EP0170680A1

EP0170680A1 - Terminally sterilizable isotonic drug compositions

Info

Publication number: EP0170680A1
Application number: EP19850900876
Authority: EP
Inventors: Maurice S. Goldstein; Nicholas J. Kartinos
Original assignee: Baxter Travenol Laboratories Inc
Current assignee: Baxter International Inc
Priority date: 1984-01-27
Filing date: 1985-01-15
Publication date: 1986-02-12
Also published as: JPS61501148A; CA1244771A; EP0170680A4; WO1985003202A1

Abstract

Des compositions de médicaments à stérilisation finale sont préparées en utilisant du glycérol en tant qu'agent isotonique dans une solution avec de l'héparine, de la gentamicine, de la dopamine ou de la cimétidine.Final sterilization drug compositions are prepared using glycerol as an isotonic agent in a solution with heparin, gentamicin, dopamine or cimetidine.

Description

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TERMINALLY STERILIZABLE ISOTONIC DRUG COMPOSITIONS

This invention relates to solutions of the drugs heparin, dopamine, cimetidine and gentamicin, especially for parenteral administration. In particular, this invention relates to heat sterilizing solutions of these drugs while preserving their short and long term stability in dilute aqueous solution.

Dopamine, having the systematic name 4-(2-aminoethyl )-l , 2-benzenedioV, is commercially available as the hydrochloride salt. Its therapeutic utility is to correct he odynamic imbalances in the treatment of shock due to myocardial infarction, trauma, septicemia, open heart surgery, renal failure or congestive heart failure. It heretofore has been dissolved in water for injection and then diluted into a diluent solution selected from the group of 0.9% sodium chloride, 5% dextrose, 5% dextrose with 0.9% sodium chloride, 5% dextrose with 0.45% sodium chloride, lactated Ringer's solution, 5% dextrose in lactated Ringer's solution, or 1/6 M sodium lactate (American Hospital Formulary Service, 12:12 [1976]). Dopamine solutions are infused in accord with standard procedures and dosage rates, ordinarily intravenously at a rate of 1 to 5 mg/Kg body weight/ in. with increases in dosage until the desired elevation in venous pressure is achieved.

Heparin is a naturally occurring, high molecular weight mucopolysaccharide with a high content of esterified sulfuric acid. It is commercially available as the sodium salt, although other pharmacologically acceptable salts are to be considered within the scope of the term heparin as used herein. For the treatment of thrombotic disorders, 10,000 to 40,000 U.S. P. units are dissolved in one or two liters of diluent and administered intravenously or intramuscularly at varying dosages dependent upon the administration route and patient weight. Dosage will be titrated based on blood clotting time assays. The formulation and administration of therapeutic doses is well known in the art.

Heparin has been reported to be "compatible" with infusion solutions containing dextrose, sodium chloride, invert sugar, Ringer's solution, lactated Ringers's and 1/6 M sodium lactate (American Hospital Formulary Service 20:12.04 [1976]).

Gentamicin is a well known antibiotic. It is commercially available as the sulfate salt, although other pharmacologically acceptable organic or mineral salts shall fall within the meaning of gentamicin as used herein. Also, the various known gentamicin components, e.g. C, , C_2- C-, and A shall be construed as encompassed by the term gentamicin.

Gentamicin has been dissolved in the following intravenous solutions at a potency of 0.2 to 2.5 mg/ml.: 10 per cent dextran 40 with 5 per cent dextrose; 5 per cent dextrose; 10 per cent dextrose; 5 per cent dextrose in Polysal® solution; 5 per cent dextrose in Polysal®-M solution; Isolyte® P solution with 5 per cent dextrose; Isolyte® M solution with 5 per cent dextrose; Isolyte® E solution with 5 percent dextrose; lactated Ringer's injection; Nor osol® M solution in

5% dextrose; Normosol®-R; Normosol®-R pH 7.4; Normosol®-R solution in 5% dextrose; Ringer's injection; 0.9 per cent sodium chloride injection; 5 per cent Travert® solution with Electrolyte No.2; and ^• 10 per cent Travert® solution with Electrolyte No.3. Gentamicin at concentrations of 400 meg. per ml. and 800 eg. per ml. also maintains potency for 24 hours at room temperature in a 20 per cent mannitol solution (American Hospital Formulary Service 8:12.28 [1976]).

Ci etidine is a histamine H₂ receptor antagonist having the systematic name N''-cyano-N-methyl-N'-[2-[[(5-methly-l H-imidazol-4-yl ) methyl] thio]-ethyl]-guanidine. It is used in the treatment or prophylaxis of duodenal ulcers and hypersecretory conditions. Recommended intravenous dosage is 300 mg. of cimetidine dissolved in dilute solutions haying concentrations from about 3 mg/ml to 12 mg/ml and delivered over a period of up to 6 hours. A number of intravenous solutions have been found to be compatible with cimetidine for one week under ambient room temperature (Myerson, "Tagamet® brand of Cimetidine" [1981]). These included 10% mannitol and various dextrose-containing diluents.

