US2487975A - Therapeutic preparations for intramuscular or subcutaneous injection and methods of making the same - Google Patents

Description

Patented Nov. 15, 1949 THERAPEUTIC PREPARATIONS FOR INTRA- UBCUTANEOUS INJEC- TION AND METHODS OF MAKING THE MUSCULAR OR S SAME Jean U. Kore, New York, Jacques Loewe Resear York, N. Y., a corpora No Drawing. Applicati Serial No.

13 Claims.

The present invention relates to therapeutic preparations and is more particularly directed toward therapeutic preparations and the methods of making the same so that they can be made commercially and be readily available for professional use.

In the preparation of many drugs for use by the medical profession, it has heretofore been customary to dissolve them in an aqueous vehicle. Whenever such drugs are in aqueous solution, consideration must be given to various factors. Some solutions, such as penicillin, are not stable, and must befreshly made. Where the solutions contain a colloid such as gelatin, there is susceptibility of damage when the gelatin is kept heated substantially above body temperature. Ordinary freezing and thawing may also damage the solution or the container and cause loss.

The present invention relates to dehydrated injectible gelatin therapeutic preparations prepared in such a manner that they may be supplied to the profession in a substantially waterfree condition, ready for immediate use upon redissolving them in the requisite amount of water, and with the same therapeutic properties as though in original, fresh liquid form.

Medical literature contains many references to the use of retarding agents with injectible drugs and such use is quite common even though it may involve injection of difiicultly absorbable material such as beeswax and peanut oil with penicillin, or it does not sufliciently effect prolongation of release of the drug to materially obviate the need of frequent injection. Also such retarding agents may inflict pain.

The administration of the antibiotics penicillin and streptomycin, where no retarding agent is used, customarily involves repeated intramuscular injections at relatively close intervals-for example, every three hours, or continuous vein drip in saline solution.

During the extended periods necessary for the treatment required to cure many infections, the mode of treatment is irksome, distressing and disturbing to the patient. It is expensive and requires frequent professional attention. Furthermore, with the fractional intramuscular treatment, there are, on account of the rapid elimination of the penicillin and streptomycin from the blood by the kidneys, sharp rises and falls in blood concentration of the antibiotic and for considerable fractions of the period of treatment, there.

may be no effective level of penicillin or streptomycin in the blood.

N. Y., asslgnor to The ch Foundation, Inc., New f. tion of New York on February 14, 1947,

The present invention contemplates improvements in the administration of such antibiotics whereby a single injection may be effective to maintain continuous levels of the antibiotic drug in the blood over long periods, for example, 12

to 24 hours or even longer. The injection may be of a shallow or deep intramuscular or deep subcutaneous type. The infrequency of the treatments required has very great advantages: the patient is relieved of to 87% of the injections and relieved of the resultant pain and discomfort, the medical and nursing attention is reduced, hospitalization may in many cases be avoided, the cost is lessened, and the continued presence of effective levels of the drug in the blood is far more curative than alternate high and low levels obtained by former methods.

Heparin is an anticoagulant.- It is a costly drug and the patient is generally heparinized by the drip method which requires the highest possible quality of heparin and large amounts of it. It also requires very close supervision with laboratory determination of clotting time.

While the heparin is a sufficiently stable dru to withstand the free acetic acid of the Pitkin Menstruum (12% to 30% gelatin, 5% to 12% dextrose, 0.3 to 1.5% acetic acid) this free acid causes irritation of the local tissues which is more apparent after subcutaneous administration. Also the local breakdown of red blood cells, while favoring further encapsulation of the injected drug, tends to be excessive in the presence of an anticoagulant such as heparin.

The present invention provides a heparin preparation which can be given as a deep subcutaneous or shallow intramuscular injection. The dose of heparin, which may average about 300 mg., is slowly released to the blood stream so that it will suffice for at least 48 hours. This contrasts with the daily requirement of at least 350 mg. to 450 mg. when given in solution by the customary intravenous route.

According to the present invention, these objectives are achieved by administering the antibiotic, the heparin or the other drug with a retarding agent which not only retards the release of the drug to the blood, but causes little pain at the time of injection or following injection.

A further object of the invention is to provide the drug and retarding agent in such form that the preparations may be manufactured in quantity under sterile conditions and kept, either at ordinary temperatures or refrigerated, in safe condition for future use, and used easily without hazard.

