US2619447A

US2619447A - Injectable penicillin preparations

Info

Publication number: US2619447A
Application number: US81024A
Authority: US
Inventors: Wilbur G Malcolm; John J Vance
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1949-03-11
Filing date: 1949-03-11
Publication date: 1952-11-25
Anticipated expiration: 1969-11-25

Description

Patented Nov. 25, 1952 INJ ECTABLE PENICILLIN PREPARATIONS Wilbur G. Malcolm, Nyack, N. Y., and John J. Vance, Park Ridge, N. J assignors to American Oyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application March 11, 1949, Serial No. 81,024

26 Claims. 1

This invention relates to a new therapeutic preparation containing penicillin and to methods of preparing the material for use. More particularly, the invention relates to a combination of procaine penicillin and a crystalline penicillin such as sodium penicillin, into a single dosage unit in which certain modifiers are added so that the crystal structure, crystal size, and stability are advantageously modified whereby the material is particularly convenient to use; and thereby our product will cause both a high immediate blood level, and a prolonged blood level of penicillin in a recipient.

The therapeutic properties of penicillin are widely known and the material is daily becoming more widely used by the medical profession for the alleviation of disease. In the past the use of penicillin has been inconvenient because oral methods of administration require a disproportionately large increase in dosage size and because under many conditions the certainty of the penicillin finding its way into the blood stream is such that the medical profession would prefer to use a more positive procedure.

The normal method of administration has been parenteral, i. e. injection by a needle. Because of the comparatively high rate of inactivation or excretion of the penicillin within the body, it has been found necessary when using ordinary crystalline penicillin, as the sodium or potassium salt for instance, to administer a new dose approximately every three hours. Besides being painful to the patient, this high frequency has to a. large extent restricted the use of penicillin to hospital patients under the constant supervision of a nurse.

It has been found that certain comparatively insoluble salts of penicillin may be injected into the tissues of the body so that the penicillin is slowly adsorbed and made available to the circulatory system whereby, because the penicillin was more slowly released, it was in turn more slowly removed from the effective theater of use, and accordingly a less frequent administration was required.

By this our invention, it has been found that therapeutically a mixture of procaine penicillin and crystalline penicillin possesses marked advantages found in neither alone. The use of crystalline penicillin as for example the sodium or other salt such as the calcium salt. etc., permits the high initial build-up of penicillin within the blood so that within amatter of minutes a therapeutically effective concentration is built up, which effect is not possible with procaine penicil- 2 lin alone, and by the same token the concentration remains therapeutically effective for a prolonged period, an effect not possible with crystalline penicillin alone.

The simple mixture of crystalline penicillin and procaine pencillin, while possessing advantages of use, has marked disadvantages because of difliculties of administration. The procaine penicillin tends to be formed in the nature of long needle-like crystals which will mat or clog in a needle and which will settle out so as to render it extremely difilcult to get an accurately measured dose. By this our invention, we have found that when carboxymethylcellulose, or certain similar materials, is added, it acts as a suspending agent and prevents the rapid settling of the procaine penicillin in the aqueous suspension for injection so that it is comparatively easy to administer uniform doses.

As a further step in this invention, we have found that the use of a wetting agent such as the material sold commercially as Tween (believed to be a polyoxyalkylene sorbitan monooleate, i. e. the reaction product of ethylene oxide with a product such as described in Patent 2,322,820 to Brown) and other similar materials of the nature of the polyalkylene oxide ethers of the polyhydric esters of long chain fatty acids stabilizes and renders more smooth the crystals, so that they may be administered through a smaller needle, and accelerate the speed of solution. As a still further improvement in our invention we have found that the addition of a buffering agent, such as sodium citrate, to the material increases the stability of the solutions so that the material as prepared for administration will be stable for a matter of several days at room temperature in spite of the auto-catalytic effect of the decomposition products of penicillin and its salts. Whereas sodium citrate is particularly efficient and its therapeutic propertie are well known, other materials may be used. The material must qualify as one which will maintain the pH within a range such that the crystalline penicillin G will not decompose at too great a rate. Normally speaking, it is preferred that the pH remain within the range of about 6 to about 7 although decomposition is inhibited even slightly outside of these ranges. Among the materials which may be used are any of the non-toxic bufferlng agents which will buffer the solution within this range. This includes such materials as sodium glycinate, sodium acetate, sodium carbonate, sodium pyrophosphate, trisodium phosphate, disodium phosphate, dipotassium phosphate, etc. Sodium borate may be used but is less desirable because the borate are somewhat toxic. Sodium lactate may be used but because it is a liquid, it is normally more advantageously added with the diluent rather than to the powders at the time of their initial preparation.

