Emulsion performancesin compounds in the gas transport properties
(57) Abstract:The invention relates to medicine and colloid chemistry and can be used to obtain blood substitutes in the gas transport function based emulsions performancesin compounds (PFC). The purpose of the invention, the reduced toxicity and increased stability during storage of the emulsions SFC. Emulsion SFC with the gas transport properties contains as a carrier gas, bystrovytsia the perfluorocarbons, volumetric concentration in the emulsion is from 40 to 50 vol.%, high-molecular perforated additive, the concentration of which ranges from 1 to 10 vol.%, and phospholipids in a concentration of from 2 to 6 wt.%. As high-molecular perforated additives can be used PERFLUORO-n-methyl-cyclohexylpiperidine. 2 C. p. F.-ly, 2 ill., table 4. The invention relates to medicine and colloid chemistry and can be used to obtain blood substitutes in the gas transport function.The present invention can be used in medicine and the medical industry to obtain finely dispersed emulsions performancesin compounds (PFC), serving as a basis for making getparentdir the industry and cosmetics, as well as in research practice, for the preparation of finely dispersed emulsions based on SFC serving as coloredness component of drug and cosmetic ointments, creams.Emulsion SFC are complex colloidal systems consisting of a disperse medium solution of surface-active substances (surfactants) in water and the dispersed phase performancesthe compounds or mixtures of several SFC.SFC is a key component of the emulsion. They are chemically inert. However, SFC is well physically dissolved gases, in particular oxygen and carbon dioxide. But, unfortunately, the SFC does not dissolve in water and they have to emulsify in the manufacture of blood substitutes and perfusion media. One of the main problems kislorodprovodyashchikh emulsions SFC is to capture and accumulation of particles SFC different bodies. The period of providentia from the body SFC is one of the indicators of quality emulsions SFC. The amount remaining in the body SFC at some point in time depends on the properties of PPS (e.g. vapour pressure) and the magnitude of the administered dose.As surfactants are non-toxic high-molecular substances, in particular, praxeologies only for the purpose of dispersing the SFC. However, surfactants affect the toxicity and reactogenicity emulsion SFC. The influence of emulsions SFC on the body is of a double nature and physico-chemical effect, i.e. physico-chemical effects of surfactants on the body's cells with the immune response, changes in metabolism, etc. and b) physico-mechanical effects, for example, through a dispersion of particles of the emulsion, which should not be larger than 200 nm because of the danger of blockage of the capillaries and the occurrence of embolism, and less than 50 nm because of too rapid exit from the bloodstream to the organs. Therefore, the average particle diameter of the emulsions SFC, toxicity and reactogenicity are important indicators of the quality of emulsions SFC.Toxicity emulsions SFC judged by the metric LD50that is the dose entered emulsion in ml per kg of body weight of the animal, at which survives 50% of the animals. Moreover, various animals, usually of laboratory mice, rats or rabbits have different sensitivity and give different size LD50. The most sensitive are the rabbits. Consequently, they are used to determine apirogennost emulsion SFC.Emulgiruet emulsions SFC depends on the surfactant properties and affinity of the SFC to PAHs, naptosa serves as a measure of lipophilicity SFC.Emulsion SFC should have a long shelf life, and storage conditions should be simple. Indicator storage emulsions SFC is the change in the mean diameter of the particles over time and as a special case, the average particle diameter for 6 months or 12 months.The following indicators are defined in obtaining emulsions SFC:
1) average particle diameter of the emulsion;
2) the period of providentia SFC from the body;
3) toxicity, the measure of which is the value of LD50;
4) vapor pressure;
5) oxygen capacity;
