RU2535001C1 - Microcolloidal solution of propofol for anaesthesia - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: aqueous composition for anaesthesia is proposed, which comprises propofol as an active agent, the PEG-660-12-hydroxystearate as a solubiliser, benzyl alcohol, or chloroethanol or parabens as preservative, the tocopherol and arginine or glycine at a specific content of components wt %. The GABA agonists can be additionally added to the composition, e.g. aminophenyl-butyric acid, local anesthetics such as lidocaine, alpha-2-adrenoceptor agonists such as xylazine. The method is proposed for implementing anaesthesia comprising administering to a patient of an effective amount of the claimed composition.

EFFECT: invention provides low toxicity of dosage form and high efficiency.

5 cl, 3 tbl, 1 ex

Description

The invention relates to the field of medicine and veterinary medicine and can be used to induce and maintain anesthesia.

Propofol (2,6-diisopropylphenol) is a short-acting anesthetic that is used to induce and maintain general anesthesia and sedation with local surgery. Propofol preparations are administered in a single intravenous dose or in a repeated dose in the form of a bolus, continuous infusion is also possible.

Propofol was first obtained in the research unit of ICI Corporation (Great Britain) through chemical synthesis. In the 70-80 years of the last century, ICI received several patents for the composition and use of propofol as an anesthetic - US Pat. 4056635 "2,6-Diisopropylphenol as an anesthetic agent", US Pat. 4452817 "Anesthetic composition containing 2,6-Diisopropylphenol", US Pat. 4798846 "Pharmaceutical compositions". These patents disclose water-based organic formulations containing, as a solubilizer, Cremophor EL (polyoxyethylated castor oil) or other similar compounds.

Subsequently, with the widespread use of cremophor-based drugs, a large number of patients had numerous anaphylactic (allergic) reactions and these drugs were withdrawn from medical practice.

The main necessary condition for the bioavailability and effectiveness of the propofol dosage form is its solubility in water. Propofol is a hydrophobic substance and can be mixed with water only in the presence of solubilizers (surfactants). However, most surface-active substances (surfactants) are not compatible with humans and animals, therefore, development was carried out only with surfactants permitted by pharmacopoeias.

The best-known propofol-based drug composition contains, as an emulsifier / solubilizer, a mixture of soybean oil and egg lecithin and has the following composition:

Propofol - 1%; Refined soybean oil - 10%; Egg lecithin - 12%; Glycerin - 22.5%; Sodium hydroxide - up to pH 8.5; Water - up to 100%. When these substances are mixed with water, an opaque white emulsion is obtained, which is very sensitive to temperature changes.

In 1986, Astra-Zeneca (Great Britain) introduced this formulation into the medical and veterinary market under the commercial name Diprivan, for Rapinovet veterinary medicine. This drug was widely used in world anesthesiology, but already in the first years of use, the main drawback of this drug was identified - instability to microbial contamination and, as a result, the threat of general infection of the patient. The reason for this instability is the great sensitivity of the emulsion to the presence of ionic and hydrophobic compounds, since this violates the surface charge of the microdroplets of the emulsion and leads to delamination of the solution. Therefore, the developers refused to introduce preservatives, antioxidants and other substances into the formulation that affect the physicochemical stability of the drug.

Subsequently, Astra-Zeneca employees tried to improve this formulation in the following patents: RF Patent No. 2147432 "Oil-in-water emulsions containing propofol and edetate" and US Pat. 7125909 "Sterile parenteral nutrition compositions". In these patents, resistance to microbial contamination was increased to 24 hours due to the introduction of sodium edetate (EDTA) in the formulation, but this is also insufficient due to the high consumption of the drug and the weak antimicrobial effect of EDTA.

