KR100358243B1 - Oil-in-water emulsions containing propofol and editate - Google Patents

Abstract

The present invention relates to the use of a pharmaceutical composition containing 2,6-diisopropylphenol (propofol) as an anesthetic. A method of making a pharmaceutical composition for use in causing anesthesia, including general induction and maintenance of anesthesia and sedation.

Description

Oil-in-water emulsions containing propofol and edetate

Propofol is an anesthetic for injection with hypnotic properties and can be used to induce and maintain general anesthesia and for sedation in, for example, an intensive care unit (intensive care unit). Propofol is a highly successful anesthetic and is sold under the trade name 'Diprivan' for human treatment and 'Rapinovet' for veterinary use.

Injectable anesthetics such as propofol are administered directly into the bloodstream. The anesthesia then starts almost completely affected by the rate of anesthetics passing through the blood brain barrier. Therefore, there is a need for an anesthetic that has sufficient fat solubility to pass through this gate and inhibit the associated mechanisms of the brain. In general, however, high fat-soluble molecules are poorly soluble in water and therefore difficult to formulate for intravenous injection. In some cases it was possible to obtain a water soluble salt of an anesthetic that releases a fat soluble free base in vivo, but this was not possible in most cases, and despite considerable research it was not found to be suitable for propofol. Therefore, it was necessary to conduct substantial research and development on the preparation of propofol to obtain pharmaceutical compositions for the administration of warm-blooded animals, including humans.

Applicant confirmed the anesthesia properties of propofol and filed UK patent application 13739/74 and was granted UK patent 1472793. The patent is also registered in the United States (USP 4056635, USP 4452817 and USP 4798846) and elsewhere.

The patent specifically claims for a sterile pharmaceutical composition containing propofol in combination with a pharmaceutically acceptable sterile diluent or carrier, which composition is suitable for parenteral administration either directly or after dilution with a liquid diluent.

In one aspect, UK 1472793 discloses an aqueous composition containing propofol in a sterile mixture of water and a surfactant or other solubilizer.

In another embodiment, an aqueous composition containing a protocol is disclosed in a sterile mixture of water and a further water-miscible non-aqueous solvent. In a further embodiment, an oil-in-water emulsion composition is disclosed in which propofol dissolved alone or in a water-immiscible solvent is emulsified in water with a surfactant. In yet further embodiments the composition is disclosed as a sterile solid or semisolid mixture of solid diluent (eg, lactose, saccharin sodium or cyclodextran) with propofol and the composition is suitable for dilution with sterile aqueous diluent.

The patent describes specific examples of injectable compositions comprising capopopol, including examples using various surfactants, various solubilizers, additional solvents, additional components (selected from stabilizers, preservatives and antioxidants), buffers and osmotic modifiers. It is described.

Applicants have conducted extensive research to determine the form of formulation most suitable for developing a formulation for sale. As a result of considerable effort, formulations of propofol and surfactant Cremophor EL in water (Cremophor is the trade name for the polyoxyethylene castor oil derivatives) were selected. Dissolve an existing intravenous anesthetic alphaxsalon / alphadolone ('Althesin') using Cremophor EL as a carrier, and dissolve intravenous anesthetic propaneide ('Epontol') using a modified form of cremofo as a carrier. I was.

Applicants conducted a series of detailed studies on animals and administered the formulation to 1000 humans. However, about 5 or 6 years later, anaphylactic response has been reported in very few patients. Anaphylactic reactions are allergic reactions. It is not clear whether Cremophor EL causes the anaphylactic reaction in all cases, but Applicants decided to undertake the discovery and development of a substitute for propofol.

Subsequent studies have been conducted on the surrogate formulations, and finally the oil-in-water emulsions have been selected and developed in 1986 under the trade name 'Diprivan' for a number of sales markets. Since then, this formulation has been shipped to sales markets all over the world and Propofol has been regarded as an anesthetic, a highly successful drug with unique properties that has been so successful. In summary, Propofol is a short-acting anesthetic that is used in the induction and maintenance of general anesthesia, sedation that complements local analgesia, sedation in ventilated intensive care units, and surgical and diagnostic procedures in intensive care units. Appropriate for significant sedation. Propofol can be administered by single or repeated intravenous bullous injections or by continuous infusion. It is removed from the blood very quickly and metabolized. Therefore, the degree of anesthesia can be easily controlled, the patient's recovery rate is generally faster when the drug is discontinued, and the patient exhibits a more pronounced spirit compared to after the administration of other anesthetics. Side effects such as nausea and vomiting occur significantly less frequently after propofol administration than after other general anesthesia techniques such as inhalation anesthesia.