6), the temperature of dissolution in hexane;
7) change in the mean diameter of the particles for 6 months or for 12 months at a constant temperature storage.The combination and the value of these parameters allows to determine the advantage of the single-emulsion SFC front of the other.It should be noted that at the present time known emulsion SFC "first" and "second generation". Emulsion SFC "first generation" was developed on the basis of a nonionic surfactant and has a concentration of SFC of not more than about 20. Hence their limited oxygen capacity of not more than about 7. To achieve greater concentration SFC fails due to sharp in the nil as a pilot, although used in them are very promising SFC.Emulsion "second generation" developed on the basis of phospholipid surfactants and can have a concentration of SFC to about 50. without significantly increasing the viscosity of the emulsion. Therefore, they may have an oxygen capacity of up to about 25. However, these emulsions have their drawbacks, for example, a larger average particle diameter than the emulsion of the "first generation".Widely known emulsion SFC containing perpendicular (PFD) in an amount of 10 to 20 wt. and stable proximally (plutonium) and phospholipids [1, 2] This emulsion refers to the first generation.PFD is the most common and easily available performancesin connection used for biomedical purposes. Injected emulsified PFD, as well as other PFCs accumulate in the liver, spleen and bone marrow, however, is not metabolized in biochemical reactions. From the body unchanged molecule PFD excreted in exhaled air with a half-life of 7 days. The relative harmlessness of perfluorocarbon emulsions containing PFD shown by many experiments, starting with research R. Geyer  about the SS="ptx2">However, it is well known that the emulsion is stable PFD 3 4% solution of proxanol is chosen 268 weakly stable in time and splits in a few days at a storage temperature of +4oC. in Addition, the emulsion PFD, stable solution proxanol is chosen 268, is toxic to rabbits starting with the value LD50more than 10 to 15 ml/kg 
Emulsion PFD stable proxanol is chosen and phospholipids has some of the best stability, but generally has the same drawbacks.Toxicity emulsion PFD is not associated with its high pressure vapor or liquid, and, apparently, due to the low aggregation stability of emulsion particles in the bloodstream.The phenomenon of the death of rabbits with the introduction of the emulsion PFD necessitates the creation of new compositions of emulsions containing SFC PFD and do not cause the death of the rabbits.It was found that small additions of some compounds significantly increase the shelf life of the emulsion PFD.Known emulsion SFC containing perpendicular (PFD) in an amount of 20 wt. and high-molecular additive C-16 HBPO (performancerelated) in an amount of 1 weight. stabilized the polycyclic hydrocarbon (preferably performancerelated) with a higher boiling point, than the main perperoglou (PFD) is added to improve the stability of the emulsion. This emulsion is an emulsion of the "first generation" and is stored for more than 1 month at a temperature of +4oC (PL. 1).However, the emulsion PFD with the addition of C-16 HBPO has the same disadvantages inherent in the emulsions PFD, namely:
has a low stability of the emulsion during storage;
has a small oxygen tank;
is toxic to rabbits;
is reactogenic.Widely known emulsion SFC, containing a mixture of two perfluorocarbons, so-called binary mixture SFC. One of the components of the binary mixture is bystrovytsia SFC, and the second is excreted relatively slowly. Melanomatosis component significantly improves the stability of the emulsions during storage.This emulsion SFC contains PFD and PERFLUORO-n-methylcyclohexylamine (PFMRP) in the ratio PFD:PFMSP=2:1 with the concentration of the dispersed phase of about 10-20. and stable proxanol is chosen 268 in the amount of about 4-8. or proxanol is chosen 268 in the amount of about 4-8. together with phospholipids of egg yolk (egg yolk lecithin) in the amount of 0.5 weight.  This emulsion is also known as "Perftoran".
