

The solid penicillin ingredients having a specific surface of 24,000 cm. /gm. are combined in accordance with the procedure described in Example I to provide an aqueous penicillin G suspension having a concentration of 450,000 units penicillin per cc. The foregoing aqueous suspension exhibits a rheogram as shown in curve Y of Figure 7 and an average Ta value of 132,000 dyne-centimeters. Upon injecting into muscle tissue or a 2% aqueous gelatin gel a generally oval shaped depot is formed. The said suspension when injected into humans provides improved blood level values over aqueous penicillin suspensions of equal potency which do not employ the present invention.

EXAMPLE IX Materials for 1000 cc. of suspension containing 552,000 units of procaine penicillin per cc.:

Sterile penicillin G procaine, coarse micronized, 990

u./mg. (specific surface=19,l00 cm. /grn.) gm 557.6

The above ingredients are combined precisely as described in Example I to provide 1000 cc. of an aqueous procaine penicillin G suspension containing 552,000 units of penicillin per cc.

The aqueous penicillin suspension prepared in the above manner exhibits a rheogram as shown by curve W of Figure 6 and an average T3 value of 572,000 dyne-centimeters. The specific surface of the dry sterilized finelydivided procaine penicillin G in the above suspension is 19,100 square centimeters per gram. The said procaine penicillin G has 27% by weight of particles within the range of 0-5 microns. The particle size distribution curve of the said aqueous suspension has a maximum at 7.5 microns with a secondary maximum or plateau at about 70 microns with a relative weight per cent of 45 at the 7.5 micron maximum. Upon injecting the said aqueous suspension through a standard ZO-gauge hypodermic needle into muscle tissue or into 2% aqueous gelatin gel a compact spherical depot is formed and clinical data show that unexpectedly prolonged and high penicillin blood levels are produced by the said suspension.

EXAMPLE X Materials for 1000 cc. of suspension containing 552,000 units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990 u./

mg. (specific surface=6,330 cm. /gm..) gm 223.0 Penicillin G procaine, crystalline, micronized,

The above ingredients are combined precisely as described in Example I'to provide 1000 cc. of an aqueous pi'o'caine -penicillinsttspensien-enntaiein 5 2,000 units of penicillin per cc.

The above aqueousgsuspension exhibits arheogram'as shown by curve V of Figure 6 and an average-T3 value of 414,000 dyne-cntimeters. The dry sterile finely divided procaine penicillin G of the above suspension-immediately prior to admixing with the aqueous vehicle has a specific surface of 25,000 square centimeters 'per'gram. The

said suspension is readily injected through a standard 20- gauge hypodermic needle and form a compact spherical depot when injecting intolnuscleitissue era 2% aqueous gelatin gel. Substantiallyimproved and prolongedpenicillin blood levels are "produced by thesaidcomposition when injected intramuscula1'ly"into humans.

EXAMPLE XI *M'at'erials for 1000"cc. of suspension containing 552,000 units procainepenicillin Gpercc; Penicillin G procaine, crystalline, milled, 990 u./

mg. (specific surface= 5,660 .cm. /gm.) gm 139.4 Penicillin G procaine, crystalline, rnicronized,

gm.) gm- 418.2 S odium cit rate gm 14.0 Wetting agent, Tween 80 gm 1.00 Methyl Paraben gm 1.00 Propyl Paraben 'gm 0.100 Water, pure for injection cc.. 545.4

The above ingredients are combindpreciselyas described in Example I to provide 1000 cc. of an aqueous procaine penicillin G suspension containing 552,000 units of penicillin per cc.

The above. aqueous. penicillin suspension exhibits =a rheogram asshown in curveXof Figure 7"-and' an average T3 of 102,000 (tyne-centimeters.

