Microcolloidal solution of propofol for anaesthesia

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

 

The invention relates to the field of medicine and veterinary medicine and can be used for induction and maintenance of anesthesia.

Propofol (2,6-diisopropylphenol) - short-acting anesthetic used for induction and maintenance of General anesthesia and sedation with local surgical intervention. Preparations of propofol administered in a single intravenous dose or in repeated dose bolus may also continuous infusion introduction.

Propofol first obtained in the research division of the Corporation ICI (UK) via chemical synthesis. In 70-80 years of the last century Corporation ICI received several patents on compositions and the use of propofol as an anesthetic funds - US Pat. 4056635 "2,6-Diisopropylphenol as an anaesthetic agent, US Pat. 4452817 "Anesthetic composition containing 2,6-Diisopropylphenol", US Pat. 4798846 "Pharmaceutical compositions". In these patents the claimed compositions in water-organic base containing as a solubilizer Cremophor EL (polyoxyethylene castor oil), or other similar connection.

Subsequently, when the widespread use of drugs on the basis of removerow, and large numbers of patients were marked by numerous anaphylactic (allergic) reactions and these drugs were withdrawn from the practice of medicine.

The main prerequisite bioavailability and the effect is vnesti dosage forms of propofol - the solubility in water. Propofol hydrophobic substance and can be mixed with water only in the presence of solubilization (surfactants). However, most surface-active substances (surfactants) are not compatible with humans and animals, so the development was carried out only with Awami permitted by the pharmacopoeias.

The most famous composition of the medicinal product on the basis of propofol contains as an emulsifier/solubilizer mixture of soybean oil and egg lecithin and has the following composition:

Propofol - 1%; Soybean oil cleaned - 10%; egg Lecithin - 12%; Glycerol - 22,5%; sodium Hydroxide to pH 8.5; Water to 100%. When mixing these substances with water it turns opaque white emulsion is very sensitive to temperature changes.

In 1986 the company Astra-Zeneca (UK) has introduced this recipe to medical and veterinary market under the commercial name "Diprivan" for veterinary use "Rabinovich". This drug was widely used in world practice anaesthetics, but already in the first years of use has been identified the main drawback of this drug is non-resistant to microbial contamination and, as a consequence, the threat of a General infection of the patient. The reason for this instability in the large sensitivity of the emulsion to the presence of ionic and hydrophob what's connections, so as it breaks the surface energy of droplets of the emulsion and causes delamination of the solution. Therefore, the developers have refrained from having the formulation of preservatives, antioxidants and other substances that affect the physical and chemical stability of the drug.

Further, employees of the company Astra-Zeneca tried to improve this recipe in the following patents: Patent RF №2147432 "Emulsion of the type oil-in-water containing propofol and edentate and US Pat. 7125909 "Sterile parenteral nutrition compositions". In these patents resistant to microbial contamination was increased to 24 hours due to the introduction of the formulation of the edetate sodium (EDTA), but it is also insufficient due to the large consumption of the drug and weak antimicrobial activity of EDTA.

Known patents, in which as a solubilizer used poloxamer (pluronic): RF patent №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 comprising propofol", WO/2003/017977 "Anaesthetic formulations of propofol". In these patents shows the formulation of the dosage form of propofol following composition: propofol of 0.1 - 10%; poloxamer 407/188/237/108/234 (in different proportions) is 5-20%; preservatives (EDTA) - 0,005-0,1%; water for injection to 100%. The example above is typical of all of these patents, USPat. 6623765 "Microemulsion and micelle systems for solubilizing drugs added simulatory (polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycols, polyoxyethylene esters).

The compounds presented in the above patents, meet the essential criteria of the physico-chemical stability adopted for drugs. However, these compounds have appreciable viscosity, which makes them difficult parenteral administration. In addition, a colloidal solution of propofol in the aqueous poloxamer 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 needed to improve the pharmacological properties of the drug, but leads to a sharp drop physico-chemical stability of dosage forms containing poloxamer.

Patent US Pat. 7138387 " Clear aqueous composition comprising propofol and hydroxypropyl-beta-cyclodextrin and EP 1928412 "Aqueous anaesthetic compositions comprising propofol" the claimed dosage forms on the basis of a complex of cyclodextrin with propofol following composition: Propofol - 1 g; 2-hydroxypropyl-beta-cyclodextrin - 30 g; Glycerol - 2.25 g; Edetate sodium - 0.005 g; Water to 100 ml.

