Gas mixtures useful as ultrasound contrast media.
Abstract
The invention relates to injectable media for ultrasonic echography in the form of microbubbles or microballoons comprising at least two biocompatible substances A and B (gaseous at the body temperature) forming a mixture which when in suspension with usual surfactants, additives and stabilisers provides useful ultrasound contrast agents. At least one of the components (B) in the mixture is a gas whose molecular weight is greater than 80 daltons and whose solubility in water is below 0.0283 ml per ml of water at standard conditions. The presence of the first component (B) in the contrast medium may vary between 0.5 and 41 volume percent. The other component (A) of the ultrasound contrast media is a gas or a mixture of gases whose molecular weight is below 80 daltons. The second component is present in a proportion of between 59-99.5% by vol., and is preferably chosen from oxygen, air, nitrogen, carbon dioxide or mixtures thereof. Gas mixtures described are found to be very effective as ultrasound contrast media. The invention also comprises a method of making the ultrasound contrast medium, the contrast agent and the ultrasound agent kit.

Term
Term ended
Expired 12 December 2014, 11.8 years ago.
- Priority
- Filed
- Granted
- Expired
- Today
23 claims: 6 independent, 17 dependent
- 1KRÖFUR 1. Inndælanlegt úthljóðsskuggaefni sem felur í sér Iíflræðilega samiýmanleg efni sem eru í gasfasa við líkamshitastig sem þegar þau eru í grugglausn í vatnskenndum burðarvökva sem inniheldur hefðbundin yfirborðavirk efrii, íblðndunarefiii og stoðandi efhi láta í té skuggamiðla fyrir úthljódsómskodun, sem einkennist afþvi að efnið er blanda af gösum (A) og (B) þar sem ad minnsta kosti eitt af gösunum (B) er til staðar í magni á bilinu 0.5 - 41% miðað vid rúmmál og hefur sameindaþyngd hærri en 80 dalton og leysanleiki þess í vatni er undir 0.0283 ml af gasi í ml af vatni við stadaladstædur, afgangur blöndunnar er gas (A).
- 2Úthljóðsskuggaefriið úr kröfu 1, þar sem gas (B) er flúor-innihaldandi lífíræðilega samiýmanlegt gas.
- 3Úthljóðsskuggaefnió úr kröfu 2, þar sem flúor-innihaldandi gasið er valid úr hópnum sem í eru SF 6 , CF 4 , CjFg, CjFg, C^F 6 , CgF g , C 4 F 6 , θ4^*8» C 4 Fi 0 , C 5 F 1o , CgF 12 og blöndur þeirra.
- 4Úthljóðsskuggaefhið úr kröfu 3, þar sem flúor-innihaldandi gasið er brennisteins hexaflúorið eda oktaflúoró sýklóbútan.
- 5Úthljóðsskuggaefnið úr krðfu 1, þar sem gas A er valid úr hópnum sem i eru andrúmsloft, súrefni, köfhunarefni, koldíoxíð og blöndur þeirra.
- 6Inndælanlegur úthljódsskuggamidillsem felur ísérgruælausn gasfylltra örbóla eda örbladra í lífeðlisfræðilega hæfum vatnskenndum burðarvökva sem inniheldur hefðbundin yfirborðsvirk efrii, íblöndunarefni og stodandi efrii, sem einkennist afþví ad gasið er blanda af ad minnsta kosti tveimur líSræðilega samrýmanlegum gðsum A og B þar sem að minnsta kosti extt gas (B) er til staðar í magni á bilinu 0.5 - 41% miðað við nímmál og hefur sameindaþyngd hærri en 80 dalton og leysanleiki þess í vatni er undir 0.0283 ml af gasi í ml af vatni við staðalaðstæður, afgangur blöndunnar er gps (A).
- 7Úthljódsskuggamidillinn úr krófu. 6, þar sem gas (B) er flúorinnihaldandi líöfædilega samiýmanlegt gas.
- 8Úthljódsskuggamidillinn úr kröfu 7, þar sem flúor-innihaldandi lofttegundin er valid úr hópnum sem í eru SFð, CF 4 , CjFð, C 2 F 8 , C 3 F 6 , C 3 F a , C 4 F 6 , C 4 F 8 , C 4 F 10 , C 5 F 10 , C 5 F 12 og blöndur þeirra.
- 9Úthljódsskuggamidillinn úr krðfu 6 eða 7, þar sem gas A er valid úr hópnum sem í eru andrúmsloft, súrefrii, köfriunarefni, koldíoxíd eða blóndur þeirra.
- 10Úthljódsskuggamidillinn úr kröfu 6, þar sem yfirbordsvirku efiiin fela í sér ad minnsta kosti eitt himnumyndandi yfirbordsvirkt efni sem er til staðar á þynnu- og/eða flðguformi, og mðgulega vatnsfælin stodandi efiii. .
- 11Úthljódsskuggamidillinn úr kröfu 10, þar sem himnumyndandi yfirbordsvirka efhid er fosfólípíd.
- 12Úthljódsskuggamidillinn úr kröfu 11, þar sem fosfölípídid er 25 valid úr hópnum sem í eru fosfatiðsýra, fosfatidýlkólín, fosfatidýletanólamín, fosfatidýlserín, fosfatidýlglýseról, fosfatidýlinósítól, hjartalípín, sfingómýelín og blöndur þeirra.
- 13Úthljódsskuggamidillinn úr krðfu 11, þar sem auk 30 fosfólípíðsins felur vatnskenndi burdarfasinn í sér blandfjöllidur af pólýoxýetýlen og pólýoxýprópýlen, og glýseról.
- 14Úthljóðsskuggamiðillinn úr kröfu 6, þar sem yfirborðsvirku efnin eru sojabaunaolia, Tween* og/eða sorbitol.
- 15Þurr samsetning sem felur í sér yfirborðsvirk efhi, íblðndunareíhi og stoðandi efhi geymd undir blöndu af efhum sem við líkamshitastig eru lífíræðilega samiýmanleg gös, þar sem að minnsta kosti eitt af gösunum hefur sameindamassa hærri en 80 dalton, og leysanleika i vatni sem er undir 0.0283 ml ί hverjum ml af vatni við staðalaðstæður.
- 16Þurra blandan úr kröfu 15, þar sem gasið er flúor-innihaldandi líffræðilega samiýmanlegt gas.
- 17Þurra blandan úr kröfu 16, þar sem flúor-innihaldandi gasið er til stadar í blöndunni í magni á bilinu 0.5 - 41% miðað við rúmmál, og afgangurinn 59 - 99.5% miiðað vid rúmmál er andrúmsloft, súrefni, köfhunareíni, koldíoxíð eða blðndur þeirra.
- 18Tveggja þátta sámstæða sem felur í sér, sem fyrsta þátt, þurra samsetningu yfirborðsvirkra efiia, íblöndunarefna og stoðandi efiia geymda undir blðndu af efnum sem við líkamshitastig eru gðs og, sem annan þáttinn, lífeðlisfræðilega hæfan burðarvðkva, sem við blöndun við fyrri þáttinn lætur í té, sem grugglausn þáttanna tveggja, úthljóðsskuggaefni, sem einkennist af því að að minnsta kosti eitt af gösunum ί blöndunni er gas sem hefur sameindamassa hærri en 80 dalton, og leysanleika ί vatni undir 0.0283 ml ί hverjum ml af vatni við staðalaðstæður.
- 19Tveggja þátta samstœðan úr kröfu 18, þar sem gasið er flúor-innihaldandi lífíræðilega samrýmanlegt gas sem er til staðar í blöndunni í magni á bilinu 0.5 - 41% miðað við rúmmál, og afgangurinn er andrúmsloft, súrefni, kðfhunarefni, koldíoxíð eða blöndur þeirra.
- 20Tveggja þátta samstæðan úr krðfu 18 eða 19, þar sem flúor-innihaldandi gasið er valid úr hópnum sem i eru SF e , CF 4 , C^Fg, C^Fg, C 3 F 6 , Capa, C 4 F 6 , C 4 F b , C 4 F 1o , CgF 10 , C 5 F 12 og blöndur þeirra.
