MXPA00007790A - Propofol composition containing sulfite - Google Patents

Abstract

Sterile pharmaceutical compositions for parenteral administration containing 2, 6-diisopropylphenol (propofol) are described for use as anesthetics. The compositions comprise an oil-in-water emulsion of propofol additionally comprising an amount of sulfite sufficient to prevent significant growth of microorganisms for at least 24 h after adventitious contamination.

Description

COMPOSITION OF PROPOFOL CONTAINING SULFIT DESCRIPTION OF THE INVENTION The present application is a continuation er. part of serial application number 09 / 021,671, filed on February 10, 1998, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION In one aspect, the present invention deals with new pharmaceutical compositions containing 2, > : -diisopropylphenol, known as propofol, and sulfite .. In another aspect, the present invention deals with the use of these compositions to elicit anesthesia. mammals, increasing sedation and induction and maintenance of general anesthesia. In still another aspect, the present invention generally deals with the use of sulfite as a preservative for oil-in-water emulsions administered parenterally. In still another aspect, the present invention relates to a process for the manufacture of oil-in-water emulsions containing sulfite as a preservative.

REF: 122029 BACKGROUND OF THE INVENTION 2,6-Diisopropylphenol, generically termed propofol, is a well-known and widely used injectable anesthetic with hypnotic properties employed both as a sedative, and as a cause and maintenance of general anesthesia. It is sold as Diprivan (Zeneca brand) for human use and Rapinovet (Zeneca brand) for veterinary use. Propofol is administered directly into the bloodstream or by bolus injection or infusion. Because the initiation of anesthesia is largely controlled by the rate of infusion of the drug through the blood-brain barrier, the lipophilicity of propofol is key to its rapid activity. This lipophilicity, however, makes propofol relatively insoluble in water, so it must be administered together with solubilizing agents, surfactants, or solvents; or as oil-in-water emulsions (Jones et al. (1998) American Patent No. 5,714,520). All the references cited here are incorporated by reference in their entirety. As an agent administered parenterally, the sterility of the -formulations of propofol is essential. Commercial formulations are oil-in-water emulsions containing approximately 1% -2% propofol in 10% soybean oil. These formulations also typically contain a surfactant, 1.2% egg phosphatide, for example, 2.25% glycerol to make the formulation isotonic, sodium hydroxide to adjust the pH to a physiological pH, and 0.005% EDTA equivalent (as edetate) to retard microbiological development (all approximate weights) (Id.). The formulations containing edetate are not preserved in antimicrobial form by American pharmacopoeia standards; however, microbial development is retarded. (Id.). The unpreserved oil-in-water propofol-emulsion formulations have significant disadvantages that arise from the fact that these formulations support microbial growth; strict aseptic handling technique is required; The maximum useful time is 12 hours after entry into the bottle. Management recommendations include immediate administration after entry into the vial, and disposition of infusion assemblies and unused material after 12 hours. However, nosocomial infection reports that result from adventitious contamination are not uncommon (Bennet et al. (1995) N. Engl. J. Med. 333: 147-154). Inappropriate management techniques include delayed administration after the transfer of the vial to the syringe, use of 50 and 100 ml products as multiple use, for multiple patients, and use of 50 and 100 ml products over a period of time. dragged on. An application for which preserved propofol formulations are particularly advantageous is their use as a long-term sedative by continuous infusion. The risk of unprotected microbial contamination of propofol in infusion devices increases both with the residence time in the infusion set and with the increased handling of the device. The useful time of the formulations containing EDTA salts (edetates) it is at least 24 hours compared to non-preserved formulations (Jones et al.). A longer formulation means that fewer manipulations are required. The resulting reduced handling accumulates a number of important benefits: reduced probability of microbial contamination, reduced operator error probability, reduced drug waste, and reduced work intensity - all of which combine to increase safety and reduce costs.

BRIEF DESCRIPTION OF THE INVENTION An extensive and vigorous evaluation of known antimicrobial agents for parenteral products led to the unexpected discovery that sulfite can be included in an oil-in-water emulsion of propofol in a non-toxic amount that is soluble in the aqueous phase and does not split in the organic phase, and that retards or suppresses the development of probable microbial contaminants, without destabilizing the emulsion and without reacting adversely with other components of the formulation. These results are especially surprising in light of the published data indicating that sodium metabisulfite is totally ineffective for this particular application (1% Diprivan (Zeneca) 0.1% Na2S205) (Jones et al.). Sodium metabisulfite is a salt of a sulfurous acid (formerly methanesulfuric acid). The present invention includes all the pharmaceutical acceptance derivatives of sulphurous acid (orthosulfuric acid) and metasulfuric acid approved by the Administration of drugs and food for human use (sulfites) and any combination thereof. These compounds include, but are not limited to, sodium sulfite, sodium bisulfite, potassium sulfite, potassium bisulfite, metabisulfite and potassium metabisulfite.

Accordingly, the present invention provides a sterile composition for parenteral administration, which comprises an oil-in-water emulsion in which propofol is dissolved in an immiscible solvent in water that is emulsified with water wherein said emulsion is stabilized by of a surfactant. The composition further comprises an amount of a sulfite sufficient to exhibit antimicrobial activity against microorganisms that have the greatest likelihood of contaminating the propofol preparation. The present invention also includes the use of sulfites as preservatives for any sterile water-in-oil emulsion administered parenterally. In addition to the propofol compositions, such formulations include total parenteral nutrition formulations, or oil-in-water carriers for other pharmaceutical or therapeutic agents. Additionally, the present invention includes a process for the manufacture of sterile oil-in-water propofol emulsions for parenteral administration comprising propofol dissolved in a water-immiscible liquid emulsified with water, wherein said emulsion is stabilized by means of a surfactant and which also includes effective amounts of a sulfite as a preservative. The timing of the addition of the sulfite and the control of the temperature of the process are both critical for the maintenance of antimicrobial activity in the composition. This aspect of the invention may be advantageously applied to other drugs formulated as an oil-in-water emulsion.