-6mol/liter. The emulsion has a toxicity LD50=136 ml/kg for rats. Toxicity for rabbits it is noticeably lower than other binary emulsin SFC (PL. 1).Emulsion PFD/PFMRP (2:1) has the following disadvantages:
low oxygen capacity;
the low stability of the emulsion during storage without freezing;
for long term storage it is necessary freezing;
contains a large number of relatively slow output PFMSP;
At present, the emulsion of the "second generation", which are either already known, or new SFC, stabilized only by phospholipids. These emulsions allow to emulsify high percentage of SFC and are, therefore, high oxygen capacity. At the same time they have lower toxicity and progenote.The closest entity to the claimed emulsion SFC emulsion is described in  and taken as a prototype.This emulsion SFC is an emulsion of the "second generation" and contains perforative (PFOB) in an amount of from 20 to 125 wt. and stabilized by phospholipids in an amount of 5 vol. The half-life of PFOB 4 days. The average diameter ie 18 months at a temperature of +4oC. After 15 months and 22 days, the average diameter is increased to 406 nm. The stability index D0/Dtto this emulsion is 1.4 (D0the average diameter of the particles immediately after production of the emulsion, Dtthe average particle diameter after storage time t, (PL. 1). Emulsion is a good x-ray and ULTRASOUND contrast agent and has an oxygen storage capacity equal to about 25. The emulsion has a low toxicity for rabbits (table. 1).However, emulsion PFOB, not being an inducer of cytochrome P-450, undergoes metabolism in the liver cells with the release of bromine ions and radicals  in Addition, with greater solubility in lipids (35mm) than PFD (26 mm), it is more likely to break or modify the structure and function of biochemical membranes. These circumstances cast doubt on the safety of PFOB.Emulsion PROB has the following disadvantages:
a large average particle diameter of the emulsion (>250 nm);
not enough high stability;
PFOB involved in the metabolism with the release of bromine ions and radicals;
obtaining emulsion PROB 10 times more expensive than obtaining emulsion PFD;
The aim of the invention is to reduce toxicity and increase stabilisa bistabilities performancesee compound in an amount of from about 40 to about 50. high molecular weight perfluorinated additive in an amount of from 5 to about 10. and surfactant from 2 to 6 weight. However, as bystrovytsia performancesthe connection transporting gases used perpendicular (PFD) or perforative (PFOB), and as high molecular weight perfluorinated additive - PERFLUORO-n-methylcyclohexylamine (PFMRP). As surfactants are phospholipids, for example, phospholipids, soybean or egg yolk.In the proposed emulsion perpendicular (PFD, C10F18or perforative (PFOB, C8F17Br) is the main component of perfluorocarbon blood substitute and they are moving the main quantity of oxygen to the tissues. Perfor-n-methylcyclohexylamine (PFMRP) is used as a stabilizer of the emulsion, although he also carries oxygen to the tissues.Control emulsion prepared by high-pressure homogenizer at a pressure of 40 MPa in aseptic conditions ensuring the sterility and apyrogenicity of the emulsion. The average particle diameter of the emulsion was measured by photon-correlation spectrometer "Coulter N4". Investigated emulsions of STI emulsions made on gray rabbits male weight 2,5-3,0 kg The emulsion was injected into the marginal ear vein.First was the magnitude of toxicity emulsion PFD for rabbits. LD50emulsion PFD for rabbits is in the range of 10-15 ml/kg, which is equivalent to 2-3 g of pure PFD per 1 kg of body weight of the animal. The dose of the emulsion 20 ml/kg is absolutely fatal.After intravenous emulsion PFD at a dose of 20 ml/kg death rabbits occurs after 5-7 days. With the introduction of lower doses of 15 ml/kg, all pathological processes are developing more slowly. The first 5-7 days animals outwardly behave normally, no shortness of breath, appetite and weight. After 7-10 days appears clearly expressed hypoxia, loss of appetite and weight. The death of the rabbit comes in 2-3 weeks.In table. 2 shows the survival rate of rabbits after injection of the emulsion PFD.It has been suggested that the death of the rabbits with the introduction of the emulsion PFD comes as a result of gas embolism resulting in blockade of pulmonary capillaries  To test this assumption was administered to rabbits emulsion PVTPA, the vapor pressure of 20 mm Hg at 37oC, which is significantly higher than the same parameter for the PFD 12 mm Hg. Emulsion PPTP entered wnanie rabbits.On the other hand, the reason for the destruction of rabbits could be the ability PFD to indoctinate cytochrome P-450 in the liver , or cause any other changes that are associated with a relatively high solubility PFD in the lipid phase of biological membranes  To test this assumption rabbits were injected emulsion of PFOB, the solubility of which in lipids in 2 times above, than at PFD. However, emulsion PFOB at a dose of 20 ml/kg did not cause any loss of rabbits, nor any noticeable changes in their condition.It is interesting to note that the emulsion PFD is not toxic to mice and rats even at a dose of 40-60 ml/kgIn our opinion, the death of rabbits after injection of the emulsion PFD may be associated with a unique set of physico-chemical properties characteristic of the perfluorocarbons. In particular, the low strength of the adsorption layer formed by molecules of surface-active substances on the surface of particles of the emulsion PFD, makes this emulsion prone to aggregation [14, 15] According to our records the formation of dense aggregates of particles of the emulsion PFD with dimensions of tens of microns is observed in the bloodstream of rabbits in 1-2 days after injection of the emulsion.The introduction of the PERFLUORO-n-mi are given in table. 