- 21Adferd til framleiðslu úthljóðsskuggamiðilsins úr kröfu. 6, þar sem gasblanda med ad minnsta kosti tvo lífíræðilega samiýmanlegra þætti (A og B) er dreift út í lífedlisfræðilega hæfan vatnskenndan burðarvökva sem inniheldur heídbundin yfirborðsvirk efhi, íblöndunarefni og stodandi efni, til ad mynda gasfylltar ðrbólur eda örblödrur, sem einkennist a f þ v í ad lágmarks virknihlutfall ad minnsta kosti eins gasþáttar í nefhdri blðndu gasa er ákvarðaður samkvæmt skilyrðunum B c % = K/e bMwt +C þar sem B c % (midad vid rúmmál) er heildarmagn þáttar B í blöndunni, K, C og b eru fastar med gildin 140, -10.8 og 0.012, í þessari rod, er mólmassi þáttar B sem er > 80.
- 22Aðferðin til framleiðslu úthljóðsskuggamiðilsins í kröfu 21, þar sem yfirborðsvirka efnið er fosfólípíd valid úr hópnum sem í eru fosfatíðsýra, fosfatidýlkólín, fosfatidýletanólamin, fosfatidýlserín, fosfatidýlglýseról, fosfatidýlinósítól, hjartalípín, sfingomýelín og blöndur þeirra.
- 23Notkun úthljóðsskuggaefnisins úr kröfu 1 vid framleiðslu úthljódsskuggamidla.
Independent claims23
147 paragraphs in 9 sections, as filed
SCOPE, SCIENCES INCLUDING SUBJECT MATTERS AND METHODS
Tasknisvid
The invention relates to contrast agents for oesophageal oesophageal and injectable ultrasound shadow media containing scarred ovaries (acne, diarrhea, microorganisms) carrying contrast agents. In addition to the emulsions, the shadow agent contains physiologically acceptable aqueous carrier fluid containing surfactant, additive and stiffening agent. The invention also relates to methods for the production of ultrasound contrast agents and shading agents and behaviors when used.
Bakgnumw:
Recognition of the usefulness of injectable gruel solutions of gas microspheres as useful ultrasound shadowing agents in diagnostic studies has stimulated considerable research and development towards improved scattering of gas-filled microblasts or microbubbles with greater stability, better resistance to pressure changes, good echogenicity, audible framing, use and storage. Many suggestions for ultrasound shadows in such a blast have been reversed. For example, there is a failure of an aqueous suspension which can be used as an ultrasound photomicrograph in WO-A-91/15244 (Schneider et al.), WO-A-92/11873 (Beller et al.) Et al. EP-A- 0 077 752 (Schering).
WO-A-91/15244 (Schneider et al.) Discloses microbial cloud solutions containing membrane-forming surfactant compounds on blister and / or blister form and, optionally, a hydrophobic stiffening agent. The slurry solution is obtained by a surfactant surfactant which is made of flakes coming into contact with the gas at the time of mixing with
1739 2 aqueous phase. Transformation of membrane-forming surfactant compounds into a flame form is performed in accordance with variable techniques including high pressure or sonication (sonicatone) homogenesis at a silent ultrasound. The expressed strength of the bubbles in these slurries is between 10 and 10 bubbles / mL. The slurries described are fairly stable during storage.
WO-A-94/09829 (Schneider et al.) Shows that concentrations of the phospholipids in a blister and / or blend form used in the preparation of highly stable aqueous suspensions may be so small that they correspond to a single molecule of the phospholipids around the bubbles in the slurry. Stable low-phospholipid suspensions (down to few pg / ml) have long been stored without noticeable loss in the number of immune properties.
Adaptation to increased stiffness towards thrombotic changes in dandruffs of microorganisms which are used as ultrasound shielding agents is EP-A-0 554 213 (Schneider et al.). There has been a significant increase in suppositories in the inflammation versus compression due to pressure changes during the injection of a feast when air, kinetic other commonly used solvents is at least partially replaced by gases where the solubility in water is expressed in kilograms of gas per liter of water at standard ratios divided by the square root of the molecular weight in daltons does not exceed 0.003. Gós discussed which satisfies the above criteria are, for example, SeF<sub>6</sub>, SF<sub>6</sub>, CF<sub>4</sub>, CaFg,, QF<sub>10</sub> etc. It has been shown that these gizzards give long-lasting microblisters, which are very stable in the body (m vivo) and give high quality imagery.
WO-A-92/17212 and WO-A-92/17213 (Klaveness et al.) Contain ultrasound shadow media containing bladder blisters made of cross-linked non-proteinaceous non-protein amphiphilic non-protein substances (e.g., phospholipids) and cross-linked proteins (eg albumin). Microorganisms are encapsulated on a table by air, oxygen, hydrogen, quinquering, helium, argon, CH<sub>4</sub>, SF<sub>6</sub> your gas forwarder on a table with sodium and ammonium bicarbonate.
WO-A-93/06869 (Mallinckrodt Medical Inc.) contains behavior in immunosuppression of blood-labeled animals in which pharmaceutically acceptable gauze mixtures of yeast are administered to animals and the animal is scanned by immunosuppressants. Gases and gas mixtures are injected and clear by inhalation of the mixture for several minutes, microblisters form the blood flow of the hot blood and the onset of the tissue changes. The gases of the gas mixtures are oxygen, nitric oxide, C 2 H 6, SF<sub>6</sub>, xenon, perflourocarbon, osfiv. Very good and gas-blending are those that tend to form larger bloods in the blood and can obviously turn xenon oxide nitrates and other low-activity active detergents on a table at sulfur hexafluoride. Blinds described contain either 20% oxygen, 60-80% sulfur hexafluoride, and / or 20% nitrogen, xenon, nitric oxide or ethylene 20% oxygen and 60% xenon oxide nitride. The behavior is based on a comparison of ozone labels as a result of two different scans.
A noteworthy idea has been set forth in WO-A-93/05819 (Quay). Documentation contains the blisters of softened dope fluoropentane and decafluorobutane and sorbitol in water which, by injection, form gaseous pressures that resist pressure changes and give a good immune system. The emulsion, in fluid at ambient temperature, is very volatile and easily vaporized to generate body temperature and generate gas-permeable fluid disturbances. in a carrier fluid containing anhydrous and auxiliary substance on a table at sorbitol. During injection, fast volatile substances rapidly scatter and form a considerable amount of very durable microbes. microbubbles containing only selected secondary, ie Dope fluoro pentane in a pure form without oxygen or other gas is supported by solid compounds, for example. sorbitol, Tween®20 and soya bean oil, which are present in the soft drink burger. Generally, Quay was found because the foregoing technology could be used for a variety of other non-aqueous chemical substances (gaseous), which were used with criteria defined as the relationship between volume of edible mass, solubility and diffusivity (study Q). In the document, there are many similar gossips with a study Q greater than 5, which are potentially useful as resources, and a list of 180 gauge / vectors satisfying the assumptions. It also encompasses the document until it reaches the desired qualities, shadow media is made of materials with a Q study than 5. The defined assumptions are Q - 4.0 x 10 " Generally, Quay was found because the foregoing technology could be used for a variety of other non-aqueous chemical substances (gaseous), which were used with criteria defined as the relationship between volume of edible mass, solubility and diffusivity (study Q). In the document, there are many similar gossips with a study Q greater than 5, which are potentially useful as resources, and a list of 180 gauge / vectors satisfying the assumptions. It also encompasses the document until it reaches the desired qualities, shadow media is made of materials with a Q study than 5. The defined assumptions are Q - 4.0 x 10 " Generally, Quay was found because the foregoing technology could be used for a variety of other non-aqueous chemical substances (gaseous), which were used with criteria defined as the relationship between volume of edible mass, solubility and diffusivity (study Q). In the document, there are many similar gossips with a study Q greater than 5, which are potentially useful as resources, and a list of 180 gauge / vectors satisfying the assumptions. It also encompasses the document until it reaches the desired qualities, shadow media is made of materials with a Q study than 5. The defined assumptions are Q - 4.0 x 10 " In the document, there are many similar gossips with a study Q greater than 5, which are potentially useful as resources, and a list of 180 gauge / vectors satisfying the assumptions. It also encompasses the document until it reaches the desired qualities, shadow media is made of materials with a Q study than 5. The defined assumptions are Q - 4.0 x 10 " In the document, there are many similar gossips with a study Q greater than 5, which are potentially useful as resources, and a list of 180 gauge / vectors satisfying the assumptions. It also encompasses the document until it reaches the desired qualities, shadow media is made of materials with a Q study than 5. The defined assumptions are Q - 4.0 x 10 "<sup>7</sup>xp / C, D where p is the edible mass of the gas, D is the dispersion of the gas in solution and C<sub>a</sub> is the solubility of the gas in water, and this has been developed by using a simple model, pairs of dispersion and solubility of gas in water are used as approaches to the realm. Shadow media as solid from non-bulky materials. which are selected according to the assumptions above have given encouraging nidurstod. Shadow diamonds that have been tested during experimental experiments have given rise to an epidemic for ultrasound monitoring of cardiac mood following supra-oral injection (see Beppu S. et al., In a memorandum from 66. American Heart Association Scientific Meeting,
Atlanta, October 1993). Had the dose, has shown that injections of 2.2% buffered deodorafluoropentan give a median opacification for up to 85 minutes. In contrast, with doses in which left ventricular vertigo was observed, there was a reduction in oxygen and saturation in arterial blood and an increase in pulmonary artery pressure.