By the use of suitable preparations, it is possible to prepare powders which may be diluted for use which will remain stable in solution for as long as a week at room temperature. In the past it has been necessary to prepare penicillin solutions immediately before their use rendering it necessary to use very small vial sizes for small users. This restricted the use of the larger vials to institutions maintaining a large number of patients under penicillin therapy. By this our invention, it is rendered possible for a larger and therefore more economical size of container to be used so that a Single individual may enjoy the economic advantages heretofore restricted to hospitals.

Whereas it is to be distinctly understood that the ratios of the various materials to be present, particularly the ratio of procaine penicillin to sodium penicillin, may vary within wide limits, current medical usage desires a comparatively uniform size of dosage. A very convenient dose which is in current use prescribes for each administration a mixture of 300,000 units of procaine penicillin and 100,000 units of sodium penicillin. Up to about 600,000 units of procaine penicillin per cc. may be used. More than thi renders the mixture unduly thick and apt to clog in the needle. Any lesser amount may be used, but medical preference dictates about 300,000 units per cc. as preferred. For some organisms a. concentration of 20,000 units of an alkali metal salt of penicillin would be satisfactory, but 50,000 to 100,000 are safer levels, in that these quantities immediately build up a. concentration effective against most organisms. A concentration as great as 300,000 units per cc. may be used if preferred by a particular physician. For maintenance of therapeutic levels, the quantity of sodium penicillin can readily be reduced or even completely eliminated, but as a matter of operating expedience it is usually more convenient to use the same mixture for the subsequent as for the initial dose, and the economic advantages of using but a single preparation more than outweigh the additional cost of the mixture; and therapeutically, the use of the mixture containing both procaine penicillin and sodium penicillin is at least as eifective as the use of procaine penicillin alone after the initial establishments of therapeutic levels of penicillin in the blood stream.

Procaine penicillin decomposes on heating and accordingly for the preparation of a product, it is necessary that the procaine penicillin be sterilely prepared. The other materials can be heat sterilized, and accordingly it is particularly convenient to mix them, then heat sterilize the mixture, rather than preparing each of them sterilely and mixing them under sterile conditions. The carboxymethylcellulose and sodium citrate as well as the sodium citrate as well as the sodium penicillin G are solids and may be ground and powdered together. The Tween 80, a wetting agent, the addition of which is optional, is a liquid and accordingly is most conveniently added to the carboxymethylcellulose and sodium citrate and ground with them before the addition of the penicillin G, although any order of addition and grinding is perfectly satisfactory. The fineness of the sodium citrate, carboxymethylcellulose penicillion G mixture is not critical and if reasonably finely ground, they will all dissolve almost instantly. The speed of solution is increased by the addition of the wetting agent.