3.It is seen that the presence of perfluorocarbon phase emulsion PFD small amounts PFMSP leads to the disappearance of toxicity emulsion PFD. However, it is known that PFMSP used to produce stable emulsions, characterized by low values of vapor pressure and liquid and as a consequence slowly excreted from the body  Therefore, the reduction of its content in the emulsion PFD without loss of stability has a large positive value, because at low concentrations PFMSP in the emulsion, it remains in the body less.From table. 3 shows that despite the fact that all rabbits entered lethal dose PFD, the death of animals is not observed when using emulsions with addition PFMRP.To ensure that PFMSP reduces the toxicity of the emulsion PFD, in several series of experiments, the rabbits were injected emulsion PFMSP both before and after the emulsion PFD. Emulsion PFMSP prevented lethal effect of the emulsion PFD. Control was introduced proxanol is chosen 268, reopoliglyukin and suspension of lecithin. These data are shown in table. 4.The survival rate of rabbits with the introduction of the emulsion PFOB and emulsion PFOB/PFMRP (2:1) at a dose of 20 ml/kg was RB. with the addition of PFMSP in the amount of from 5 to about 10. stabilized by phospholipids, for example soy or egg yolk, in the amount of from 2 to 6 wt. has a lower toxicity than the same emulsion PFD.In addition to the effect of reducing the toxicity of the addition of small amounts PFMSP leads to a substantial stability of the emulsion during storage.In Fig. 1 shows the dependence of the change in the average particle diameter of the emulsions PFD/PFMRP (9:1)=40. emulsified different amounts of phospholipids from the retention time.It is evident from Fig. 1 shows that the emulsion PFD/PFMRP (9:1)=40. emulsified phospholipids with a concentration of about 2-6. quite stable when stored for more than 12 months. However, with the decrease of the concentration of phospholipids average particle diameter increases, as in the preparation and during storage, indicating a dependence of the stability of the emulsions on the concentration of phospholipids. In the first month of storage is the reconcretion particle emulsions (Astaldo maturation), which is manifested in the change of the average diameter of the particles. Reaching equilibrium parameters, the emulsion is stored for a long time with virtually no change in average particle diameter.On f and PROB=40 rpm. (prototype), stable soybean phospholipids in a concentration of about 3. It is evident from Fig. 2 shows that the addition to the PFD or PFOB small number PFMSP leads to a significant stabilization of the average diameter of the particles.In table. 1 presents a comparative analysis of stability during storage analogues, prototype and offer the emulsion on the stability index D0/Dtwhere D0the average diameter of the particles immediately after production of the emulsion, and Dtthe average particle diameter after storage time t. From the data table. 1 shows that the average particle diameter of the emulsion of the prototype increases after 11 months, 87% at a concentration of phospholipids 5% and offer the emulsion is changed only by 23% at a concentration of phospholipids 3% and almost no changes (reduction of 2%) at a concentration of phospholipids 6%
The following are specific examples of the composition of the proposed perfluorocarbon emulsion with gas transport properties.Example 1. Emulsion with a concentration of PFD about 40. with the addition of PFMSP in the amount of about 10. stabilized by phospholipids of soybean in the amount of 6 wt. She has an average particle diameter after the manufacture of 240 nm. 12 months average particle diameter of the emulsion became 2 is as LD50=240 ml/kg Survival of rabbits at the dose introduced PFD 20 ml/equal to 100%
Example 2. Emulsion with a concentration of PFD 50. with the addition of PFMSP in the amount of about 5. stabilized by phospholipids of soybean in the amount of 2 wt. She has an average particle diameter after the manufacture of 265 nm. 12 months average particle diameter of the emulsion was 320 nm, i.e., the index of stability of this emulsion 12 months is 1.21. The toxicity of the emulsion to rats equal LD50= 245 ml/kph. The survival rate of rabbits at the dose introduced PFD 20 ml/kg of 100%
