CA1338507C

CA1338507C - Ultrasonic contrast medium made up of small gas bubbles and fatty-acid-containing microparticles

Info

Publication number: CA1338507C
Application number: CA000597471A
Authority: CA
Inventors: Lothar Lange; Jurgen Hilmann; Thomas Fritzsch; Joachim Siegert
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1988-10-07
Filing date: 1989-04-21
Publication date: 1996-08-06
Anticipated expiration: 2013-08-06
Also published as: AU627456B2; EP0365467B1; CN1044225A; NO178139C; NO178139B; DK99789D0; IE65243B1; DE3834705A1; ES2059814T3; FI890749A; FI100170B; IL90028A0; NO890609D0; DE58905318D1; DK99789A; PT91523A; KR970001433B1; KR900005939A; LU90004I2; EP0365467A2

Abstract

Contrast media for ultrasonie diagnostics are made up of small gas bubbles and microparticles, characterized in that they contain, as the microparticles, a mixture of at least one (C10-C20)-fatty aeid with at least one solid that is not a surfactant, suspended in a liquid vehicle.
They permit, upon ultrasonic imaging after intravenous administration, the contrasting of the right heart and left heart, of the mycardium, as well as other organs, such as liver, spleen, and kidneys.

Description

~ 338~07 The invention relates to contrast media useful ~or ultrasonic diagnostics made up of small gas bubbles and microparticles; these media are characterized in that they contain as the microparticles a mixture of at least one (C10-C20)-fatty acid with at least one solid that is not a surfactant, ~ucp~n~ in a liquid vehicle.
The ultrasonic examination of organs (sonography) is a diagnostic method that has been popular and has been practiced for several years. Ultrasonic waves in the 10 megahertz range (above 2 megahertz with wavelengths of between 1 and 0.2 mm~ are reflected on interfaces of varlous type3 of tissue. The thus-produced echoes are amplified and made visible. In this connection, the examination of the heart with the use of this method, called echocardiography, is of special significance (Haft, J. I . et al . ~
Echocardiography", Futura, Mount Kisco, New York 1978;
Kohler, E., "Klinische Echokardiographie" [Clinical Echocardiography], Enke, Stuttgart 1979: Stefan, G., et al.:
"Echokardiographie" [Echocardiography], Thieme, Stuttgart-28 New York 1981; G Biamino, 1.. Lange: "Echokardiographie", Hoechst AG, 1983).
Since liquids -- blood as well -- yield ultrasonic contrast in the B-scan image only if there are differences in density with respect to the surroundings, ~c ~ ~ 338507 possibilities were investigated for making the blood and its flow visible for ultrasonic B-scan image analysis.
This has indeed been made feasible by the addition of extremely fine gas bubbles.
The blood flow can be imaged even without contrast media by using, during ultrasonic investigation of the heart or the vessels, the weak reflections of ultrasound on the red blood corpuscles and by utilizing the so-called doppler phenomenon. Elowever, in this method the addition of small gas bubbles into the blood flow is likewise advantageous because the stronger reflections on the small gas bubbles permit better utilization of the image [Z. Kardiol, 77: 227-232 (1988) ] .
Several methods for the production and stabilization of the small gas bubbles have been known from the literature. They can be produced, for example, prior to in; ection into the bloodstream by vigorous shaking or stirring of solutions, such as saline solutions, dye solutions, or previously drawn blood.
Although ultrasonic contrast imaging has thereby been attained, these methods display grave disadvantages manifesting themselves in poor reproducibility, greatly fluctuating size of the small gas bubbles, and -- due to a proportion of visible, large bubbles -- a certain risk of embolism.
These drawbacks have been overcome, in part, by other manufacturing methods, such as, for example, by the process disclosed in U.S. Patent 3,640,271 wherein small bubbles of reproducible size are formed by filtration or by the use of an electrode unit under direct surrent. The advantage of having the possibility of being able to prepare small gas bubbles of reproducible size must be weighed against the disadvantage of considerable technical expenditure.
U S. Patent 4,276,885 describes the production of small gas bubbles having a de~inite size, these bubbles - 3 - 1 3 ~ 8 5 ~ 7 being YuLL~-ul.ded by a gelatin envelop protecting against coalescence. The finished bubbles can only be stored in the "frozen" condition, for example by storage at refrigerator temperature; for use, they must again be brought to body temperature.
U.S. Patent 4,265,251 discloses the manufacture and use of small gas bubbles with a solid ~uLL~ ull-iing wall of saccharides which can be filled with a pressurized gas. If the bubbles are under normal ~r~ ,uL~,they can be utilized as ultrasonic contrast media; when using increased internal pressure, the bubbles serve for measuring tke blood ~Les,.uLe.
Although here the storage of the solid gas bubbles does not present a problem, t~rhn~ expenditure during production represents a considerable cost factor.
The risks inherent in these and other contrast media available in accordance with the state of the art are evoked by two factoræ: size and number of the solid particles as well a6 of the small gas bubbles.
The state of the art as r~is--llssl~d thus far permits production of ultra60nic contrast media which in all instances exhibit merely some of the required properties:
~1) Elimination of risk of embolism - small gas bubbles (size and number);
- solid particles (size and number).
( 2 ) Rep roduc ib il ity .
(3) Adequately long stability.