The procaine penicillin is not water soluble and a great deal of its efficacy comes from the fact that it is injected into the body in crystalline form, which crystals are slowly absorbed by the body thereby slowly releasing the penicillin G as a therapeutic agent. Accordingly it is necessary that the procaine penicillin be in such form that it is absorbed by the body at the proper rate. Similarly the crystal structure must be such that the material will comparatively readily flow through a hypodermic needle. An 18 or 20 gauge needle is a convenient size and the crystalline procaine penicillin should be such that when suspended, it will readily flow through such a needle. Various methods are known in the prior art and have been practiced by others to obtain procaine penicillin in a desirable form, and such forms as heretofore have been used separately may be combined in accordance with this invention. The quantity of pencillin i not critical and may be varied over wide limits, theoretically, but from the practical standpoint the medical profession prefers, as a matter of operating convenience, that a sufficient quantity for a therapeutic dose by dissolved in a reasonable volume of fluid. Purely from a matter of suitability for the attending physician, it is generally found desirable to suspend 300,000 units of crystalline procaine penicillin G and 100,000 unit of crystalline penicillin G sodium in each cubic centimeter of liquid for injection. A sterile normal saline solution or pyrogen-free water are convenient as diluents. The quantities of carboxymethylcellulose and Tween are such that the solution is sufliciently thick that the crystalline procaine penicillin will remain suspended and will not settle out or clog the needle. Because carboxymethylcellulose varies in its characteristics depending upon source, th exact quantity for best results may vary from batch to batch. Of the material known commercially as high viscosity carboxymethylcellulose, a variation of around 5 to 30 mg. per cc. normally gives satisfactory results. More is required of the lower viscosity preparations. The concentration should be below that at which a gel is initially formed. With low viscosity carboxymethylcellulose up to about mg. per cc. may be used. The smaller amount of the high viscosity material is preferred because it is desirable to introduce as small a quantity a possible of a foreign material into the body. The quantity of Tween 80 is not critical as it is an extremely effective wetting agent and as little as 1% mg. per cc. is helpful yet 10 mg. per cc. does not appear to be in any way deleterious.

The quantity of sodium citrate or other buffer is not too critical. The buffer assists in maintaining the proper pH as well as forming a material which will combine with any acid products formed by decomposition. The exact function and purpose of the sodium citrate or other buffer is extremely complex. A smaller quantity will assist in maintaining stability but larger quantities are necessary to give powders which when dissolved will give a solution which is stable at room temperatures for more than a week without appreciable decomposition. A solution containing 1.4 mg. of sodium citrate per cc. was satisfac torily fluid at the end of 18 hours at 38 C. but was gelled at the end of 42 hours. Material which contained mg. of sodium citrate per cc. remained stable for more than 42 hours at 38 C. and gave a very satisfactory solution with a comparatively high pH at the end of this period. Larger quantities of sodium citrate should not be deleterious but if the penicillin will remain stable and of high potency for one week at room temperature, the concentration is as high as is needed for present medical practices. The concentration of sodium citrate effectively varies proportional to the concentration of crystalline penicillin G. The effective concentration of both the carboxymethylcellulose and the Tween 80 depends upon their concentration per cc. in the final material, independent of the penicillin content.

In the preparation of the compound, it is most convenient to fill the dry mixture into vials sterilely, under which conditions it may be kept until ready for use. Tests would indicate that the dry powder maintains its therapeutic efficacy when stored at room temperature for at least a year and probably considerably longer.

The following examples show certain concentrations and procedures which have proved satisfactory in practice and which have been found to be acceptable to the medical profession. To those skilled in the art modifications and variations will immediately suggest themselves.

Example 1 A vial containing the equivalent of five daily doses was prepared from the following materials:

Crystalline sodium penicillin G units 500,000

The crystalline sodium penicillin, the sodium citrate and the carboxymethylcellulose and Tween 80 were ground together until thoroughly mixed and homogeneous, then sterilized by heating to 110 C. for 10 hours. To the sterile powder under aseptic conditions was added the procaine penicillin, the mixture thoroughly blended and filled aseptically into a vial. When ready for use the dry material is to be diluted to 5 cc. with either pure water or normal saline solution. As so diluted at room temperature, the material is stable for over a week and maintains a proper and usable viscosity for this period. 1 cc. of the suspension is a standard therapeutic dose.

Example 2 A vial containing the equivalent of five daily doses was prepared from the following materials:

Sodium penicillin units 250,000 Procaine penicillin do 3,000,000 Carboxymethylcellulose (high viscosity) mg 33 Sodium citrate (U. S. P.) mg 48 Tween 80 -mg 1 The mixture was prepared by blending together make 5 cc. by volume, which mixture is a thickish suspension containing 600,000 units per cc. of procaine penicillin, but the material is sufiiciently fiuid to be withdrawn and injected by hypodermic needle and remains stable and usable at room temperature for at least one week.

