DE2555408A1 - EMULSION OF A PERFLUORIZED COMPOUND IN WATER - Google Patents

Description

CHILDREN'S HOSPITAL MEDICAL CENTER

DA-Il 924

priority

December 9, IS74, U S A, No. 530 791 May 22, 1975, USA, No. 579 766

Emulsion of a perfluorinated compound in water

It is well known that there is a need for synthetic blood as a blood substitute consists. Blood is becoming more and more expensive, is subject to spoilage, -must match the blood type of the recipient and by the Transfusion itself can cause hepatitis if strict measures are not followed. In addition, there is a blood donation the tendency to fluctuations over time and their point in time often do not agree with that which is generally statistically distributed Requirement for it.

Synthetic blood must have several distinctive properties. First of all, what is obvious, it must have high solubility for oxygen and carbon dioxide because of its main function consists in transporting oxygen and carbon dioxide. Synthetic blood must also be non-toxic, and in that regard it is desirable that when synthetic blood is replaced with natural blood, there should be no residue of the synthetic blood remain behind in vital body organs.

609824/0972

Another characteristic of blood substitutes is that that this must meet certain requirements with regard to the vapor pressure. The blood substitutes leave the body through Exhalation and by evaporation through the skin. Preferably, the blood substitute leaves the body at about the same rate as new natural blood is made by the body. If the vapor pressure of the blood substitute is too low, it remains closed long in the body; on the other hand, if it is too high, it evaporates it passes through the entire surface of the body and causes phenomena that are similar to compressed air sickness.

Blood substitute materials must also have the ability to form very stable emulsions, and this ability is the case with perfusion materials more important is. Blood substitutes are usually immiscible with blood and could if used alone cause embolism. This difficulty becomes eliminated by its application in an aqueous emulsion and it is evident that this emulsion changes during use or storage must not separate. In the case of perfusion materials, these are stability requirements even stricter because of the oxygen-releasing substances that are used be very high in order to supply oxygen to the perfusion material Cause vision and break almost all stable emulsions to lead. Another reason that aqueous emulsions are used is that salts are added to the water maintain the body salt balance.

The Green Cross Corporation, Osaka, Japan requested one on September 11th 1974 published brochure on emulsions of perfluorocompounds as oxygen and carbon dioxide carriers. Clark et al. some of the compounds described herein are reported in "Microvascular Research", Vol. 8/3 1974, and this report was also presented at the Oxygen Transport to Tissue Symposium, Atlantic City, N.J., April 11, 1974. The blood substitute and the perfusion material of choice has thus far been perfluorodecalin. This compound has several desirable properties; however, the compounds used according to the invention are better than perfluorodecalin in several respects.

609824/097 2

The invention is based on the object of an emulsion of a perfluorinated To provide material in water available, which is advantageous as blood substitute material and perfusion material suitable and the oxygen drainage sport in tissues, such as animal Tissue, made possible.

This object is achieved according to the invention using new blood substitute materials and perfusion materials, the perfluorinated polyeyelisehe compounds having 9 to 18 carbon atoms and at least 2 bridgehead carbon atoms. These compounds show extremely high dissolving power for oxygen, very low residues in the body, form a lot stable emulsions and have extremely satisfactory vapor pressures for either type of application.

The invention therefore provides an emulsion of a perfluorinated Material in water that is suitable for transporting oxygen into tissues, especially human and animal tissues and which contains more than 40 volumes of water. This emulsion contains a non-toxic emulsifier and a perfluorinated material which is produced by the fluorination (l) of a compound in which at least 2 carbon atoms belong to 3 rings and which do not Represents adamantane, or (2) of methyladamantane, ethyladamantane, Ethylmethyladamantane, ethyldimethyladamantane, triethyladamantane or adamantane was obtained.

These emulsions of perfluorinated compounds are particularly suitable good as blood substitute materials or as perfusion materials for storing organs such as kidneys before they are transplanted. Those from the perfluorinated polycyclic compounds produced emulsions show extremely high stability, no or extremely little residue formation in the body and one Vapor pressure which is adapted to the use in the body in such a way that no disturbing side effects are caused.