(4) Ability of passing through the lungs, for example to obtain ultrasonic contrast of the left portion of the heart.

(5) Ability to pa6s through capillaries.

(6) Sterility and freedom from pyrogen6 to be displayed by the preparation.

(7) Ease of manufacture at tolerable cost.

(8) Storage without problems.

European Patent Application, Publication No.
52575 ~C;~n;~ n patent 1,170, 569) does disclose the production of small gas bubbles supposedly exhibiting these necessary properties. For their manufacture, microparticles of a solid crystalline ~ ~ollnfl, e.g., galactose, are suspended in a liquid vehicle; the gas that is adsorbed on the particle surface is occluded in cavities between the particles or in inter-crystalline cavities, forming the gas bubbles. The resultant 10 suspension of small gas bubbles and microparticles is in~ected within 10 minutes. Although it is asserted in European Patent Application 52575 that the suspension prepared according to the disclosed method is suitable for appearing, after in~ ection into a peripheral vein, on the right side of the heart as well as, after passing through the lungs, in the left side of the heart, and for rendering the blood and its flow visible at that location upon ultrasonic examination, this assertion collapses when subjected to analysis. Thus, it has been 20 found that the contrast medium produced according to the method described in European Application 52575 and in~ ected into a peripheral vein did not evoke any ultrasonic echoes in the left portion of the heart.
EP-A-77752 (t~;~n;ltl; ;In patent l, l99, 577) likewise discloses the preparation of a liquid mixture for use as ~ 1 338507 contrzst medium consisting, in turn, of a mixture of atenside or an aqueous solution of the tenside, and an aqueous, viscous carrier liquid.
In a p-lhl; ched European patent application (Publication No. 0122624 (t~n~l;An patent 1,23g,092) ), an agent enhancing ultrasonic contrast and containing microparticles and small gas bubbles is described which is suitable for ~nh~n~-i n~, after intravenous administration and passage through the lungs, contrast 10 imaging of the left side of the heart, of the myocardium, as well as other organs, such as the liver, the spleen, and the kidneys. Although this application also cites fatty acids [nsaturated or unsaturated (C4-C20)-fatty acidsn] as being suitable for the production of the microparticles, ~nnfi rr~tion by example has only been provided for their esters or salts as surfactant substances, such as, for example, ascorbyl palmitate or sucrose monopalmitate. These, however, exhibit the drawback that they are relatively quickly decomposed in 20 the formulation even when stored under normal conditions (25C) (see the table below~. This is deleterious in regard to a commercial preparation and its purity requirements. The related imaging agent of USP 4, 442, 843 is also deficient.