Example 3. Emulsion with a concentration of PFOB about 40. with the addition of PFMSP in the amount of about 10. stabilized by phospholipids of egg yolk in the amount of 6 wt. She has an average particle diameter after the manufacture of 220 nm. 12 months average particle diameter of the emulsion was 246 nm, i.e., the index of stability of this emulsion 12 months is 1.12. The toxicity of the emulsion to rats equal LD50=235 ml/kg Survival of rabbits at the dose introduced PFD 20 ml/kg of 100%
Example 4. Emulsion with a concentration of PFOB about 50. with the addition of PFMSP in the amount of about 5. stabilized by phospholipids of egg yolk in the amount of 2 weight. She has an average particle diameter after the manufacture of 240 nm. After 12 MESFET 0,983. The toxicity of the emulsion to rats equal LD50=240 ml/kg Survival of rabbits at the dose introduced PFD 20 ml/kg of 100%
The results of the analysis of samples of the proposed emulsions are given in comparison with analogues and prototype in the table. 1.As can be seen from the table. 1, the proposed perfluorocarbon emulsion with gas transport properties has the following advantages:
good survival of rabbits with the introduction of the lethal dose of PFD;
the best storage stability (better stability index);
after introduction into the body in organs remains fewer PFMSP due to its smaller amount in the emulsion;
decreases pulmonary edema;
is relative cheap, because it consists of easily synthesized SFC. 1. Emulsion performancesin compounds in the gas transport properties containing bistabilities performancesee connection, high molecular weight perfluorinated additive and phospholipids, characterized in that the content of bystrovytsia performancesthe compounds in the emulsion is 40 to 50 rpm. high molecular weight perfluorinated additive 1 to about 10. and phospholipids 2 to about 6.2. Emuls the-p-methylcyclohexylamine.3. The emulsion under item 1, characterized in that as bystrovytsia performancesthe connection is used perpendicular or perforative.
FIELD: medicine, surgical stomatology.
SUBSTANCE: in case of patient's average-severe or severe state before surgical interference or at satisfactory state - after surgical interference one should intravenously once introduce perfluorane at the dosage of 1-3 ml/kg body weight followed by daily treatment of the wound with perfluorane, washing and introducing perfluorane-impregnated gauze tampons till the end of exudation phase. The method enables to widen the number of preparations to treat odontogenic phlegmons of oral area, simplify therapeutic technique due to excluding the work with patient's blood, accelerate the process of purification and regeneration of soft tissues in the region of inflammation and shorten therapy terms.
EFFECT: higher efficiency of therapy.
SUBSTANCE: method involves introducing perfluoran bubbled with ozone-and-oxygen mixture with given ozone concentration of 3000 mkg/l during 15 min.
EFFECT: restricted peritoneal inflammation.
SUBSTANCE: the present innovation deals with treating different wounds. The suggested perfluorocarbon emulsion is being used as the medium in case of ultrasound treatment of wounds. Moreover, the enhancement of reparative processes is observed in the wound along with accelerated wound healing due to development of perfluorophages in area of inflammatory process and to higher gas saturation of perfluorocarbon emulsion against other media applied before. The emulsion under the action of low-frequency ultrasound obtains other properties (increased specific weight, increased fluidity, higher wettability of purified surface, the presence of abrasive properties) necessary for achieving technical result. All these measures, thus, enhance reparative processes in the wound because low-frequency ultrasound raise to a higher power the action of perfluorocarbon emulsion both regarding ultrasound purification and its curative action upon wound.
EFFECT: higher efficiency.
5 dwg, 1 ex
FIELD: cosmetology, dermatology.
SUBSTANCE: the present innovation deals with applying preparations affecting the values of blood microcirculation in skin. The suggested preparation is the emulsion of perfluorocarbons that increases skin resistance to negative impacts and favorably affects microcirculation by steadily increasing its total level that enables to improve the state of microcirculatory canal of skin.
EFFECT: higher efficiency.
FIELD: medical engineering.
SUBSTANCE: method involves exposing an intraocular neoplasm after vitrectomy and retinotomy, smoothening retina with perfluororganic compound later substituted with silicon oil. After having removed the neoplasm, intravenous 10% Perfluorane emulsion transfusion is carried out at a rate of 60 drops per 1 min in the amount of 80-100 ml. Next to it, photosensitizer is intravenously drop-by-drop introduced into cubital vein of the same arm. Laser irradiation of blood is carried out with power of 20-50 mW through laser light guide set in advance into cubital vein of the other arm in 5-15 min after starting introducing Perfluorane. When applying 0.1-1% water solution of Khlorine as photosensitizer at a dose of 0.2-0.5 mg/kg, irradiation is carried out at wavelength of 630-633 nm during 10-45 min. The treatment is administered twice with 5 days long pause.