The present invention relates to 2,6-diisopropylphenol, known as propofol, and in particular to novel pharmaceutical compositions containing propofol.

Applicants have considered expanding the range of propofol formulations to enable anesthesiologists to select the appropriate drug from a wider variety of medical products. For example, Applicants developed a propofol oil-in-water emulsion formulation as a substitute, in which case the concentration of propofol is twice the concentration of pharmaceutical products currently sold.

Given the appropriate additional formulation, it provides a formulation that is easy for the anesthesiologist or ICU specialist to operate, while maintaining the quality that provides the benefits of 'Diprivan' as described above and having acceptable chemical and physical stability. It is desirable to.

Diprivan has been increasingly used to calm critically ill patients, especially in the intensive care unit. In the case of sedation of these critical patients, administration of 'Diprivan' is usually by infusion. An infusion set requires a 'giving set', in which a propofol reservoir (usually a bottle or syringe) is connected to a luer connection via a suitable tube and from there into the patient's vein. It involves connecting with a needle.

Microbial contamination of the parenteral circulation used in this type of 'infusion set' has been recognized as one of the many causes of pathogenic infections in ICU patients. Thus, for example, in the United States, the Food and Drug Administration (FDA) typically requires frequent replacement of the 'infusion set', and in the case of 'Diprivan' at least every six hours or every twelve hours depending on the presentation used. Each time it is required to replace the 'infusion set'.

The environment in the intensive care unit is busy, and as in other health service sectors, there is a burden of cost reduction. Replacing the 'infusion set' at least every 6 or 12 hours is relatively time consuming for highly skilled ICU nurses, intensive care unit specialists, or anesthesiologists. This is especially the case when it is necessary to simultaneously inject a large number of critical patients in the ICU.

Applicants have therefore sought to develop new propofol formulations so that the 'infusion set' can be replaced much less frequently (eg every 24 hours). This is more convenient for nurses, intensive care unit specialists, or anesthesiologists, less burden on staff, and less manipulation of the 'infusion set', saving more money in the ICU environment.

We have been conducting substantial research and found that adding small amounts of selected agents to 'Diprivan' can administer the formulation in an 'infusion set' that can be replaced much less frequently than currently used; That is, the administration time and infusion set replacement time were significantly improved. As these times increase, the package size increases, making it easier for the user to handle and reducing costs by reducing the waste of 'Diprivan'.

Moreover, the probability of mishandling causing accidental external contamination is also small, minimizing the growth opportunities of the microorganisms in the formulation.

UK patent 1472793 discloses that propofol formulations include stabilizers, preservatives and antioxidants such as paraben derivatives (eg propyl p-hydroxybenzoate, butylated hydroxytoluene derivatives, ascorbic acid and sodium metabisulfite), metals Ion separators such as sodium edetate; And one or more additional components selected from antifoams such as silicone derivatives (eg, dimethicone or simethicone).

It is difficult to add known preservatives to oil-in-water emulsions such as 'Diprivan'. As mentioned above, 'Diprivan' is an anesthetic used for the induction and maintenance of general anesthesia and sedation. Especially in the case of sedation, the dosage is not small. Thus, a significant amount of preservative may be administered to the patient being treated. Therefore, additives must be carefully selected to satisfy the medicinal authority; In particular, the use of preservatives in a single, finally sterile, parenteral injectable material is not proposed in the various guidelines (eg US, UK and European Pharmacopoeia) and / or is of concern.

Moreover, the inclusion of additives in oil-in-water emulsions for parenteral administration poses a particular problem. In efficacy, it has been believed that the antimicrobial properties of any preservative are exerted on the aqueous phase. Thus, lipophilic preservatives used at typical dosage concentrations are somewhat effective between the phases but are not effective as they are insufficient material in the aqueous phase. Increasing the total amount of these preservatives results in at least toxicity issues due to unacceptable high concentrations of preservatives in the lipid layer.

On the other hand, the addition of preservatives (eg, ionic materials) with hydrophilic properties also causes problems. Adding ionic substances to oil-in-water emulsions makes the emulsions unstable. The use of higher ionic loads (i.e. concentrations of ionic materials) can change the stabilizing electrical charge (zeta potential) on the oily droplets. These changes in electrical charge increase the probability of droplet collisions, increasing the physical instability of the emulsion.