In the practical reproduction of this composition in the laboratory, it is found that the complex formation is strongly dependent on the characteristics of si is thesis of the original substance cyclodextrin (used commercial substance cyclodextrin different manufacturers) and the content of propofol in a stable dosage forms did not exceed 0.3%, that is not enough for effective anesthesia.

Closest to the proposed solution are dosage forms that are claimed in the patent US 7326735 "Formulations for anaesthetic use". This patent describes the formulation of the dosage form of propofol following composition: propofol - 0,5-1,5%; solvent glucotrol) - 10-30%; the co-solvent (Solutol HS 15 (PEG-660 12-hydroxystearate), esters of polyethylene glycol and 12-hydroxystearate acid) is 5-20%; a viscosity modifier (ethanol) is 0.5 - 5%; preservatives (EDTA) - 0,005-0,1%; benzyl alcohol and 0.1 - 10%; water for injection to 100%.

In the proposed dosage form required the presence of solvent (glucotrol), which leads to increased cost of the drug. Also, the authors of the invention have not announced the introduction of the biologically active substances that improve pharmacological properties and reduce the toxicity of the solvent, the authors of the patent claim by the pharmacological action of the proposed dosage form is similar to Diprivan (Astra-Zeneca).

The present invention is the design of injectable anesthesia on the basis of propofol with low toxicity, high efficiency (bioavailability) and high physical and chemical stability with the introduction of biologically active substances which improve the above-mentioned parameters.

the technical result is lower toxicity dosage forms and high efficiency in comparison with the known compounds.

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

propofol0,1-10
the solubilizer5,0-40
preservative0.1 to 2
tocopherol0,1-10
arginine or glycine0,1-10
water for injectionrest

The composition may further contain GABA agonists, for example, aminophenylalanine acid in an amount of from 0.01 to 10 wt.%, as well as local anesthetics, such as lidocaine in an amount of from 0.05 to 5 wt.%. In addition, the composition can be added to the alpha 2-adrenoceptor agonist, e.g., xylazine in an amount of from 0.01 to 10 wt.%.

The problem is solved also by the fact that the means of implementing the anesthesia includes introduction what their patient an effective amount of a composition of the above composition.

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

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

Table 1
The parameters of acute toxicity of compositions (dosage forms) of propofol when vnutribruchinnom introduction to white mice
Name of the componentMr. the R variant of the dosage form
Component content, %
IIIIIIIVVVIVIIVIIIIX
Propofol1,01,01,01,01,01,01,01,01,0
PEG-12-hydroxystearate15,015,015,015,015,015,015,015,015,0
Benzyl alcohol:1,01,01,01,01,01,01,01,01,0
Tocopherol- 0,250,7--0,250,70,70,25
Arginine---2,55,02,55,0--
Glycine-------5,010,0
Water for injection100100100100100100100100100
LD16(mg/kg)42,046,152,255,9 56,366,191,474,8102,2
LD50(mg/kg)78,681,088,088,597,5by 115.7127,0122,8141,1
LD84(mg/kg)133,4111,9123,8121, 1million138,6190,1162,67170,8192,7

Introduction to basic pharmaceutical form of propofol components such as tocopherol or amino acids arginine/glycine, reduces the acute toxicity of the anesthetic composition (LD50in 1.1 and 1.2 times respectively. Simultaneous inclusion of basic pharmaceutical form of propofol tocopherol with amino acid has a synergistic effect on the reduction of toxicity of the anesthetic composition is from 1.5 to 1.8 times (options VI, VIII, IX).

Introduction basic LF of propofol with tocopherol, but without amino acids etc which has led to a significant increase in such index, as a stand without support, 4,50 vs. 1.25 and 1.75 for formulations of propofol containing amino acids arginine and glycine, respectively. The remaining indicators in rats groups that received LF of propofol without amino acids, such as a front pillar, a short grooming, the number of crossed squares, in the center, unreliable were higher than in groups, which was introduced propofol in combination with amino acids. The level of anxiety in groups of animals, which was introduced basic dosage form of propofol with tocopherol and tocopherol and amino acids (argmin/glycine) was significantly lower levels of anxiety in the control group.

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

Technology of preparation of dosage forms of propofol following.