Many of the compositions in previous writings are valid and can be found in high clinical trials. Multiple them at different levels of oppression. On the other hand, different reports show that there is a small amount of evidence available to utilize all forms of diagnostic maladministration as well as immune coding. Thus, only a few shadow media are really useful and help the medical profession benefit from diagnostic technology, which, otherwise, provides one of the best non-invasive methods for diagnosing lipids in the human body. Few mediums allow the exploitation of all kinds of ultrasound, and this impedes wider use of technology and / or the shadow media. Research on the well-known media has shown that some of them do not adequately backscatter to ensure good strength and contrast, or provide useful images for solely a hundred percent of the numbers that limit their utility as a diagnostic device for general use. Others, due to low resistance to pressure changes, are too short to allow meaningful measurements or useful images. Typically, shadow media where microbubbles or microblisters are filled with gas with xnikla solubility in water have low resistance to pressure changes. Glued solutions of microbes, where the packaging is made of rigid efrium, are also useless because they do not interact with sound waves sufficiently. Interestingly, shadow media with high resistance to pressure changes are those using low solubility gases in aqueous carrier free. The direct result of low solubility is the low rate of absorption and slow removal of the Hkam. Imaging agents made from such highly insoluble gases are circulating for a longer period of time and cause relapse or recirculation of the gas bubbles that cause interference with images produced at the initial stage of the test. Such shading agents are generally useful in the formation of the left heart, but due to slow retardation or abduction, it is not advisable to use them effectively for flow measurement. Volatility measurements are usually performed by aggregation of the secondary response graph, which produces a typical Gaussianfall, which occurs after a "one-turn" of the image protection medium. Reverse or recurrence after " Clearly, it is highly desirable to change the thrust resistance or tolerance of the shadow agent after injection, ie. The use of bubbles (or microblowers) which are designed with a suitable pressure measurement have a controlled life cycle in the circuit. This requirement is fulfilled in the invention below.
Exemplary of the invention
In summary, the invention relates to injectable ultrasound contrast media in the form of microbubbles or microbubbles containing at least two biologically compatible gas-gaseous gases, substances A and B that form a composition which is already abrasive with normal surfactants, emulsifiers and antioxidants provides useful ultrasound shadow columns. At least one of the components (B) of the blank is a gas having a molecular weight greater than 80 daltons and solubility in water less than 0.0283 ml of gas per ml of water under standard conditions. 1 This document refers to the solubility of gas for the matching of Bunsen coefficients and the molecular weights greater than 80 daltons are considered relatively high, while molecular weights below 80 daltons are considered relatively low.
In the ultrasound contrast agent of the invention, a gasid having a molecular weight of more than 80 daltons may comprise a mixture of gases mixture of substances which are gas-ignited at a temperature which, at ambient temperature, can be wet. Such gas-known products can be useful in the shadowing of the invention as long as the molecular weight of each chemical substance is greater than 80 daltons and the solubility of each of the substances in water is less than 0.0283 ml of gas per ml of water at the stadium loading process.
When filled with the contrast agents of the invention and dispersed in aqueous carrier containing conventional topically active agents, additives and solidifying agents, the injectors formed into injectable shadow media for ultrasound images, with controlled resistance to pressure changes and adjusted stiffness after injection. In addition to the bubbles, the shadow agent of the invention contains a surfactant as a mixture of gas / vasculobutyl chloride, and, optionally, hydrophobic agents and other blotting agents. fbldndunarefhin may contain we rode block copolymer of polyoxypropylene and polyoxyethylene (poloxamers), polyoxyethylene-sorbitans, sorbitol, glycerol-polyalkylene stearate, glycerol-polyalkylene stearate, homo- and a copolymer of polyalkylene glycols, soybean-oil as well as hydrogenated derivatives, ethers and esters of sucrose or other carbohydrates with fatty acids, fatty alcohols, soybean oil glycerides, dextran, sucrose and carbohydrates. Surfactants can not cause membrane formation, and may contain extensible biocompatible compounds of the type linoleyl-readitinated polyethylene dodecanoate. Heist contains surfactant containing more skin-forming surfactants on blisters such as phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphetidylinosititol, cardiac lipid, sphingomyeline and blunt thereof. Surfactants can not cause membrane formation, and may contain extensible biocompatible compounds of the type linoleyl-readitinated polyethylene dodecanoate. Heist contains surfactant containing more skin-forming surfactants on blisters such as phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphetidylinosititol, cardiac lipid, sphingomyeline and blunt thereof. Surfactants can not cause membrane formation, and may contain extensible biocompatible compounds of the type linoleyl-readitinated polyethylene dodecanoate. Heist contains surfactant containing more skin-forming surfactants on blisters such as phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphetidylinosititol, cardiac lipid, sphingomyeline and blunt thereof.
The invention also includes a method of producing ultrasound shadow media by placing in a biologically acceptable carrier containing ordinary tabletop, gas filled bubbles or microblowers containing a mixture of gases wherein at least one of the gases as the minimum effective amount in the mixture can be determined by illustration:
B<sub>c</sub>% = K / e<sup>b Mwt</sup>+ C where B<sub>e</sub>% (by volume) is the total amount of the factor B in the mixture, K, C & 15 b is fixed with the values 140, -10.8 and 0.012 in this row, Mwt, the molecular weight of factor B is greater than 80. Shadow diameters produced according to this behavior contain turbidity or thrombocytes with excellent resistance to pressure changes and controlled sedation time.
.
The invention also contains a kit (kit) containing a dry composition usually stored under a mixture of gases and / or vapors transformed into gases at temperature. When dispersed in a biochemically acceptable carrier fluid, the dry composition forms a mixture of gases and / or vaginal shadow media of the invention. Behavior of the dry dry lyophilised composition in the vidurvist ultrasound contrast agent is also included.
The invention further relates to the behavior of a shadow medium with microbes containing ultrasound contrast agents, as well as their use in forming organs in the same human being of each animal.
Brief description of the drawings
Drawing 1 is a pictorial representation of an ultrasonic contrast agent in accordance with the invention.
Drawing 2 is a graphical representation of the ground pressure (Pc) of the contrast media as a function of the amount of gas produced in the mixture.
Drawing 3 is an extraction of the target pressure (Pc) of contrast agent made from octafluorocyclobutane (C<sub>4</sub>F<sub>8</sub>) and dodecane fluoropentane (C<sub>5</sub>F<sub>12</sub>) which fell by the amount of gas in the blend.
Drawing 4 is a summary of the minimum amount of gas in the mixture falling from the molecular weight.
Drawing 5 is a pictorial representation of the immune response in the liver similar to the time of the left ventricle in minipig after injection of a contrast medium containing variable amounts of SF<sub>6</sub>.
Drawing 6 is a summary of the immune response in the body of the body, which is obtained by time with contrast medium containing variable strengths of C<sub>4</sub>F<sub>8</sub>.
