Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions

Definitions

• the present invention relates to a novel composition for injection including propofol and a preparation method of the same.
• Propofol (2,6-disopropylphenol) is a short-acting and quickly metabolized general anesthesia. Its high rate of metabolization leaves almost no residue in the body, so it is useful not only for short term anesthesia but also for long term anesthesia. Moreover, propofol enables better control of the depth of anesthesia while a patient is under anesthesia, and patients in general recover quickly from the anesthetic state. When patients recover, they are in a fully conscious state and hardly experience any adverse drug reactions like nausea, emesis, and others.
• an injectable propofol composition uses Cremophor EL as a surfactant, anaphylactoid reactions occur.
• lipids such as soybean oil, egg lecithin, and others are used as the solubilizer of a microemulsion, a high dose of svch lipids for a long surgery may cause side effects including hyperlipidemia, thrombosis and so on.
• extra caution is required in handling formulations thereof.
• Another object of the present invention is to provide a preparation method of the injectable composition described above.
• an injectable composition that comprises propofol at a concentration of about 1-2% w/v, poloxamer 188 at a concentration of about 6-15% w/v, macrogol about 15 hydroxystearate at a concentration of about 0.2-1% w/v, and edetate at a concentration of about 0.0001-0.001% w/v.
• a preparation method of an injectable composition which comprises: a) dissolving about 6-15% w/v poloxamer 188 in purified water; b) adding about 1-2% w/v propofol to the solution of step a) and stirring the mixture; c) adding macrogol 15 hydroxystearate and edetate to the mixture of step b) until the mixture contains about 0.2-1% w/v macrogol 15 hydroxystearate and about 0.0001-0.001% w/v edetate at room temperature; and d) adding a pH-control agent to adjust a pH value of the resulting solution of step c) to be roughly between 6.0 and 8.5.
• An injectable propofol composition according to a preferred example of the present invention is safe even for high-dose administration, remains transparent during a storage period, and is thermodynamically stable, thereby being sterilizable under high pressure steam. Further, the inventive composition shows no change in transparency and particle size when it is mixed in aqueous solution or stored at high and low temperatures.
• An injectable composition according to a preferred example of the present invention contains about 1-2% w/v propofol, about 1-6% w/v poloxamer 188, about 0.2-1% w/v marcrogol 15 hydroxy-stearate, about 0.0001-0.001% w/v edetate, glycerin, sodium ascorbate, and sodium hydroxide.
• a microemulsion is a kind of emulsifiable concentrate (or emulsion)that is transparent or diaphanous unlike regular emulsions.
• the microemulsion can be prepared as a thermodynamically stable formulation consisting of micro-particles not larger than 100 nm.
• An injectable composition according to one example of the present invention is a transparent microemulsion having a particle size not larger than 100 nm, and can undergo a sterile filtration as well as high pressure steam sterilization (described later). Because the microemulsion is transparent, it can be visually examined to detect any foreign matters therein. Also, the microemulsion formulations have become simplified and a possible risk of contamination from foreign matter can be prevented in advance.
• the injectable composition according to a preferred example of the present invention contains about 1-2% w/v propofol.
• Propofol (2,6-disopropylphenol) is used for induction and maintenance of general anesthesia, sedation of mechanically ventilated intensive care patients, and others.
• 1.5-2.5 mg/kg propofol is used to induce general anesthesia
• propofol blood concentration for maintenance of clinical anesthesia ranges from 2-10 ⁇ g/ml with an actual dose of 4-12 mg/ hr/kg.
• the injectable composition according to a preferred example of the present invention is safe even under high-dose conditions like lL/day.
• An injectable propofol composition may be pharmaceutically unstable due to a reversible oxidative reaction. Even though propofol exists in the form of a colorless monomer, it can be converted through oxidation to form yellow propofol dimmer quinine (Free Radical and Drug Oxidation Products in an Intensive Care Unit Sedative: Propofol with Sulfite. Max T. Baker, Marc S. Gregerson, Sean M. Martin, Garry R. Buettner. Crit Care Med 2003, Vol. 31, No. 3, 787-792). This discoloration is reversible and sometimes oxurs corresponding to an energy state.
• propofol is colorless or transparent in a high energy state (i.e., catalyzed by light), but becomes yellowish in a low energy state (i.e., in the absence of light), which is reversible.