Example 3 A vial containing a comparatively low amount of sodium penicillin, for organisms not particularly resistant to penicillin, is prepared from the following:

Sodium penicillin units 100,000 Procaine penicillin do 1,500,000 Carboxymethylcellulose (high viscosity) mg 33 Sodium citrate (U. S. P.) mg 12 The sodium penicillin, carboxymethylcellulose and sodium citrate were ground and blended together, sterilized by heating, aseptically mixed with the procaine penicillin and filled into a vial. The thus prepared material is stable for at least one year in the dry state, and when diluted to 5 cc. with physiological saline solution remains therapeutically effective for at least one week at normal room temperature.

Example 4 A composition which gives an extremely high initial concentration of penicillin for use with extremely resistive organisms is prepared in a five dose vial by using the following:

Sodium penicillin "units" 1,500,000 Procaine penicillin do 1,500,000 Carboxymethylcellulose (high viscosity) mg 33 Sodium citrate (U. S. P.) mg 65 The sodium penicillin, the sodium citrate and the carboxymethylcellulose were ground together until thoroughly mixed and blended, heat sterilized, aseptically mixed with procaine penicillin, the mixture blended and filled aseptically into a vial. The material will remain therapeutically effective for a period of over a year in the dry state and when diluted to 5 cc. with either pure water or normal saline for therapeutic injection will remain therapeutically effective for a period of over one week at room temperature and maintains a proper and usable viscosity for this period. One cc. of the suspension is a standard therapeutic dose.

Example 5 A somewhat thicker solution was prepared by using slightly more carboxymethylcellulose, from the following:

Crystalline potassium penicillin G units 250,000 Procaine penicillin G do 1,500,000 Carboxymethylcellulose (high viscosity) -mg Tween 80 mg 1 Sodium citrate mg 48 The materials other than the procaine penicillin were blended and ground together, then heat sterilized. The sterile procaine penicillin was added sterilely mixed into the mixture and sterilely filled and sealed in a vial. Upon dilution to 5 cc. with either distilled water or physiological saline solution there results a comparatively viscous suspension of procaine penicillin in the solution which is therapeutically stable and effective for a period of at least one week at room temperature and which maintains a usable viscosity for this period.

Example 6 A five dose vial may be prepared, using a lower viscosity carboxymethylcellulose, from the following:

Sodium penicillin units 500,000 Procaine penicillin do- 1,500,000 Sodium citrate mg 33 Carboxymethylcellulose (low viscosity) mg 200 Example 7 A mixture was prepared containing:

Potassium penicillin crystalline units 500,000

Procaine penicillin do 1,500,000 Carboxymethylcellulose (high viscosity) mg 30 Sodium citrate (U. S. P.) mg 69 Example 8 A single daily dose vial was prepared by blending together under sterile conditions the following sterile materials and sterilely filling into a vial:

Crystalline potassium penicillin G units 100,000 Crystalline procaine penicillin G do 300.000 Carboxymethylcellulose mg 6 Potassium citrate mg 14 The vial was sealed, providing a single dose container of materials which are stable when dry in the vial for over one year and which when diluted to 1 cc. with water for injection will remain therapeutically stable and usable for over one week at room temperature.

Example 9 A single dose vial was prepared from:

Crystalline sodium penicillin units 100,000 Crystalline procaine penicillin do 300,000

Carboxymethylcellulose mg 6 Sodium citrate (anhydrous) mg 10 The sodium penicillin, carboxymethycellulose and sodium citrate were ground together to a line impalpable powder and sterilized by heating to 110 C. for not less than 10 hours. To

the sterile mixture was then added the sterile procaine penicillin G. The material was blended together under sterile conditions and filled sterilely into a vial. The material as so filled is stable for over one year and for use is diluted with physiological saline solution, forming a preparation which remains therapeutically stable and usable for over one week at room temperature.