DETAILED DESCRIPTION OF THE INVENTION 25
This invention is based on the unexpected discovery of ultrasound contrast media containing bubbles filled with bubbles of at least two biocompatible gaseous liquids at the level of gaseous chemical A (relative to relative molecular weight) and B (effective relative high molecular weight) give a slight dissolution with normal surface active agents, adjuvants and stagnant efiium, injectable ultrasonic shadow media that combine desirably with pressure and shorter lifespan in the cycle, as both of these elements are controllable at will. As long as at least one of the (activating) components of the mixture with a molecular weight of less than 80 daltons (relative high molecular weight) is present in a certain minimum proportion and as long as its solubility in water is less than 0. 0283 ml of gas per ml of water at state conditions, the ultrasonic material provides non-functional properties as good as those fixed when pure materials are used alone. By "activation" refers to the factor that imparts its editing properties to the other components of the mixture, which provides the imperative properties and resistance to pressure changes, just as much as the secondary factor alone (clearly form). The amount of first, high molecular weight activator, the component of the contrast agent is in the majority of cases from 0.5 vol.% (For high molecular weight and low solubility in water) to 41 vol.%. Experiments have shown efhid with molecular weight lower than 80 daltons ("relative low molecular weight" ) are not suitable as active factors, and it is difficult to find the upper molecular weight of the molecule because the dll substances that were tested were effective, provided that their molecular weight was a relative host ie. higher than 80.
It has been developed with a molecular weight of 240 daltons on a table at the decafluorobutyl ether 290 on a table at perflouropentan, which are highly efficient actives. Also shown on the table at
1,2,3-undecane tricarboxylic acid, 2-hydroxy-trimethyl ester with molecular weight just above 500 daltons can also be used as a high molecular weight activator. The "adal" factor is similar in size to 59 to 99.5% by volume, and can reverse gas dissipation, which is more soluble in water than kdf solids (0.0144 ml / ml water under standard conditions). The other factor is oxygen, air, dust, carbon dioxide and mixtures of them and all oxygenated air. On the other hand, as part A, other unusual gds can be used on tables at argon, xenon, kiypton, CHC1F<sub>2</sub> nitric oxide. Some of these more common gases may have a molecular weight greater than 0<sub>2</sub>, N<sub>2</sub>, ceiling, CO<sub>2</sub>, etc., for example, more than
<img file="IS1739B_D0001.tif" />
dalton and, in this case, their solubility in water is greater than the solubility of the gases of class B ie is greater than 0.0283 ml / ml of water.
It was quite unexpected to find that a water-based cargo mixture made up of a single 0.5% volume of tops such as dodecane fluoropentane, or 0.8% by volume of decafluorobutane, in a mixture of air would give a great bubble in the body's body and resistance to pressure changes. This is especially unexpected, as it has been considered necessary to get good left ventures in the left heart and heart muscle so far, that these substances, and indeed many others, should be used for 100% support, ie. in pure form (without air). Experiments with mixtures containing different amounts of these low-dissolving chemicals in water and air show that the imaging image is as good as the ones that apply to similar situations using non-ionic soles only from pure chemical.
Older studies have shown that airborne aerosol propagation in the cycle is worthwhile as this otherwise lifelike, passive gas rapidly dissipates with the dilution and immunity of the bubbles using different surface active agents, additives and stiffening substances. In the development of the invention, there have also been reversed microbloods of dandelions with a hideous wall. microblisters with walls made from natural flax pellets such as fatulog (liposome) or edible protein such as albumin filled with air or CO<sub>2</sub> have turned his temper.
Poor resistance to pressure changes and subsequent loss of immune properties in older shadow media have prompted searches for gaseous particles with greater resistance to pressure changes occurring in the blood stream. There is a full-fledged surface like sulfur hexafluoride and even more canned fluorescent pentane reverses the design. Experiments with these gizzards have been shown by injection, as drowsiness of dolphins solely made from these gds are precisely with great resistance to aggregation in the blood circulation. As a result of these initial findings, close to 200 gauze prices have been confirmed as useful for the efficient production of ultrasound shadow media. It has therefore been discovered unexpectedly that by mixing oxygen or air with some of the gases resistant to pressure, it is possible to obtain ultrasound media having physiologically better resistance and / or shorter absorption half-life than pure sulfur hexafluoride or dodefluoro pentane, but has than the good pressure crank that these gos have alone. It is stated that such unequal behavior in the ultrasound of the invention is due to the fact that in the gas-containing gas bubbles, the dispersion of air into the surrounding liquid is possible because there are large molecules of gas or gases that have solubility in water similar to or less than for air or oxygen. Although the reasons for this unexpected behavior are still unexplained, it is possible to assert that gas molecules with high molecular weight, even in very small amounts, "close the holes" on the surface of the microbubbles, thus preventing low molecular weight molecules from escaping through the membrane. The pictorial representation of this model is shown in Figure 1, where the microbubble containing air (1) mixed with gas having a molecular weight greater than 80 daltons (2) is placed in an aqueous material (3).
Short-term outer layer (4) is supported by surfactant (eg phospholipids), but keeps the gas mixture within a certain volume that defines the microbubble. Activating or in a smaller part of the gas B is distributed evenly throughout the volume of the microbubble, it has slower flow and eventually closes the bubbles and is automatically formed in the aqueous solution as a surface of a celestial coating, thus preventing the rapid elimination of memory and the usually soluble primary component A . In contrast, the active or lower gas component (B) has a higher degree of perspiration in the lipophilic portion of the surfactant used to support the short-lived coating rather than oxygen or air. Therefore, in conjunction with another hypothesis, these gos have the tendency to densify in the vicinity of the sky, thus preventing or reducing the flow of smaller gas / gas through the sky. Whoever it is, then a compilation of experimental results suggests that the amount of the activation gas in the mixture is equivalent to the closure of the absorbance of a particular membrane or to the amount required for a single layer formed on the inner wall of the microbubbles. Therefore, the minimum amount required is what is required to close the holes or cover the inner wall of the membrane to prevent the low molecular weight absorption and absorption of the factor.
It is also contemplated that the excipient properties of the ultrasonic contrast agent of the invention are due to the combined use of carbon monoxide, carbon dioxide, oxygen free or air (essentially oxygen / kinetic compound) with other gases. In practice, these biologically and physiologically sanitary gases provide the most important properties for the subject in question, thus enabling their advantageous properties. If the obscuration shadows of the invention can be made from a number of other gas as the main component A, then oxygen and air are used. 1 context of this document is air treated as "single factor" gas.
In accordance with the invention, ultrasound contrast media with high resistance to pressure changes, together with a relatively rapid absorption, i.e. cleansing of the body is achieved by using gas or gases having a molecular weight of less than 80 daltons in a mixture with gas or gases having a greater solubility in water than 0.0144 ml / ml of water and molecular weight generally less than 80 daltons. Gases such as oxygen or air are mixed with Ekamshita gums, which can be liquid at ambient temperature, forming a metal medium that possesses all of the beneficial properties of the gases in the mixture. In other words, when these mixtures are injected into microspheres, they give clear and concise images with sharp faces (usually for high resistance bubbles against pressure changes), and at the same time they are absorbed as easily as they were filled with air or oxygen alone . Thus, by combining air, carbon dioxide, carbon dioxide or oxygen with a certain amount of controlled substances that are biologically compatible with high molecular weight body masses, ultrasound contrast agents are provided with significant and completely depressed economic properties. As it is clear, they give the best of each aspect, ie. good resistance to pressure changes from one and the relatively fast saturation of others, and at the same time, the corresponding disadvantages of each of the factors, if left alone, eliminated. This is especially unexpected, as it would be expected that properties that would be average of those who had each ice-cream would have time.
As long as the molecular weight of such biologically compatible compounds (B) is greater than 80 daltons and their solubility in water is less than 0.0283 ml of gas per ml of water under standard conditions, the secondary compound in a gas or liquid form is useful for the contrast agents of the invention. Although in connection with acceptable surfactants and stabilizers, gases like sulfur hexafluoride, tetrailúorómetan, chlorotrifluoromethane, dichlorodifluoro-methane, brómótriflúorómetan, brómóklóródíflúorómetan, dibromo-difluoromethane díklórótetraflúoróetan, chloropentafluoroethane, hexafluoroethane, hexafluoropropylene, octafluoropropane, hexaflúoró20 butadiene, octafluoro -2-butene, octafluorocyclobutane, decafluorobutane, perfluorocyclopentane, dodefluoroacetan pentane and sulfur hexafluoride and / or octafluorocyclobutane, in the category Ð,
Another surprising and unbelievable feature of the invention is the fact that when the assumptions of WO 93/05819 are applied to the medium of this invention, the Q coefficient as a party for gas mixtures is lower than 5.
This is unbelievable since, according to WO 93/05819, substances with Q coefficients of less than 5 are excluded from gases suitable for the production of useful ultrasound contrast media. Nevertheless, it has been discovered that homogeneous gas mixtures of this invention having a factor of substantially less than 5 give shadow media useful in ultrasound imaging.