Patents are known in which poloxamers (pluronics) are used as a solubilizer: RF patent No. 2250101 "Anesthetic formulations", US Pat. 4798846 "Pharmaceutical compositions", US Pat. 6623765 "Microemulsion and micelle systems for solubilizing drugs", US Pat. 7915317 "Aqueous 2,6-diisopropylphenol pharmaceutical compositions", US Pat. 6743436 "Anesthetic composition for intravenous injection resulting propofol", WO / 2003/017977 "Anaesthetic formulations of propofol". In these patents, the formulations of the propofol dosage form are as follows: propofol - 0.1-10%; poloxamers 407/188/237/108/234 (in different ratios) - 5-20%; preservative (EDTA) - 0.005-0.1%; water for injection - up to 100%. An example specific to all of these patents is given in US Pat. 6623765 “Microemulsion and micelle systems for solubilizing drugs” added co-emulsifiers (polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycols, polyoxyethylene ethers).

The compositions presented in the above patents meet the basic criteria of physico-chemical stability adopted for drugs. However, these compositions have a noticeable viscosity, which makes their parenteral administration difficult. In addition, a colloidal solution of propofol in an aqueous poloxamer is sensitive to the introduction of additional components - antioxidants, preservatives, biologically active substances that affect the bioavailability and reduce the toxicity of propofol. The introduction of these substances is necessary to improve the pharmacological properties of the drug, but leads to a sharp drop in the physico-chemical stability of dosage forms containing poloxamers.

In US Pat. 7138387 "Clear aqueous composition comprising propofol and hydroxypropyl-beta-cyclodextrin" and EP 1928412 "Aqueous anaesthetic composition propofol" claimed dosage forms based on a complex of cyclodextrins with propofol of the following composition: Propofol - 1 g; 2-hydroxypropyl-beta-cyclodextrin - 30 g; Glycerin - 2.25 g; Sodium edetate - 0.005 g; Water up to 100 ml.

In the practical reproduction of this composition in the laboratory, it is found that the formation of the complex strongly depends on the synthesis features of the initial substance of cyclodextrin (commercial substances of cyclodextrin of different manufacturers were used) and the content of propofol in stable dosage forms did not exceed 0.3%, which is insufficient for effective anesthesia.

Closest to the proposed solution are the dosage forms claimed in patent US 7326735 "Formulations for anaesthetic use". This patent describes the formulation of a propofol dosage form of the following composition: propofol - 0.5-1.5%; solvent (glycofurol) - 10-30%; co-solvent (Solutol HS 15 (PEG-660 12-hydroxystearate), esters of polyethylene glycol and 12-hydroxystearic acid) - 5-20%; viscosity modifier (ethanol) - 0.5-5%; preservatives (EDTA) - 0.005-0.1%; benzyl alcohol - 0.1-10%; water for injection - up to 100%.

In the proposed dosage form, the presence of a solvent (glycofurol) is mandatory, which leads to an increase in the cost of the drug. Also, the inventors did not declare the introduction of biologically active substances that improve the pharmacological properties and reduce the toxicity of the solvent, while the patent authors claim that the proposed dosage form is similar to Diprivan (Astra-Zeneca) in pharmacological action.

The present invention is the construction of an injectable preparation for anesthesia based on propofol, which has low toxicity, high efficiency (bioavailability) and high physico-chemical stability with the introduction of biologically active substances that improve the above parameters.

The technical result is a lower toxicity of the dosage form and high efficiency compared with known drugs.

The problem is solved in that the aqueous composition for anesthesia containing propofol as an active substance, PEG-660-12-hydroxystearate as a solubilizer, benzyl alcohol, or chlorethone, or parabens as a preservative, according to the invention additionally contains tocopherol and arginine or glycine in the following components, wt.%:

propofol 0,1-10 solubilizer 5,0-40 preservative 0.1 to 2 tocopherol 0,1-10 arginine or glycine 0,1-10 water for injections rest

The composition may further contain GABA agonists, for example, aminophenylbutyric acid in an amount of from 0.01 to 10 wt.%, As well as local anesthetics, for example, lidocaine in an amount of from 0.05 to 5 wt.%. In addition, alpha-2-adrenergic agonists, for example, xylazine in an amount of 0.01 to 10% by weight, may be added to the composition.

The problem is also solved by the fact that the method of performing anesthesia involves administering to the patient an effective amount of a composition of the above composition.