For the purposes of the invention, polycyclic compounds are suitable, which have 2 bridgehead carbon atoms, the Bridgehead carbon atom is common to 3 rings. Inventive

60 9 824/0972

accordingly are polycyclic compounds with 9 to 18 carbon atoms used, including adamantanes, in particular lower alkyladamantanes, such as methyladamantane, ethyladamantane, ethylmethyladamantane, Ethyldimethyladamantane and triethyladamantane. Suitable non-adamantanes are tetrahydrodicyclopentadiene and its lower alkyl derivatives, such as tetrahydromethyldicyclopentadiene and tetrahydrodimethyldicyclopentadiene, lower alky! bicyclooctanes, in particular methylbicyclooctane and dimethylbicyclooctane, tricyclononane, like tricyclo / 3.3.l / nonane; Tetrahydrobinor-S; lower Alkyl diamantanes such as methyl diamantane, trimethyl diamantane, and Ethylmethyldiamantan, as well as dimethanodecalin and its lower ones Alkyl derivatives such as methyldimethanodecalin and dimethyldimethanodecalin, and the same. These compounds can be made using known methods. Preferably the one used contains polycyclic compound 9 to 12 carbon atoms and generally has no more than 4 rings, usually 2 to 3 Rings.

For use on synthetic blood, perfluorinated Cg compounds have too high a vapor pressure to be suitable. The corresponding perfluorinated compounds having 10 and 11 carbon atoms are particularly suitable, while the C _q compounds are at the upper limit with regard to the vapor pressure and the Cj ₂ compounds are at the lower limit. The C ₁₀ and C-jn compounds have atmospheric boiling points between about 125 and 165 C, which is a satisfactory criterion. The preferred range for the atmospheric boiling point is between 125 and 145 ° C. Inside thei
are mainly C-, Q-compounds,

between 125 and 145 ° C. Within this preferred range

It should be emphasized that although C ₁₂ compounds are not so well suited as blood substitutes, these and compounds with up to 18 carbon atoms can be used as perfusion materials because the vapor pressure is not so important in this application. In the case of compounds with more than 18 carbon atoms, however, the oxygen solubility of the material is generally too low.

609824/0972

The polycyclic compounds are used in the perfluorinated form. For the purposes of the invention, the term “perfluorinated” should be understood to mean Cg to Ο, ο-polycyclic compounds which are completely fluorinated to at least 95% by weight (ie, perfluorinated in the narrow sense), preferably at least 98% 6 and especially to $ 100>. In all cases where the compounds are perfluorinated to less than 100 $, the remainder of the compounds will of course be highly fluorinated.

The fluorination is carried out using known methods. For example, the hydrocarbon is slowly passed at a temperature of 250 to 275 ° C. over a layer of Co] ?, we. "_ Before it contains 2 to 3 times the stoichiometric amount of fluorine, as a result of which the partial fluorination takes place method is v / iederholt ⁰ C then at 300 to 35O, the complete fluorination of the compounds is carried out, with the exception of some percent impurities, which represent saturated, partially fluorinated compounds and olefinic fluorocarbons. the saturated partially fluorinated compounds boiling at least 10 C higher than the desired perfluorocompounds and are removed by distillation. The last-mentioned impurities boil essentially at the same temperature and are extracted with the aid of an amine, such as diethylamine (DEA). Remaining amine is removed with concentrated sulfuric acid. The excess acid is removed with a 1 $ NaHCO ^ solution is removed, which is then ex is traced. The remaining acetone is finally distilled off.

The perfluorinated polycyclic ^ compound is in the form of an aqueous Emulsion containing more than 40 volumes of water is used. Preferably the emulsion contains 10 to 30 volumes of the perfluorinated polycyclic compound. Usually the emulsion contains 1 to 5 volumes of an emulsifier. The special one used Emulsifier is not critical, but it should be non-toxic and form a stable emulsion. The preferred emulsifier is Egg yolk phospholipid, as this is known to be harmless to the organism. Polyoxyethylenes are also suitable for perfusion purposes and polyoxypropylenes sold under the name "Pluronics" in

609824/0 972

Are commercially available. "Pluronic P-68" has a molecular weight of 8350 and forms a very stable emulsion.