DEFINITIONS In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated otherwise: The term "edetate" refers to an anion derived from the deprotonation of EDTA . EDTA is a tetrabasic acid, so that an edetate may be mono-, di-, tri- or tetraanionic. The term "edetate" may also refer to a salt of an edetate anion. The term "oil-in-water emulsion" refers to a system other than two phases which is an equilibrium and in effect, as a whole, is kinetically stable and thermodynamically unstable. The term "condom" refers to an agent or agents that suppress or prevent microbiological development at 24 hours in no more than 10 times compared to zero-time. The term "sulfite" refers to all of the pharmaceutical acceptance derivatives of sulphurous acid (orthosulfuric acid) and metasulfuric acid approved by the Food and Drug Administration now or in the future for human use. These compounds include sodium sulfite, sodium bisulfite, potassium sulfite, potassium bisulfite, sodium metabisulfite, and potassium metabisulfite.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. The diagram for the manufacturing process for oil-in-water propofol emulsion formulations containing sodium metabisulfite.

DETAILED DESCRIPTION OF THE INVENTION The development of oil-in-water emulsion formulations containing condoms is a daunting task. The key requirements for the condom include: a. Soluble in the aqueous phase, it is not divided into the organic phase; b. Low tity, since large volumes are commonly used; c. Delay / suppression of the development of probable microbial contaminants; d. Compatibility with all other components of the formulation; and. Does not destabilize the emulsion. Many condoms currently used are lipolyfilic and thus would be ineffective for use in oil-in-water emulsions due to requirement a. The physical stability of the emulsion and the clinical performance depend critically on the particle size distribution and the number of large particles (requirement a) (Dabbah et al. (19959 in USP Open Conference-My crobi ol ogi cal Compendial Issues. from the United States Pharmacopoeia, pp. 87-96) Sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, and potassium sulfite are used in many parenteral formulations as antiants and / or antimicrobials in concentrations of 0.025 - 0.66% The antimicrobial activity, however, requires a pH in the range of 2.5 - 5.5 The oil-in-water emulsions, on the other hand, are typically formulated at a pH 6 - 9 to ensure the ionization of the groups of the phospholipid surfactants incorporated therein The resulting electrostatic repulsion favors the formation of small oil particles and discourages their coalescence Over time, we have discovered stable emulsions that contain each of the sulfite-containing compounds that fall in the range of pH 4.5 - 6.4, which nevertheless exhibit antimicrobial activity. We have also discovered a process for the manufacture of these emulsions that minimizes the loss of sulfite-containing compounds through auto-ation. While we do not wish to be limited to this mechanism, we believe that the inhibition and destruction of microorganisms by sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, and potassium sulfite is higher at higher pH values. It is believed that the primary activity of these compounds is due to the formation of sulfurous acid (H2S03) and bisulfite ions. It is believed that the antimicrobial action is due to the inhibition of the enzymatic systems, especially through the ation of SH groups in enzymes and proteins. Bisulfite ions may also interact with pyrimidine bases (Foegeding, PM and Busta, FF "Chemical Food Preservatives," pp. 802-832, in Disinfection, Sterilization and Preservation, Fourth Edition, Ed. SS Block, 1991, Pub. Lea and Febiger, William and Wiikins, Philadelphia, United States United of America). 1. Pharmaceutical Compositions The composition of the present invention comprises a sulfite, preferably a salt of the metasulfuric acid. More preferably, the sulfite is sodium metabisulfite and other sulphurous acid salts such as sodium bisulfite, sodium sulfite, potassium metabisulfite or potassium sulfite. The sulfite will typically be present in an amount from about 0.0075% to about 0.66% by weight. Preferably, the sulfite is present in the range of about 0.0075% to about 0.1% by weight and most preferably about 0.025% by weight. It will be apparent to the person skilled in the art that other sulfites may be used in these compositions and that their percentages by weight will depend on the particular sulfite employed. Maximum sulfite dosages will occur in long-term infusion situations, for example, when used as a sedative. Typical dosages of propofol are 0.3 - 3 mg / kg / h, but may range up to 10 mg / kg / h in exceptional cases, equivalent to 1.68 1 emulsion / day / 70 kg. Under these conditions, the total sulphite administered is well below the limit indicated by the World Health Organization (WHO) (7.0 mg / kg as 302) and is below the amount infused in the total amino acid formulations of parenteral nutrition , as well as during peritoneal dialysis (Gunnison and Jacobsen (1987) Cri., Rev. Toxi col 17: 186-214). The composition of the present invention typically comprises from 0.1 to 5% by weight of propofol. Preferred compositions comprise about 1% to about 2% by weight of propofol. The most preferable compositions are about 1% by weight and about 2% by weight of propofol. The propofol can be dissolved in a solvent immiscible in the pharmaceutically acceptable water and emulsified in water and said emulsion can be stabilized by means of a surfactant.; or the propofol itself may be emulsified in water without the addition of a water-immiscible solvent and said emulsion stabilized by means of a surfactant. Water-immiscible solvents suitable for the preparation of oil-in-water emulsions suitable for parenteral administration are well known to those skilled in the pharmaceutical arts (Handbook of Pharma ceuti cal Excipi en ts Wade and Weller, Eds. (1994) American Pharmaceutical Association, The Pharmaceutical Press: London, pp. 451-453). Typically, the immiscible solvent in water will be a vegetable oil: for example, soy, saffron, cottonseed, corn, sunflower, peanut and castor. The water-immiscible solvent may also be a total or partially manufactured material, for example, acid esters of mono-, di-, and triglyceride grades or chemically and / or physically modified vegetable oils. The present invention may also comprise any combination of said immiscible solvents in water. When employed, the solvent insoluble in water comprises up to about 30% by weight of the composition, preferably in the range of about 5% to about 25% by weight, more preferably in the range of about 10% to about 20% by weight, most preferably about 10% by weight. The composition of the present invention comprises a pharmaceutically acceptable surfactant that aids in the emulsification of the immiscible phase in water in water and stabilizes said emulsion (Id.). Suitable surfactants include naturally occurring surfactants: for example, egg or soy phosphatides, either in their native or modified forms; nonionic surfactants manufactured, for example, a polyethylene glycol or its esters; or any mixture thereof. Preferred surfactants are egg or soy phosphatides, for example egg yolk phospholipid. The amount of surfactant effective in the production and maintenance of a stable oil-in-water emulsion will depend on the particular formulation. The factors and their relationships are well known to those skilled in the pharmaceutical arts. These factors include the presence or absence of an immiscible solvent in the water, the solvent immiscible in the particular water used, the particular surfactant used, the presence of salts and the pH of the composition. Preferably, the total number of fat globules / 0.1 ml in the particle size range of 1-20 μm is < 600,000 and in the particle size range of 5-20 μm is < 200,000. Preferably, the% by volume of the total fat globules / 0.1 ml in the particle size range of 1-20 μm is < 0.3 and it is < 0.2 in the size range of 5-20 μm. Preferably, the average fat globule size is less than 500 nm, and more preferably less than 250 nm. The composition of the present invention is formulated with a pH in the range of about 4.5 to about 6.4. The pH may be adjusted to the extent required by the addition of an alkali, for example, sodium hydroxide, or an acid, for example, hydrochloric acid. The composition of the present invention may be rendered isotonic with blood by the incorporation of a suitable tonicity modifier, for example, glycerin (Id.). The compositions of the present invention are sterile aqueous formulations and are prepared by standard manufacturing techniques using, for example, aseptic manufacturing methods and autoclaving. The compositions of the present invention may be formulated to coincide with commercial formulations in terms of clinical performance and physical properties. Table 1 below compares the composition of the preferred embodiment of the present invention with Diprivan. Table 2 below compares the physical properties of these two formulations.