EXAMPLE XII Material for 1000 cc.of aqueous suspension containing 400,000 units N-methyl-l,2 diphenyl-2-hydroxyethylamine penicillin G salt per cc.: N-methyH,2 diphenyl-2-hydroxyethylamine penicillin G salt, microcrystalline mixture grn 350 Sodium citrate gm 18.80 Wetting agent, Tween 80 gm 1.17 MethylParab'en gm 1.26 Propyl Paraben -gm .14 Water, pure for injection cc 720 The above ingredients, otherthan the penicillinsalt, are dissolved in water and thereafter the aqueous solution is slowly added to the powdered penicillin salt with thorough stirring to provide an aqueous penicillin suspension containing 400,000'units of penicillin per cc.

The above aqueous penicillin suspension exhibits a rheogram as shown by curve H of Figure 2 and has a T3 value of 1,015,000 dyne-centimeters. The dry sterile penicillin salt powder has a specific surface value of 3 5,000 cm. gm. and has a maximum weight per centparticle distribution peak below 5 microns. through a standard 20-gauge hypodermic needle into -muscle tissue and into-a 2% aqueous gelatin gel acornpact spherical depot is formed.

EXAMPLE XIII Material-for 1000ccl of aqueous suspension containing 500,000 units N,N-dibenzylethylenediamine penicillin G salt per cc.:

N;N-dibenzylethylenediamine penicillin G salt, I

microcrystalline mixture gm 476 Sodium citrate gm -16.0 'Wetting agent, Tween 80 gm- 1.0 I Methyl Paraben 1 gm 1.08 Propyl Paraben gm 0.12 Water, pure 1501' ll'1j0tl()fl.;:; 4;...' ..:LQCC 598 Upon injecting depot is formed.

EXAMPLE XIV Materials for 1000 cc. ofaqueous suspension 'containing 400,000 units procaine penicillin G per 00.:

Penicillin G. procaine, milled, 990 u./n1g. (specific surface='5,700 Cru /gm.) gm 101.0 Penicillin G procaine, micronized, 990 u./rng. specific surface=63,700 sq. cm./gin.) gm 303.0 Sodium citrate gm 18.8 "Tween 80,"wetting agent gm 1.17 Methyl Par'aben gm 1.26 'PropylPar aben gm .14 Water, pure for injection cc 666.7

The'above ingredients, other than 'the'penicillin salt, arei'dissolv edun' the water and thereafter the aqueous solution is slowly added to the powdered penicillin salt with thorough stirring to provide an aqueousp'enicillin suspension containing 400,000 units of penicillin per cc. The above aqueous penicillin suspension exhibits a Tav'alue of 490,000 dyne-centimeters. The penicillin salt componenthas aspecificsurfacevalue of 49,200 cm. gm. and has" amaximum weight per cent particle distribution 'peak below 5 'microns. T he aqueous suspension is readily 'irijectable through a standard ZO-gauge hypodermic needle to form a compact sphericaldepot in muscle tissue.

EXAMPLE XV Materials for aqueous suspension containing 700,000 units of procaine penicillin G per 00.:

' Penicillin G procaine, n1illed, 990 u./rng. (specific I surface: 5,700 cm. /gm.) h gm 184.5

Penicillin G procaine, micromilled, 990 u./mg.

(specific surface=10,000 cm. /gm.) g1n 61.5 Sodium citrate gm 4.04 Tween 80, wetting agent gm 0.25 Methyl Paraben -gm 0.27 "Propyl Paraben gm 0.16 Water, pure for injection cc 148.4

' The above ingredients, other than the penicillin sa1t,'arc dissolved'inthe water and thereaiterthe aqueous solution is slowly added to the powdered penicillin salt wi'ththorbugh stirring to provide an aqueous penicillin suspension containing 400,000 units of penicillin per cc.

The above aqueous penicillin suspension exhibits a characteri'sticrheo'gram with a T3 value of 275,000 dyne-centimeters.

EXAMPLE XVI Material for 1000 cc. of aqueoussuspens'ion containing 750000 units procaine penicillin G per cc.:

PenicillinG procaine, milled, 99 u./mg. (specific "'surface'=5;700 cm. /gm.) "gm" 568.2

' Penicillin G procaine, micromilled, 990 u./mg.

