DK165171B - MICROPARTICLE AND GAS BUBBLE CONTAINING ULTRA SOUND CONTRACTING AGENT AND EQUIPMENT AND PROCEDURE FOR ITS MANUFACTURING - Google Patents

Abstract

1. Contrast medium containing microparticles and gas bubbles for ultrasound diagnostics, characterised in that it contains microparticles of a solid surface-active substance, optionally in combination with microparticles of a non-surface-active solid, in a liquid carrier.

Description

DK 165171 B

The invention relates to the objects characterized in the claims.

The examination of organs with ultrasound (sonography) is a well established and practiced diagnostic method for 5 years. . Ultrasonic waves in the megahertz range (over 2 megahertz with wavelengths between 1 and 0.2 mm) are reflected * at interfaces of different tissue types. The resulting echoes are amplified and made visible. Of particular importance here is the examination of the heart by this method, which is called echocardiography (Haft, J.I. et al: Clinical Echocardiography, Futura,

Mount Kisco, New York 1978, Kohler, E. Clinical Echocardiography, Enke, Stuttgart 1979, Stefan, G. et al: Echocar Diography, Thieme, Stuttgart-New York 1981, G. Biamino, 15 L. Lange: Echocardiography, Hoechst AG, 1983).

Since fluids - including blood - only provide ultrasound contrast when there are differences in density relative to the surroundings, opportunities were made to make the blood and its flow visible for an ultrasound examination, which is also possible by the addition of fine gas bubbles.

From the literature, several methods for producing and stabilizing gas bubbles are known. For example, they can be produce 25 by vigorously shaking or stirring solutions such as saline, dye solutions, or pre-drawn blood prior to injection into the blood stream.

Thus, while achieving ultrasound contrast rendering, these 30 methods are associated with weighty drawbacks that manifest themselves with poor reproducibility, strongly fluctuating size of the gas bubbles, and - p.g.a. some visible large bubbles - some risk of blood clots. These disadvantages were partially overcome by other methods of preparation, such as e.g.

35 U.S. Patent No. 3,640,271, in which bubbles of reproducible size are produced by filtration or by using a direct current electrode apparatus. The advantage

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2 on the possibility of producing gas bubbles of reproducible size face the disadvantage of the significant technical costs.

5 US Patent No. 4,276,885 describes the preparation of defined size gas bubbles which, prior to confluence, have been surrounded with a protective gelatin sheath. The finished bubbles can only be stored in the "frozen" state, e.g. when stored at refrigerator temperature, whereupon they must be brought back to body temperature for use.

U.S. Patent No. 4,265,251 describes the manufacture and use of solid saccharide sheath gas bubbles, which may be filled with pressurized gas. If under normal pressure, they can be used as an ultrasonic contrast agent; when used at elevated internal pressure, they serve for blood pressure measurement.

20 Although the storage of the solid gas bubbles does not present a problem, the technical procurement in the manufacture is a significant cost factor.

The risks of the 25 contrast agents available at the state of the art are caused by two factors: the size and number of both the solid particles and the gas bubbles.

The state of the art so far depicted allows the production of ultrasound contrast agents which always possess only some of the required 30 properties: 1) Exclusion of blood clot risk - gas bubbles (size and number) - solid particles (size and number) 35 2) reproducibility 3) Sufficient long stability

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3 4) Can enter the lungs, e.g. to achieve ultrasound contrast of the left side of the heart 5) Carp enter the capillaries 5 6) Sterility and pyrogenic freedom during cooking 7) Easy manufacturability with a reasonable cost and 10 8) trouble-free storage.

The European patent application with publication number 52575 discloses the production of gas bubbles which should possess these necessary properties. For the preparation of these gas bubbles, microparticles are suspended from a solid crystalline substance, e.g. galactose, in a carrier liquid, whereby the gas adsorbed to the particle surface or enclosed in voids between the particles or in intercrystalline voids forms the gas bubbles. The suspension of gas bubbles and microparticles thus formed is injected within 10 minutes. Although in European Patent No. 52575 it is claimed that the suspension prepared by the method described is suitable for, after injection into a peripheral vein, both on the right side of the heart and after passage of the lung into the left side of the heart, to appear and where the blood and its flow are made visible by ultrasound examination, this claim does not withstand a test.