Table 1. Comparison of the formulation of a composition of the present invention with a commercial formulation.

Component Emulsion DI PRIVAN injectable Emulsion Propofol 1% injectable 1% Propofol, mg / ml 10 10 Soybean oil, mg / mL 100 100 Glycerin, mg / ml 22.5 22.5 Egg yolk phospholipid, mg / ml 12 12 Disodium edetate, mg / ml 0.05 Sodium metabisulphite, mg / ml 0.25 WFI qs a 1 mi pH 5.4 - 6.4 7.0 8.5 Diprivan trademark of Zeneca.

Table 2. Comparison of the physical properties of a composition of the present invention with a commercial formulation.

Parameter 1% Emulsion DIPRIVAN 1% injection injectable physicochemical emulsion propofol Appearance White emulsion without white emulsion without oil drops Visible visible oil drops Density 0.995 0.995 Osmolality, mg / ml 300 300 Viscosity, 1.6 1.6 - 1.7 centistokes Diprivan registered trademark of Zeneca. The following Table 3 shows that the particle size distribution of the emulsion containing sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, or potassium sulfite are comparable with Zeneca product containing 0.005% EDTA. The data show that the addition of any of the salts did not cause an increase in the number of large particles, which is a concern for injectable emulsions. The size of the particles with a submicron diameter (<1 μm) is monitored using Nicomp 370, manufactured by Particle Sizing Systems, Santa Barbara, C.A. This instrument measures an apparent size and distribution of the average particle. The size and number of fat globules greater than 1 μm are determined using the AccuSizer ™ 770 manufactured by Particle Sizinq Systems, Santa Barbara, California. This technique allows the monitoring separately of the number of particles and the volume% of the oil absorbed by these particles for the ranges of 1-20 μm and -5-20 μm in diameter.