~ l 338507 ~ ccordingly, this invention provides, inter alia, media as well as methods that do not exhibit this disadvantage. This invention employs free fatty acids Isaturated) as the surfactant c u--ds, instead of their salts or esters, for the production of microparticles used in contrast media. In this connection, the fatty acids containing 10-20 carbon atoms are especially suitable, such as, for example, lauric, myristic, palmi-tic, stearic, or arachic acid, 10 or mixtures thereof. Thus, the ultrasound contrast media are made up of small gas bubbles and micro-particles, characterized in that they contain, as the microparticles, a mixture of at least one (C10-C20)-fatty acid with at least one solid that is not a surfactant, suspended in a liquid vehicle.
The ultrasonic contrast media according to this invention, obtained by suspending the microparticles of this invention in a liquid vehicle, are capable of v~sl-sl1;7in~
for ultrasound, upon intravenous ad~inistration, the blood 20 and its flow characteristics not only on the right-hand side of the heart, but also, after passing through the capillary bed of the lungs, on the left-hand side of the heart.
Moreover, they surprisingly show a higher intensification effect, - 5a -- 6 - 1 3 3 8~ ~ 7 stability and better reproducibility of the ultrasonic contrast than the ultrasonic contrast media of the prior art .
TABLE -- STABILITY STUDY

Formulation: A Galactose + 0.134% Ascorbyl Palmitate B Galactose + 0.1% Palmitic Acid Chemical Stability of Additives in Dependence on Storage Temperature and Time Storage Period F O R M U L A T I o N
A
% (m/m) Ascorbyl % (m/m) Pal-p~l~nitate mitic Acid St~rt 100% 10Q%
6 weeks Room Temperature 84.3% Not analyzed 20 40rc 67.9% Not analyzed 50-C 33.6% 97.4%
12 weeks Room Temperature 79 . 8% 98 . 0%
25 40 C 53 . 7% 98 . 4%
50 C 18 . 7% 95 . 1%
Contrast Intensity: A reduction in additive content is a~ n; ed by decrease in left-heart cDntrast.
The surfactant compound in the microparticles is usually utilized in a concentration of 0 . 01-5% by weight, preferably 0 . 04-1% by weight.
The microparticles comprise a mixture of at least one of the surfactant compounds with at least one physiologically compatible solid. Organic and inorganic materials can be utilized fDr this purpose, e.g., salts, such as sodium chloride, sodium _ _ _ _ _ - 7 - l 338507 citrate, sodlum acetate or sodium tartrate, monosaccha-rides, such as glucose, fructose or galactose, disaccha-rides, such as sucrose, lactose or maltose, pentoses, such as arabinose, xylose or ribose, or cyclodextrins, such as ~-, B- or Y-cyclodextrin, where galactose, fruc-tose, glucose, lactose and d-cyclodextrin are preferred.
They are contained in the microparticles in a concentra-tion of 95-99.99% by weight, preferably, 99-99.96%.
In order to prepare the microparticles, the com-pounds intended therefor are recrystallized under asep-tic conditions. Subsequently, they are comminuted under aseptic conditions , e . g ., by grinding in an air ~ et mill, until the desired particle size has been obtained.
A desirable particle size is one comparable to erythro-cytes, e.g., of < 10 llm, preferably < 8 ~lm. The median value of the micronized product is 1-3 ~lm. The particle size is determined in suitable conventional measuring devices. The thus-produced microparticles consist of a mixture of a surfactant compound and a solid that is not 2 0 a surfactant .
The size of the microparticles attained by the comminuting method as well as the size of the small gas bubbles contained in the contrast medium of this invention ensure hazardless passage of the capillary system and the capillary bed of the lungs, and preclude the formation of embolisms.
The gas volume required for contrast imaging is transported by the microparticles. This volume is, in part, adsorbed on the surface of the microparticles, present in the cavities between the microparticles, or occluded in intercrystalline fashion. The gas (e.g., air, nitrogen or argon) volume transported by the microparticles in the form of small gas bubbles is 0 . 02 - 0. 6 ml per gram of microparticles.
The liquid vehicle can be water, aqueous solutions of one or more inorganic salts, such as physiological _ _ _ .