We have studied the possibility of addition to oil-in-water emulsions for a number of antibacterial agents. Such antimicrobial agents should not cause significant harm to the physical and chemical stability of the emulsion and should provide the antimicrobial activity desired.

Many potential antimicrobials have been found to induce instability in emulsions. Other possible formulations did not provide the desired level of antimicrobial activity. In addition, we wanted to find agents that provide activity levels at the lowest possible concentration to minimize the potential for physical instability and minimize safety concerns.

Consideration of known preservatives phenylmercuric acetate, phenylmercuric nitrate, benzyl alcohol, chlorobutanol, chlorocresol and phenol and known preservatives sodium metabisulfite, sodium sulfite, sodium methyl hydroxybenzoate and sodium propyl hydroxy Even after considerable effort, including the study of benzoate, no adjuvant could be found that satisfies the needs of the present inventors. Then other available agents that may have the desired activity were investigated. We unexpectedly found edetate, which was not considered a broad spectrum antimicrobial but was an agent that met our needs. As mentioned above, edetate as sodium salt is mentioned in UK patent 1472793 as a possible metal ion separator. Sodium edetate is included in two of the many cremofo-containing examples of that patent.

Accordingly, the present invention is intended to inhibit oil-in-water emulsions prepared by emulsifying propofol dissolved in water immiscible solvents with water and stabilized with a surfactant, and further inhibiting significant growth of microorganisms (if there is an accidental external contamination) for more than 24 hours. It provides a sterile pharmaceutical composition for parenteral administration containing a sufficient amount of edetate.

Oil-in-water emulsions are distinct two-phase systems that are generally in equilibrium, effective, kinetically stable and thermodynamically unstable. This is in stark contrast to thermodynamically stable micelle formulations (eg, Cremophor EL).

The term "edateate" refers to ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, for example the disodium derivative is known as disodium edetate. In general, suitable edetates of the present invention are salts having a lower affinity for EDTA than calcium. In particular, derivatives used in the present invention include trisodium edetate, tetrasodium edetate and disodium calcium edetate. Suppresses significant growth of microorganisms for more than 24 hours in the presence of accidental external contamination (eg, in the temperature range of 20-25 ° C, growth after 10 times less than low levels of external contamination such as 10-10 ³ colony forming units) The properties of the edetate are not important so long as the function of As can be seen from the experiment, sodium calcium edetate is advantageous over other additives, but disodium edetate is special. Thus, the most preferred edetate is disodium edetate.

Typically the edetate will be present in the composition of the present invention at a concentration ranging from 3 × 10 ⁻⁵ to 9 × 10 ⁻⁴ (relative to EDTA free acid). The edetate is preferably in the range of 3 × 10 ⁻⁵ to 7.5 × 10 ⁻⁴ , for example in the range of 5 × 10 ⁻⁵ to 5 × 10 ^{−4, and in the} range of 1.5 × 10 ⁻⁴ to 3.0 × 10 ⁻⁴ More preferred, about 1.5 × 10 ⁻⁴ .

Compositions of the present invention typically comprise 0.1% to 5% by weight of propofol. It is preferred that the composition comprises 1% to 2%, in particular about 1% or about 2% by weight of propofol.

In another embodiment of the present invention, a surfactant is used to emulsify propofol alone with water. It is preferred to dissolve propofol in a water-immiscible solvent prior to emulsification.

The water-immiscible solvent is suitably present at up to 30% by weight of the composition, 5-25% is more suitable, preferably at 10-20%, in particular about 10%.

A wide range of non-miscible solvents can be used in the compositions of the present invention. Typically the water-immiscible solvent is a vegetable oil such as, for example, soybean, safflower, cotton, corn, sunflower, arachis, castor or olive oil. Alternative water-immiscible solvents include esters of medium or long chain fatty acids such as monoglycerides, diglycerides or triglycerides; Or chemically modified or prepared materials such as ethyl oleate, isopropyl myristate, isopropyl palmitate, glycerol esters or polyoxyl hydrogenated castor oils. Additional surrogate water-immiscible solvents can be dissolved oils, such as oils derived from cod liver or other fish. Suitable solvents also include fractionally distilled oils, such as fractionally distilled coconut oil or modified soybean oil. In addition, the composition of the present invention may comprise a mixture of two or more of the above water-immiscible solvents.