Example 1 0 A single dose vial was prepared by blending together under sterile conditions:

Crystalline potassium penicillin G units 100,000 Crystalline procaine penicillin do 300,000 Sodium citrate mg 10 The sterile materials were blended together and filled into a vial. The powdered materials remain stable for over a. year when dry, and when diluted with 1 cc. of water form a solution which is therapeutically stable and usable for over one week. Because of the absence or carboxymethylcellulose, the crystals showed a marked tendency to separate and the vial had to be shaken and agitated thoroughly immediately before use to prevent the procaine penicillin crystals from settling out. A slightly larger needle was found desirable.

Example 11 A single dose vial was prepared by blending together under sterile conditions 100,000 units of crystalline sodium penicillin and 300,000 units of crystalline procaine penicillin which were filled into a vial and sterilely sealed. The materials in the vial are stable for over a year. For use, a diluent was prepared containing 6 mg. of carboxymethylcellulose and 14 mg. of sodium citrate per cc. The vial has added thereto 1 cc. of the diluent thereby forming a preparation containing the sodium penicillin, carboxymethylcellulose and the bufl'er in solution and the procaine penicillin in suspension. As thus constituted, the preparation is therapeutically stable and usable for over one week at room temperature.

Example 12 A single dose vial was prepared by blending together under sterile conditions a mixture of:

Crystalline potassium penicillin G units 100,000 Procaine penicillin do 300,000 Carboxymethylcellulose mg 6 Example 13 A vial containing the equivalent of 5 daily doses was prepared from the following materials:

Crystalline sodium penicillin G units 500,000 Procaine penicillin G do 1,500,000 Carboxyrnethylcellulose mg 30 Butler mg 706 Sodium glycinate was used as a bulTer being blended together under sterile conditions with the above mentioned materials and filled sterilely into a vial. As so prepared when diluted to cc. with pure water the material maintains its viscosity such as to be usable for therapeutic purposes for a period of over one week. One cc. of suspension is a standard therapeutic dose.

Example 14 A vial containing the equivalent of five daily doses was prepared in accordance with Example 13, using as a buffer sodium acetate. The material was therapeutically satisfactory.

Example 15 A vial containing the equivalent of five daily doses was prepared in accordance with Example 13, using as a buffer sodium carbonate. The material was therapeutically satisfactory.

Example 16 A vial containing the equivalent of five daily doses was prepared in accordance with Example 13, using as a buffer sodium pyrophosphate. The material was therapeutically satisfactory.

Example 17 A vial containing the equivalent of five daily doses was prepared in accordance with Example 13, using as a builer trisodium phosphate. The material was therapeutically satisfactory.

Example 18 A vial containing the equivalent of five daily doses was prepared in accordance with Example 13, using as a buffer disodium phosphate. The material was therapeutically satisfactory.

Example 19 A vial containing the equivalent of five daily doses was prepared in accordance with Example 13, using as a buffer dipotassium phosphate. The material was therapeutically satisfactory.

Example 20 A vial containing the equivalent of five daily doses of a penicillin preparation was prepared from:

Crystalline sodium penicillin units 500,000 Procaine penicillin do 1,500,000 Carboxymethylcellulose mg 30 The materials were sterilely admixed and filled into a vial. To the dried powdered materials in the vial was added a diluent consisting of 5 cc. of water having incorporated therein 70 mg. of sodium lactate. The suspension as thus prepared proved equally therapeutically as satisfactory as vials containing the buiTer in the original dry mixture, remaining at a therapeutically useful viscosity for a period of over one week.

It is to be understood of course that the above examples are by way of illustration. For specific purposes, it may be convenient to blend large batches of the material and divide the material, within proportions of this invention, into individual vials containing one or more therapeutic doses per vial. The above examples pertain mainly to five daily dose vials because this particular size of vial appears to be most convenient for the medical profession, but it is to be understood that any number of doses per vial may be prepared for specific applications.