~33 - 8 - ~35i~7 sodium chloride solution and buffer solutions, aqueous solutions of mono- or disaccharides, such as galactose, glucose or lactose, mono- or polyhydride alcohols inso-far as they are physiologically compatible, such as ethanol, propanol, isopropyl alcohol, polyethylene glycol, ethylene glycol, glycerol, propylene glycol, propylene glycol methyl ether, or their aqueous solu-tions. Preferred vehicles are water and physiological electrolyte solutions, such as physiological sodium chloride solution, as well as aqueous sugar solutions, such as, for example, galactose, glucose, fructose and lactose. If solutions are employed, the concentration of the dissolved compound is 0.1-30% by weight, prefer-ably 0.5-15% by weight; in particular, water, 0.9%
aqueous sodium chloride solution, or 5-6% aqueous galactose solution is utilized. In general, 1-500, preferably 10-400 mg of microaprticles are used per ml of suspension.
The invention also relates to a process for the preparation of the agent of this invention characterized in that microparticles comprising at least one (C10-C20)-fatty acid and at least one solid that is not a surfactant are combined with a liquid vehicle and shaken until a homogeneous suspension has been obtained.
In order to produce the ready-for-use ultrasonic contrast medium, the sterile liquid vehicle is added to the sterile combination, present in the form of micro-particles, of at least one (C10-C20)-fatty acid with at least one material that is not a surfactant, and this mixture is shaken until a homogeneous suspension has been formed, for which purpose about 5-10 seconds are required. The resultant suspellsion is injected immedi-ately af ter its preparation, but at the latest 5 minutes thereafter, in the form of a bolus into a peripheral vein or an already inserted catheter, typically admini-stering 0 . 01 ml to 1 ml per kg of body weight.

_ 9 _ 1 338~a7 For practical reasons, the components required for preparing the medium of this invention, such as the liquid vehicle (A) and microparticles of the combination (C10-C20)-fatty acid and soli~ that is not a surfactant (B) are preferably stored sterile in the quantity required for one examination in two vessels. Both vessels (vials) preferably have seals permitting withdrawal and filling by means of an injection syringe under sterile conditions. The size of vessel B is such that the content of vessel A can be transferred by in~ ection syringe into B and the combined components can be shaken.
The use of the contrast medium according to this invention will be demonstrated by performing an echocardiographic examination on a baboon weighing 10 kg:
8.5 ml of liquid vehicle (see preparation examples) is withdrawn with an injection syringe from a vial and added to 3 g of microparticles present in a second vial, and shaken for about 5-10 seconds until a homogeneous suspension has been formed. Of this suspension, 2 ml if injected into a pprirhpral vein (V. jugularis, br~C~h;Al ;~ or gaphena) by way of a three-way valve at an infusion rate of at least 1 ml/sec, better at 2-3 ml/sec. The in; ection of 10 ml of physiological sodium chloride solution immediately follows the in~ection of contrast medium at the same rate, 80 that the contrast medium bolus remains intact as long as possible.
Before, during, and after injection, a commercially available transducer for echocardiography is held against the thorax of the test animal 80 that a typical cros6 section is obtained through the right and left heart. Thi6 testing arrangement corresponds to the state of the art and is known to those skilled in the 3 5 art .
Once the ultrasonic contrast medium has reached the - lo _ ~ 3385~7 right heart, an observation can be made in the 2-D echo image or in the N-mode echo image of how the blood labeled by the contrast medium f irst reaches the level of the right atrium, then the level of the right 5 ventricle and the p~ ry artery, homogeneous filling prevailing for a time period adequate for diagnostic examination. While the cavities of the right heart become empty again in the ultrasonic image, the blood labeled with contrast medium reappears, after passing 10 through the lungs, in the plll- -ry veins, fills the left atrium, the left ventricle, and the aorta in a homogeneous fashion, the contrast l ~nln~ longer than on the right side of the heart. In addition to imaging of the blood flow through the cavities of the left 15 heart, a contrast image of the myocardium is likewise obtained, reflecting blood circulation.
The use of the ultrasonic contrast medium of this invention is, however, not limited to rendering the bloodstream visible in the arterial portion of the heart 20 after venous administration; rather, with excellent success, the contrast medium is also employed in the examination of the right heart and other organs by contrast medium.
The use and administration of the contrast medium 25 of thi6 invention is analogous to the procedures described, e.g., in the disclosures cited above.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description; utilize the present invention to its 30 fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all 35 temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.