Thus, it was determined that, according to the method described in European Application No. 52575, contrast agent injected into a peripheral vein did not produce ultrasound echoes in the left side of the heart.

The object of the present invention was to provide an ultrasound diagnostic contrast agent capable of, after intravenous insertion, making the blood and its flow conditions visible to ultrasound not only on the right side of the heart but also after the passage of the lung

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4 capillary layers on the left side of the heart. In addition, it should also allow bleeding of other organs, such as the myocardium, liver, spleen, and kidneys.

0 novel agents according to the invention, and according to claims 1-10, possess all the properties expected of such a contrast agent and listed on pages 2-3.

Surprisingly, it was found that by suspending micro particles of a solid interface active substance, optionally in combination with microparticles of a non-interface active solid in a carrier liquid, an ultrasonic contrast agent is obtained which, after injection into a peripheral vein, also allows reproducible ultrasound recordings. of blood in the arterial left side of the heart. Since the left side of the heart can be reached with the ultrasound contrast agent of the invention after intravenous insertion, ultrasound contrasts of other aortic and blood supply organs are also possible after intravenous insertion, such as in the myocardium, liver, spleen, kidneys, etc. It is understood that the ultrasound contrast agent of the invention is also suitable for contrasts in the right side of the heart and for all conventional uses as ultrasound contrast agent.

Thus, the invention relates to a microparticle and gas bubble containing contrast agent for ultrasound diagnostics, which is characterized in that it contains microparticles of a solid interface active agent selected from C4-C20 fatty acids or sucrose esters or ascorbic esters thereof or a concentration of 0.01 to 5% by weight, optionally in combination with microparticles of a non-interface active solid selected from cyclodextrins, monosaccharides or disaccharides, preferably galactose, lactose or α-cyclodextrins, at a concentration of 5 to 50% by weight, preferably 9 to 40% by weight, in a liquid carrier.

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5

As mentioned above, C4-C20 · fatty acids or sucrose esters or their ascorbyl esters or metal salts thereof are used as the C4-C20 interface. These are all in the quantities used physiologically compatible, ie. possess a low toxicity and -5 / or are biodegradable, and have a melting point higher than room temperature. Examples include sucrose dipalmate, sucrose monolaurate, ascorbyl palmitate, calcium stearate, sucrose ester of lauric acid, stearic acid and palmitic acid. Particularly preferred are magnesium stearate, ascorbyl palmitate, sucrose monopalmitate, sucrose monostearate or sucrose distearate.

The interface active substance is used at a concentration of 0.01 to 5% by weight, preferably 0.04 to 0.5% by weight.

15

If desired, the microparticles of the surfactant can be combined with microparticles of a physiologically compatible crystalline solid. Monosaccharides such as glucose, fructose or galactose, disaccharides such as sucrose, lactose or maltose, or cyclodextrins such as α-, β- or γ-cyclodextrin, where galactose, lactose and α-cyclodextrin are preferred, may be used. They are present at a concentration of from 5 to 50% by weight, preferably from 9 to 40% by weight, in the compositions of the invention.

25

For the preparation of the microparticles, the calculated substances are recrystallized under sterile conditions. They are then comminuted under sterile conditions, e.g. by milling in an air-jet mill until the desired particle size is reached.

A particle size of <1 - 50 µm, preferably 1 - 10 µm, is obtained. The particle size is determined by suitable measuring instruments. The microparticles produced either consist of the finely divided interface active substance alone or of a mixture of the microparticles of the interface active substance and non-interface active solid. In this case, the weight ratio of solid interface active substance to non-interface active solid is 0.02-100: 100.

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6 Both the size of the microparticles obtained by the comminution process, as well as the size of the gas bubbles contained in the contrast agent of the invention, ensure a harmless passage of the capillary system and of the kidney capillary layer and 5 precludes the formation of blood clots.

•

The gas bubbles required for contrasting are partially transported through the suspended microparticles, absorbed to the surface of the microparticles and enclosed within the voids between the microparticles or intercrystalline.

The volume of gas transported by the microparticles in the form of gas bubbles is 0.02 to 0.6 ml per gram of microparticles.

In addition to the transport function, the carrier liquid has the task of stabilizing the suspension of microparticles and gas bubbles, e.g. prevent the sedimentation of microparticles and the confluence of gas bubbles and delay the dissolution process of the microparticles 2Q.