(specific -surf'ace=10,000 cmfl/gm.) gm 189.4 Sodium-citrate.- grn 10.72 Twe'enj 80, wetti ng agent gm .666 "Methyl'Parabena grn ".716 Propyl Paraben; gm -079 Water, pure for injection 'cc 386.4

The above ingredients, other than the penicillin salt, are dissolved in the water and thereafter the aqueous solution is slowly added to the powdered penicillin salt with thorough stirring to provide anaqueous penicillin suspension containing 400,000 units of penicillin per cc.

The above aqueous penicillin suspension exhibits a characteristic rheogram with a T3 value of 900,000 dynecentimeters.

EXAMPLE XVII Material for 1000 cc. of aqueous suspension containing about 550,000 units penicillin per 00.:

Pencillin G procaine, milled, 990 u./mg. (specific surface=5,700 cmP/gm.) gm- 138.9 N,N-bis-dehydroabietylethylenediamine dipenicillin G salt, 939 u./mg gm 458.3 Sodium citrate gm 15.0 Tween 80, wetting agent gm .928 Methyl Paraben gm 1.00 Propyl Paraben gm 0.112 Water, pure for injection cc 482.6

The above ingredients, other than the penicillin salt, are dissolved in the Water and thereafter the aqueous solution is slowly added to the powdered pencillin salt with thorough stirring to provide an aqueous penicillin suspension containing 550,000 units of penicillin per cc.

The above aqueous penicillin suspension is readily injected through a standard ZO-gauge hypodermic needle and forms a compact spherical depot when injected into muscle tissue.

TABLE V Summary of penicillin blood level medians, penicillin units per cc. blood at indicated hours after injection Aqueous Suspension 4 24 48 72 96 Pro u hours hours hours hours hours Example V 2. 5 1. 25 0. 624 Example VI. 10.0 2. 5 0. 624 Example VIL. 7. 5 2. 5 0. 624 Example VIII... 0.936 0. 624 0.312 Example IX. 1.25 O. 468 0. 624 Example X 0. 936 O. 468 0. 312 Example XI. 0. 312 0. 312 0.156

Median Values 1. 25 0. 624 0. 624

The data of Table V summarizing the clinical blood level studies were obtanied from clinical use of the indicated aqueous penicillin suspensions in humans under actual therapeutic use conditions. It will be evident from Table V and the specific examples to which reference is made that the preferred suspensions of the present invention having a T3 value between 300,000 and 700,000 dynecentimeters maintains high therapeutic penicillin blood levels for a period of at least 72 hours after intramuscular injection and all of the aqueous suspensions having a T3 value above 100,000 dyne-centimeters maintains a penicillin blood level substantially in excess of the minimum therapeutic blood level of .03 unit penicillin per cc. for at least 72 hours.

The data of Table V also makes it possible to correlate the several physical characteristics of the aqueous penicillin suspensions of the present invention with the ability of the suspensions to maintain penicillin blood levels in humans. Accordingly, it has been observed that the readaccordance with the foregoing disclosure maintains a prolonged therapeutic blood level out of all proportion to the increased dosage and also permits administration intramuscularly through a standard hypodermic needle without objectionable plugging. It is believed that the great increase in therapeutic effectiveness and improved injectable properties is contingent on or correlated with the assortment of particle sizes of the relatively water insoluble or sparingly soluble penicillin salt employed which appears to greatly increase the original penicillin concentration of the depot formed upon injecting the suspensions intramuscularly, while at the same time permitting the high potency, compact depot forming, aqueous penicillin suspensions being readily injectable into muscle tissue through a standard ZO-gauge hypodermic needle.