The problem is solved in that the dosage form is a stable (physico-chemically stable) microcolloidal solution of propofol in water, PEG660-12-hydroxystearate is used as a solubilizer, the physicochemical stability of the solution is ensured by a certain ratio of propofol / solubilizer / preservative / water, low toxicity and high bioavailability are achieved due to the introduction of tocopherol and arginine or glycine into the dosage form.

The pharmacological parameters (toxicity and efficacy of sedation (anesthesia)) of the most stable dosage forms of propofol are given below (Tables 1 and 2). The dosage form of propofol with the optimal ratio of propofol / solubilizer / preservative / water (basic LF) was taken as the basis. This composition is the most physico-chemically stable and resistant to microbial contamination. The number of components of the basic LF are shown in example 1.

Table 1 Parameters of acute toxicity of propofol compositions (dosage forms) when administered intraperitoneally to white mice Name of components Dosage Option Number
The content of components,% I II III IV V VI VII VIII IX Propofol 1,0 1,0 1,0 1,0 1,0 1,0 1,0 1,0 1,0 PEG660-12-hydroxystearate 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 Benzyl alcohol 1,0 1,0 1,0 1,0 1,0 1,0 1,0 1,0 1,0 Tocopherol - 0.25 0.7 - - 0.25 0.7 0.7 0.25 Arginine - - - 2,5 5,0 2,5 5,0 - - Glycine - - - - - - - 5,0 10.0 Water for injections Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 Up to 100 LD ₁₆ (mg / kg) 42.0 46.1 52,2 55.9 56.3 66.1 91.4 74.8 102,2 LD ₅₀ (mg / kg) 78.6 81.0 88.0 88.5 97.5 115.7 127.0 122.8 141.1 LD ₈₄ (mg / kg) 133.4 111.9 123.8 121.1 138.6 190.1 162.67 170.8 192.7

The introduction of such components as tocopherol or amino acids arginine / glycine into the basic dosage form of propofol reduces the acute toxicity of the anesthetic composition (LD ₅₀ ) by 1.1 and 1.2 times, respectively. The simultaneous inclusion of tocopherol with amino acids in the basic dosage form of propofol has a mutually reinforcing effect on reducing the toxicity of the anesthetic composition from 1.5 to 1.8 times (options VI, VIII, IX).

The introduction of a basic LF of propofol with tocopherol, but without amino acids, led to a significant increase in such an indicator as a stand without support, 4.50 versus 1.25 and 1.75 for propofol dosage forms containing arginine and glycine amino acids, respectively. The remaining parameters in rats of the group receiving LF of propofol without amino acids, such as a stance with support, short grooming, the number of crossed squares, and exit to the center, were unreliably higher than in the groups that were administered propofol in combination with amino acids. The level of anxiety in groups of animals that were introduced the basic dosage form of propofol with tocopherol and with tocopherol and amino acids (arginine / glycine) was significantly lower than the level of anxiety in the control group.

Below is the technology for the preparation of dosage forms of propofol and the most significant examples of formulations.

The technology for preparing propofol dosage forms is as follows.

A PEG660-12-hydroxystearate (solutol) weighed is placed in a suitable glass container, heated until it melts, weighed propofol and preservative are added, and mixed until a homogeneous mixture is obtained. The temperature of the mixture is + 40-50 ° C.

A sample of water for injection is placed in a separate container and samples of the remaining components are added, mixed until completely dissolved.

Then add a mixture of salute-propofol-preservative in a container with an aqueous solution with constant stirring. The resulting transparent slightly opalescent solution is filtered through a 0.22 μm membrane filter and packaged in sterile glass vials.

EXAMPLE 1

The basic composition of the dosage form of propofol and the optimal amount of other necessary components

Name of components Basic LF
The content of components,% Optimal LF
The content of components,% Propofol 1,0 1,0 PEG660-12-hydroxystearate (solutol) 15.0 15.0 Benzyl alcohol 1,0 1,0 Tocopherol acetate - 0.7 Arginine - 5,0 Lidocaine hydrochloride - 0.1 Water for injections Up to 100 Up to 100

Table 3 shows examples illustrating the limits of the physicochemical stability of the propofol LF formulations, as well as options for excipients that can be used in the LF.