When the microbubbles formed have been filled with the shadow agent of the invention and dispersed in an aqueous carrier containing surfactant, emulsifying agent and solidifying agent, they provide a shadow medium for ultrasound formation. In addition to the microbials, the contrast agent of the invention contains surfactant, surfactants, and stubborn substances. Surfactants may contain one or more more membrane-forming surfactants on a blister and / or flap form used for the short-term gas / fluid coating of the bubble. Moisturizing agents on a table at lactose such as sucrose, dextran, starch, and polyacrylamides such as other conventional surfactants on a board of polyoxypropylene glycol and polyoxyethylene glycol; ether of fatty alcohols with polyoxyalkylene glycols; esters of fatty acids with polyoxyalkyl ether sorbitol; soaps; glycerol-polyalkylene stearate;
glycerol-polyoxyethylene risinoleate; homogeneous and mixed polymer of polyalkylene glycols; polyethoxylated soybean oil and castor oil as well as watercolors derived; ethers and esters of sucrose and ddrum carbohydrates with fatty acids, fatty alcohols, where they are possibly polyoxyalkyl ether; mono-, di- and triglycerides of methane and non-fatty acids; glyceride of soybean oil and sucrose can also be used. Surfactants may also be film-forming and may contain polyhydric acid-based base-containing compounds of rosin linoleyl-lecithin and polyethylene dodecanoate. Heist are the topically active film-forming agents, and all of them are phospholipid selected from phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinosititol, cardiac lipid, sphingomyelin and blended.
Clearly, the present invention is not limited to shadow media, wherein only viruses are used as a carrier for the ultrasound shadow media of the invention. What a good dune that is filled with ultrasound shadow media, ie liposomes or microblisters that have a haircut made of artificial or natural polymers or proteins can be used in a healthy manner. It has been shown that microblisters made from albumin, or liposome mesotransmitters or iodoimide ethyl ester permeable particles, when filled with ultrasound contrast agents of the invention, provide a good osmotic agent. Glued solutions where spheres were stubborn with sorbitol or non-ionic surfactants such as polyoxyethylene / polyaxypropylene polymers (known as Pluronic®) have shown a good imaging relationship to original combinations made from pure materials alone. It is therefore believed that the invention provides a more general idea of ultrasound content and provides a better insight into ultrasound imaging issues as well as better control of shadow media properties. The objects and shadow members containing the subject matter of the invention are thus considered to be a product that brings technology one step forward in its development.
The invention also includes a method of producing an ultrasound shield medium wherein the gas mixture of at least two components is placed in a physiologically acceptable aqueous carrier fluid containing a general surface active agent and auxiliary to form gas-filled microspheres or microblocks characterized in that the minimum ratio of at least The advantages of one gaseous component (B) in the aforementioned mixture of gases are determined according to the assumptions
B<sub>c</sub>% = K / e<sup>b Mwt</sup>+ C where Bc% (by volume) is the total amount of the factor - in the blend, K & C are anxieties with values 140 and -10.8 in this order, Mwt is the molecular weight factor B above 80 and b is a complex which is a complex drop of processing temperature and the thickness of the membrane (liposuction) that supports the microbial disorder; but because the temperature of the body is mostly stable and stable, the membrane structure is largely independent of lipids, the value b is in the range of 0.011-0.012 and can be regarded as solid. Shadow diamonds produced in combination with the behavior include microbial microspheres with excellent resistance to pressure changes and relatively rapid onset. Both properties are managed adequately to virtually any special funds available.
The invention also includes a dry composition comprising a dominant substance, anesthetic and a solidifying agent which is stored under a binder of liquid gaseous efits and at least one of which has a molecular weight greater than 80 daltons and a solubility in water less than 0.0283 ml per ml of water at the stadium stadium. For injection, the composition comprising lyophilized film-forming hydrophobic and antifouling agents such as polyethylene glycol or other conventional hydrophobic material is mixed with physiologically acceptable burden tissues for the induced ultrasound shadow molecule of the invention. A membrane-forming surfactant is a hardened phospholipid valid from phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinitol, cardiolipin, sphingomyeline and mixtures thereof.
In a modified manner, the short-range gas / vascular membrane microspheres can be monitored with nonionic surfactants such as polyoxyethylene and polyoxypropylene copolymers in combination with a membrane-forming surfactant on a table at dipalmitoylphosphididylglycerol. As previously mentioned, the aqueous carrier may further contain water-based emulsifiers on a table at glycerol, PEG, sorbitol, etc. Furthermore, the present invention is useful in salt solutions containing Tween® 20, soybean oil, and optionally other additives.
Also included is a two-component assembly containing as a first component a dry composition of surfactants, emulsifiers and solidifying agents stored under a mixture of gases and as a second part of the physiologically acceptable carrier fluid that comes into contact with the first episode gives ultrasound contrast. The group may contain a system of two separate vials, each of which contains one of the components that are linked so that the acf mixes are assembled in a conventional manner before the contrast agent is used. Clearly, the pharmaceutical bottle containing the dry composition contains on the same time ultrasound of the invention. In a conventional manner, the assembly may be in the form of a pre-filled two-chamber syringe which may further comprise a device for connecting a needle to another end thereof.
The invention further includes a method of bending to shadow media with microbes containing the ultrasound shadow freeze, as well as their use in forming organs in human and animal bodies.
When used for imaging of organs human or animal then úthljósskuggaefrii invention administered to a patient in the form vantskenndrar suspensions in physiologically liquid carriers described above and the patient is scanned with an ultrasonic probe where the image of the organ or part of fikamanum that is generated is induced.
The following examples further illustrate the invention:
Example 1
Multilamellar vesicles (MLVs) were prepared by dissolving 120 mg daracidylphosphatidylcholine (DAPC, Avanti Polar Lipids) and 5 mg Dippalmitoylphosphatidic Acid (DPPA Acid Form, Avanti Polar Lipids) in 25 ml hexane / ethanol (8 / 2, v / v) then the solvents are evaporated completely into a spherical flask using a rotary evaporator. The resulting fatty membrane was dried under vacuum and after adding water (5 ml), the mixture was allowed to warm to 90 ° C for 30 minutes with stirring. The resulting solution was pressed at 85 ° C through a 80 μm polycarbonate filter (Nuclepore®). This formulation was added to 45 ml of 167 mg / ml solution of dextran 10.000 MW (Fluka) in water. The solution was carefully blended, transferred to a 500 ml spherical bottle, frozen at ~ 45 ° C and lyophilized with
13.33 Nt / m<sup>2</sup> (0.1 Torr). Total dry degeneration on the ice was obtained overnight. Dosage (100 mg) of lyophilised substance. were placed in a 20 ml glass cartridge. The capsules were sealed with rubber stoppers and the air removed from the capsules using vacuum. Blinds of air with different amounts of sulfur hexafluoride were placed in the capsules with a needle around the cap.
Vaccine solutions were obtained by injection into each capsule 10 ml of 3% glycerol solution in water followed by a strong mixture. microbubbles that were formed were counted using a blister (hemasytometer). The average size was 2.0 pm. On-site measurements (defined as ί ΕΡ-Δ-0 554 213) at ground pressure (Pc), immobilization (ie backscatter) and the number of different samples were performed (see Table 1).
As can be seen from the findings, wind turbines containing 100% air (sample A) have low resistance to pressure, but with only 5% SF<sub>6</sub>, the resistance to the pressure increases considerably (sample B). With 25% SF<sub>6</sub>
TABLE 1
<td>Showing</td><td>air % space</td><td>SF<sub>e</sub>% space</td><td>Q index</td><td>Pc mmHg</td><td>Resonance properties 1 / (sm.sr) x 100</td><td>strength (Bubbles / ml)</td>
<td>A</td><td>100</td><td>0</td><td>1.0</td><td>43</td><td>1.6</td><td>1.5x10®</td>
<td>B</td><td>95</td><td>5</td><td>1.3</td><td>68</td><td>2.1</td><td>1.4x10®</td>
<td>C</td><td>90</td><td>10</td><td>1.6</td><td>85</td><td>2.4</td><td>1.5x10®</td>
<td>D</td><td>75</td><td>25</td><td>3.1</td><td>101</td><td>2.3</td><td>1.4x10®</td>
<td>E</td><td>65</td><td>35</td><td>4.7</td><td>106</td><td>2.4</td><td>1.5x10®</td>
<td>F</td><td>59</td><td>41</td><td>5.8</td><td>108</td><td>2.4</td><td>1.6x10®</td>
<td>G</td><td>0</td><td>100</td><td>722.3</td><td>115</td><td>2.3</td><td>1.5x10®</td>
the resistance to pressure is almost as at 100% SF<sub>6</sub>. However, concentrations of pimples, mean pimples and horseradish hives are almost independent percent of SF<sub>6</sub>.