• the injectable composition according to a preferred embodiment of the present invention contains about 0.0001-0.001% w/v edentate to overcome the pharmaceutical instability caused by the reversible oxidative reaction of propofol.
• Edetate means Ethylenediamine Tetraacetic Add (EDTA) and its derivatives.
• EDTA Ethylenediamine Tetraacetic Add
• disodium derivative is known as edentate disodium.
• Edetate above a certain concentration demonstrates inhibition of microbial proliferation, but it does not show such effects within the concentration range used for the injectable composition according to a preferred example of the present invention.
• edetate is not involved in the inhibition of microbial proliferation for the injectable composition according to a preferred example of the present invention, it may be utilized to overcome the pharmaceutical instability of the composition caused by the reversible oxidation of propofol.
• edetate as a chelating agent, is capable of not only suppressing a reaction with a very small amount of metal ions through chelating in solution phase, but also removing free radicals in the solution to suppress oxidative reactions by ions.
• about 0.0001-0.001% w/v, more specifically, about 0.0001-0.0008% w/v edetate can prevent yellowing of a propofol composition and serve to maintain a colorless, transparent propofol formulation.
• the injectable composition according to a preferred example of the present invention contains about 6-15% w/v poloxamer 188 as a surfactant.
• poloxamers are non-(cyto)toxic polymer surfactants and poly(a-oxyethylene-b-oxypropylene-a-oxyethylene) triblock copolymers. They usually have good water solubility, but properties of individual poloxamer are substantially diverse.
• the pharmaceutical compatibility of various poloxamers are well established, and particularly poloxamer 407 and poloxamer 188 (P407 and Pl 88) were approved for parenteral administration.
• poloxamer 188 is used for intravenous injection and no adverse effect has been reported for the clinical use of propofol at a dose of 2960 mg/kgfor a day (Safety of Purified Poloxamer 188 in Sickle Cell Disease: Phase I Study of a Non-ionic Surfactant in the Management of Acute Chest Syncrome. Samir K. Ballas, Beatrice Files, Lori Lirhtman- Jones, Lennette Benjamin, Paul Swerdlow. Hemoglobin 2004, Vol. 28, No. 3, 85-102), again confirms the safety of clinical use of the high-dose injectable propofol composition. Suppose that an injectable propofol composition was used at a dose of 2960 mg/kg for a day.
• a clinically permitted concentration of poloxamer 188 can be about 15% w/v.
• Poloxamer is a block copolymer composed of hydrophilic polyoxyethylene and hydrophobic polyoxypropylene and forms micelles, in which the hydrophobic region is sealed inside while the hydrophilic (or water-soluble) region is hydrated by outside water.
• the injectable composition according to a preferred example of the present invention contains poloxamer 188 at about 10-15% w/v concentration.
• poloxamer 188 at about 10-15% w/v concentration.
• propofol can be dissolved in poloxamer 188 at about 6% w/v concentration
• a suitable concentration for poloxamer 188 is above about 10% w/v, 10.1% w/v for example, so that phase stability can be maintained even when poloxamer 188 is mixed with an aqueous solution or another injection formulation for clinical use.
• Poloxamer 188 at about 15% w/v concentration or less is safe for clinical use.
• the injectable composition according to a preferred embodiment of the present invention contains about 0.2-1% w/v, more specifically, about 0.7-1% w/v macrogol 15 hydroxystearate (Solutol HS 15T, BASF, Germany).
• phase stability of the injectable composition according to a preferred embodiment of the present invention is secured by containing about 0.2-1% w/v macrogol 15 hydroxyestearate.
• an injectable composition containing about 0.1% macrogol 15 hydroxystearate can become turbid or opaque when it is diluted in an aqueous solution. If poloxamer 188 was the only solubilizer used, particles in the injectable composition may become larger at a low temperature and the composition can become turbid again. However, with use of macrogol 15 hydroxystearate as a supplementary solubilizer together with poloxamer 188, the injectable composition of the present invention becomes pharmaceutically stable at all temperatures. Meanwhile, if macrogol 15 hydroxystearate with greater than about 1% w/v concentration is used at high doses, stability of the composition can be problematic and the composition may become white-turbid during the high-pressure steam sterilization process.