Propofol dissolved alone or in a water-immiscible solvent is emulsified with a surfactant. Suitable surfactants include synthetic non-ionic active agents (eg, ethoxylated ethers, ethoxylated esters and polypropylene-polyethylene block copolymers), and natural phosphatides (eg, egg (egg) and soybean phosphatides) And modified or artificially manipulated phosphatides (eg, prepared by physical fractionation and / or chromatography), or mixtures thereof. Preferred surfactants are egg phosphatides and soybean phosphatides.

The composition of the present invention is suitably formulated using alkali such as sodium hydroxide, if necessary, so as to have a physiologically neutral pH, usually 6.0 to 8.5.

The composition of the present invention is prepared to be isotonic with blood using a suitable osmotic modifier such as, for example, glycerol.

Compositions of the present invention are typically sterile aqueous formulations and are prepared using conventional manufacturing techniques such as aseptic preparation or final sterilization by autoclave operation.

The compositions of the present invention are useful as anesthetics including induction and maintenance of sedation and general anesthesia. Accordingly, a further aspect of the present invention provides a method of causing anesthesia (including soothing action and induction and induction of general anesthesia) in warm blooded animals, including humans, by emulsifying propofol alone or in a water-immiscible solvent with water and Parenterally administering an oil-in-water emulsion prepared by stabilizing with a surfactant, and additionally a sterile aqueous pharmaceutical composition comprising an effective amount of edetate.

Induces general anesthesia (eg about 2.0 mg / kg to 2.5 mg / kg in adults) and maintenance (eg about 4 mg / kg / hr to 12 mg / kg / hr) and sedative effects (eg Concentrations of propofol to provide for example from 0.3 mg / kg / hr to 4.5 mg / kg / hr can be deduced from the actual literature on propofol. Moreover, anesthesiologists and / or physicians can vary the dosage to achieve the desired effect on any particular patient according to the general art of the art.

The above-mentioned advantage of including edetate in propofol compositions is also applicable to intravenous fat emulsions that are usually administered to patients in need thereof for a period of one or more days. Intravenous fat emulsions (also known as parenteral nutritional emulsions) are generally administered by infusion to patients in need of additional calories and proper nutrition, and oral or other methods of administration are undesirable or not possible. Intravenous fat emulsions usually maintain a positive nitrogen balance and provide an appropriate energy source (eg fat), vitamins and trace elements. This emulsion is usually used in the intensive care environment but can also be used in other hospitals and home facilities. Examples of this intravenous emulsion include Intralipid (available from Pharmacia), Lipofundin (available from Brown) and Travamulsion (available from Bacter). Intralipid, Lipofundin and Travamulsion are all trade names.

In another embodiment, the present invention provides an intravenous fat emulsion comprising a sufficient amount of edetate that can inhibit the growth of significant microorganisms over 24 hours. In particular, the present invention is for parenteral administration comprising an oil-in-water emulsion prepared by emulsifying a water-immiscible solvent with water and stabilizing with a surfactant, and additionally an amount of edetate sufficient to inhibit significant growth of microorganisms for at least 24 hours. It provides a sterile aqueous composition.

In addition, various drugs have been proposed to be administered in oil-in-water emulsions (see, eg, US Pat. No. 4168308). Thus, in a further embodiment, the present invention provides an oil-in-water emulsion prepared by emulsifying a therapeutic or pharmaceutical agent alone or dissolved in a water-immiscible solvent with water and stabilized with a surfactant, and further remarkable growth of microorganisms for at least 24 hours. Provided are sterile aqueous compositions for parenteral administration comprising a sufficient amount of edetate that can be inhibited.

Suitable therapeutic or pharmaceutical agents are those that can be administered parenterally in an oil-in-water emulsion. Typically such agents are lipophilic compounds and can be, for example, antifungal agents, anesthetics, antibacterial agents, anticancer agents, antiemetic agents, agents acting on the central nerve such as diazepam, steroids, barbiturates and vitamin preparations. In particular, the present invention relates generally to oil-in-water emulsions administered to patients in need thereof for a period of one or more days.

The description of the composition and preparation of the typical and preferred propofol of the present invention can be adapted to intravenous fat emulsions and oil-in-water emulsions containing a therapeutic or pharmaceutical agent, if necessary modified.

Experiment

amount:

Produce:

All process steps are carried out under nitrogen and the weight is the weight in the final volume.