The slurry that would be poured into a dandelion on a piggy bank (Pitman
Moore) at a dose of 0.5 ml per 10 kg and left ventricular vesicle imagery were recorded on vivo live cell imagery, Acuson XP128 ultrasound system (7), and 7-MHz (MHz) diaphragm. Contrast concentration was measured by video densitometry using Dextra Inc. (Dextra Inc.). Drawing 5 shows a video clip of left ventricular metastatic measurements. A significant difference between case line 100% air (sample A) and 95% toft (sample B) is still observed. Especially, with 5% SF<sub>6</sub> is the maximum concentration when reached and the cycle half-life also shows a very rapid rise. With 10% SF<sub>6</sub>, there is no additional increase in strength but only a longer half-life. The example shows that using more than 10% to 25% SF<sub>6</sub> The gas mixture gives no special benefit. It is noteworthy to note that the values for the Q scaffold attached to the blend of composites are well below the target value 5 given in WO-A25 93/05819.
»I
Example 2
Doses (25 mg) of PEG / DAPC / DPPA lyophilisate were obtained as shown in Example 1 (using PEG 4000 instead of dextran 10,000) in 10 ml glass vial. Tedlar® sachets were filled with air and octafluorocyclobutane (C<sub>4</sub>F<sub>8</sub>). Known volumes were extracted from syringes and their contents were mixed with a three-way cranial system. Selected gas mixtures were then placed in the glass container (previously emptied). The lyophilised product was then placed in 2.5 ml brine (0.9% NaCl). The results are shown below showing resistance to the pressure, the strength of the bubbles and the backing factor of the abrasive. 1 case 100% C<sub>4</sub>F<sub>8</sub> the resistance to the pressure is 225 mm Hg (compared to 43 mm Hg in the case of air). Again, a significant increase in pressure relief is observed with only 5% C<sub>4</sub>F<sub>8</sub> (Pc = 117 mmHg).
Following an intravenous x-ray injection (0.03 ml / kg), a slight increase in myocardial infarction was observed immediately at 2% C<sub>4</sub>F<sub>8</sub> (mid-air). But with 5% c<sub>4</sub>f<sub>8</sub>, the opposition time increased sharply, as above the threshold value of the resistance to pressure, the tolerance of the buoys increased enormously (see Figure 6).
TABLE 2
<td>Showing</td><td>air % space</td><td>c<sub>4</sub>f<sub>8</sub>% space</td><td>Q factor</td><td>Pc mmHg</td><td>echogenicity 1 / (sm.sr) x100</td><td>strength (Bubbles / ml)</td>
<td>A</td><td>100</td><td>0</td><td>1.0</td><td>43</td><td>1.6</td><td>1.8x10®</td>
<td>B</td><td>95</td><td>5</td><td>1.4</td><td>117</td><td>2.2</td><td>3.1x10®</td>
<td>C</td><td>90</td><td>10</td><td>1.7</td><td>152</td><td>3.1</td><td>4.7x10®</td>
<td>D</td><td>75</td><td>25</td><td>3.3</td><td>197</td><td>3.5</td><td>4.9x10®</td>
<td>E</td><td>65</td><td>35</td><td>4.6</td><td>209</td><td>3.4</td><td>4.3x10®</td>
<td>F</td><td>59</td><td>41</td><td>5.5</td><td>218</td><td>2.8</td><td>4.0x10®</td>
<td>G</td><td>0</td><td>100</td><td>1531</td><td>225</td><td>2.3</td><td>3.8x10®</td>
Again, this combination of gases produced very good pictures with 5% of gas B in the mixture, with excellent left heart images obtained with mixtures containing up to 25% of octafluoro cyclobutan.
Corresponding diagram of ground pressure as a function of C<sub>4</sub>F<sub>8</sub> in the mixture with air is shown in Figure 2. This example again shows that the use of a mixture of gas improves the resistance of air bubbles to pressure quite simply by adding a small percentage of high molecular weight gas / low solubility. The drawing further shows that with a suitable choice of gas mixture it is possible to get any resistance to the pressure to be avoided. .
Example 3
The same lyophilisate used and is described in Example 5. The gas phase was made from dodecane fluoropentane (C<sub>5</sub>F<sub>12</sub>) and air. C<sub>5</sub>F<sub>12</sub> is liquid at room temperature with boiling point 29.5 ° C. 24 ml glass capsule each containing 50 mg of lyophilized PEG / DSPC / DPPG obtained as described in Example 5 were suspended in vacuo, closed under vacuum, then heated at 45 ° C. The small volume (few micrites) of C<sub>5</sub>F<sub>12</sub> were injected into the capsules still at 45 ° C throughout the cap. A ceiling was then moved in to cover the pressures of the capsules. After cooling at room temperature, saline solution
TABLE 3
<td>Showing</td><td>air % space</td><td>CsFi<sub>2 </sub>% space</td><td>Q index</td><td>Pc mmHg</td><td>Ómunareiginl. (Sm.sr) '<sup>1</sup></td><td>SL (Cradle / ml)</td><td>Helm. * time (T, zz) sec</td><td>St. Gray points</td><td>AUC (Ha)</td>
<td>A</td><td>100</td><td>0</td><td>1.0</td><td>43</td><td>0017</td><td>1.8x10®</td><td>11</td><td>22</td><td>78</td>
<td>B</td><td>99.5</td><td>0.5</td><td>1.0</td><td>80 *</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td>
<td>C</td><td>98.6</td><td>1.4</td><td>1.1</td><td>133</td><td>0026</td><td>3.9x10®</td><td>14</td><td>97</td><td>609</td>
<td>D</td><td>97.1</td><td>2.9</td><td>1.4</td><td>182</td><td>0028</td><td>3.9x10®</td><td>17</td><td>98</td><td>860</td>
<td>E</td><td>94.2</td><td>5.8</td><td>1.7</td><td>295</td><td>0040</td><td>5.2x10®</td><td>59</td><td>99</td><td>3682</td>
<td>F</td><td>85.5</td><td>14.5</td><td>3.4</td><td>394</td><td>0036</td><td>4.5x10®</td><td>78</td><td>97</td><td>5141</td>
* Intended (5 ml) was passed through the stopper and the capsules shaken gently. Actual percentage C<sub>5</sub>F<sub>12</sub> The gas phase was calculated assuming the complete evaporation of the liquid that was absorbed. This is a fullmikid estimate since at this temperature part of the liquid is not a gas phase. As shown in Figure 3, an increase in resistance to pressure could only be detected by only 0.5% C<sub>S</sub>F<sub>12</sub> in the air. At 1.4% C<sub>5</sub>F<sub>12</sub> the resistance to pressure is above 130 mm Hg. These slurries were also injected into the nib (0.5 ml per 15 kg). Strength was measured by video-level measurement as described in Example 1. As shown in claim 3, the maximum exposure was obtained when with 1.4% C<sub>5</sub>F<sub>12</sub>. Higher percentage of C<sub>5</sub>F<sub>12</sub> occur in longer half-lives and increase in AUC. Half-life (ί ^<sub>2</sub>) was determined as the interval between injections and the time the concentration has fallen to 50% of its maximum value. The area under the curve (AUC) was measured until t<sub>x</sub>y<sub>2</sub>.
Examples 1-3 also show that, contrary to the claims in WO-A-93/05819, it is possible to obtain excellent shadow retardants from gas blanks which have a Q value lower and in some cases much lower than
5.
Example 4
Fifty-eight ml of diaracidylphosphatidylcholine (DAPC), 2.4 mg dialpalmitoylphosphatidic acid (DPPA) from Avanti Polar Lipids (USA) and 3.98 g of polyethyleneglycol (PEG 4000 from Siegfried) were dissolved at 60 ° C in tert-butanol (20 ml ) in spherical glass. The tea solution was rapidly reduced to -45 ° C and freeze drying. Posology (25 mg) of white core obtained was placed 10 ml glass capsule.