However, there are some unconfirmed communications about that materials of the Pluronics plasma protein type precipitate and that the use of these materials is therefore preferred should be limited to perfusion materials, while for blood substitutes the commercially available egg yolk phospholipids Be used.

The emulsion can be formed with conventional high shear emulsifying equipment such as a Manton Caulin homogenizer. Typically the particle size of the perfluorinated polycyclic hydrocarbon in the emulsion is 0.001 to 10 microns, more often 0.01 to 10 microns, especially 0.05 to 0.5 microns, and preferably 50 % of the particles are 0.05 to 0 in diameter , 3 microns. In a known manner, the particle size can be adjusted by the applied shear. The actual particle size of the emulsion is not as critical as the stability of the emulsion, which will be explained later.

As indicated above, the retention of the material in the body is important. The table below shows the corresponding data for perfluorinated (Pi ¹ ) dimethyladamantane (DMA.) And methyladamantane (MA) in comparison with perfluorinated tributylamine (TBA), decalin (D) and methyldecalin (MD). These materials are currently the best blood substitutes and compounds for perfusion. To carry out the test, emulsions containing 10 % of the test compound, surfactant and water were prepared and tested in the manner described in Science, Volume 181, August 1973, page 681. Mice received injections of the various Emulsions Mice were sacrificed at intervals thereafter, the liver was analyzed and the percentage of the amount of perfluorinated material originally injected in the liver was determined * The results are shown below.

609824/0972

2 6th 12th 20th 2 2 2 2 30th 19th 2 2 38 30th 30th 30th 35 28 23 2 7th 1

Percentage in the liver after the specified number of weeks

Material PFD PPMO PI ¹ TBA PPDMA PPMA

It is evident that PFMA (which is a small amount of a containing higher boiling impurities that delayed its release from the body) is as good or better than PPD. Self PFDMA reaches the 2 ^ limit of PPD, but takes longer.

The relative stability of a PFDMA emulsion and of PPMA is excellent in that it is ^{indefinitely stable (ie more than 6 months) at 4 to 7 0} C, while a PFD emulsion in several days at room temperature and in several weeks at 4 to 7 ⁰ C breaks. PPTBA also gives excellent results (for example "The Journal of Microvascular Research", August 1974). In addition to stability, emulsions made from PPDMA and PPD (in the same way) show optical densities of 0.1 and 0.4, respectively, which means that the particle size of the first-mentioned emulsion is much smaller and that this compound therefore is far easier to emulsify. PPMA also leads to an optical density of 0.65, which is far lower than the optical density of 2.2 achieved with PPTBA.

It has also been found that the perfluorinated compounds used according to the invention are extremely non-toxic. The erfindungsgeinäß used materials show (in comparison with other materials) after the infusion the following values of (ml / kg):

609824/0972

190 160 159 > 2OO 175 175 > 200 > 200 > 200 > 200 120 120

Emulsion 1 hour 3 days 7 days

10.9 ί> PFD
10 % PPDMA

5 1 ° PPMA
10 io PPTBA

As indicated above, the perfluorinated materials used in the present invention have high dissolving power for oxygen and carbon dioxide. For example, the fluorinated materials can usually contain about 40 to 60 cm of oxygen per "Z

100 cm of the fluorocarbon contained and the solubility for carbon dioxide is about 2 times this value. $ Normal Blood absorbs about 20 cm of oxygen per 100 cm of des Blood, where the carbon dioxide solubility is 2 times that of oxygen. The materials according to the invention normally contain

3 3

wise 30 to 60 cm of oxygen per 100 cm of the perfluorinated material, however, lower ratios, such as 10 cnr

3 3 3

per 100 cm and higher amounts such as 100 cm per 100 cm can be used if possible and necessary. The above solubilities relate to 25 ° C 'and 760 mm of mercury. The compounds at the upper end of the range from Cq to C-, g for the carbon atoms (C-jp ^ ^is ^ ₁₈ ) show the behavior described above, with the exception that their oxygen-dissolving power decreases. Above C-, ο the solubility is not high enough to make these compounds suitable materials.