While the U. S. P. grade of sodium citrate is shown in many of the examples, an equivalent amount of the anhydrous may be used. Some of the water of hydration may be driven off in the sterilization procedure. The use of the carboxymethylcellulose as a suspending agent and the buffer is important to produce a stable easily injected solution. It is to be noted that they may be used in the diluent, rather than being initially present in the vial, but from the standpoint of convenience, it is preferable that all material except water or physiological saline be present in the vial.

Having above set forth the embodiments thereof, as our invention we claim:

1. A therapeutic composition comprising a dry mixture of a water-soluble penicillin salt and procaine penicillin, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

2. A sterile, dry, therapeutic preparation comprising crystalline procaine penicillin and a crystalline alkali metal penicillin salt, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

3. A sterile. dry, therapeutic composition comprising crystalline procaine penicillin, a crystalline alkali metal penicillin salt, a non-toxic, parenterally acceptable bufler to produce a pH of about 6 to about '7 when used in therapeutic dilution, and carboxymethylcellulose, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

4. A sterile, dry, therapeutic composition comprising crystalline procaine penicillin, crystalline penicillin sodium, sodium citrate, carboxymethylcellulose, and a non-toxic, parenterally acceptable wetting agent, said mixture when incorporated in an aqueous solvent for said penicillin sodium forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

5. A sterile, dry, therapeutic composition comprising crystalline procaine penicillin, carboxymethylcellulose, crystalline penicillin sodium, and sodium citrate, said mixture when incorporated in an aqueous solvent for said penicillin sodium forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

6. A sterile, dry, therapeutic composition comprising crystalline procaine penicillin, carboxymethylcellulose, crystalline penicillin potassium, and sodium citrate, said mixture when incorporated in an aqueous solvent for said penicillin potassium forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

7. A sterile. dry, therapeutic composition comprising crystalline procaine penicillin, carboxymethylcellulose, crystalline penicillin potassium, and potassium citrate, said mixture when incorporated in an aqueous solvent for said penicillin potassium forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

8. A sterile, dry, therapeutic composition comprising crystalline procaine penicillin, crystalline penicillin sodium, carboxymethylcellulose. and a non-toxic, parenterally acceptable wetting agent, said mixture when incorporated in an aqueous solvent for said penicillin sodium forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

9. A sterile, dry, therapeutic composition comprising crystalline procaine penicillin, crystalline penicillin'sodium, and sodium citrate. said mixture when incorporated in an aqueous solvent for said penicillin sodium forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

10. A sterile, dry, therapeutic composition comprising crystalline procaine penicillin, crystalline penicillin potassium, and sodium citrate, said mixture when incorporated in an aqueous solvent for said potassium penicillin forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

11. A therapeutic composition in sterile dry dosage form comprising sufficient crystalline procaine penicillin G, crystalline sodium penicillin G, sodium citrate, and carboxymethylcellulose so that when diluted with water, there is obtained a sterile aqueous therapeutic preparation comprising approximately:

Crystalline sodium penicillin G 100,000 units per cc. lrocaine penicillin 300,000 units per cc. Sodium citrate 14 mg. per cc. Carboxymethylcellmose 6 mg. per cc.

12. An injectable comparatively stable penicillin preparation comprising per cc. approximately:

Sodtllmqaenicillin G units- 100,000 Procaine penicillin do 300,000 Sodium citrate .mg 14 Carboxymethylcellulose mg 6 13. An injectible comparatively stable penicillin preparation comprising per cc. approximately:

An alkali .metal salt of penicillin G units 100,000 Procaine penicillin G do 300,000 Non-toxic bufler to a pH of about 6 to about '7 mg 14 Carboxymethyicellulose mg- 6 14. A therapeutically useful parenterally ac- Non-toxic buiier to a pH of about 6 to about 7 not more than approximately mg. per cc. Carboxymethylcellulose 4 to 50 mg. per cc.