TABLE 3 Total number% Volume of Fatty globules Size of fat globules /0.1 ml total / 0.1 ml of fat Size of Size of Size of particle size particle particle particle 1-20 μm 5. 0 μm 1-20 μ 5.20 μm Diprivan 1% Injectable Emulsion 312.911 ± 17.095 ± 0.050 ± 0.025 ± 194 ± 6 (Average of 117,479 6,398 0.019 0.010 3 different lots) Injectable emulsion of propofol 0.255% 311.894 ± 3.122 ± 0.022 ± 0.009 ± 198 ± 2 Metabisulfite 71.940 642 0.005 0.002 sodium (Average different) Propofol injectable emulsion (0.0258) of: Sodium bisulphite 100.691 3.341 0.012 0.004 201 Sodium sulphite 128.338 6.689 0.021 0.010 239 Potassium metabisulphite 156.569 6.470 0.022 0.011 197 Potassium sulphite 50.151 1.716 0.006 0.005 202 The compositions of the present invention are useful as anesthetics including sedation and the induction and maintenance of general anesthesia. Thus, in another aspect, the present invention provides a method for causing anesthesia in mammals, which comprises the parenteral administration of an aqueous and sterile pharmaceutical composition comprising an oil-in-water emulsion in which propofol is emulsified, either alone or dissolved in an immiscible solvent in water, where said emulsion is stabilized by means of a surfactant; which also comprises an effective amount of sulfite. The appropriate dosage levels for the induction of the desired degree of anesthesia, for example, sedation, or the induction or maintenance of general anesthesia, by the compositions of the present invention will depend on the type of mammal being treated and the physical characteristics of the animal. specific mammal that is being considered. These factors and their relationship in determining this amount are well known to those versed in medical techniques. Approximate dosage levels may derive from the substantial literature on propofol, may be designed to achieve maximum efficiency, and will be contingent on the thousands of factors recognized by those versed in medical techniques including weight, diet, and concurrent medication. The antimicrobial effects of sulfites may also be advantageously applied to other sterile oil-in-water emulsions for parenteral administration. Examples include total parenteral nutrition formulations and oil-in-water emulsions of other pharmaceutical or therapeutic agents. Formulations of total parenteral nutrition of oil in water emulsion are administered by infusion to patients for whom oral nutrition is impossible, undesirable or insufficient. The emulsified lipids provide a concentrated caloric content. These formulations may also contain other nutrients, for example, amino acids, vitamins and minerals. Commercial examples of such formulations include Intralipid (trademark of Pharmacia), Lipofundin (trademark of Braun), and Travamulsion (trademark of Baxter). Accordingly, the present invention provides a sterile formulation for total parenteral nutrition comprising lipids or fats emulsified in water, which further comprises an effective amount of sulfite as a preservative. A wide variety of current and potential pharmaceutical or therapeutic agents are highly lipophilic, for example, spheroids, prostaglandins, leukotrienes and fat-soluble vitamins. Such compounds may be advantageously administered in oil-in-water emulsion vehicles comprising a sulfite as a preservative, particularly when its administration will occur over a prolonged period. Accordingly, the present invention provides a sterile therapeutic composition comprising a lophophilic pharmaceutical or therapeutic agent, either alone or dissolved in an immiscible solvent in water, emulsified in water, which further comprises an amount of sulfite effective as a preservative. 2. Manufacturing process Figure 1 shows a scheme for the manufacture of compositions of the present invention.

The present invention provides a process for the manufacture of the compositions of the present invention, which comprises the steps of: 1. Preparing an aqueous phase by adding glycerin and sodium hydroxide at approximately 80% WFI in a compound-forming tank while maintaining the temperature at about 40 ° C; 2. Add the egg yolk phospholipid to said aqueous phase; 3. Homogenize said aqueous phase; 4. Filter said aqueous phase through a 5.0 μm filter; 5. Prepare an oil phase by dissolving the propofol in soybean oil; 6. Filter said oil phase through a 0.45 μm filter; 7. Combine and homogenize said aqueous and oil phases; 8. Add a solution of a dissolved sulfite compound in WFI near the end of the homogenization weight; 9. Add solution of sodium hydroxide or hydrochloric acid to adjust the pH; 10. Adjust to a specified volume with SWFI; 11. Microfluidize the crude emulsion to the target globule size and particle size distribution while maintaining the temperature at approximately 30 ° C; 12. Filter the propofol oil-in-water emulsion into a filling container; 13. Fill and seal containers under nitrogen; and 14. Subjecting said vessels to autoclave. Typically, 12 mg / l of sodium hydroxide is added in step 3. Preferably, all steps are carried out under a nitrogen atmosphere. The concentration of the sulfate addition is critical. If it dissolves in the aqueous phase in step 3 or 4, the antimicrobial activity is lost, presumably due to the loss of bisulfite during the process. Optimal antimicrobial activity was obtained when the sulfite was added in step 10. Typically, sulfite is added by a concentrated base solution of approximately 54 g / 1 after 25 minutes of homogenization. Typically, the mixture is homogenized for an additional 5 minutes. In addition, the thermal lability and sensitivity to oxidation of sulphites require precise temperature control and a nitrogen or other inert gas environment in the manufacturing process. This process may be modified to prepare other compositions of the present invention by substituting other immiscible solvents in the water for soybean oil, other surfactants for the egg yolk phospholipid, other acids or bases to adjust the pH instead of sodium hydroxide. , and / or other tonicity modifiers for glycerin. The procedure may also be modified to prepare other drugs in an oil-in-water preserved emulsion or those for parenteral nutrition. 3. Microbiological activity The ability to retard the growth of the injectable emulsion of 1% propofol containing sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, or potassium sulfite were evaluated using membrane filtration technique and cultures of broth. Approximately, in each formulation, 50-200 colony forming units (&FU) were inoculated by me of four standard organisms recommended by the United States Pharmacopeia (USP) for condom efficacy tests.