Table 3 Examples of compositions (dosage forms) of propofol. Name of components Example No.
The content of components,% I II III IV V VI VII VIII IX Propofol 1,0 2.0 5,0 10.0 1,0 0.5 1,0 1,0 1,0 PEG-660-12-hydroxystearate (solutol) 8.0 20,0 27.0 30,0 10.0 5,0 15.0 15.0 18.0 Benzyl alcohol 1,0 1,0 1,0 1,0 1,0 1,0 1,0 1,0 2.0 Tocopherol acetate 0.7 0.7 5,0 10.0 0.7 0.25 0.7 0.7 0.7 Arginine 10.0 5,0 1,0 - - 5,0 5,0 5,0 5,0 Glycine - - - 1,0 10.0 - - - - Lidocaine hydrochloride 0.1 0.1 1,0 2.0 0.1 0.1 0.1 0.1 0.1 Dimethylacetamide - - 15.0 35.0 - - - - - Aminophenylbutyric acid - - - - - - 10.0 - - Xylazine - - - - - - - 10.0 - Water for injections up to 100 up to 100 up to 100 up to 100 up to 100 up to 100 up to 100 up to 100 up to 100

Composition I. The maximum content of arginine (with the use of glycine, similar processes occur). A further increase in the content of arginine or glycine leads to physical and chemical instability of the system (separation and turbidity of the solution).

Composition II. An increase in propofol content to 2.0% leads to an increase in the concentration of the solubilizer, which makes the solution more viscous, especially at temperatures below + 20 ° C.

Compositions III and IV. A further increase in the content of propofol (up to 10%) leads to a sharp increase in the viscosity and instability of the solution. For such drugs, the introduction of an organic solvent into the composition is necessary, which negatively affects the pharmacological properties of the drug. To reduce the side effects of the organic solvent, it is necessary to increase the concentration of lidocaine, which leads to a limitation of the methods of introducing LF data (only intramuscularly or subcutaneously). An increase in the concentration of tocopherol acetate partially neutralizes the side effect of high concentrations of lidocaine.

Composition V. Maximum glycine content. With a further increase in the glycine content, the solution is stratified.

Composition VI. The minimum content of the solubilizer (PEG-660-12-hydroxystearate). The content of propofol and tocopherol is also reduced in this composition due to the physicochemical instability of this drug at elevated concentrations of the above components.

Compositions VII, VIII. The maximum content of substances that increase the effectiveness of anesthesia (GABA agonists and alpha-2-adrenergic agonists). With a further increase in the content of these substances, the physicochemical stability of the solution drops sharply (precipitation, separation).

Composition IX. The maximum content of preservative. An increase in the concentration of preservative leads to an unacceptable increase in the toxicity of the dosage form.

Claims (5)

1. An aqueous composition for anesthesia containing propofol as an active substance, PEG-660-12-hydroxystearate as a solubilizer, benzyl alcohol, or chlorethone, or parabens as a preservative, characterized in that it additionally contains tocopherol and arginine or glycine with the following content of components, wt.%:
propofol 0,1-10 solubilizer 5,0-40 preservative 0.1 to 2 tocopherol 0,1-10 arginine or glycine 0,1-10 water for injections rest 2. The composition according to claim 1, characterized in that it added GABA agonists, for example aminophenylbutyric acid in an amount of from 0.01 to 10 wt.%. 3. The composition according to claim 1, characterized in that local anesthetics are added to it, for example, lidocaine in an amount of from 0.05 to 5 wt.%. 4. The composition according to claim 1, characterized in that alpha-2-adrenergic agonists, for example xylazine in an amount of from 0.01 to 10 wt.%, Are added to it. 5. A method of performing anesthesia, comprising administering to the patient an effective amount of a composition according to any one of claims 1 to 4.