The present invention contemplates that the penicillin or streptomycin, heparin or other drug will have been prepared according to the conventional methods. The penicillin is usually in the form of dry crystalline sodium, or potassium, or dry amorphous calcium salt of penicillin, the streptomycin in the form of the dry amorphous sulfate or hydrochloride, and the other drugs in dry powdered form.

Recent clinical researches, particularly where heparin, or penicillin, or heparin and penicillin together, were employed, have indicated that the free acetic acid of the Pitkin Menstruum is not essential, as was formerly believed. It also seemed to be the causative factor of an irritating effect on the local tissues, particularly more apparent after a subcutaneous administration. The acetic acid employed brought about a final pH well on the acid or negative side. Such pH seems to have no adverse effect on many of the more stable drugs such as morphine, heparin, adrenalin, epinephrin and ephedrin.

'The stability of the drugs combined with the retarding agent is of great importance if they are to be made commercially available to the profession. The liquid menstruum should be kept under controlled conditions as to temperature, so as to avoid damage from too high or too low temperatures, and it cannot be used where penicillin is to be stored because of the inactivation of penicillin in water, or in acid.

A dry preparation was made by removing all the moisture from the injectible preparation in the Pitkin Menstruum by freeze drying it. In the process of removing the moisture, free acetic acid which is volatile, was driven off so that free acid is no longer present in the freeze dried product to be stored. The freeze dried product was found to be satisfactory for use after storage for considerable periods of time.

According to the present invention it is possible to prepare retarding agents having no acetic or other acid initially and the present invention is directed toward gelatin-dextrose preparations characterized by the absence of free acid.

For successful use as an injectible drug it is necessary that the material in the ampoule (or other parenteral container) when reconstituted with the proper amount of water, be and remain sufiiciently fluid at the usual room temperatures for a sufficient time, say up to or minutes, to permit the physician or nurse to go through the necessary routine for making the injection. The fluidity of the preparation should be such that it can be withdrawn through a No. 18 or No. 19 needle and readily injected through a No. 20 needle without undue pressure on the plunger. If the preparation is more fluid than this it is absorbed into the system too quickly rather than prolonging the release of the drug, and if it is more viscous than this it may gel in the syringe and is difficult of administration. Should it be forced into the patient it forms a mass which is absorbed too slowly.

Viscosity of the ultimate product is, therefore,

a very important feature and it can be expressed refined to be edible or suitable for pharmaceutical purposes, it has widely varying properties, If prepared by acid extraction of hides it is positively charged. If obtained by lime treatment of bones it is negatively charged. The jellying property or Bloom test affords an approximation of the non-electrical characteristics of the gelatin. A low Bloom number for commercial pharmaceutical or edible gelatin is approximately 100 but such gelatins have Bloom numbers up to or in excess of 300. These commercial gelatins are not, however, suitable for use directly with dextrose (or alone) to form a suitable retarding agent. The average molecular weight of such gelatin is so high that it will not properly function before injection or after injection. There is too high a viscosity.

The preferable method of preparation of the material is as follows: 1 part of commercial pharmaceutical grade gelatin, preferably about 200 Bloom test positive gelatin and /2 part of glucose or dextrose are dissolved in hot water to have a strength of about 10% to 15% gelatin. These proportions are not critical for the proportions may range from equal parts of gelatin and dextrose to 2 times as much gelatin as dextrose, and one can use gelatin of from say 100 Bloom test to at least 300 Bloom test. Solutions more dilute than a 10% solution may be used, but entail evaporation of unnecessary amounts of water, about 5% being as low as one should go. 16% is about the maximum concentration which can be satisfactorily filtered.

Hydrolysis and pH adjustment by addition of alkali such as sodium hydroxide then follow in either order. The pH should be such that the best results will be obtained with the drugs employed. This may be as low as pH 5 for heparin, or 5.5 for penicillin, but in general, to avoid pain it is brought up nearly to pH 7. The vasoconstrictors, however, tend to be less stable over long periods at the higher pHs. The solution is heated to temperatures of about C. to C., to degrade, or hydrolyze the gelatin so that it has a lower average molecular weight or lower viscosity. The time required at these temperatures will vary from hour to 4 hours depending upon the nature of the gelatin employed. It can be reduced by boiling under pressure. An optimum time for 200 Bloom test gelatin is from 30 to minutes.