Heretofore the conventional method for intravenous administration of these drugs was reconstitution and dilution into a diluent containing a solute so as to render the resulting solution substantially isotonic with blood. The most commonly used diluents have been saline and aqueous solutions of dextrose. These solutions have been prepared conventionally in hospital pharmacies on order for short-term storage, up to about one week. However, the- assignee hereof has pioneered a program for preparing these drugs in an industrial setting off-site from the facilities of the ultimate users. Under this program solutions of the drugs are prepared in concentrations suitable for immediate parenteral administration without further dilution prior to infusion. Then the solutions are filled into containers and terminally sterilized. Terminal sterilization means heating the containers and their solutions until all adventitious microbes are killed. The sterilization conditions are harsh, ordinarily greater than 121^δC for about from 24 minutes to one hour depending upon the container size and characteristics. If the manufactured drug solutions are to be suitable for parenteral administration they must contain an agent for osmotic control of the solution at the approximate isotonicity of blood. The drug itself will not be in a concentration suitable for this purpose, although it may make a modest contribution. The most commonly used osmotic agents have been sodium chloride and dextrose. While the aforementioned drugs can be terminally sterilized and stored for lengthy periods (1 week to two years) in saline, they are not stable in dextrose. Discoloration and activity losses will be encountered. On the other hand, saline is not in favor as diluent because of its high sodium content, particularly in the case of cimetidine treatments. Thus, a need has existed for an isotonicity solute which will, be medically acceptable and which will not adversely interact with heparin, gentamicin, cimetidine or dopamine upon terminal sterilization and long term storage.

Summary of the Invention

The above need has been met by the use of glycerol , mannitol and/or sorbitol as the isotonicity agent in solutions of the above four drugs. Unlike dextrose, these three agents do not adversely interact with the drugs to produce color changes or activity losses upon terminal steril zation and storage.

Detailed Description

The glycerol, mannitol or sorbitol may be employed in combination admixture or as the sole agent, either in combination with one another or with other known isotonicity agents such as sodium chloride, pharmacologically acceptable polymers and the like. It is preferred to use glycerol alone as the principal isotonic agent, although buffers, nutrients, the drug, salts, antioxidants or other solutes may make_, a minor contribution. Mannitol and sorbitol are not the preferred agents. The glycerol, mannitol or sorbitol may be employed at concentrations ranging about from 0.5% to 5.0% by weight depending on the agent used. A lesser quantity of glycerol than 5.0% ordinarily would be used because its molecular weight is less than mannitol and sorbitol. The upper limit is critical since greater amounts will lead to side effects e.g. dehydration, that are undesirable in most patients, particularly if the drug solution also contains other components such as electrolytes and other solutes. Desirably, the upper limit is accommodated, i.e., reduced, by the osmotic contribution of other solutes. so that the solution is not other than substantially isotonic. The lower limit is not critical and only reflects the degree to which osmotic agents other than glycerol, mannitol or sorbitol can be employed in the solutions and the contribution by other solutes. The final solution, however, must not be hypotonic since this may result in hemolysis and ^• phlebitis.

As noted above the solutions herein may contain buffers, antioxidants such as ascorbic acid, a bisulfite or metabisulfite, salts such as potassium or other electrolytes, other stabilizers and substances previously used in the formulation of sterile, dilute solutions of heparin, cimetidine, gentamicin and dopamine. The solutions also may contain amino acids for nutritional purposes. The pH of the solutions will be adjusted with a pharmacologically acceptable acid or base in order to provide the optimal pH for drug stability. The dilute solutions herein are not of general utility for enteral or intramuscular administration.

A further advantage of glycerol, mannitol or sorbitol over dextrose is that dextrose is only optimally stable at pH 3.5, whereas glycerol, mannitol and sorbitol are stable throughout the range of pH 3 to 11. Thus, they offer an advantage when used with heparin, cimetidine and gentamicin, all of which have optimal stability at pH levels greater than 3.5. The above solutions typically are made by dissolving the glycerol, mannitol and/or sorbitol, drug and other desired solutes in water, filling them into containers, hermetically sealing the containers and heat sterilizing the contents. The containers may be any glass or flexible containers specially adapted for infusion into patients, i.e., containers including ports, caps or other means for communicating in sterile fashion with a conduit (administration set) for delivering the solution by infusion into a patient. Containers of this type are commercially available and well know, e.g. as disclosed in U.S. patents 4,046,276 and 4,393,909 and as constituted by the Viaflex® container sold by Travenol Laboratories, Inc.