• the injectable composition according to a preferred embodiment of the present invention contains about 0.2-1% w/v macrogol 15 hydroxystearate and about 6-15% w/v poloxamer 188, and can be sterilizable under high-pressure steam conditions. Sterile filtration through sterile works or a sterile filter is exposed to high contamination during a preparation process, and the preparation process is not only difficult but also costly. As such, the high pressure steam sterilization is the next preferable option to prepare an aseptic composition for injection, provided that the composition is thermodynamically stable so as not to undergo any phase change through high pressure sterilization and become turbid again. As discussed earlier, the injectable composition according to a preferred embodiment of the present invention does not experience changes in particles or transparency even under high pressure sterilization conditions.
• the injectable composition according to a preferred embodiment of the present invention contains an anti-oxidant.
• the anti-oxidant include, but are not limited to, sodium ascorbate, ascorbic add, sulfite compounds, cystein, propylgallate, thiodipropionic add, monothioglycerol and others.
• sodium ascorbate may be used as an anti-oxidant, an oxidative reaction of propofol is suppressed so that the injectable composition can maintain the same phase before and after the high pressure steam sterilization.
• Sodium ascorbate may be used at a concentration of about 0.005-4.8% w/v, and more spedfically at a concentration of about 0.005-0.1%.
• the injectable composition according to a preferred embodiment of the present invention may contain a pH-control agent such as sodium hydroxide if needed to be physiologically neutral with a pH typically between 6.0 and 8.5.
• a pH-control agent such as sodium hydroxide
• examples of the pH-control agent include, but are not limited to, sodium hydroxide, dtric add, acetic add, phosphoric add, gluconic add, ascorbic add, succinic add, and others.
• the injectable composition according to a preferred embodiment of the present invention may contain a proper osmotic modifier to become isotonic with blood.
• a proper osmotic modifier include, but are not limited to, glycerin, trehalose, dextrose, solbitol, mannitol, and others.
• the injectable composition according to a preferred embodiment of the present invention does not experience physical changes in particle size, phase and so on in the presence of other drugs, it can be mixed with other aqueous solutions or drugs for clinical use. Further, it is very stable at all temperatures and there is hardly any change in particle size or phase due to temperature changes which may occur during distribution of propofol formulations. [27] In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention.
• an injectable composition according to a preferred example of the present invention, about 6-15% w/v poloxamer 188 is first dissolved in purified water, and about 1-2% w/v propofol is added thereto and stirred together. Then, macrogol 15 hy- droxystearate and edetate are added to the mixture at room temperature to obtain macrogol 15 hydroxystearate with a concentration of about 0.2-1% w/v and edetate with a concentration of about 0.0001-0.001% w/v in the mixture. Next, a pH-control agent is added to control the pH of the composition to be roughly between 6.0 and 8.5.
• the injectable composition prepared by a preferred example of the present invention takes a transparent microemulsion form.
• the injectable propofol composition of the present invention maintains its transparent phase even after the high pressure steam sterilization treatment.
• the preparation method of an injectable composition according to a preferred example of the present invention may further include adding an anti-oxidant, before adding a pH-control agent to adjust the solution to roughly between 6.0 and 8.5.
• the preparation method of an injectable composition according to a preferred example of the present invention may further include adding an osmotic modifier, before adding a pH-oontrol agent to adjust the solution to roughly between 6.0 and 8.5.
• poloxamer 188 is added at a concentraion of about 10-15% w/v.
• macrogol 15 hydroxystearate is added at a concentration of about 0.5-0.7% w/v.
• an injectable propofol microemulsion is prepared as follows. Every step of the preparation process takes place under nitrogen purging and the weight of each one of the ingredients is a weight in a final volume. 1Og of Poloxamer 188 was dissolved in 80 ml of distilled water, and Ig of propofol was added thereto at about 60-7ObC and stirred together for about 2 hours. The mixture containing propofol was then left aside at room temperature. Later, the mixture was added with 0.7g of macrogol 15 hydroxystearate, followed by Ig of glycerin, O.Olg of sodium ascorbate, and 0.0008g of disodium edetate.
• the pH of the resulting composition was adjusted to 8 by sodium hydroxide. After the pH adjustment, a nitrogen fill was performed, followed by a filtration step at about 121 0 C for about 20 minutes with the aid of a high-pressure sterilizer (SH-29A, Human sciences). Lastly, the pH of the resolution solution was adjusted to a final pH of about 7.