The viscosities of the preliminary solutions of gelatin and dextrose, whatever the concentration, have, it will be understood, a definite relation to the viscosity of the injectible product. Control tests of viscosity may, therefore, be made of the solution to see that the hydrolysis has been properly carried out to secure the desired end product. Coincident with the degrading of the gelatin, reaction of the amino acids and polypeptides of the gelatin and aldehyde groups of the dextrose takes place. In general the hydrolysis is carried out so as to obtain a decided lowering of the viscosity of the mixture, to say 40% to 70% its original viscosity. For example, 30 gm. of 200 Bloom test gelatin and 15 gm. of dextrose dissolved in 250 cc. of water may have such a viscosity at 60 C. as to require from 96 to 106 second: for drainage from a Saybolt viscosimeter, and after heat treatment, this viscosity is reduced to require but 58 to '72 seconds. Such viscosities have been found to produce the desired fluidity of the ultimate product to be injected.

Vasoconstrictors, such as ephedrin sulphate, epinephrin hydrochloride, and neo-synephrin hydrochloride, etc., and local anaesthetics such as eucupin dihydrochloride, chlorbutanol, and procaine hydrochloride, etc., are added directly or dissolved and then added. The amount of these vasoconstrictors and local anaesthetics used will depend on the total dosage of the gelatin, dextrose and drug to be used, for the amount of the vasoconstrictors and local anaesthetics which may be used with one injection is limited, as is well known. The hot solution of hydrolyzed gelatin, dextrose and vasoconstrictors is then filtered through a bacterial filter.

This filtered solution of retarding agent, vasoconstrictors and local anaesthetics may be used in various ways. One way is to let it cool slowly and gel, and dry it under vacuum. It is preferable to keep the temperature below the congealing point of the mix employed, say 10 C., so as to avoid foaming. Foaming may be permitted if a large enough container is used. A very high vacuum will freeze the material. One can also dry the mixture in a stream of air as is customary in the manufacture of gelatin, provided sterile conditions be maintained. The drying should be carried out in such a way that the final moisture content is below 1%. Should a freeze drying method be employed, the solution of hydrolyzed gelatin and dextrose, with or without vasoconstrictors, and local anaesthetics, is preferably diluted, for example, to 6% gelatin, 3% dextrose, before freeze drying.

The dried material prepared in any of the ways mentioned above, is then ground so as to be a fine granular material. Weighed quantities of the dried material and dru in proportions determined by the desired ultimate dosage are thoroughly mixed and the mixture bottled or ampouled using sterile precautions.

An amount sufficient for a single dose is preferably placed in each parenteral container. The dehydrated material can be stored for long periods of time without danger of deterioration in any climate.

Instead of vacuum drying, or freeze-drying the retarding agent with vasoconstrictor, as above set forth, a filtered solution may be allowed to cool to a temperature low enough not to affect the drug but still liquid enough to permit ready mixing-say 40 C.whereupn the drug is added and dissolved. Then the mixture is allowed to cool until it gels and is then dried by vacuum, freeze drying, or any other methods, ground and bottled or ampouled.

Since the drug is added to a retardin mixture having a pH of approximately 7, it is possible to employ drugs which are unsuitable for use in a medium of relatively high acidity or one may use a lower pH or higher pH within physiological tolerance where advantages accrue.

Instead of preparing a dried retarding agent and mixing it with the dried therapeutic agent, it is possible to mix a retarding agent solution and a solution of the therapeutic agent or agents in the proper portions and then dehydrate the mixed solutions. This procedure is more suitable for stable drugs than for those likely to lose potency when in solution, as for example penicillin.

The dry preparations are stable and potent over long periods of time. They may be stored at any temperature likely to occur in any climate. The dry powder form of retarding agent enables one to prepare a fresh solution of materials such as antibiotics which are too unstable to ship in solution. The preparations readily go into solution at room temperature but the solution can be accelerated by gentle heat (from 40 C. to 55 C.), which must be well below the unsafe temperature for the drug. They are administered without difficulty with a minimum of local reaction and dis omfort, and one treatment suffices for a long period so that continuous effective medication may be assured. In the dry state, the individual dosage can be readily increased or additional water-soluble drugs added as required.

The preferred ratio of gelatin to dextrose is 2:1. While the vasoconstrictors may be omitted, it is preferable to use themwithiwtherfzfiiissibl dosage, which for ephedrin, and epinephrin is about 25 mg. and 1 mg. respectively. A local anaesthetic such as 1 mg. of eucupin is also preferred. The preferable amount of retarding agent to use in an ampoule is from 0.8 to 1.2 grams. The preferable amount of water to be added to the ampoule is 2.0 cc., as there is only a small residual loss in the ampoule when the preparation is withdrawn. One can however, use as little as 1.5 cc. or as much as 3 cc. of water. This gives a ratio of solute to retarding agent of from 1 A to 4:1. An attempt to use as little as 1 cc. of water is not advised as there is too much possibility of loss, also the preparation may solidify or gel in the syringe. The weight of drug used will depend on dosage, for example, 300,000- 500,000 units of sodium penicillin weighing 0.18 to 0.3 gram, streptomycin sulphate weighing 0.6-1.2 gm.; mg. heparin, per cc., etc.