In a suitable container of glass is placed a portion PEG-12-hydroxystearate (solutol), heated to melt, add a shot of propofol and preservative and mix until a homogeneous mixture. The temperature of the mixture +40-50°C.

In a separate container placed a portion of water for injection and add a sample of other ingredients, mix until dissolved.

Then add the mixture solutol-propofol-preservative in the container of aqueous solution with constant stirring. Received about is this at all slightly opalescent solution is filtered through a membrane filter of 0.22 μm and filled into sterile glass vials.

EXAMPLE 1

The basic composition of the dosage form of propofol, and the optimal number of other prerequisites

Name of the componentBasic LF
Component content, %
Optimal LF
Component content, %
Propofol1,01,0
PEG-12-hydroxystearate (solutol)15,015,0
Benzyl alcohol:1,01,0
Tocopherol acetate-0,7
Arginine-5,0
Lidocaine hydrochloride-0,1
Water for injection100100

Table 3 provides examples that illustrate the limits of the physico-chemical stability of the compositions LF of propofol, as well as variants of excipients that can be and is used in LF.

Table 3
Examples of compositions (dosage forms) of propofol.
Name of the componentExample No.
Component content, %
IIIIIIIVVVIVIIVIIIIX
Propofol1,02,05,010,01,00,51,01,01,0
PEG-660-12-hydroxystearate (solutol)8,020,027,030,010,05,015,015,018,0
Benzyl alcohol:1,0/td> 1,01,01,01,01,01,01,02,0
Tocopherol acetate0,70,75,010,00,70,250,70,70,7
Arginine10,05,01,0--5,05,05,05,0
Glycine---1,010,0----
Lidocaine hydrochloride0,10,11,02,0 0,10,10,10,10,1
Dimethylacetamide--15,035,0-----
Aminophenylalanine acid------10,0--
The xylazine-------10,0-
Water for injection100100100100100100100 100100

Composition I. the Maximum content of arginine (when using glycine occur similar processes). Further increase in the content of arginine or glycine leads to physico-chemical system instability (stratification and the turbidity of the solution).

Composition II. The increase in the content of propofol 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. Further increase in the content of propofol (10%) leads to a sharp increase in viscosity and instability of the solution. For such LF necessary the introduction of the organic solvent, which has a negative effect on the pharmacological properties of the drug. To reduce the side effects of an organic solvent to increase the concentration of lidocaine, resulting in limiting ways of entering data LF (only intramuscularly or subcutaneously). Increasing the concentration of tocopherol acetate partially neutralizes the adverse effects of high concentrations of lidocaine.

Composition V. the Maximum content of glycine. With further increase of the content of glycine is the stratification of the solution.

Composition VI. The minimum content of solubilizer (PEG-660-12-hydroxystearate). In this composition is also reduced content of propofol and tocopherol in connection with the physico-chemical instability of this LF at elevated concentrations of the above components.

Composition VII, VIII. The maximum content of substances that increase the efficiency of anesthesia (GABA agonists and alpha-2-adrenoceptor agonist). With further increase of the content of these substances physico-chemical stability of the solution decreases sharply (precipitation, stratification).

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

1. Aqueous composition for anesthesia containing propofol as active-active substance, PEG-660-12-hydroxystearate as a solubilizer, benzyl alcohol, or chlorate, or parabens as a preservative, characterized in that it further comprises tocopherol and arginine or glycine at the following content, wt.%:

propofol0,1-10
the solubilizer5,0-40
preservative0.1 to 2
tocopherol0,1-10
arginine or glycine0,1-10
water for injectionrest

2.The composition according to p. 1, characterized in that it added GABA agonists, such as aminophenylalanine acid in an amount of from 0.01 to 10 wt.%.

3. The composition according to p. 1, characterized in that it added to local anesthetics, such as lidocaine in an amount of from 0.05 to 5 wt.%.

4. The composition according to p. 1, characterized in that it added the alpha 2-adrenoceptor agonists such as xylazine in an amount of from 0.01 to 10 wt.%.

5. The manner of exercise of anesthesia, including an introduction to the patient an effective amount of a composition according to any one of paragraphs.1-4.