- l~a -~ 1 3385C7 (A) Liquid Vehicle; Water for purposes of in j ection (B) Preparation of Microparticles:
I 1,998 g of galactose in 1,080 g of water is purified, dissolved, filtered under sterile conditions, and cooled under aseptic conditions to 6-10 C.
II 2 g of palmitic acid is dissolved in 120 g of ethanol, filtered under sterile conditions, and added to I
under agitation.
III The combined solutions are dried under aseptic condi-tions at about 40 C and under a vacuum of 50 mbar.
IV The recrystallized product is comminuted under aseptic conditions by means of an air jet mill to the following grain size distribution:
D10 c 1 llm D50 2.5 um D90 ~ 5 llm Determination of the grain size distribution takes 20 place after suspending the micronized product in alcohol with the use of a particle measuring device (e.g. Cilas Granulometer 715).
V Packaging of the microparticles is effected into 20 ml vials at respectively 3 g.

~ - 12 - I 3 3 8 5 07 (C) Production of Ready-For-Use Ultrasonic Contrast Medium By means of an injection syringe, 8.5 ml of water for injection purposes is transferred into the 5 20 ml vial containing 3 g of microparticles, and the vial is shaken until a homogeneous suspension is obtained (5-10 seconds).

~A) Liquid Vehicle: Water for injection purposes lB) Preparation of Microparticles:
1,998 g of galactose in 1,080 g of water is purified, dissolved, filtered under sterile conditions, and cooled under aseptic conditions to 6-10 C.
II 2 g of myristic acid is dissolved in 120 g of ethanol, filtered under sterile conditions, and added to I
under agitation.
III The combined solutions are dried under aseptic condi-tions at about 4D C and under a vacuum of 50 mbar.
IV The recrystallized product is comminuted under aseptic conditions with an air ]et mill to the following grain size distribution:
D l o ~ m D50 ~ 2.5 ~m 9 0 ~ 11 Determination of grain size distribution takes place after suspending the micronized product in alco~lol with _ _ _, . _ .. .. .. . . .. . ... . .. . . . . .. .... . . .. .. .. .... . . ..

~ - 13 - 1 3 3 8 5 û 7 a particle measuring instrument (e . g. Cilas Granulometer 715) .
V Packaging of the microparticles takes place into 20 ml vials with respectively 3 g.
(C) Production of ~eady-For-Use Ultrasonic Contrast Medium Using an injection syringe, 8.5 ml of water for injection purposes is transferred into the Z0 ml vial containing 3 g of microparticles, and the vial is 10 shaken until a homogeneous suspension is produced ( 5-10 seconds ) .

(A~ Liquid Vehicle: Water for injection purposes (B) Preparation of Microparticles:
I 1,998 g of galactose in 1,080 g of water is purified, dissolved, filtered in sterile state, and cooled under aseptic conditions to 6-10 C.
II 2 g of stearic acid is dissolved in 120 g o~ ethanol, filtered under sterile conditions, and added to I
with stirring.
III The combined solutions are brought to the dry condi-tion in an aseptic environment at about 40 C and under a vacuum of 50 mbar.
IV The recrys~l 1; 7~d product is comminuted under aseptic conditions by means of an air jet mill to the following grain size distributlon:

~ - 14 - 1 3~850~
D 10 ~ m D50 ~ 2.5 ,um g O ~ m Determination of grain size distribution is made 5 after suspending the micronized product in alcohol using a particle measuring device~(e.g. C~ilas Granulometel 715 ) .
V The microparticles are packaged into 20 ml vials with respectively 3 g.
(C) Production of Ready-For-Use Ultrasonic Contrast Medium With the use of an injection syringe, 8.5 ml of water for injection purposes is transferred into the 20 ml vial containing 3 g of microparticles, and the vial is 15 shaken until a homogeneous suspension is obtained (5-10 seconds).

(A) Liquid ~lehicle: Water for injection purposes (s) Preparation of Microparticles:
I 1,998 g of galactose in 1,080 g of water is purified, dissolved, filtered in the sterile state, and cooled to 6-10 C under aseptic conditions.
II 1 g of myristic acid + 1 g of arachic acid are dis-solved in 120 g of ethanol, filtered under sterile conditions, and added to I under stirring.
III The combined solutions are brought to dryness under aseptic conditions at about 40 C and under a vacuum of 50 mbar.
_ _ _ _ .