Where a 2: 1 gelatin dextrose retarding agent is used with penicillin and vasoconstrictor as above in 1.5 cc. to 3.0 cc. of water, the injectible preparation has from 13% to 24% gelatin 6.5% to 12% dextrose 14% to 28% gelatin 6% to 14% dextrose It is preferable to employ a positively charged gelatin when the therapeutic agent used is acidic or anionic, and a negatively charged gel when the therapeutic agent used is basic or cationic, for example, in the form of its sulphate or similar salt.

The employment of positive gels with acidic therapeutic agents and negative gels with basic therapeutic agents gives better and more uniform results then are obtained where the gel is not selected according to its proper charge.

The coagulation time responses have been satisfactorily prolonged and protracted following the administration of heparin in this new retarding agent. As against a control coagulation time of 9 to 15 minutes the clotting time has been maintained at 30 to 60 minutes for 48 hours or longer. It has been possible to effectively treat patients with thrombotic diseases by means of this heparin-gelatin-dextrose preparation.

Experience has shown that the administration of penicillin salts of 300,000 units to 600,000 units with the retarding agent, may be relied upon to give continuous penicillin levels in an effective range for periods of at least 12 hours and in many cases up to and in excess of 24 hours. Similarly 1,000,000-2,000,000 units of streptomycin may be employed to obtain effective streptomycin levels in the blood for similar periods of time and 300 mg. of heparin may be employed to suffice for at least 48 hours. Where other water soluble therapeutic agents are to be employed, the only change ordinarily necessary is to substitute the proper amount of such therapeutic agent.

This application is a continuation-in-part of my earlier application Serial No. 663,631 filed April 19, 1946.

Having thus described in some detail certain embodiments of the invention, what is claimed is:

1. The method of making a retarding agent for use with subcutaneously and intramuscularly injectible drugs which comprises preparing an aqueous solution of pharmaceutical gelatin having a Bloom test of about 200 and dextrose in the proportion of from equal parts of said gelatin and dextrose to 2 /2 times as much gelatin as dextrose and of a strength of from about 5% to about 16% gelatin, and heating the mixture to substantially reduce the average molecular weight of the gelatin until the solution has a viscosity of from 40% to 70% of the viscosity before heating.

2. The method of claim 1 characterized in that the pH of the solution is adjusted to approximately pH 7. I

3. The method of claim 1 characterized in that the solution is adjusted to approximately pH 7, cooled to form a gel, and then dehydrated.

4. The method of making a retarding agent for use with subcutaneously and intramuscularly injectible drugs which comprises preparing an aqueous solution of gelatin and dextrose in the proportion of from equal parts of gelatin and dextrose to 2 times as much gelatin as dextrose and of a strength of from about 5% to about 16% gelatin and known viscosity, heating the mixture to substantially reduce the average molecular weight of the gelatin, as indicated by a viscosity of from 40% to 70% of the viscosity before heating, adding a vasoconstrictor to the solution, filtering it, and cooling it to form a el.

5. The method of making a vasoconstrictorcarrying retarding agent for use with subcutaneously and intramuscularly injectible drugs which comprises preparing an aqueous solution of pharmaceutical gelatin having 9. Bloom test of about 200 and dextrose in the proportion of from equal parts of said gelatin and dextrose to 2 times as much gelatin as dextrose and of a strength of from about 5% to about 16% gelatin, and heating the mixture to substantially reduce the molecular weight of he gelatin until the solution has a viscosity of from 40% to 70% of the viscosity before heating, adding a vasoconstrictor agent, adjusting pH to approximately pH 7, and dehydrating the material.

6. The method of making a retarding agent for use with subcutaneously and intramuscularly injectible drugs which comprises preparing an aqueous solution of pharmaceutical gelatin having 9, Bloom test of about 200 and dextrose in proportions of substantially 25:1 and of a strength of from about 5% to about 16% of gelatin of determinate viscosity, and then adjusting the pH of the solution to approximately pH 7 and heating the mixture nearly to the boiling point for from 30 to 120 minutes to reduce the viscosity.