As a liquid carrier, water, aqueous solutions of one or more inorganic salts, such as physiological saline and buffer solutions, aqueous solutions of mono- and 2g disaccharides such as galactose, glycose or lactose, mono or polyhydric alcohols are provided as far as they are physiologically compatible. , such as ethanol, propanol, isopropyl alcohol, polyethylene glycol, ethylene glycol, glycerol, propylene glycol, propylene glycol methyl ester, or aqueous solutions thereof, in the case of:

Water and physiological electrolyte solutions such as physiological saline and aqueous solutions of galactose and lactose are preferred. If solutions are used, the concentration of solutes is 0.1 to 30% by weight, preferably

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7 0.5 to 25% by weight, and in particular a 0.9% aqueous saline solution or a 20% aqueous galactose solution is used.

The invention also relates to a process for the preparation of the agent which is characterized by combining microparticles of a physiologically compatible solid surfactant selected from C blandt ^ ^ fatty acids or their sucrose or ascorbyl esters or metal salts thereof, optionally in combination. with microparticles of a physiologically compatible non-surfactant solid selected from cyclodextrins, monosaccharides or disaccharides, preferably galactose, lactose or α-cyclodextrin, with such an amount of a physiologically compatible carrier liquid that the concentration of the microparticulate substance is 0.01-5 to 15% by weight based on the total weight of the agent and shakes until a homogeneous suspension occurs.

To prepare a ready-to-use ultrasonic contrast agent, the sterile carrier liquid is added to the sterile solid interface active substance, optionally combined with a sterile non-interfacial agent, and this mixture is shaken until a homogeneous suspension has formed, which requires approx. 5-10 seconds. The suspension formed immediately after its preparation and at the latest after 5 minutes. injected into a peripheral vein or into an already existing catheter as a total amount injecting from 0.01 to 1 ml / kg body weight.

For convenience, the components necessary for the preparation of the agent of the invention are stored as carrier liquid (A) and microparticles of an interface active substance, optionally combined with microparticles of a non-interface surfactant (B) sterile in a study necessary amount in two separate containers. Both containers have closures that allow removal and addition by means of a syringe under sterile conditions (small medicine vials). The size of container B must be such that the contents of container A can be transferred to B by means of a syringe and the combined components can be shaken. The invention therefore also relates to an equipment according to claim 11.

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8

The conduct of an echocardiographic examination on a 10 kg heavy baboon should demonstrate the use of the contrast agent of the invention: å 5 ml of carrier fluid (prepared according to Example 1A) is withdrawn from a small vial with a syringe and added to 2 grams of microparticles (prepared after EX IB), which is in another medicine bottle and is shaken for approx. 5-10 seconds until a homogeneous suspension is formed. 2 ml of this suspension is injected into a peripheral vein (V. jugularis, brachialis or saphena) over a 3-way cock with an infusion rate of at least 1 ml per second, and more preferably 2-3 ml per second.

Immediately after the contrast agent injection, an injection of 10 ml of physiological saline solution is followed at the same rate, so that the amount of contrast agent is maintained as much as possible until it reaches the right side of the heart. Before, during and after the injection, a conventional echo-cardiography head is held against the test animal's chest, so that a typical cross-sectional 2Q is obtained through the right and left sides of the heart. This experimental arrangement corresponds to the state of the art and is known to those skilled in the art.

When the ultrasound contrast agent reaches the right side of the heart, on the 2-D echo image or on the M-mode echo image, it is possible to follow how the blood marked with the contrast agent first reaches the apex of the right ventricle, then of the right ventricle and of the pulmonary artery, whereby for approx.

10 seconds a homogeneous filling occurs. As the cavities in the 30 right side of the heart are emptied again, contrast-marked blood appears again after passage of the lung into the pulmonary veins, filling the left ventricle, the left ventricle and the aorta, thereby maintaining the contrast 2 to 3 times longer than in the right side. the heart. In addition to the preparation of the flow of blood through the caves in the left side of the heart, a preparation of the myocardium reflecting the bleeding is also provided.

9 DK 165171 B

However, the use of the ultrasound contrast agent of the invention is not limited to the visibility of blood flow into the arterial part of the heart after venous insertion, but is also used with excellent results in the examination of the right side of the heart and other organs as a contrast agent.