In the examples below, as has already been explained above, perfluorinated polycyclic hydrocarbons are used as starting materials which are completely fluorinated, ie perfluorinated, to an extent of at least 95% by weight, preferably at least 98% by weight and in particular 100% by weight, are. However, those compounds that are less than 100 % fluorinated are still highly fluorinated.

609Ö24 / 0972

example 1

5 g of the emulsifier are added to 10 ml of perfluorotricyclo / 5.3.17nonane Pluronic 168 given. Distilled water is then added to the mixture to a total volume of 50 ml. The solution will be filtered through a 10 micrometer millipore filter and the obtained solution, which has been cooled to about 0 to 5 ° C with the aid of an ice bath, is extracted with the aid of an ultrasonic vibrator treated with ultrasound. During the ultrasound treatment, the optical density of 5 cm samples is measured at regular intervals measured until a constant optical density value is reached, indicating that an emulsion containing the smallest possible particle size was obtained. The ultrasound treatment is then interrupted and the stable aqueous emulsion of 20 volume perfluorotricyclo / 3.3.17 redonane is removed.

Example 2

According to the procedure described in Example 1, but under Using perfluoromethyladamantane instead of the nonane derivative and using egg yolk phospholipid as an emulsifier a stable aqueous emulsion of 20 volume ^ perfluoromethyladamantane obtain.

Example 5

25 g of Pluronic are added to 5 ml of perfluorotetrahydrodicyclopentadiene 168 given as an emulsifier. Distilled water is then added to the mixture until a total volume of 500 ml is reached. The solution is filtered through a 10 micrometer millipore filter and then homogenized in a Manton-Gaulin homogenizer with is provided with a cooler. During the homogenization, the optical Density of 5 ml samples of the emulsion measured at regular intervals until a constant value of the optical density is reached indicating that the smallest possible particle size emulsion was obtained. The homogenization is then interrupted. A stable aqueous emulsion of 10 vol. ^ Perfluorotetrahydrodicyclopentadiene is obtained.

609824/0972

Example 4

■ Hach the procedure described in Example 3, but below Use of perfluoromethylbicyclooctane instead of the cyclopentadiene derivative and using egg yolk phospholipid, a stable aqueous emulsion of 10 volume ^ perfluoromethylbicyclooctane is made obtain.

Example 5

To 100 ml of perfluoroethylbicyclooctane v / ground 50 g of the emulsifier Pluronic E68 given. Then the mixture becomes distilled water added until a total volume of 500 ml is reached. The solution is filtered through a 10 micrometer Millipore filter and homogenized in a Manton-Gaulin homogenizer equipped with a cooler. During the homogenization, the optical density of 5 ml samples of the emulsion measured at regular intervals until a constant value for the optical density is reached. The homogenization is then interrupted, leaving a stable aqueous emulsion of 20 volume $ perfluoroethylbicyclooctane is won.

Example 6

Following the same procedure as in Example 5, but using perfluoroethylmethyladamantane instead of the bicyclooctane derivative becomes a stable aqueous emulsion of 20 Volum- ^ perfluoroethylmethyladamantane obtain. ν

Example 7

Hach the same procedure as in Example 1, but using perfluoroethyldimethyladamantane as the starting compound, becomes a stable aqueous emulsion of 10% by volume of perfluoroethyldimethy! adamantane obtain.

609824/0 972

Example 8

According to the procedure described in Example 1 ", but under Use of perfluorotetrahydrobinor-S instead of the nonane derivative, becomes a stable aqueous emulsion of 20 volume ^ perfluorotetrahydrobinor-S achieved.

Example 9

According to the procedure described in Example 3, but under Using perfluoromethyldiamantane as a starting compound and egg yolk phospholipid as an emulsifier, becomes a stable aqueous Obtained emulsion of 10 volume? £ of the perfluoromethyldiamantane.