Tedlar® gas sampling bags were filled with gas, one with air and one with sulfur hexafluoride (SF<sub>amide</sub>). A pre-determined volume of gases was a safhad from each sachet by dividing two separate syringes and the contents mixed with a graduated leida crane. Gas mixtures that were formed were placed in 10 ml glass vials which were vacuumed and closed with a rubber stopper while the pau was still under vacuum. A sick capsule contained gas mixtures of air and SF<sub>6</sub> in different proportions.
The strength of SF<sub>6</sub> was between 0 to 100%. Actual percentage of SF<sub>6</sub> In the gas phase, concentration was measured (A. pair of meters). Salt solution (0.9% NaCl) was then pumped through the cap into each capsule (5 ml on capsule) and the powder dissolved by shaking thoroughly. Microbial solutions that were found were evaluated in the city and in living bodies. The resistance to the pressure Pc was determined using a nephelometric assay and the backdrop chromatography was measured using a pvx using a resonant installation (both described in EP-A-0 554 213). The strength of the pellets and medal bubbles were determined by analysis with Coulter Multisizer II (Coulter Electronics Ltd). The results obtained were, in fact, the same as the pairs given in Case 1.
Table 4
<td>Gas A</td><td>Gasba</td><td>Gasba % space</td><td>Pc mmHg</td><td>Gas A</td><td>Gasba MWT</td><td>solubility * Gas A</td><td>solubility * Gasba</td>
<td rowspan="2">02</td><td>c<sub>4</sub>f<sub>b</sub></td><td>0</td><td>40</td><td>32</td><td>200</td><td>0083</td><td>0016</td>
<td>c<sub>4</sub>f<sub>8</sub></td><td>5</td><td>112</td><td></td><td></td><td></td><td></td>
<td></td><td>c<sub>4</sub>f<sub>8</sub></td><td>10</td><td>148</td><td></td><td></td><td></td><td></td>
<td>CO<sub>2</sub></td><td>c<sub>4</sub>f<sub>8</sub></td><td>0</td><td>50</td><td>44</td><td>200</td><td>0.74</td><td>0016</td>
<td></td><td>c<sub>4</sub>f<sub>8</sub></td><td>5</td><td></td><td></td><td></td><td></td><td></td>
<td></td><td>c<sub>4</sub>f<sub>8</sub></td><td>10</td><td>204</td><td></td><td></td><td></td><td></td>
<td>CHCF<sub>2</sub></td><td>c<sub>4</sub>f<sub>8</sub></td><td>0</td><td></td><td>86.5</td><td>200</td><td>0.78</td><td>0016</td>
<td></td><td>c<sub>4</sub>f<sub>8</sub></td><td>5</td><td>106</td><td></td><td></td><td></td><td></td>
<td></td><td>c<sub>4</sub>f<sub>8</sub></td><td>10</td><td>163</td><td></td><td></td><td></td><td></td>
<td>xenon</td><td>c<sub>4</sub>f<sub>8</sub></td><td>0</td><td>50</td><td>131</td><td>200</td><td>0108</td><td>0016</td>
<td></td><td>c<sub>4</sub>f<sub>8</sub></td><td>5</td><td>147</td><td></td><td></td><td></td><td></td>
<td></td><td>0Λ</td><td>10</td><td>181</td><td></td><td></td><td></td><td></td>
<td rowspan="2">SF<sub>e</sub></td><td>c<sub>4</sub>f<sub>8</sub></td><td>0</td><td>124</td><td>146</td><td>200</td><td>0005</td><td>0016</td>
<td>0 <Ρ<sub>8</sub></td><td>5</td><td>159</td><td></td><td></td><td></td><td></td>
<td></td><td>C<sub>4</sub>F<sub>8</sub></td><td>10</td><td>193</td><td></td><td></td><td></td><td></td>
<td>n<sub>2</sub></td><td>SF<sub>e</sub>SF<sub>e</sub>SF<sub>e</sub></td><td>0 5 10</td><td>55 80 108</td><td>28</td><td>146</td><td>0.0144</td><td>0005</td>
<td>cf<sub>4</sub></td><td>sf<sub>6</sub>SF<sub>e</sub>SF<sub>e</sub></td><td>0 5 10</td><td>84 91 106</td><td>182</td><td>146</td><td>0.0038</td><td>0005</td>
<td>Xenon</td><td>SF<sub>e</sub>SF<sub>e</sub>SF<sub>e</sub></td><td>0 5 10</td><td>50 67 83</td><td>131</td><td>146</td><td>0108</td><td>0005</td>
* Bunsen coefficient
Deemi 5
Lyophilized PEG / DSPC / DPPG was prepared as described in Example 4 using 30 mg of distearoylphosphatidylcholine (DSPC) and 30 mg of dipalmitoyl-phosphetidylglycerol (DPPG) (both from SYGENA, Switzerland). Doses (25 mg) of the cake that were formed were placed in a 10 ml glass cartridge. Different gas mixtures were pumped into different capsules by dragging the appropriate volume of Tedlar® gas vials filled with different gases. Table 4 shows the gas mixtures that were detected, their molecular weight and their solubility (given in Bunsen coefficients) and resistance to pressure in the orbits obtained. It is especially interesting to see that gases that are highly soluble, such as CO<sub>2</sub>, xenon, CHC1F<sub>2</sub> which are very poorly formed to form stubborn bumps with resistance are nevertheless able to form very stable bubbles on the condition that a small percentage of gas such as SF<sub>Z</sub> or C<sub>4</sub>F<sub>8</sub> to be added.
EXAMPLE NO
The process of the invention was applied to an aerosol buffer solution prepared as described in Example 1 of WO 92/11873. Three grams of Pluronic® F68 (polyoxyethylene-polyoxypropylene copolymer with
TAFLA5
<td>air</td><td>C<sub>4</sub>F<sub>e</sub></td><td>Pc</td><td>right</td><td>ventricular</td><td>opacity</td><td>the left</td><td>ventricular</td><td>ðgegnsæi</td>
<td>% space</td><td>% nim</td><td>(MmHg)</td><td>»1/2</td><td>strength</td><td>AUC</td><td>tic</td><td>strength</td><td>AUC</td>
<td>100</td><td>0</td><td>54</td><td>4</td><td>96</td><td>280</td><td>9</td><td>101</td><td>514</td>
<td>99</td><td>1</td><td>89</td><td>7</td><td>98</td><td>377</td><td>12</td><td>98</td><td>632</td>
<td>95</td><td>5</td><td>136</td><td>14</td><td>94</td><td>629</td><td>40</td><td>101</td><td>2693</td>
<td>air</td><td>c<sub>5</sub>f<sub>12</sub></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>
<td>95</td><td>5</td><td>177</td><td>*</td><td>*</td><td>*</td><td>43</td><td>111</td><td>3249</td>
♦ Shadow molecular weight 8400), 1 g of dipalmitoyl phosphatidyl glycerol and 3.6 g of glycerol were added to 80 ml of distilled water. After reaching 80 ° C, a clear homogeneous solution was obtained. The surfactant (tenside) solution was cooled to room temperature and volume was adjusted to 100 ml. Bug fixation was achieved by using two needles that were connected to a three-way cranial system. One of the syringes was filled with 5 ml of surfactant solution and the other was filled with 0.5 ml of air / C<sub>4</sub>F<sub>8 </sub>blended (see Table 5). The three-lead cap was filled with a surfactant solution before it was connected to the gas-injected syringe. By steering the two rods, the tensile solution was moved back and forth between the two syringes (5 times in each direction) and milky dandruff solutions. After dilution (1/50) with distilled water saturated with air, resistance to pressure (Pc) was determined. Dosage was injected into the anaesthethized rabbit (0.03 ml / kg) and left ventricular images were recorded. The area under the curve (AUC) and the half-life (AUC) were determined. Significant prolongation of half-life and AUC was observed when used was 5% C<sub>4</sub>F<sub>8</sub> (mid by the ceiling). Similar nidurtures were obtained with 5% C<sub>5</sub>F<sub>12</sub>.