7. The method of claim 6, characterized in that the solution is cooled to form a gel and then dehydrated.

8. A retarding agent for use with subcutaneously and intramuscularly injectible drugs, comprising the dried residue of an acid-free solution of from equal parts of pharmaceutical gelatin and dextrose to 2 times as much said gelatin as dextrose, characterized in that the gelatin is degraded from natural gelatin by heat hydrolysis in solution with the dextrose in an amount such that when the retarding agent with admixed drug is reconstituted by solution in from 1 to 4 times its weight of water to form a retarding menstruum of the thus modified gelatin and dextrose the latter solution can be withdrawn by a Number 18 needle and inJected with a Number 20 needle.

9. The method of making from gelatin, dextrose, and a water soluble therapeutic agent, a

dry preparation for subcutaneous or intramuscular injection after redissolving in water, which comprises preparing an aqueous solution of pharmaceutical gelatin having a Bloom test of about 200 and dextrose in the proportion of from equal parts of gelatin and dextrose to 2 times as much said gelatin as dextrose and of a strength of from about 5% to about 16% gelatin, heating the mixture to substantially reduce the average molecular weight of the gelatin until the solution has a viscosity of from 40% to of the viscosity before heating, adjusting the pH to approximately pH '7, preparing from the solution and the therapeutic agent a dry mixture, and sealing a quantity of the dry mixture in a parenteral container.

10. The method of making from gelatin, dex trose, and penicillin, a dry preparation for subcutaneous or intramuscular injection after redissolving in water, which comprises preparing an aqueous solution of pharmaceutical gelatin having a Bloom test of about 200 and dextrose in the proportion of from equal parts of said gelatin and dextrose to 2 times as much gelatin as dextrose and of a strength of from about 5% to about 16% gelatin, heating the mixture to substantially reduce the average molecular weight of the gelatin until the solution has a viscosity of from 40% to 70% of the viscosity before heating, adjusting the pH to approximately pH 7, preparing from the solution and the penicillin a dry mixture, and sealing a quantity of the dry mixture in a parenteral container.

11. The method of making from gelatin, dex trose, and streptomycin, a dry preparation for subcutaneous or intramuscular injection after redissolving in water, which comprises preparing an aqueous solution of pharmaceutical gelatin having a Bloom test of about 200 and dextrose in the proportion of from equal parts of said gelatin and dextrose to 2 /2 times as much gelatin as dextrose and of a strength of from about 5% to about 16% gelatin, heating the mixture to substantially reduce the average molecular weight of the gelatin until the solution has a viscosity of from 40% to 70% of the viscosity before heating, adjusting the pH to approximately pH 7, preparing from the solution and the streptomycin a dry mixture, and sealing a quantity of the dry mixture in a parenteral container.

12. The method of making from gelatin, dextrose, and heparin, a dry preparation for subcutaneous or intramuscular injection after redissolving in water, which comprises preparing an aqueous solution of pharmaceutical gelatin having a Bloom test of about 200 and dextrose in the proportion of from equal parts of said gelatin and dextrose to 2 /2 times as much gelatin as dextrose and of a strength of from about 5% to about 18% gelatin, heating the mixture to substantially reduce the average molecular weight of the gelatin until the solution has a viscosity of from 40% to 70% of the viscosity before heating, adjusting the pH to approximately pH 7, preparing from the solution and the heparin, a dry mixture, and sealing a quantity of the dry mixture in a parenteral container.

13. A therapeutic preparation for subcutaneous and intramuscular injection, comprising a retarding agent in the form of a dehydratedpowder comprising the reaction products produced by heat hydrolysis of a mixture of pharmaceutical gelatin and dextrose in solution in the proportion of from equal parts of gelatin and dextrose to 2 times as much gelatin as dextrose at a pH 01' not over pH '7, and a dry water soluble therapeutic agent mixed with the retarding agent, the

10 mixture being soluble in water at room temperature to produce a viscous solution with from 10% to 28% gelatin and suitable for injection through a Number 20 needle.

JEAN U. KoREE.

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

Article by Loewe, Amer. J. Med. Sci., July 1944, pages 54-63.

Proc. Soc. Exptl. Biol. and Med., Jan. 1945, pages 74-76. r

Science, Feb. 23, 19457page203 and 205.

Committee on Medical Research, OSRD, Contract No. OEMcmr, 56, Progress Report, Nov. 15, 1944 (3 pages).

Images