These four organisms are identified as Staphylococcus aureus (ATCC 6538), Escheri chia coli (ATCC 8739), Pseudomonas eeruginosa (ATCC 9027), and Candida albicans (ATCC 10231). In addition to these organisms, S was also tested. epidermidi s (ATCC 12228) and S. a ureus (coagulase negative, ATCC 27734). The antimicrobial activity of propofol containing sodium metabisulfite was compared with propofol containing 0.005% disodium ethylenediaminetetraacetic acid (Diprivan EDTA, trademark Zeneca), and a control propofol formulation lacking a preservative. After the inoculation of test organisms, the test formulations were incubated at 33-35 ° C. The viable count of the test organism was determined immediately following the inoculation and after 24 h of incubation at 30-35 ° C. Each data for the composition of metabisulfite is the average of eight determinations made in two fresh 20 ml bottles, two 20 ml bottles with 1 month stability, two fresh 100 ml bottles, and two 100 ml bottles with 1 ml stability. month. The Diprivan samples came from four fresh 50 ml jars. The unprotected propofol samples contained the same ingredients, except that they did not contain preservatives. The condom was considered effective if microbial growth was suppressed or an increase of not more than 10 times in development was allowed compared to the viable zero-hour account (body count immediately following inoculation) of each of the organisms test. The following Tables 4-12 compare the antimicrobial efficacy of sodium metabisulfite and other sulphite formulations with that of Diprivan and unpreserved propofol. These results indicate that sodium metabisulfite and the other sulfite compounds are competent to prevent the significant development of microorganisms for at least 29 hours after adventitious extrinsic contamination.

Table 4. Comparison of retarding activity of the microbial development of several formulations against S. a ureus (ATCC 6538).

Formulation Viable count of decrease (Number of samples) surviving survivors logl0 CFU / ml ± SD 0 h 24 h logio CFU / ml Propofol metabisulfite (8) 2.08 ± 0.28 ND 2. 08 Diprivan EDTA (4) 2.37 ± 0.26 1.55 ± 0.58 0.02 Unpreserved Propofol (2) 2.0 5.5 NA NA: Not applicable. ND: No viable organisms were detected in a 1-ml aliquot. SD: standard deviation.

TABLE 5. Comparison of retarding activity of the microbial development of several formulations against 5. epi dermidi s (ATCC 12228).

Formulation A viable reduction of (Number of samples) surviving survivors log10 CEU / ml ± SD 0 h 24 h ogio CFU / ml Propofol metabisulfite (8) 2. 27 ± 0. 04 ND 2.27 Diprivan EDTA (4) 2.20 ± 0.34 1.05 ± 0.35 0.82 Propofol unpreserved 2.4 4.55 ± 0.07 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation.

TABLE 6. Comparison of retarding activity of. the microbial activity against E. Coil (ATCC 8739) of various formulations.

Formulation A viable reduction of (Number of samples) surviving survivors logio CEU / ml ± SD 0 h 24 h Logll} CFU / ml Propofol metabisulfite (8) 2.26 ± 0.05 2.28 ± 0.13 NA Diprivan EDTA (4) 2.37 ± 0.09 0.275 ± 0.55 2. 095 Propofol unpreserved 2.3 7.25 ± 0.07 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation.

TABLE 7. Comparison of retarding activity of microbial development of several formulations against P. eeruginosa (ATCC 8739).

Formulation A viable reduction of (Number of samples) surviving survivors l CEU / ml ± SD 0 h 24 h Log10 CFU / ml Propofol metabisulfite (8) 1.97 ± 0.26 ND 1.97 Diprivan EDTA (4) 1.97 ± 0.17 2.50 ± 0.47 NA Propofol unpreserved 2.35 ± 0.07 6.8 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation.

TABLE 8. Comparison of retarding activity of microbial development against S. a ureus (coagulase negative, ATCC 27734) of various formulations.

Formulation A viable reduction of (Number of samples) surviving survivors l g1Q CEU / ml ± SD 0 h 24 h Logl? CFU / ml Propofol metabisulfite (8) 2.28 ± 0.22 ND 2.28 Diprivan EDTA (4) 2.28 ± 0.05 2.07 ± 0.28 0.80 Propofol unpreserved 3.15 ± 0.07 7.05 ± 0.07 NA NA: Applicable Nc. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation.

TABLE 9 Comparison of the retarding activity of microbial development against C. albicans (ATCC 10231) of several formulations.

Formulation A viable reduction of (Number of samples) surviving survivors l CEU / ml ± SD 0 h 24 h L L? O (g10 CFU / ml Propofol metabisulfite (8) 2.24 ± 0.08 3.13 ± 0.22 NA Diprivan EDTA (4) 2.30 ± 0.08 3.20 ± 0.28 NA Propofol unpreserved 2.3 5.10 ± 0.14 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation.

TABLE 10. Comparison of retarding activity of microbial development against E. coli (ATCC 8739) of various injectable emulsion formulations containing propofol (0.025%).

Formulation Viable count of surviving survivors' decrease log1 CEU / ml ± SD 0 h 24 h Log10 CFU / ml Injectable injectable propofol with: Sodium bisulfite 2.3 1.7 0.6 2.3 2.2 0.1 Sodium sulphite 2.3 1.3 1.0 2.3 1.4 0.9 Potassium metabisulfite 2.3 2.0 0.3 2.3 2.0 0.3 Potassium sulfite1 2.3 4.8 NA 2.3 4.7 NA Diprivan (50 ml) 2.5 0.5 2.0 2.5 0.3 2.2 Propofol without antimicrobial agent 2.3 7.3 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation. 1 The bisulfite contained 0.03 mg / ml or 0.003% potassium sulfite. The inventors believe that a higher level of potassium sulfite will improve the inhibition of microbial growth.