Case 7
A slurry of bubbles is obtained as described in WO-A-93/05819 using a mixture of air and octafluorocyclobutane C<sub>4</sub>F<sub>8</sub>. Aqueous solution containing sorbitol (20 g), NaCl (0.9 g) of soya bean oil (6 ml)
TABLE 6
<td>air % space</td><td>C<sub>4</sub>Money % space</td><td>right ventricular impermeable.</td><td>the left ventricular impermeable.</td><td>air % space</td><td>C5F12 % space</td><td>right ventricular impermeable.</td><td>the left ventricular impermeable.</td>
<td>100</td><td>0</td><td>+</td><td>-</td><td>100</td><td>0</td><td>+</td><td>-</td>
<td>99</td><td>1</td><td>+</td><td>-</td><td>99</td><td>1</td><td>+</td><td>+</td>
<td>95</td><td>5</td><td>++</td><td>-</td><td>95</td><td>5</td><td>++</td><td>++</td>
no opaque "+" normal opacity "++" good opacity
Tween 20 (0.5 ml) was prepared and adjusted to 100 ml with distilled water. 10 ml of this solution were taken up in a syringe. Onnur 10 ml syringe was filled with blondes of air and C<sub>4</sub>F<sub>8</sub>. Sprayers were connected to a three-led cranial system. By steering the two sticks, the tensile solution was moved back and forth between the two syringes a total of 20 times, milky turbid solutions. These turbidity solutions were tested for resistance to pressure. Sclerosis was also injected into anesthetized rabbits (0.1 ml / kg) and left hemispheric images were recorded. Interestingly, no opposition was measured in the left-hand hole with 1% or equivalent 5% of C<sub>4</sub>F<sub>8</sub>. On the other hand, left ventricular opacification was increased by 1% and increased by 5% of C<sub>5</sub>F<sub>12</sub>.
Dasmifi
Lyophilized PEG / DSPC / DPPG was prepared as described in Example 4 using 30 mg of distearoylphosphatidylcholine (DSPC, and 30 mg dipalmitoyl-phosphatidylglycerol (DPPG) (baedi from SYGENA, Switzerland). Doses (25 mg) of The crystals formed were placed in 10 ml glass capsules. Different gas bottles were injected into different capsules by reducing the volume of Tedlar * gas samples filled with different gds. Tafia 7 shows the gas mixtures that were known, and the resistance to pressure in the microbubbles obtained. It is noteworthy that high molecular weight gas can even use a combination of two more high molecular weight solvents and solubility (given in Bunsen studs)
TAFLA7
<td>Showing</td><td>C<sub>4</sub>Money % space</td><td>cf<sub>4</sub>% space</td><td>air % other</td><td>Pc mmHg</td><td>absorbance</td>
<td>A</td><td>5</td><td>15</td><td>80</td><td>113</td><td>0284</td>
<td>Az</td><td>10</td><td>10</td><td>80</td><td>147</td><td>0281</td>
<td>A3</td><td>15</td><td>5</td><td>80</td><td>167</td><td>0281</td>
less than 0.0283). It is included in the city of one gas (B), one can also use blondes of two more more effective, smaller gas components. In this example, the relative pressure ratio is proportional to the percentages of the heavier of the two factors, since it is believed that ad-hoc combinations of gases can further reduce the total amount of insoluble gas / gas in synergy.
Contents9
6 sheets
Sheet 1 Sheet 2 Sheet 3 Sheet 4 Sheet 5 Sheet 6
253 members in 29 offices
Priority claims1
| Document | Office | Kind | Date |
|---|---|---|---|
| 93810885 | European Patent Office (EPO) | A |
Members253
| Document | Office | Kind | |
|---|---|---|---|
| CA2056371A1 | Canada | A1 | |
| IS3686A7 | Iceland | A7 | |
| IE911048A1 | Ireland | A1 | |
| CN1055298A | China | A | |
| WO9115244A2 | World Intellectual Property Organization (WIPO) | A2 | |
| AU7582891A | Australia | A | |
| WO9115244A3 | World Intellectual Property Organization (WIPO) | A3 | |
| CA2042722A1 | Canada | A1 | |
| IS3707A7 | Iceland | A7 | |
| AU7614491A | Australia | A | |
| EP0458745A1 | European Patent Office (EPO) | A1 | |
| HU911646D0 | Hungary | D0 | |
| CN1056634A | China | A | |
| KR910019643A | Republic of Korea | A | |
| ZA912427B | South Africa | B | |
| ZA913729B | South Africa | B | |
| EP0474833A1 | European Patent Office (EPO) | A1 | |
| HUT58508A | Hungary | A | |
| IL97730D0 | Israel | D0 | |
| IL98143D0 | Israel | D0 | |
| NZ237637A | New Zealand | A | |
| KR920700699A | Republic of Korea | A | |
| JPH04226923A | Japan | A | |
| AU630030B2 | Australia | B2 | |
| JPH04506670A | Japan | A | |
| NO930041D0 | Norway | D0 | |
| HU9300179D0 | Hungary | D0 | |
| AU636481B2 | Australia | B2 | |
| IN172208B | India | B | |
| IL104084D0 | Israel | D0 | |
| CA2085525A1 | Canada | A1 | |
| FI930258A | Finland | A | |
| FI930258L | Finland | L | |
| IS3971A | Iceland | A | |
| NO930041L | Norway | L | |
| CN1074619A | China | A | |
| AU3186093A | Australia | A | |
| MX9300345A | Mexico | A | |
| EP0554213A1 | European Patent Office (EPO) | A1 | |
| KR930016105A | Republic of Korea | A | |
| JPH05255127A | Japan | A | |
| US5271928A | United States of America | A | |
| NZ238160A | New Zealand | A | |
| IL107453D0 | Israel | D0 | |
| ZA9210127B | South Africa | B | |
| HUT65225A | Hungary | A | |
| IS4089A | Iceland | A | |
| CA2125027A1 | Canada | A1 | |
| WO9409829A1 | World Intellectual Property Organization (WIPO) | A1 | |
| AU5336294A | Australia | A | |
| ZA938117B | South Africa | B | |
| CN1088456A | China | A | |
| NO942476D0 | Norway | D0 | |
| NO942476L | Norway | L | |
| FI943167A | Finland | A | |
| FI943167L | Finland | L | |
| HU9401409D0 | Hungary | D0 | |
| EP0458745B1 | European Patent Office (EPO) | B1 | |
| AT112173T | Austria | T | |
| ATE112173T1 | Austria | T1 | |
| EP0619743A1 | European Patent Office (EPO) | A1 | |
| NZ245724A | New Zealand | A | |
| DE69104264D1 | Germany | D1 | |
| DK0458745T3 | Denmark | T3 | |
| ES2061217T3 | Spain | T3 | |
| KR940703691A | Republic of Korea | A | |
| US5380519A | United States of America | A | |
| DE69104264T2 | Germany | T2 | |
| IL111977D0 | Israel | D0 | |
| JPH07503254A | Japan | A | |
| AU658470B2 | Australia | B2 | |
| US5413774A | United States of America | A | |
| IS4239A | Iceland | A | |
| CA2154867A1 | Canada | A1 | |
| WO9516467A1 | World Intellectual Property Organization (WIPO) | A1 | |
| PL166827B1 | Poland | B1 | |
| AU1033095A | Australia | A | |
| EP0474833B1 | European Patent Office (EPO) | B1 | |
| NO953141D0 | Norway | D0 | |
| NO953141L | Norway | L | |
| FI953843A | Finland | A | |
| FI953843L | Finland | L | |
| NO953195D0 | Norway | D0 | |
| AT125711T | Austria | T | |
| ATE125711T1 | Austria | T1 | |
| ZA949983B | South Africa | B | |
| US5445813A | United States of America | A | |
| DE69111719D1 | Germany | D1 | |
| ES2075438T3 | Spain | T3 | |
| DK0474833T3 | Denmark | T3 | |
| HU9502390D0 | Hungary | D0 | |
| IL98143A | Israel | A | |
| EP0682530A1 | European Patent Office (EPO) | A1 | |
| PL310172A1 | Poland | A1 | |
| IL97730A | Israel | A | |
| GR3017324T3 | Greece | T3 | |
| AU3431795A | Australia | A | |
| CZ208995A3 | Czechia | A3 | |
| AU666238B2 | Australia | B2 | |
| IE66895B1 | Ireland | B1 |
Numbers
- Application
- 4239
Titles2
- English
- Audio Shadow Media, Materials Containing Media and Methods of Manufacturing and Using
- Icelandic
- Úthljóðsskuggagjafarmiðlar, efni sem innihalda miðlana og aðferð til framleiðslu þeirra og notkunar
Classification
- CPC, 3
- A61K49/223
- A61K49/00
- A61K49/225
- IPC, 5
- A61K49 00
- A61B8 13
- A61K49 18
- A61K49 22
- A61K51 00