The particle size distribution data disclosed in the foregoing description and specified in the claims were obtained by suspending the finely divided penicillin salt in an aqueous menstruum of substantially the same composition as the vehicle used in the specific examples to prepare the injectable suspension and examining a sealed representative sample thereof first under a Bausch and Lomb Model LC-4 polarizing microscope with Nicol prisms removed, the image of which is preferably thrown upon the ground glass screen of a Bausch and Lomb Model L photomicrographic camera, and the particles counted in increment groups of 10 microns down to the 20-30 micron group while using a total magnification of 200 diameters. Thereafter photomicrographs are taken with the said apparatus using a total magnification of 1000 diameters and the final three divisions, namely the 10-20 micron group, the 5 to 10 micron group, and the 0.01 to 5 micron groups, are counted. The average Weight per cent values are calculated in the usual manner from the foregoing numerical count after determining the average length and width of the particles in each increment group, except the two smallest groups for which the length to width ratio is assumed to approach unity exponentially as the particle size approaches zero and the further empirical assumption that the depth to width ratio is the same as the width to length ratio, an assumption which was found to conform with the actual measurements made. The term relative weight is an approximation of the proportionate weight of various size groupings, and is based upon the microscopically measured size and number of crystals multiplied to give their volume, which is in turn proportional to the weight since all crystals of a given penicillin salt are assumed to have the same density.

While procaine penicillin has been used most extensively to illustrate the present invention, in the instant description and claims the term relatively water insoluble penicillin salt designates any therapeutically useful penicillin salt having a water solubility equal to procaine penicillin and also those having a water solubility less than procaine penicillin which is approximately 7000 units penicillin per cc. Among the class of sparingly soluble penicillin salts herein designated as relatively water insoluble penicillin salts in addition to procaine penicillin are N-methyl- 1,2-diphenyl-2-hydroxyethylamine penicillin salt, N,N- dibenzylethylenediamine penicillin salt, and N,N-bisdehydroabietylethylenediarnine penicillin salt and other sparingly soluble rosin amine penicillin salts. It should be understood that the improved compositions of the present invention can be prepared by forming an aqueous suspension of any one of the relatively water insoluble penicillin salts of the above type in the specified finely divided state or by suspending a mixture of two or more of the said relatively water insoluble penicillin salts in the specified finely divided state. When the composition is prepared entirely from a water insoluble penicillin salt, such as N,N-dibenzylethylenediamine penicillin G salt, penicillin is detectable in the blood for several months after being injected intramuscularly. In some instances, however, it is preferable to combine procaine penicillin 15 with a less soluble'penicillin salt, suchas N,N'. dibenzyl- "ethylened'iamine penicillin G salt, according to the manner specifiedherein in.anydesired proportion and thereby obtain a therapeutic bood level for a period substantially longer-than is possible when procaine penicillin. alone is used.

Theterm high potency as used herein and in the claimsdesignates a penicillin. composition having a unit concentration in excess of a 'unit' volume concentration of 300,000 units per cc. and having at least 400,000 units penicillin'per cc. In the preferred embodiment of the invention the compositions have a unit concentration of at leastab'out 500,000 and preferably between 550,000'and "750,000units penicillin'per' cc. it should be apparent from the specific examples, however, that by choosing and ,proportioning a"penicillinsaltor' mixture of penicillin "saltsof'thespecified'type having the properparticle size distribution andspecificsurface, itis possible to prepare "an aqueous penicillin suspensionhaving a unit concentration'Within the above'specified limits which has a'T value suflic'ient' toprovide the composition with the desirable characteristics specified herein.

The specific embodiments of'the invention disclosed hereinhave employed a parenterally acceptable aqueous vehicle'which has been made approximately. isotonic by the addition of sodium citrate so as to minimize the degreeof pain incident with intramuscular injections. How- '"ever, any physiologically compatible isotonic solution, such as a sodium chloride solution or even puredistilled'water may be used for the suspension. The use of any parenteral'ly acceptable wetting agent,'such as Tween 80, facilitates -"the'preparation of the suspension and the use of preservatives, such as Methyl and Propyl'Paraben; are desirable where it'is intended 'to'store the'preparation prior to administration.

This application is a 'continuation-in-part application of applicants co-pending application, Serial No. 134,138,

filed December 20, 1949, and now abandoned.

' Others'may readily adapt theinvention for'use under various conditions of service by employing one or more of the novel features disclosed or equivalents thereof. As presently advised with respect to the apparent scope "of our invention, we desire to claim the following subject '"matter.