TABLE 11. Comparison of microbial growth retardant activity against C. albicans (ATCC 10231) of various injectable emulsion formulations of propofol containing sulfite.

Formulation Viable count of survivor survivors reduction log CEU / ml ± SD 0 h 24 h Log10 CFU / ml Injectable emulsion of propofol with: Sodium bisulfite 2.3 1.6 0.7 2.3 1.4 0.9 Sodium sulphite 2.3 ND 2.3 2.3 ND 2.3 Potassium metabisulfite 2.3 1.8 0.4 2.3 2.0 0.3 Potassium sulfite2 2.5 4.5 NA 2.4 4.5 NA Diprivan (50 ml) 2.5 3.4 NA 2.5 3.4 NA Propofol without antimicrobial agent 2.3 5.1 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ral. SD: standard deviation. 2 The formulation contained 0.03 mg / ml or 0.003% potassium sulfite. The inventors believe that a higher level of potassium sulfite will improve the inhibition of microbial growth.

TABLE 12. Comparison of the retarding activity of microbial development against P. aeruginosa (ATCC 9027) of several formulations of injectable emulsion of propofol containing sulfite (0.025%).

Formulation Viable count of survivor survivors decrease l CEU / ml ± SD 0 h 24 h Log10 CFU / ml Injectable injectable propofol with: Sodium bisulfite 1.8 ND 1.8 1.8 ND 1.8 Sodium sulfite 1.5 ND 1.5 1.4 ND 1.4 Potassium metabisulfite 2.4 ND 2.4 2.4 ND 2.4 Potassium sulfite2 2.3 ND 2.3 2.3 ND 2.3 Diprivan (50 ml) 2.5 3.4 NA 2.4 3.3 NA Propofol without antimicrobial agent 2.4 6.8 NA NA: Not applicable. ND: No viable organisms were detected in aliquots of 1 ml. SD: standard deviation. 3 The formulation contained O.03 mg / ml 6 0.003E of potassium sulfite. Despite this low concentration, potassium sulfite was still effective in inhibiting the development of P. aeruginosa.

The present invention provides a pharmaceutical preparation of propofol comprising an amount of sulfite sufficient to prevent, significantly, the development or avoid an increase of not more than 10 times in the development of each one between S. a ureus (ATCC 6538), E Coli (ATCC 8739), P. aeruginosa (ATCC 9027), and C. Albi cans (ATCC 10231), S. epiderml di s (ATCC 12228) and S. a ureus (coagulase negative, ATCC 27734). Preferably, the sulfite is sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, or potassium sulfite. In addition, in the case of inadequate aseptic handling of the finished product leading to accidental extrinsic contamination, the present formulation will suppress, minimize or limit the possibility of microbial development for at least 24 hours.

EXAMPLES The preferred compositions are as follows: 1% propofol emulsion for injection: a. about 1% propofol; b. about 10% by weight of soybean oil; c. approximately 2.25% by weight of glycerin; d. about 1.2% by weight of egg yolk phospholipid; and. approximately 0.025% by weight of sulfite; F. sodium hydroxide; g. water up to 100%. 2% propofol emulsion for injection: a. approximately 2% propofol; b. about 10% weight of soybean oil; c. approximately 2.25% by weight of glycerin; d. about 1.2% by weight of egg yolk phospholipid; and. approximately 0.025% by weight of sulfite; F. sodium hydroxide; g. water up to 100%. Preferably, these formulations have a pH of about 4.5-6.4. The foregoing examples of the compositions and methods of manufacturing the same are for illustrative purposes and the invention is not limited to them in any way.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (53)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A sterile pharmaceutical composition for parenteral administration, which comprises an oil-in-water emulsion in which the propofol is dissolved in a solvent immiscible with the water is emulsified with water and stabilized by a surfactant, and also comprises a sufficient amount of sulfite to prevent an increase of not more than 10 times in the development of each of S taphyl ococcus a ureus (ATCC 6538), Escheri chi a coli (ATCC 8739), Pseudomonas aairugi nosa (ATCC 9027) and Candi da albi cans (ATCC 10231) for at least 24 hours according to the measurement with a test in which a suspension of each organism is added as a separate aliquot of said composition to approximately 50 colony forming units per ml and incubated at a temperature of the range of 30 - 35 ° C and are tested to determine viable accounts of said organisms after 24 hours.

2. The sterile pharmaceutical composition according to claim 1, wherein the sulfite is selected from the group consisting of sodium metabisulfite, sodium sulfite, sodium bisulfite, potassium metabisulfite and potassium sulfite.

3. The sterile pharmaceutical composition according to Claim 2, wherein said sulfite is sodium metabisulfite.

4. The sterile pharmaceutical composition according to Claim 1, which comprises up to about 30% by weight of an immiscible solvent in water.

5. The sterile pharmaceutical composition according to Claim 4, which comprises from about 10% to about 20% by weight of an immiscible solvent in water.

6. The sterile pharmaceutical composition according to claim 1, wherein the immiscible solvent in water is a vegetable oil or ester of a fatty acid.

7. The sterile pharmaceutical composition according to Claim 6, wherein the vegetable oil is soybean oil.

8. The sterile pharmaceutical composition according to Claim 1, wherein the surfactant is a naturally occurring phosphatide.

9. The sterile pharmaceutical composition according to Claim 8, wherein the phosphatide is egg phosphatide or soy phosphatide.