Example 10

Following the same procedure as in Example 5, but using perfluorotriäthyladamantan as the starting compound, becomes a stable aqueous emulsion of 20 volum- ^ perfluorotri- ■ Get ethyladamantane.

Example 11

Following the same procedure as in Example 1, but using perfluorotrimethyldiamantane as the starting compound and egg yolk phospholipid as the emulsifier, a stable aqueous emulsion of 10 vol. ^ Perfluorotrimethyldiamantane is obtained. _t

Example 12

According to the _{procedure described in 1} Example 3, but using perfluoroethyldimethyldiamantane, a stable aqueous emulsion of 10% by volume of perfluoroethyldimethyldiamantane is obtained.

80982 4/0972

Example 13

Following the same procedure as in Example 1, but using perfluorodimethanodecalin instead of the nonane * derivative and egg yolk phospholipid instead of Pluronic 68, a stable aqueous emulsion of 10 vol. ^ Perfluorodimethanodecalin is obtained.

Example 14

Following the same procedure as in Example 3, but below Using perfluoromethyldimethanodecalin instead of the nonane derivative results in a stable aqueous emulsion of 10% by volume Obtained perfluoromethyldimethanodecalin.

Example 15

Following the same procedure as in Example 1, but using perfluorotetrahydromethyldicyclopentadiene instead of the nonane derivative, a stable aqueous emulsion of 10 vol. ^ perfluorotetrahydromethyldicyclopentadiene is obtained.

Example 16

Following the same procedure as in Example 1, but using perfluoroethyladamantane instead of the nonane derivative and from egg yolk phospholipid instead of Pluronic 3? 68, becomes a stable aqueous emulsion of 10 volume ^ perfluoroethyladamantane obtain.

609824/0972

Claims (9)

Claims (Ώ "Aqueous emulsion of a perfluorinated compound, which contains more than 40 volumes of? 6 water and a non-toxic emulsifier, characterized in that it is used as perfluorinated compound one obtained by fluorinating 1) a non-adamantane compound, in which at least 2 carbon atoms 3 rings are common, or from 2) methyladamantane, ethyladamantane, Ethylmethyladamantane, ethyldimethyladamantane, triethyladamantane or contains compound formed by adamantane. 2. Emulsion according to claim 1, characterized in that that they are the perfluorinated derivatives of tetrahydrodieyclopentadiene or its lower alkyl derivatives, lower alkyl bicyclooctanes, lower alkyl diamantanes, dimethanodecalin or its lower alkyl derivatives, ricyclononanes or of contains letrahydrobinor-S. 3. Emulsion according to claim 1 or 2, characterized in that the particle size of the perfluorinated polycyclic compound in the emulsion is about 0.001 to 10 microns, preferably 50 wt. $> Of the particles a size of 0.05 to 0.5 microns to have. 4. Emulsion according to any one of claims 1 to 3, characterized in that the amount of the perfluorinated compound in the emulsion is 10 to 30 vol- ^. 609824/0972 5. Emulsion according to any one of claims 1 to 4, characterized in that the perfluorinated compound 9 to Has 12 carbon atoms. 6. Emulsion according to one of claims 1 to 5, characterized in that it contains an egg yolk phospholipid or a poly (G ₂ to C ^ alkylene oxide) as the emulsifier. 7. Emulsion according to one of claims 1 to 6, characterized in that it contains 10 to 100 cm ⁵ O ₂ at 25 ° C and 760 mm Hg per 100 cm of the perfluorinated compound. 8. A method for producing an emulsion according to any one of the claims 1 to 7, characterized in that a perfluorinated compound which is the fluorination product of 1) a polycyclic compound in which at least 2 carbon atoms 3 rings are in common, and which is not adamantane represents, or from 2) methyladamantane, ethyladamantane, ethylmethyladamantane, Ethyldimethyladamantane, triethyladamantane or Adamantane is emulsified with the help of a non-toxic emulsifier in such an amount of water that the water content of the the final emulsion obtained is more than 40? £ by volume. 9. Use of an aqueous emulsion according to one of claims 1 to 7 for the formation of blood substitutes or a perfusion material. 609824/0972