1. A high potency aqueous penicillin composition comprising a suspension of at leastone finely divided relatively-water insoluble penicillin salt in an aqueous vehicle suitable for intramuscular injection, and having a unit volume concentration between 400,000 and about 750,000

units penicillin per cc., said suspension containing a proportion of relatively very finely divided particles of the "relatively water insoluble penicillin saltadmixed with a proportion of relatively larger particles of the finely divided relatively water insoluble penicillin salt, the mixture of the finely divided relatively water insoluble penicillin "salt particles having a particle size distribution curve with one maximum thereof occurring between the to micron particle size range and a second maximum occurring above about the 50 micron particlesize range, and said suspension forming a thixotropic aqueous suspension "having a rheogram curve which exhibits a T3 value between about l00,000 and 1,000,000 dyne-centimeters.

2. A high potency aqueous penicillin composition comprising an injectable suspension of a relatively water insoluble penicillin salt dispersed in an aqueous menstruum suitable for intramuscular injection, and having a unit volume concentration in excess of about 400,000 units per cc, said insoluble penicillin salt consisting of particles of a finely clivided'relatively Water insoluble penicillin salt having the major weight fraction thereof with a par- "ticle size between 0 and 10 microns and havingthe said particles between O and 10"micro'ns'adrnixed with-par- ""-ticl'e'sof finely *divided relatively water insoluble penicillin "16 salt having an average. particle size' of" about microns, said suspension, forming a thixotropic aqueous suspension having a rheogramcurve which exhibits aTs value between about l00,000 and 1,000,000 *dyne-centimeters.

3. A high potency aqueous penicillin composition'substantially as described in claim 2 wherein the-relatively water insoluble penicillin salt is procaine penicillin.

4. A high potency aqueous penicillin composition substantially as described in claim 2 wherein the relatively water insoluble penicillin salt is' an N,N'"-b,is-dehydrcabiethylethylenediamine penicillin salt.

5. Ahigh potency aqueous penicillin composition sub stantially as described in claim 2 whereinlthe particles of the relatively water insolublepenicillin salt above 10 microns in size have an average particlesize between 30 and microns.

6. A high potency aqueous penicillin composition substantially as described in claim 2 wherein the said weight fraction increment ofparticles of the insoluble. penicillin salt between 0' and 10 microns is greater'than the sum of the 10 micron weight fraction increments of the said particles above 10 micronsin length.

prising an'injectable suspension of a relatively water insoluble penicillin salt dispersed in anaqueous menstruum suitable for-intramuscular injection and having a unit volume concentration in excess of about 400,000 units per cc., said insoluble penicillin salt consisting offinely divided particles of a relatively water insoluble penicillin saltihaving the major weight fraction thereof with a particle length between 0 and 10 microns and'having the said particles of the penicillin salt above 10 microns in length of an average particle length between about 30, and 70 microns, and said suspension forming a thixotropic aqueous suspension having a 'rheogram curve which exhibits a T3 value between about 100,000 and l,000',000 dyne-centimeters.

8. A high potency aqueous penicillin composition substantially as described in claim 7 wherein the: relatively water insoluble penicillin salt has a specific surface'between about 7,500 and 60,000 square centimeters per gram.

'9. A high potency injectableaqueous penicillin composition comprising a finely divided relatively water-insoluble penicillin salt suspended in a parenterally acceptable aqueous'vehicle and having a unit concentration of at least 400,000 units penicillin per cc., said penicillin salt consisting of between about 25 to of the said penicillin salt of about 5 micron average particle. size and the remainder of the said penicillin .salt being of about 50 micron average particle size.

10. A high potency injectable. aqueous penicillin composition comprising a finely divided relatively waterinsoluble penicillin salt suspended in a parenterally acceptable aqueous vehicle and having a unit concentration of at least 400,000 units penicillin per cc., said penicillin salt consisting of between about 25 to 75 procaine penicillin .of about 5 micron average particle size and'the remainder of the procaine penicillin being of about 50 micron average particle size.