10. The sterile pharmaceutical composition according to Claim 1, wherein the pH is between about 4.5 to about 6.4.

11. The sterile pharmaceutical composition according to Claim 10, wherein the sodium hydroxide is present.

12. The sterile pharmaceutical composition according to Claim 1, which is isotonic with blood.

13. The sterile pharmaceutical composition according to Claim 12, which is made isotonic with blood by the incorporation of glycerin.

14. The sterile pharmaceutical composition according to Claim 1, which comprises from about 1% to about 2% by weight of propofol.

15. The sterile pharmaceutical composition according to claim 14, which comprises about 1% by weight of propofol.

16. The sterile pharmaceutical composition according to claim 14, which comprises about 2% by weight of propofol.

17. The sterile pharmaceutical composition for parenteral administration which comprises an oil in water emulsion in which the propofol is dissolved in an immiscible solvent in water, emulsified with water, and stabilized by means of a surfactant, and which further comprises an amount of sulfite in which the amount of sulfite is in the range of about 0.0075% to about 0.66% by weight.

18. The sterile pharmaceutical composition according to Claim 17, wherein the amount of sulfite is in the range of about 0.0075% to about 0.1% by weight.

19. The sterile pharmaceutical composition according to Claim 18, wherein the amount of sulfite is about 0.025% by weight.

20. The sterile pharmaceutical composition according to Claims 17, 18 or 19, which comprises up to 30% by weight of an immiscible solvent in water.

21. The sterile pharmaceutical composition according to Claim 20, which comprises from 10% to about 20% by weight of an immiscible solvent in water.

22. The sterile pharmaceutical composition according to Claims 17, 18, or 19, wherein the immiscible solvent is a vegetable oil or ester of a fatty acid.

23. The sterile pharmaceutical composition according to Claim 22, wherein the vegetable oil is soybean oil.

24. The sterile pharmaceutical composition according to Claims 17, 18, or 19 wherein the surfactant is a naturally occurring phosphatide.

25. The sterile pharmaceutical composition according to Claim 24, wherein the phosphatide is an egg phosphatide or soy phosphatide.

26. The sterile pharmaceutical composition according to Claims 17, 18 or 19, wherein the pH is between about 4.5 to about 6.4.

27. The sterile pharmaceutical composition according to Claim 26, wherein the sodium hydroxide is present.

28. The sterile pharmaceutical composition according to claims 17, 18 or 19, which is isotonic with blood.

29. The sterile pharmaceutical composition according to Claim 28, which is made isotonic with blood by the incorporation of glycerin.

30. The sterile pharmaceutical composition according to Claims 17, 18 or 13, which comprises about 1% to about 2% by weight of propofol.

31. The sterile pharmaceutical composition according to Claim 30, which comprises about 1% by weight of propofol.

32. The sterile pharmaceutical composition according to Claim 30, which comprises about 2% by weight of propofol.

33. The sterile pharmaceutical composition according to Claim 17, wherein the sulfite is selected from the group consisting of sodium metabisulfite, sodium sulfite, sodium bisulfite, potassium metabisulfite and potassium sulfite.

34. The sterile pharmaceutical composition according to Claim 33, wherein said sulfite is sodium metabisulfite.

35. A sterile pharmaceutical composition for parenteral administration which comprises by weight: a. about 1% propofol; b. approximately 10% soybean oil; c. approximately 2.25% glycerin; d. about 1.2% egg yolk phospholipid; and. about 0.025% of any one of sodium metabisulfite, sodium bisulfite, potassium metabisulfite, or potassium sulfite, or any combination thereof; F. sodium hydroxide; and g. water up to 100%.

36. A sterile pharmaceutical composition for parenteral administration which comprises by weight: a. approximately 2% propofol; b. approximately 10% soybean oil; c. approximately 2.25% glycerin; d. about 1.2% egg yolk phospholipid; and. about 0.025% of any one of sodium metabisulfite, sodium bisulfite, potassium metabisulfite, or potassium sulfite, or any combination thereof; F. sodium hydroxide; and g. water up to 100%.

37. A sterile pharmaceutical composition for parenteral administration, which comprises an oil in water emulsion in which the propofol is emulsified with water, and stabilized therewith by means of a surfactant, and which also comprises an amount of sulfite sufficient to avoid an increase of not more than 10 times in the development of each of Staphyl ococcus aureus (ATCC), Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027) and Candida albi cans (ATCC 10231) for at least 24 hours, with the measurement being made - by a test in which a washed suspension of each organism is added to a separate aliquot of said composition at about 50 colony forming units per ml and incubated at a temperature in the range of 30-35 ° C and tested to determine viable counts of said organisms after 24 hours.

38. A sterile composition of total parenteral nutrition for parenteral administration which comprises an oil in water emulsion in which a lipid is emulsified with water and which further comprises an amount of sulfite sufficient to avoid an increase of not more than 10 times in the development of each of Staphyl ococcus aureus (ATCC), Escherichia coli (ATCC 8739), Pseudomonas s eruginosa (ATCC 9027) and Candi da albi cans (ATCC 10231) for at least 24 hours, with the measurement being made by a Test in which a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony forming units per ml and incubated at a temperature in the range of 30-35 ° C and tested to determine viable counts of said organisms after 24 hours.