IV The recrystallized product is aseptically comminuted with the use of a jet air mill to the following grain size distribution:
D ~ 1 D50 ~ 2. 5 llm Dgo ~ 5 ~m Determination of the grain size distribution takes place after suspending the micronized product in alcohol using a particle measuring device (e . g . Cilas Granulometer 715 ) .
V The microparticles are packaged into 20 ml vials with respectively 3 g.
(C) Production of Ready-For-Use Ultrasonic Contrast Medium By means of an injection syringe, 8.5 ml of water fqr injection purposes is transferred into the 20 ml vial containing 3 g of microparticles, and the vial is shaken until a homogeneous suspension is obtained (5-10 seconds).

(A) Production of Liquid Vehicle:
55 g of galactose is dissolved in water for injection purposes, filled up to a volume of 1,000 ml, filte~ed through a 0,2 llm filter, respectively 10 ml of 25 the filtered solution .is d~spensed into 10 ml vials, and sterilized for 15 minutes at 121 C.

(s) Preparation of Microparticles:
1,998 g of galactose in 1,080 g of water is purified, dissolved, filtered under sterile conditions, and aseptically cooled to 6-10 C.
5 II 1 g of palmitic acid + 1 g of stearic acid are dissolved in 120 g of ethanol, filtered under sterile conditions, and added to I under agitation.
II The eombined solutions are aseptically dried at about 40 C and under a vaeuum of 50 mbar.
10 IV The reerystallized produet is eomminuted under aseptie conditions with an air ]et mill to the following grain size distribution:
D l o ~ m D50 ~ 2-5 um Dgo _ 5 llm Determination of the grain size distribution is effeeted after suspending the mieronized produet in alcohol, using a particle size measuring device (e.g.
Cilas Granulometer 715).
V The microparticles are packaged into 20 ml vials with respectively 3 g.

~ - 17 - 1 3 3 8 5 07 .
(C) Production of Ready-For-Use Ultrasonic Contrast Medium Using an injection syringe, 8.5 ml of galactose solution A is transferred into the 20 ml vial 5 which contains 3 g of microparticles, and the vial is shaken until a homogeneous suspension is obtained l 5-10 seconds ) .

Claims

1. Ultrasound contrast medium containing micro-particles and gas bubbles suspended in a liquid carrier, characterised in that the microparticles comprise myristic acid, palmitic acid, stearic acid, arachic acid or a mixture thereof and at least one solid that is not a surfactant.

2. Ultrasound contrast medium according to claim 1, characterized in that the microparticles contain myristic acid, palmitic acid, stearic acid, arachic acid or a mixture thereof at a concentration of from 0.01 to 5% by weight.

3. Ultrasound contrast medium according to claim 1, characterised in that the microparticles contain myristic acid, palmitic acid, stearic acid, arachic acid or a mixture thereof at a concentration of from 0.04 to 1% by weight

4. Ultrasound contrast medium according to claim 1, characterised in that the microparticles contain as a solid that is not a surfactant galactose, fructose, glucose, lactose, .alpha.-cyclodextrin or a mixture thereof.

5. Ultrasound contrast medium according to claim 1, characterised that the liquid carrier is water, a physiological electrolyte solution, an aqueous solution of a monohydric or polyhydric alcohol, propylene glycol methyl ether, glycerol polyethylene glycol, or an aqueous solution of a mono- or di-saccharide.

6. Ultrasound contrast medium according to claim 1, characterised that the liquid carrier is water, physiological saline solution or a 5 to 6% aqueous galactose solution.

7. Ultrasound contrast medium according to claim 1, characterised that the microparticles contain a mixture of palmitic acid and galactose, and the liquid carrier is water.

8. Ultrasound contrast medium according to claim 1, characterised that the microparticles contain a mixture of myristic acid and galactose, and the liquid carrier is water.

9. Ultrasound contrast medium according to claim 1, characterised that the microparticles contain a mixture of stearic acid and galactose, and the liquid carrier is water.

10. Ultrasound contrast medium according to claim 1, characterised in that the microparticles have a size less than 10 µm.

11. A kit useful for the preparation of an ultrasonic contrast medium according to any one of claims 1 to 10, consisting of a first container, containing microparticles comprising myristic acid, palmitic acid, stearic acid, arachic acid or a mixture thereof, and galactose, fructose, glucose, lactose, .alpha.-cyclodextrin or a mixture thereof, and a second container, containing a licluid vehicle, wherein the size of the first container is such that the contents of the second container can be transferred therein.