The sterile drug solutions may be placed into long term storage, i.e. greater than about one week and up to 2 or more years. They may be stored at room temperature, and need not be frozen.

They are administered to patients in exactly the same fashion as the dilute solutions of the aforementioned drugs have, been administered previously, primarily by intravenous infusion. Generally, the drug is continuously or intermittently infused by peripheral catheter at therapeutic dosages as discussed above.

The following examples are intended to be merely illustrative and are not to be construed as limiting the scope of the claims.

EXAMPLE 1

25,000 U.S.P units of sodium heparin U.S.P. are dissolved in 400 ml of phosphate buffer at pH 7. 12.5 gm of glycerol are added to the solution, followed by a sufficient volume of phosphate buffer to produce a final volume of 500 ml having a final heparin concentration of approximately 50 U.S.P. units/ml. This solution is filled into a 600 ml capacity Viaflex® bag and the bag sealed. The bag and contents are autoclaved at 121°C for 1 hour, cooled and stored. EXAMPLE 2 Example 1 is repeated except that the initial amount of heparin was adjusted so that the final heparin concentration is 20, 40, 80 or 100 U.S.P. units/ml.

EXAMPLE 3 400 mg of dopamine hydrochloride is dissolved in 200 ml of a solution containing 2.5% wt/vol glycerol and 0.05% wt/vol sodium bisulphite, the pH adjusted with NaOH or HCl to pH 3.5, and q.s. to 250 ml with the same solution to produce a 250 ml final volume having an approximate dopamine concentration of 1.6 mg/ml. The solution is filled into an approximately 300 ml capacity Viaflex® bag and the bag sealed. The bag and contents are heated at 121°C for 24 min, cooled and stored for up to two years.

EXAMPLE 4 Example 3 was repeated except that the concentration of dopamine is adjusted to approximately 0.4, 0.8 or 3.^'2 mg/ml.

EXAMPLE 5 100 mg of gentamicin sulfate U.S.P. is dissolved in 100 ml of an aqueous solution containing 2.5% wt/vol glycerol and the pH adjusted to 4.0 with NaOH or HCl. A Viaflex® container is filled with the solution, sealed, heat sterilized at 121°C for 30 min. and cooled. It may be stored for up to two years. The foregoing procedure is repeated with 40, 60, 80, 120, 200 or 240 mg of gentamicin sulfate U.S.P.

EXAMPLE 6 Example 5 is repeated except that cimetidine hydrochloride (Tagamet® brand) in amounts of 300, 600 and 1200 mg was substituted for the gentamicin and the pH was adjusted to 6.0 rather than 4.0.

The sterilized solution could be stored in the Viaflex® bags for up to two years.

Claims

WHAT IS CLAIMED IS:

1. A substantially isotonic, sterile solution comprising glycerol and a drug selected from the group of heparin, gentamicin, dopamine or cimetidine.

2. The solution of claim 1 which is essentially free of water insoluble fat, protein, body fluids, blood cells, or drugs other than heparin, gentamicin, dopamine or cimetidine.

3. The solution of claim 1 wherein the glycerol is present in a concentration of less than about 5.0% weight/volume.

4. The solution of claim 3 wherein the glycerol is present in a concentration of about from 1 to 2.5% weight/volume.

5. The solution of claim 1 wherein none of the glycerol or drugs contain a radioactive isotope.

6. The solution of claim 1 which is essentially free of an isotonically effective concentration of sodium chloride.

7. The solution of claim 1 further comprising an am no acid or an antioxidant.

8. The solution of claim 1 which is essentially free of mono-όr disaccharides.

9. The solution of claim 8 which is essentially free of dextrose.

10. The solution of claim 1 wherein the drug is heparin.

11. The solution of claim 1 wherein the drug is gentamicin.

12. The solution of claim 1 wherein the drug is dopamine.

13. The solution of claim 1 wherein the^' drug is cimetidine.

14. A method comprising parenterally administering the solution of claim 1 to a patient.

15. A sterile solution consisting of (a) water, (b) glycerol, (c) a therapeutically effective amount of heparin, gentamicin, dopamine or cimetidine and (d) buffer or antioxidant, wherein the amount of glycerol is such as to make the composition substantially isotonic.

16. An assembly comprising the composition of claim 1 in a container having means for sterile communication with a means for delivering the solution into a patient.

17. A method comprising (a) dissolving in water glycerol and a drug selected from the group of heparin, gentamicin, dopamine, or cimetidine, and (b) heat sterilizing the solution of part (a).

18. The method of claim 17 wherein the solution is transferred to a container and the container hermetically sealed prior to heat sterilizing.

19. The method of claim 18 wherein the container is flexible.

20. The method of claim 18 wherein the container has means for sterile communication with a means for delivery of the sol tion into a patient.