 

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4 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely anaesthesia, and may be used as a postoperative anaesthesia accompanying low- and medium-injury operations. For this purpose, at the stages of anaesthetising and de-anaesthetising, nonsteroidal anti-inflammatory compounds (NSAICs) are introduced intravenously. The NSAIC dose is equivalent to ketorol 0.5-3.0 ml. The introduction is performed 1-3 times.

EFFECT: method provides the complete prevention of developing postoperative pain syndrome ensured by the intravenous introduction of the NSAIC at the specific stages of anaesthesia in certain doses.

1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: presented group of inventions refers to anaesthesiology, and may be used in performing X-ray endovascular heart, aorta and other great vessel surgeries in infants and young children. For this purpose, 10-12 hours before the surgery, a patient is pre-medicated by administering benzodiazepine, antihistamine and blocker H2. The anaesthetic administration is enabled by fast induction of sevoflurane before the first surgical stage. Then, a two-flap laryngeal mask is used, its drainage duct is used to pass a gastric probe a correct placement of which is monitored by X-ray, and the gastric contents is evacuated. The probe is removed, and the same duct is used to insert an echocardiographic probe. The anaesthesia is maintained by infusion of propofol in a dose of 6-8 mg/kg/h and bolus introduction of an opioid analgesic. The artificial pulmonary ventilation is conducted through the laryngeal mask, and the patient is transferred to unassisted respiration with a dose of propofol to be reduced to 4-5 mg/kg/h. The principal stage of the surgery and ultrasonic control, or control with introducing a contrast agent, the echocardiographic probe is removed. Infusion of propofol is terminated after suturing and compression hemostasis. In the period of escaping the anaesthesia with the laryngopharyngeal reflexes recovered, air is evacuated from a cuff of the laryngeal mask, and after adequate respiration recovered, the same mask is removed.

EFFECT: group of inventions ensures the adequate anaesthesia in these patients by means of the developed method of lung ventilation using no myorelaxants, and prevented regurgitation of the gastric contents.

8 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, in particular to anesthesiology and intensive care, and may be used if preoperative preparation of the patients with chronic pancreatitis and manifested pain syndrome required. For this purpose, back skin of a sitting patient is treated within a puncture at the Th7-Th8 level. Then, an epidural space is punctured, and a puncture catheter needle is introduced therein, and the catheter is pushed forward in the cranial direction to a depth of 3 cm. The needle is removed, and the catheter is placed along the spine and is brought out to the subclavian region while strapped all over. Thereafter, a test dose of 2% lidocaine 3.0 ml is introduced. If observing no effects of spinal block, prolonged permanent introduction of 0.2% ropivacaine at rate 4-5 ml/hour 3 times a day. With underlying it, 30 minutes before a meal, fractional introduction of 0.75% ropivacaine 3.0 ml and 0.005% fentanyl 1.0 ml for 4-5 days is performed.

EFFECT: method provides the adequate preparation of the patients for pancreatic surgery due to pain relief that enables supplying proteins and eliminating hypovolemia, as well as due to improved pancreatic-duodenal microcirculation.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new derivatives of ((phenyl)imidazolyl)methylheteroaryl of formula wherein A represents pyridyl or thienyl having 0 or 1 substitute; B represents phenyl having 0, 1 or 2 substitutes; wherein each substitute independently represents alkyl having 1 to 8 carbon atoms, -F, -Cl, -Br or -CF3. Also, the invention refers to the use of the declared compounds for the purpose of preparing a therapeutic agent, a pharmaceutical composition on the basis of the declared compounds, and to a kit containing the pharmaceutical composition above.

EFFECT: there are prepared new derivatives of ((phenyl)imidazolyl)methylheteroaryl effective in pain management.

10 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: composition containing curcumine, an acid specified in a group consisting of citric acid, malic acid, acetic acid, tartaric acid, lactic acid, alginic acid or a mixture thereof, and an edible emulsifying agent with specific characteristics and taken in a certain amount wherein the above composition is applicable as a therapeutic agent. The composition containing curcumine, the edible emulsifying agent or a mixture thereof, the acid specified in a group consisting of citric acid, malic acid, acetic acid, tartaric acid, lactic acid, alginic acid or a mixture thereof taken in certain proportions, and additionally encapsulated into a gelatine capsule, wherein the above composition is applicable for treating or preventing an inflammation and/or diseases caused by the inflammation.

EFFECT: compositions improve the curcumine bioavailability effectively.

13 cl, 1 tbl, 6 ex

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