39. A sterile pharmaceutical composition for parenteral administration which comprises an oil in water emulsion in which a lipophilic pharmaceutical or therapeutic agent is dissolved in a water immiscible solvent, emulsified with water, and stabilized by a surfactant and further comprising an amount of sulfite sufficient to avoid an increase of not more than 10 times in the development of each of Staphyl ococcus aureus (ATCC), Escheri chia coli (ATCC 8739), Pseudomonas eruginosa (ATCC 9027) and Candi da albi cans (ATCC 10231) for at least 24 hours, with the measurement being made by a test in which a washed suspension of each organism is added to an aliquot separately from said composition at approximately 50 colony forming units per me and incubated at a temperature of the range of 30 - 35 ° C and are tested to determine the viable accounts of said organisms after 24 hours.

40. A sterile pharmaceutical composition for parenteral administration which comprises an oil-in-water emulsion in which a lipophilic pharmaceutical or therapeutic agent is emulsified with water and stabilized therein by a surfactant, and which further comprises an amount of sulfite sufficient to avoid an increase of not more than 10-fold in the development of each of Staphyl ococcus a ureus (ATCC), Escheri chia coli (ATCC 8739), Pseudomonas eruginosa (ATCC 9027) and Candida albi cans (ATCC 10231) for at least 24 hours, with the measurement being made by a test in which a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony forming units per ml, and incubated at a temperature of the range of 30 - 35 ° C and are tested to determine the viable accounts of said organisms after 24 hours.

41. A method for causing anesthesia which comprises the parenteral administration of a composition comprising an oil in water emulsion in which propofol is dissolved in an immiscible solvent in water, emulsified with water and stabilized therein by means of a surfactant, and also comprising an amount of sulfite sufficient to prevent an increase of not more than 10 times in the development of each of Staphyl ococcus a ureus (ATCC), Escheri chi a coli (ATCC 8739), Pseudomonas eruginosa (ATCC) 9027) and Candi da albi cans (ATCC 10231) for at least 24 hours, with the measurement being made by a test in which a washed suspension of each organism is added to an aliquot separately from said composition at approximately 50 forming units of colony by me and incubated at a temperature in the range of 30-35 ° C and tested to determine the viable counts of said organisms after 24 hours.

42. The method for causing anesthesia according to Claim 41, wherein the method of administration is by intravenous injection. '

43. The method for causing anesthesia according to Claim 42, wherein the injection is administered with a single injection

44. The method for causing anesthesia in accordance with Claim 42, wherein the injection is administered by multiple injections.

45. The method for causing anesthesia according to claim 41, wherein the method of administration is by continuous infusion.

46. A method for maintaining anesthesia which comprises the parenteral administration of a composition, which comprises an oil in water emulsion, in which the propofol is dissolved in an immiscible solvent in water, emulsified with water and stabilized by means of a surfactant and also comprising an amount of sulfite sufficient to prevent an increase of not more than 10 times in the development of each of Staphyl ococcus aureus (ATCC), Escheri chi a coli (ATCC 8739), Pseudomonas eruginosa (ATCC) 9027) and Candi da albi cans (ATCC 10231) for at least 24 hours, with the measurement being made by a test in which a washed suspension of each organism is added to an aliquot separately from said composition at approximately 50 colony forming units per mi and incubated at a temperature in the range of 30-35 ° C and tested to determine the viable counts of said organisms after 24 hours.

47. The method for maintaining anesthesia according to Claim 46, wherein the method of administration is by multiple bolus injections.

48. The method for maintaining anesthesia according to Claim 46, wherein the method of administration is by continuous infusion.

49. A method of sedation which comprises parenteral administration of a composition, which comprises an oil-in-water emulsion in which propofol is dissolved in a water-immiscible solvent, emulsified with water and stabilized therein by means of a surfactant, and which also comprises an amount of sulfite sufficient to prevent an increase of not more than 10 times in the development of each of Staphylococcus a ureus (ATCC), Escheri chia coli (ATCC 8739), Pseudomonas eruginosa (ATCC 9027) and Candi da albi cans (ATCC 10231) for at least 24 hours, with the measurement being made by a test in which a washed suspension of each organism is added to a separate aliquot of said composition at approximately 50 colony forming units by me. and incubated at a temperature in the range of 30-35 ° C and tested to determine the viable counts of said organisms after 24 hours.

50. The method of sedation according to claim 49, wherein the method of administration is by continuous infusion.

51. The process for manufacturing the compositions of Claims 17, 35 or 36, which comprises the steps of: a. Degassing the water for injection (WFI) by spraying with nitrogen: b. Prepare an aqueous phase by adding glycerin and sodium hydroxide to approximately 80% water for injection (WFI) in a compound-forming tank while maintaining the temperature at about 40 ° C; c. Add the egg yolk phospholipid to said aqueous phase; d. Homogenize said aqueous phase; and. Filter said aqueous phase through a 5.0 μm filter; F. Prepare an oil phase by dissolving propofol in soybean oil; g. Filter said oil phase through a 0.45 μm filter; h. Combine and homogenize said aqueous and oil phases; i. Add a solution of any one of sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, or potassium sulfite, or any combination thereof, dissolved in water for injection near the end of the homogenization step; j. Add sodium hydroxide or hydrochloric acid solution to adjust the pH; k. Adjust the volume with SWFI; 1. Microfluidize the crude emulsion to achieve the target globule size and particle size distribution while maintaining the temperature at about 30 ° C; m. Filter the oil in propofol water emulsion in a filling container; n. Fill and cool the containers under nitrogen; I. Submit said containers to autoclave.

52. The method of Claim 51, wherein all of said steps are carried out under an inert temperature.

53. The method of Claim 52, wherein said inert atmosphere is a nitrogen atmosphere.