• EXAMPLE 2 [41] The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that poloxamer 188 content was about 15% w/v (refer to Table 2).
• EXAMPLE 3 The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that macrogol 15 hydroxystearate content was about 0.5% w/v (refer to Table 3).
• EXAMPLE 4 [47] The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that macrogol 15 hydroxystearate content wsa about 0.2% w/v (refer to Table 4).
• EXAMPLE 5 [50] The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that macrogol 15 hydroxystearate content was about 1% w/v (refer to Table 5).
• EXAMPLE 6 The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that disodium edetate content is about 0.0001% w/v (refer to Table 6).
• EXAMPLE 7 [56] The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that the disodium edetate content was about 0.001% w/v (refer to Table 7).
• EXAMPLE 8 [59] The same procedure as Example 1 was carried out to obtain an injectable propofol formulation having essentially the same composition as Example 1, except that the disodium edetate content was about 0.005% w/v (refer to Table 8).
• a propofol formulation was prepared as follows. 6g of poloxamer 188 was dissolved in 80 ml of purified water, and Ig of propofol was added thereto. The mixture was stirred until the resulting solution became transparent. Afterwards, glycerin was pipetted to a desired scale mark, and the pH of the resulting microemulsion was adjusted to 8 by sodium hydroxide. After the pH adjustment, a nitrogen fill was performed, followed by a filtration step at 121 0 C for about 20 minutes with the aid of a high-pressure sterilizer (SH-29A, Human sciences). Lastly, the pH of the resolution solution was adjusted to a final pH of about 7.
• SH-29A high-pressure sterilizer
• Examples 1-8 showed no change in their phase and transparency before and after high pressure steam sterilization treatment, but some phase changes were observed in the Comparitive Examples.
• Comparitive Examples 1-5 were colorless and transparent at the time of formulation, but were subjected to oxidative reactions and became yellowish after the high pressure steam sterilization treatment. Meanwhile, examples containing sodium ascorbate remain colorless even after the high pressure steam sterilization treatment.
• Comparitive Example 3 having a high content of macrogol 15 hydroxystearate became turbid or opaque after the high pressure steam sterilization treatment and its phase became unstable.
• Example 5 containing about 1% w/v macrogol 15 hydroxystearate kept its transparency throughout the high pressure steam sterilization treatment, but it became white-turbid when the content of macrogol 15 hydroxystearate was increased above 1% w/v.
• EXPERIMENT 2 Stability test [89] After the Examples and Comparitive Examples were sterilized at 121 0 C for 20 minutes under high pressure steam conditions, they were left aside for 1 month at a relative humidity of 75% and at room temperature and 4O 0 C, respectively, and for 1 day in the absence of light. Using the same method as Experiment 1, the optical transmittance of each of the examples was measured.
• edetate as a chelating agent, is capable of not only suppressing a reaction with a very small amount of metal ions through chelating in solution phase, but also removing free radicals in the solution to suppress oxidative reactions by ions.
• a propofol anesthetic agent is usually mixed in another aqueous solution. Therefore, it is essential that the propofol anesthetic agent does not ⁇ p though any phase change in the presence of an aqueous solution.
• Examples and Comparitive Examples were diluted in 0.9% physiological saline, 5% glucose solution, and Hartmann's solution at various concentrations, and optical transmittance of each one of the examples was measured by applying the same method as Experiment 1. Table 18 below shows observation results when the examples were diluted to 1/10 concentration in each one of the aqueous solutions.
• Comparative Example No.7 containing 0.1% w/v macrogol 15 hydroxystearate lost its transparency when it was diluted in an aqueous solution and became turbid.
• Escherichia coli, Pseudomonas aeruginosa and Candida albicans were incubated respectively in 1 ml of a water-cleansed suspension at a temperature in the range of 20-25 0 C. After 24 hour-, 48 hour-, and 7 day- incubation, the number of surviving microorganisms in each incubator (or culture plate) was counted.
• Test formulations were prepared by the same process but with varying concentrations of edetate, i.e., 0 %(CO. EX. 6), 0.0008% (EX.l), 0.001% (EX. 5), and 0.005% (EX. 6). Test results are shown in Table 20 below.

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