5

The invention further relates to an ultrasound contrast agent manufacturing device which is unique in that it consists of a) a container having a volume of 5-10 ml, provided with a closure which allows the contents to be removed under sterile conditions, which container is filled with 4 ml of liquid carrier, and b) of another container having a volume of 5-10 ml, provided with a closure which allows the addition of the liquid carrier 15 under sterile conditions, which is filled with microparticles of a solid interface active substance selected from c cyclodextrins, monosaccharides or disaccharides, preferably galactose, lactose or α-cyclodextrin, with an average particle size of <1-10 µm, whereby the weight ratio of gr nsefladeaktivt substance and optionally present non-surface-active substance amounts to 0.02 to 100 25: 100, and the microparticles are present in an amount from 5 to 50% by weight, preferably from 9 to 40% by weight of the total weight.

EXAMPLE 1 30 A) Preparation of carrier liquid Dissolve 80 g of galactose in water for injection, make up to a volume of 400 ml, press through a 0.2 micrometer filter, drain into 4 ml portions of this filtrate in 5 ml of 35 vials and sterilize. 20 min. at 120 C.

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B) Preparation of microparticles:

Under sterile conditions, 198 g of galactose is intimately mixed with 2 * g of magnesium stearate by homeopathic demolition (Anreibung), 5 passed through a 0.8 mm sieve, mixed loosely and ground with an air jet mill until the following distribution of particle size travel is reached:

Average 1.9 μιη 10 99% <6 μπι 90% <3 μια

The particle size and their distribution are determined in a particle measuring apparatus after suspension in anhydrous isopropanol. The microparticles are drained into 2 g portions in 5 ml medicine bottles.

C) For the preparation of 5 ml ultrasonic contrast agent ready for use, add the contents of a 20 vial (20% galactose solution in water, A) vial to the microparticle (B) vial and shake until a homogeneous suspension is formed (5 to 10 seconds).

EXAMPLE 2 A) Preparation of carrier liquid:

Injection water is used, which is drained into 4 ml portions in 5 ml vials, and then sterilized for 20 minutes. at 120 C.

B) Preparation of microparticles:

Under sterile conditions, 198 g of galactose is intensively mixed with 2 g of ascorbyl palmitate by homeopathic grinding and further processed as described in Example 1 under B, giving the following particle size distribution:

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11

Average 1.9 mm 100% <6 nm 90% <3 mm ® The particle size is determined as described in Example 1 under B).

The microparticles are bottled in 1200 mg aliquots in 5 ml vials.

10 C) For the preparation of 4.5 ml ultrasonic contrast agent ready for use, the contents of a medicine bottle with carrier liquid (water, A) are added by means of a syringe to the bottle with microparticles B) and shaken until a homogeneous is formed. suspension (5-10 seconds).

EXAMPLE 3 A) Preparation of carrier liquid: 20

Dissolve 4.5 g of sodium chloride in water to a volume of 500 ml, then pressurize the solution through a 0.2 M 2 i filter and drain 4 ml portions of this solution into 5 ml vials sterilized for 20 min. . at 120 ° C.

25 • B) Preparation of microparticles?

Under sterile conditions, 198 g of anhydrous lactose (<0.3 mm) is intensively mixed with 2 g of ascorbyl palmitate by homeopathic tearing, and the mixture is further processed as described in Ex.

30 1 B), giving the following distribution of the particle size:

Average 2.8 mm 100% <48 µm 35 99% <12 M * n

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12

The particle size is determined as described in Example 1 under B). The microparticles are drained into 1/6 g portions in 5 ml vials.

å 5 C) For the preparation of 5 ml ultrasonic contrast agent ready for use, the contents of a medicine bottle (0.9% sodium chloride solution in water A) are added by means of a syringe to a medicine bottle with microparticles (B) and shaken, until a homogeneous suspension is formed (5-10 cycles).

EXAMPLE 4 A) Preparation of carrier liquid: * 5 As described in Example 3 under A), a 0.9% aqueous sodium chloride solution is prepared which is drained into 4 ml portions in 5 ml medicine vials which are sterilized for 20 minutes. at 120 ° C.

B) Preparation of microparticles: 20

Under sterile conditions, 199 g of α-cyclodextrin is intensively mixed with 1 g of ascorbyl palmitate by homeopathic grinding and the mixture is further processed as described in Example 1 under B) to obtain microparticles of the following size distribution:

Average 2 μπι 99% <6 μια 90% <4 μπι 30

The particle size is determined as described in Example 1 under B).