15. An injectable comparatively stable penicillin preparation, comprising, dispersed in an aqueous medium, an alkali metal salt of penicillin, procaine penicillin, a non-toxic, parenterally acceptable bufier producing a pH of about 6 to about 7 and a non-toxic, parenterally acceptable suspending agent for said procaine penicillin.

16. An injectable comparatively stable penicillin preparation comprising an alkali metal salt of penicillin, procaine penicillin, carboxymethylcellulose, and a non-toxic, parenterally acceptable buffer producing a pH of about 6 to about 7 when used in therapeutic dilution.

17. A sterile, dry, therapeutic preparation comprising crystalline procaine penicillin, a crystalline alkali metal penicillin salt, and a non-toxic, parenterally acceptable buiier to produce a pH of about 6 to about 7 when used in therapeutic dilution, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

18. A sterile, dry, therapeutic preparation comprising crystalline procaine penicillin, a crystalline alkali metal penicillin salt, and carboxymethylceilulose, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

19. A therapeutic composition comprising a dry mixture of a water-soluble penicillin salt, procaine penicillin and a non-toxic, parenterally acceptable buffer to produce a pH of about 6 to about 7 when used in therapeutic dilution, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

20. A therapeutic composition comprising a dry mixture of a water-soluble penicillin salt, pro

caine penicillin and an alkali metal citrate, s'aid mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

21. A therapeutic composition comprising a mixture of a water-soluble penicillin salt, procaine penicillin, a non-toxic, parenterally'acceptable bufier to produce a pH of about 6 to about 7 when used. in therapeutic dilution and a nontoxic, parenterallyacceptable suspending agent for said procaine penicillin, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

22. A therapeutic composition comprising a mixture of a water-soluble penicillin salt, procaine penicillin, a non-toxic, parenterally acceptable buffer to produce a pH of about 6 to about 7 when used in therapeutic dilution and a non-toxic, parenterally acceptable wetting agent, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

23. A therapeutic composition comprising a mixture of a water-soluble penicillin salt, procaine penicillin, a non-toxic, parenterally acceptable bufler to produce a pH of about 6 to about '7 when used in therapeutic dilution and a polyalkyleneoxide ether of a polyhydric ester of 'a long chain fatty acid, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension of procaine penicillin adapted for parenteral administration.

24. A therapeutic composition comprising a dry mixture of a water-soluble penicillin salt, procaine penicillin, an alkali metal citrate and a polyalkyleneoxide ether of a polyhydric ester of a long chain fatty acid, said mixture when incorporated in an aqueous solvent for said salt forming a fluid aqueous suspension 01' procaine penicillin adapted for parenteral administration.

25. A therapeutic composition comprising a dry mixture of a water-soluble penicillin salt, procaine penicillin, an alkali metal citrate, carboxymethylcellulose and a polyalkyleneoxide ether of a polyhydric ester of a long chain fatty acid.

26. A therapeutic composition comprising a dry mixture of a water-soluble penicillin salt, procaine penicillin, an alkali metal citrate, carboxymethylcellulose and polyoxyalkylene sorbltan mono-oleate.

WILBUR G. MALCOLM. JOHN J VANCE.

(References on following page) 13 14 REFERENCES CITED Pulse of Pharmacy (Wyeth), April 1948, page The followin eferences are of record in the file of this i a Pulse of Pharmacy (Wyeth), June 1948, page 10. UNITED STATES PATENTS 5 The Lancet (London), March 29, 1947, pages Number Name Date 408 to 410.

1,928,346 Axelrod Sept. 26, 1933 The Lancet (London), June 14, 1947, pages 820 2,142,537 Tisza Jan, 3, 1939 to 823. 2,207,990 Miller July 16, 1940 American Druggist. June 1948, page 105. 2,515,898 Rhodehamel July 18, 1950 10 Science, February 28, 1947, page 239.

New Modern Drugs, July 1948, page 690. OTHER REFERENCES Gutman, Modem Drug Encyclopedia. 3rd edi- Public Health Reports, volume 62, Number 1, on 194 pages 549 to 551 January 3, 1947, pages 10 to 12.