Sterile aqueous oil-in-water emulsions for parenteral administration are prepared as follows.

1. The aqueous phase is prepared from glycerol (2.25% by weight), disodium edetate dihydrate (0.0055% by weight), sodium hydroxide (typically 60 mgL ^-1 ) and water for injection. The mixture is stirred and a temperature of about 65 ° C is taken.

2. The aqueous phase is passed through a filter to remove particulates and transferred to the mixer.

3. In parallel to the above, the oily phase is prepared in soybean oil (10.0 wt.%), Propofol (1.0 wt.%) And egg phosphatide (1.2 wt.%). The mixture is stirred at a temperature of about 75 ° C. until all components are dissolved.

4. The mixture is passed through a filter to remove particulates and added to the aqueous phase through a static mixer.

5. Stir the contents of the mixer and maintain at a temperature of about 65 ° C. The mixture is circulated through a high pressure homogenizer and cooler (heat exchange system) until the desired globule size (average globule size of about 250 nm) is reached.

6. Cool the resulting oil-in-water emulsion and transfer it to the charger.

7. The emulsion is then filtered, filled into containers under nitrogen and autoclaved.

The final filtered emulsion can be filled into various volumes of containers such as ampoules (20 ml), bottles (50 ml and 100 ml) and prefilled syringes.

scheme:

Oil-in-water emulsions containing 2% by weight propofol can be prepared in a similar manner using the following amounts of components:

amount:

Oil-in-water emulsions containing 1% by weight propofol can also be prepared in a similar manner using the following amounts of components:

amount:

Biological activity

The group consisting of 10 male mice (18 g-22 g) is administered parenterally with a dose of 5 mg / kg-40 mg / kg. Sedation and anesthesia are observed in relation to dose.

Microbial Activity (Comparison)

A concentrated aqueous solution of additives was added to a commercial oil of propofol (1%) (Diprivan: trade name of Geneca Limited) to prepare a formulation comprising various additives. The pH of these formulations is about 7.5.

Four standard USP (US Pharmacopoeia) preservative efficacy test microbial juicy cultures were added to these test formulations at about 200 colony forming units per ml. Test formulations were incubated at 30 ° C. and viable counts tested 24 and 48 hours later.

result

Formulation with Sodium Metabisulfite (0.0%)

Discoloration of the formulation occurred, which shows chemical instability.

Formulation with Sodium Sulphite (0.1%)

Formulations with hydroxybenzoate (0.2% methyl / 0.02% propyl)

Formulation with Sodium Calcium Edetate (0.1%)

Formulations with disodium edetate dihydrate (0.1%)

[pH about 5.5]

Microbial activity (additional comparison results)

Washed suspensions of four standard USP (US Pharmacopoeia) preservative efficacy test microorganisms were added to these test formulations at about 100 colony forming units per ml. Test formulations were incubated at 25 ° C. and viable water was tested twice after 24 and 48 hours; The results of both cases were reported.

'Diprivan' (1% propofol)

Formulations with disodium edetate dihydrate (0.0055%)

The formulations were further evaluated for other related microorganisms.

In a similar manner, microbiological data were obtained for the formulations containing 2% propofol.

Intravenous Fat Emulsion

[Consists of soybean oil (10%), egg phosphatide (1.2%), glycerol (2.25%), sodium hydroxide (enough) and water for injection]

The intravenous fat emulsion using disodium edetate dihydrate (0.0055%)

The formulations were further evaluated for other related microorganisms.

The identified test microorganisms are Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Candida albicans ATCC 10231 to be.

In a preferred embodiment, the present invention provides an oil-in-water emulsion prepared by emulsifying propofol dissolved in a water-immiscible solvent with water and stabilized with a surfactant, and in addition to each microorganism Staphylococcus aureus ATCC 6538, S. Washed suspensions of Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027, and Candida albicans ATCC 10231, at a temperature of 20-25 ° C., at about 50 colony forming units per ml. It is added to each aliquot of the composition in the range, and the aliquot is incubated at 20-25 ° C., and measured by a test for examining surviving water after 24 hours to inhibit the growth of the microorganism by 10 times or less for 24 hours or more. It provides a sterile pharmaceutical composition further comprising a sufficient amount of edetate.