The microparticles are bottled in 400 mg protions in 5 ml vials.

C) For the preparation of 4 ml ultrasonic contrast agent that is

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13 ready for use, the contents of a medicine bottle (0.9% aqueous sodium chloride solution, A) are added by syringe to a medicine bottle with microparticles (B) and shaken until a homogeneous suspension is formed (5 to 10 5 seconds) .

EXAMPLE 5 A) Preparation of carrier liquid: Dissolve 50 g of lactose in water for injection, make up to a volume of 500 ml, squeeze through a 0.2 μπι filter, drain into 4 ml portions in 5 ml vials and sterilize 20 mine. at 120 ° C.

B) Preparation of microparticles:

The ascorbyl palmitate is dissolved in methanol, filtered sterile through a 0.2 μηι filter, recrystallized under sterile conditions, dried and passed through a 0.8 mm sieve. Then, under sterile conditions, the sterile ascorbyl palmitate is ground with an air jet mill until the following size distribution of the particles is obtained:

Mean 1.9 μπι 25 99% <6 μπι 90% <3 μπι t

The particle size and their distribution are determined in a particle measuring apparatus after suspension in cold aqueous 0.1% "Pluronic" F68 solution.

The microparticles are bottled in 40 mg aliquots in sterile 5 ml vials.

35 C) For the preparation of 4 ml ultrasonic contrast agent ready for use, the contents of a medicine bottle with carrier liquid (10% lactose solution, A) are added by means of a syringe to the medicine bottle with microparticles and shaken until a homogeneous suspension is formed.

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EXAMPLE 6 A) Preparation of shaving fluid:

Dissolve 4.5 g of sodium chloride in water to a volume of 5,500 ml, then pressurize the solution through a 0.2 μπι filter and pour 4 ml portions of this solution into 5 ml vials sterilized for 20 min. at · 120 ° Ο.

B) Preparation of micropathicles:

Under sterile conditions, a sterile filtered solution of 0.5 g of ascorbyl palmitate in 40 g of isopropanol on 199.5 g of sterile galactose particles is evaporated at 40 ° C and 200 mm Hg and comminuted with an air-jet mill until the following size distribution of the particles is achieved. : 15

Mean 1.9 μια 99% <6 μπι 90% <3 μΐη 0 π

The determination of the particle size and their distribution takes place in a particle measuring apparatus, e.g. after suspension in isopropanol. Pre-packing of the microparticles takes place in 5 ml vials of 2 g each.

25 C) For the preparation of 5 ml ultrasonic contrast agent * ready for use, the contents of a medicine bottle with carrier liquid (0.9% sodium chloride solution in water, A) are added by means of a syringe to the medicine bottle with microparticles (B) and shake until a homogeneous suspension is formed 30 (5-10 seconds).

EXAMPLE 7 A. Preparation of carrier liquid 3 5

Dissolve 4.5 g of sodium chloride in water and make up to a volume of 500 ml, after which the solution is pressed through a 0.2 μιη filter. Add 4 ml portions of this

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15 solution in 5 ml medicine vials which are sterilized for 20 minutes at 120 ° C.

B. Preparation of Microparticles 5 Under sterile conditions, 199.5 g of galactose with 0.5 g of ascorbyl palmitate is grated intensively, passed through a 0.8 mm sieve and comminuted with an air jet mill until the following size distribution of the particles is obtained: 1.9 μπι 99% <6 μπι 90% <3 μπι

The determination of the particle size and their distribution takes place in a particle measuring apparatus, e.g. after suspension in isopro-panol. The final packing of the microparticles takes place in 5 ml vials of 2 g each.

C. To prepare 5 ml ultrasound contrast agent ready for use, add the contents of a carrier bottle (0.9% sodium chloride solution in water, A) using a syringe to the microparticle (B) vial and shake it. until a homogeneous suspension is formed (5 to 10 seconds).

25

Example 8 A. Preparation of carrier liquid 30

Injection water is used, which is drained into 4 ml portions in 5 ml vials and then sterilized for 20 minutes at 120 ° C.