EFFECT: enhanced effectiveness of treatment; reduced risk of tumor cells dissemination and metastases formation.
SUBSTANCE: the suggested emulsion contains quickly excreting perfluoroorganic compounds as perfluorodecalin and perfluorooctylbromide, perfluoroorganic additive and phospholipids in the form of dispersion prepared due to homogenization at pressure of not less than 100 atm. in water-saline medium. Perfluoroorganic additive is being the mixture of perfluorated tertiary amines - perfluorotripropylamine and its co-products: cis- and trans-isomers of perfluoro-1-propyl-3.4-dimethylpyrrolidone and perfluoro-1-propyl-4-methylpiperidine. The method to obtain the emulsion deals with obtaining the dispersion of phospholipids due to homogenization at pressure of not less than 100 atm. in water-saline medium followed by thermal sterilization, then comes homogenization at pressure of the mentioned perfluoroorganic compounds in dispersion of phospholipids and thermal sterilization of the ready-to-use emulsion. The latter is indicated to treat blood losses, hypoxic and ischemic states, improve oxygen supply by blood and keep isolated perfused organs and tissues. In accordance to the present innovation stability of emulsion has been increased and its qualities have been improved. Storage period of emulsion in its unfrozen state at +4 C corresponds to 12 mo, not less, moreover, biocompatibility of emulsion with biological medium (blood, plasma or serum)has been kept.
EFFECT: higher efficiency of application.
20 cl, 13 ex, 21 tbl
FIELD: cosmetology, dermatology.
SUBSTANCE: the suggested aqueous emulsion of perfluorocompounds contains perfluorocompounds, water and emulsifier, additionally it may contain emulsion wax, moreover, as an emulsifier it contains block-copolymer of ethylene oxides and propylene, components should be taken at certain ratio. Method for obtaining aqueous emulsion deals with mixing aqueous solution of emulsifier and emulsion wax while heating in necessary quantities, cooled mass should be supplemented with perfluorocompounds at constant mixing with ultra-mixer at the rate of 15000 rot./min to homogenize then the mixture obtained, one should perform 3-5 cycles at pressure not exceeding 600 bar. The suggested method enables to obtain the emulsion of high stability and obtain wide-range spectrum of products for cutaneous application.
EFFECT: higher efficiency of application.
3 cl, 1 dwg, 6 ex, 2 tbl
FIELD: infectious diseases and surgery.
SUBSTANCE: wound surface is covered with perfluorane porcine spleen perfusate. Application is repeated daily over a period of 4-12 days depending on the wound surface area and virulence of causative agent. Perfluorane porcine spleen perfusate is prepared by passing perfluorane through spleen vessels at velocity 20-40 ml/min and total volume up to 1 L. Perfusate is used in amount 0.5-0.7 ml per 1 cm2 wound surface area.
EFFECT: activated local immunity and tissue oxygenation.
FIELD: medicine, anesthesiology, resuscitation.
SUBSTANCE: under conditions of artificial pulmonary ventilation at positive pressure at the end of expiration one should set the level of positive pressure at the end of expiration being above against pre-chosen optimal one for 4-8 cm water column. About 10-15 min later one should introduce perfluorocarbon as aerosol with the help of nebulizer for 10-15 min. The innovation enables to introduce perfluorocarbons without depressurization of respiratory contour, decreases damaging impact upon pulmonary parenchyma and, also, reduce invasiveness of the method and decrease expenses of perfluorocarbons.
EFFECT: higher efficiency of therapy.
FIELD: medicine, traumatology.
SUBSTANCE: one should puncture the wound with perfluorane at the dosage of 30 ml, not more/kg affected area once daily for 14 d, not more. The present innovation provides prophylaxis of reperfusion and purulent-necrotic complications in case of gunshot wounds and that of anaerobic infection due to oxygen supply to ischemized wound tissues at adequate quantity during pre-hospital period.
EFFECT: higher efficiency of therapy.