Claims (19)

An oil-in-water emulsion prepared by emulsifying propofol dissolved in a water-immiscible solvent with water and stabilized with a surfactant, and containing at least 3 × 10 ^-5 molar concentration and not more than 0.1 wt% of the following sterile pharmaceutical compositions. Sterile pharmaceutical compositions for parenteral administration. The sterile pharmaceutical composition comprising an oil-in-water emulsion prepared by emulsifying propofol dissolved in a water-immiscible solvent with water and stabilized with a surfactant and edetate, wherein the edetate is a microorganism Staphylococcus. Washed suspensions of each of Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 or Candida albicans ATCC 10231 When added to the sterile pharmaceutical composition at a temperature of 20-25 ° C. in colony forming units / ml, and measured as a test to examine the survival water after 24 hours of incubation of the sterile pharmaceutical composition at a temperature of 20-25 ° C. Sterile pharmaceutical composition, characterized in that it comprises an amount of inhibiting the growth of each microorganism by 10 times or less for at least 24 hours. Sterile for parenteral administration comprising an oil-in-water emulsion prepared by emulsifying propofol dissolved in a water-immiscible solvent with water and stabilized with a surfactant and an edetate in the range of 3 × 10 ^-5 to 9 × 10 ^-4 molarity. Sex pharmaceutical composition. 4. The sterile pharmaceutical composition according to claim 3, wherein the edetate is in the range of 1.5 × 10 ⁻⁴ to 3.0 × 10 ⁻⁴ molar concentration. The sterile pharmaceutical composition according to claim 4, wherein the edetate is at a concentration of about 1.5 x 10 ^-4 moles. 3. The mycobacterial pharmaceutical composition according to claim 1 or 2, wherein the source of edetate is disodium edetate. The sterile pharmaceutical composition according to any one of claims 3 to 5, wherein the source of edetate is disodium edetate. A sterile pharmaceutical composition according to claim 1 or 2, wherein the water-immiscible solvent is an ester of vegetable oil or fatty acid. The sterile pharmaceutical composition according to any one of claims 3 to 5, wherein the water-immiscible solvent is an ester of vegetable oil or fatty acid. The sterile pharmaceutical composition according to claim 1 or 2, wherein the surfactant is a natural phosphatide. A sterile pharmaceutical composition according to any one of claims 3 to 5, wherein the surfactant is a natural phosphatide. The sterile pharmaceutical composition according to claim 1 or 2, wherein the pH is between 6.0 and 8.5. The sterile pharmaceutical composition according to any one of claims 3 to 5, wherein the pH is between 6.0 and 8.5. Sterile pharmaceutical compositions for parenteral administration in the form of oil-in-water emulsions comprising a) to g): a) 1% by weight propofol b) 10% by weight of soybean oil c) 1.2% by weight of egg phosphatide d) 2.25% by weight of glycerol e) 0.005 wt% disodium edetate f) sodium hydroxide (amount to provide a physiological neutral pH ranging from 6.0 to 8.5) g) water (amount to fill the sterile pharmaceutical composition with a total of 100% by weight). Sterile pharmaceutical compositions for parenteral administration in the form of oil-in-water emulsions comprising a) to g): a) 2% by weight propofol b) 10% by weight of soybean oil c) egg phosphatide 1.2% by weight d) 2.25% by weight of glycerol e) 0.005 wt% disodium edetate f) sodium hydroxide (amount to provide a physiological neutral pH ranging from 6.0 to 8.5) g) water (amount to fill the sterile pharmaceutical composition with a total of 100% by weight). Sterile pharmaceutical compositions for parenteral administration in case of accidental external contamination, including the use of edtate in an oil-in-water emulsion prepared by emulsifying propofol dissolved in water-immiscible solvent with water and stabilized with a surfactant How to limit the growth of my microorganisms. Accidental use of edote in the range of 3 × 10 ⁻⁵ to 9 × 10 ⁻⁴ molarity in an oil-in-water emulsion prepared by emulsifying propofol dissolved in water-immiscible solvent with water and stabilized with a surfactant A method of limiting the growth of microorganisms in sterile, weak compositions for parenteral administration in the presence of external contamination. Sterile pharmaceuticals for parenteral administration comprising an oil-in-water emulsion prepared by emulsifying propofol with water and stabilized with a surfactant, and having an edetate not less than 3 × 10 ⁻⁵ molar concentration and not more than 0.1 wt% of the following sterile pharmaceutical composition. Composition. A method of improving the time of administration of an oil-in-water emulsion of propofol or the replacement of a giving set or both by incorporating edetate in an oil-in-water emulsion of propofol.