B. Preparation of Microparticles 35

Under sterile conditions, 0.5 g of sucrose monopalmitate with 199.5 g of galactose is shredded intensively, passed through

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16 a 0.8 mm sieve and ground with an air jet mill until the following size distribution of the particles is obtained:

Mean 1.9 μπι 5 min. 99% <6 μπι min. 90% <3 μιη «

Determination of the size of the particles and their distribution takes place in a particle measuring apparatus, e.g. after suspension in isopropanol. The final packing of microparicles takes place in 5 ml vials of 2 g each.

C. For the preparation of 5 ml ultrasonic contrast agent ready for use, the contents of a medicine bottle with carrier liquid (sterile water for injection, A) are added by means of a syringe to the medicine bottle with microparticles (B) and shaken until a homogeneous suspension (5 to 10 seconds).

Example 9 A. Preparation of carrier liquid

Water for injection is drained into 4 ml portions in 5 ml 25 vials and sterilized for 20 minutes at 120 ° C.

B Preparation of Microparticles'

Under sterile conditions, a sterile filtered solution of 0.5 g sucrose monopalmitate in 40 g isopropanol on 199.5 g sterile galactose particles is evaporated at 40 ° C and 200 mm mercury and ground with an air jet mill until the following size distribution of the particles: 35

Mean 1.9 μιη min. 99% <6 μπι min. 90% <3 μπι

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17

The determination of the particle size and their distribution takes place in a particle measuring apparatus, e.g. after suspension in isopro-panol. The final packing of microparticles takes place in 5 ml medicine bottles with 2 g in each.

5 C. For the preparation of 5 ml ultrasonic contrast agent ready for use, the contents of a medicine bottle with carrier liquid (water for injection, A) are added by means of a syringe to the medicine bottle with microparticles yes (B) and shaken until a homogeneous suspension is formed (5 to 10 seconds).

Example 10 15 A. Preparation of carrier liquid

Water for injection is drained into 4 ml portions in 5 ml vials and sterilized for 20 min at 120 ° C.

B. Preparation of Microparticles

Under sterile conditions, a sterile filtered solution of 0.5 g of sucrose monostearate in 40 g of isopropanol is added to 199.5 g of sterile galactose particles, evaporated isopropanol 25 at 40 ° C and 200 mm of mercury and ground with an air jet mill until the following is achieved. size distribution of the particles:

Mean 1.9 μπι min. 99% <6 by 30 mm. 90% <3 μπι

The determination of the particle size and their distribution takes place in a particle measuring apparatus, e.g. after suspension i

isopropanol. The final packing of the microparticles takes place 3 S

in 5 ml medicine bottles with 2 g each.

C. To prepare 5 ml ultrasonic contrast agent ready for use, add the contents of a medicine bottle

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18 with carrier liquid (water for injection, A) by means of a syringe for the vial of microparticles (B) and shake until a homogeneous suspension is formed (5 to 10 seconds).

5

Example 11 «A. Preparation of carrier liquid

Injection water is used, which is drained into 4 ml portions in 5 ml vials and then sterilized for 20 minutes at 120 ° C.

B. Preparation of Microparticles 15

Under sterile conditions, 0.5 g of sucrose monostearate is grated with 199.5 g of galactose, mixed intensively, passed through a 0.8 mm sieve and ground with an air jet mill until the following size distribution of the particles is obtained: 20

Mean 1.9 μπι min. 99% <6 μπι min. 90% <3 μκι 25

The determination of the particle size and their distribution takes place in a particle measuring apparatus, e.g. after suspension in isopropanol. The final packing of the microparticles takes place in 5 ml vials of 2 g each.

To prepare 5 ml of ultrasound contrast agent ready for use, put the contents of a carrier bottle (sterile water for injection, A) using a syringe for the microparticle (B) medicine bottle and shake until a homogeneous suspension is formed (5 to 10 seconds).

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19

Example 12 A. Preparation of carrier fluid 5 Water for injection is drained into 4 ml portions in 5 ml vials and sterilized for 20 minutes at 120 ° C.

4 B. Preparation of Microparticles 10 Under sterile conditions, a sterile filtered solution of 0.5 g sucrose distearate in 40 g isopropanol on 199.5 g sterile galactose particles is dried, isopropanol dried at 40 ° C and 200 mm mercury and ground with an air jet mill until the following size distribution of the particles has been obtained:

Mean 1.9 μπι min. 99% <6 mm min. 90% <3 μπι 20

The determination of the particle size and their distribution takes place in a particle measuring apparatus, e.g. after suspension in isopropanol. The final packing of microparticles takes place in 5 ml medicine bottles with 2 g in each.