11. A high potency injectable aqueous procaine penicillin composition comprising a finelydivided relatively water insoluble procaine penicillin salt suspended in a parenterally acceptable aqueous vehicle and having a,-unit concentration of at least 400,000 units procaine penicillin per cc., said penicillin salt consisting of about 75%-of the said penicillin salt of about 5 micron average particlesize and the remainder of the said penicillin salt being of about 50 micron average particle size, and a small percentage of an innocuous wetting agent.

12. A high potency aqueous injectable procaine penicillin G composition containing atleast 400,000 units of penicillin per cc., which consists of 25 to 75 of procaine penicillin having an average particle'size of substantially 5 microns, the remainderof the procaine penicillin having 17 an average particle size of substantially 50 microns, and a small percentage of an innocuous wetting agent.

13. A high potency aqueous injectable procaine penicillin G composition containing between about 400,000 and 750,000 units of penicillin per cc., which consists of at least about 25% of procaine penicillin G particles hav-- ing up to about a micron average particle size, at least about 25% of particles of the procaine penicillin of about 50 micron average size, and a small percentage of an innocuous Wetting agent.

14. An injectable penicillin composition having a potency of at least 400,000 units of penicillin per cc., consisting of 25-75% of procaine-penicillin particles having an average particle size of about 5 microns, the remainder of the procaine penicillin particles having an average size of about 50 microns, said procaine penicillin mixture being suspended in an aqueous isotonic solution containing a small amount of an innocuous wetting agent.

15. An injectable penicillin composition having a potency of at least 400,000 units of penicillin per cc., comprising about 50% of procaine penicillin particles having an average size of about 5 microns, the remainder of the procaine penicillin particles having an average size of about 50 microns, said procaine penicillin mixture being suspended in an aqueous isotonic sodium citrate solution containing a small amount of a wetting agent.

16. An injectable penicillin composition having a potency of at least 400,000 units of penicillin per cc., consisting of a mixture of milled and micronized procaine penicillin in aqueous suspension, the micronized procaine penicillin being about one-tenth as large as the milled procaine penicillin and constituting about 2575% of the mixture.

17. An injectable penicillin composition having a potency of at least about 400,000 units of penicillin per cc., comprising a mixture of procaine penicillin particles having 80% of an average length of about 5 microns and the remainder of the procaine penicillin particles having an average length of about microns, said procaine penicillin mixture being suspended in an aqueous solution containing a small amount of a wetting agent.

18. An injectable aqueous penicillin composition having a potency of at least 400,000 units of penicillin per cc., comprising suspension containing more than 45% by weight of suspended procaine penicillin, said penicillin consisting of 25-75% micronized procaine penicillin and the remainder milled procaine penicillin.

19. An injectable aqueous penicillin composition hava potency of at least 400,000 units of penicillin per cc., comprising suspension containing about by weight of suspended procaine penicillin, said penicillin consisting of 25-75% micronized procaine penicillin and the remainder milled procaine penicillin.

20. An injectable aqueous high potency penicillin composition comprising a substantial proportion of a relatively water insoluble penicillin salt suspended in an aqueous vehicle suitable for intramuscular injection having a unit volume concentration of between about 500,000 and 700,000 units per cc., said penicillin salt comprising about micronized penicillin salt. and the balance of the said penicillin salt being milled penicillin salt.

References Cited in the file of this patent UNITED STATES PATENTS Young July 14, 1953

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US2895875 *Feb 25, 1958Jul 21, 1959Erich M H RaddeSubcutaneous hormone pellets
US2897120 *May 4, 1954Jul 28, 1959Upjohn CoLow viscosity cmc pharmaceutical vehicle
US2976206 *Jan 29, 1957Mar 21, 1961Pittsburgh Plate Glass CoPesticidal composition
US3100177 *Jan 5, 1961Aug 6, 1963Parke Davis & CoPenicillin composition for pericardial introduction
US6656508Apr 17, 1997Dec 2, 2003Amgen Inc.Sustained-release alginate gels
Classifications
U.S. Classification514/192, 514/199
International ClassificationA61K31/43, A61K31/429
Cooperative ClassificationA61K31/43
European ClassificationA61K31/43