28 C. For the preparation of 5 ml ultrasonic contrast agent ready for use, the contents of a medicine bottle with carrier liquid (water for injection, A) are added by means of a syringe to the medicine bottle with microparticles 3® (B) and shaken until a homogeneous suspension is formed (5 to 10 seconds).

Example 13 35 A Preparation of carrier liquid

Injection water is used which is drained into 4 ml portions in 5 ml vials and then sterilized for 20 minutes at 120 ° C.

Claims (11)

1. Microparticle and gas bubble containing contrast agent for ultrasonic diagnostics, characterized in that it contains microparticles of a solid interface active substance selected from C4-C20 fatty acids or sucrose esters or ascorbyl esters thereof or metal salts thereof from 0.01 to 5 wt%, optionally in combination with microparticles 35 of a non-interface active solid selected from cyclodextrins, monosaccharides or disaccharides, preferably galactose, lactose or α-cyclodextrin, at a concentration of DK 165171 B 5 to 50 wt%, preferably 9 to 40% by weight, in a liquid carrier. An agent according to claim 1, characterized in that it contains magnesium stearate, ascorbyl palmitate, sucrose monopalmitate, sucrose monostearate or sucrose distearate as solid interface active substance in the form of microparticles at a concentration of 0.01 to 5% by weight, preferably 0.04 to 5%. 1% by weight. An agent according to claim 1, characterized in that it contains water as a liquid carrier, a physiological electrolyte solution, a 10% aqueous lactose solution or a 20% aqueous galactose solution. An agent according to claim 1, characterized in that it contains microparticles of magnesium stearate and of galactose in a 20% aqueous galactose solution. An agent according to claim 1, characterized in that it contains microparticles of ascorbyl palmitate and of galactose in water. An agent according to claim 1, characterized in that it contains microparticles of ascorbyl palmitate and of α-cyclodextrin in physiological saline solution. Agent according to claim 1, characterized in that it contains microparticles of ascorbyl palmitate in a 10% aqueous lactose solution. 30 An agent according to claim 1, characterized in that it contains microparticles of sucrose monopalmitate and of galactose in water. An agent according to claim 1, characterized in that it contains microparticles of sucrose monostearate and of galactose in water. DK 165171 B Agent according to claim 1, characterized in that it contains microparticles of sucrose distearate and of galactose in water. Λ Equipment for the preparation of a microparticle and gas bubble containing ultrasonic contrast agent according to claim 1, characterized in that it comprises a) a container of 5-10 ml volume, provided with a closure which allows the contents to be removed during sterile conditions which are filled with 4 ml of liquid carrier, and b) of another container with a volume of 5-10 ml, provided with a closure which allows for the addition of the liquid carrier under sterile conditions containing the container. microparticles of a solid interface active substance selected from C4-C20 fatty acids or sucrose esters or ascorbyl esters thereof or metal salts thereof in an amount of 0.01 to 5% by weight of the total weight of the agent, optionally in combination with microparticles of a non-interface active agent. solid selected from cyclodextrins, mono- and disaccharides, preferably galactose, lactose or α-cyclodextrin, with an average particle size of <1 to 10 mm, of which The weight ratio of interface active agent to any non-interfacing surfactant present is 0.02-100: 100, and the microparticles are present in an amount of from 5 to 50% by weight, preferably from 9 to 40. weight% of the total weight of the agent. Process for the preparation of a microparticle and gas bubble containing contrast agent according to claim 1 for ultrasound diagnostics, characterized by combining microparticles of a physiologically compatible solid surfactant selected from C4-C20 fatty acids or sucrose or ascorbic acid. or metal salts thereof, optionally in combination with microparticles of a physiologically compatible non-surfactant solid selected from cyclodextrins, DK 165171B mono- and disaccharides, preferably galactose, lactose or α-cyclodextri η, with such an amount of a physiologically compatible carrier For example, the concentration of the microparticles of the interface active substance is 0.01 to 5% by weight, based on the total weight of the mid-5, and shakes until a homogeneous suspension occurs. 10 * 15 20 25 30 35