Preparations comprising a fluorocarbon or a highly fluorinated compound and a lipophilic/fluorophilic compound and their uses

• US 6,113,919 A
• Filed: 06/07/1995
• Issued: 09/05/2000
• Est. Priority Date: 07/17/1991
• Status: Expired due to Fees

• Current Assignee: PFC Therapeutics, LLC
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Krafft, Marie-Pierre, Sole-Violan, Luis, Postel, Michele, Cornelus, Chantal, Reiss, Jean G.
• Primary Examiner(s): Lovering, Richard D.
• Assistant Examiner(s): Metzmaier, Daniel S
• Application Number:
  US08/483,946
• Time in Patent Office: 1,917 Days
• Field of Search: 252/312, 252/314, 514/832, 514/833, 514/938, 514/944, 514/759, 424/400, 424/450, 424/78.03, 424/70.1, 516/56, 516/76
• US Class Current: 424/400
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: C09K 23/007 Organic compounds containing halogen
• CPC Class Codes: C09K 23/017 Mixtures of compounds
• CPC Class Codes: C09K 23/14 Derivatives of phosphoric acid

Abstract

Fluorocarbon emulsions comprising a stabilizing, particle size controlling fluorophilic/hydrophilic compound which can have the formula

R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

wherein

R_F¹ is a linear, branched or cyclic C_2-14 fluorocarbon group;

R_H¹ is a linear, branched or cyclic C_2-18 saturated or unsaturated hydrocarbon group; and

W is absent or is a bivalent species chosen from the group consisting of --O--, --S--, or various fluorinated structures. Use of the fluorophilic/lipophilic compound in the dispersions of the invention provides stable particle size and efficient emulsification. The dispersions of the invention can comprise biologically useful additive and can be used for various purposes, as oxygen carriers, contrast agents, or diagnostic agents.

Claims

1. A composition in the form of an oil-in-water emulsion, comprising:

a continuous aqueous phase; and

a discontinuous phase comprising;

an amphiphilic surfactant with a hydrophilic part and a lipophilic part, or a mixture of such surfactants;

0.01-10% w/v of a lipophilic/fluorophilic compound with a lipophilic part and a fluorophilic part wherein said lipophilic part comprises a linear, branched or cyclic saturated or unsaturated alkyl group having between 4 and 18 carbon atoms, the lipophilic/fluorophilic compound being present in an effective molar ratio to the surfactant to impart the composition with enhanced particle size stability; and

a fluorocarbon liquid, wherein said fluorocarbon liquid is different than said lipophilic/fluorophilic compound;

wherein the discontinuous phase is in the form of discrete droplets of said fluorocarbon liquid comprising an outer layer of the amphiphilic surfactant oriented such that the hydrophilic part thereof is substantially associated with and the lipophilic part thereof is substantially associated with the lipophilic part of the stabilizing compound, the fluorophilic part of the stabilizing compound being substantially associated with the fluorocarbon liquid.

2. A composition according to claim 1, comprising:

an oily dispersed fluorocarbon-containing phase in a concentration of from about 10 to 130% weight/volume; and

an amphiphilic surfactant in a concentration of from about 0.05% to 10% weight/volume.

3. The composition of claim 2 wherein said lipophilic/fluorophilic compound and said surfactant are in a molar ratio that is 1:

5 to 3;

1.

4. A composition according to claim 1 wherein the lipophilic/fluorophilic compound is of the formula:

space="preserve" listing-type="equation">R.sub.F.sup.1 --W--R.sub.H.sup.1 (I)

wherein

R_F¹ is a linear, branched or cyclic C_2-14 fluorocarbon group;

R_H¹ is a linear, branched or cyclic C_4-18 saturated or unsaturated hydrocarbon group; and

W is absent or is a bivalent species selected from the group consisting of --O--, --S--, ##STR6## wherein X¹, X² and X³ are absent or are independently selected from the group consisting of --O-- and --S--;

R_F² is a fluorocarbon independently selected from the group defined for R_F¹ ;

R_H² is a hydrocarbon independently selected from the group defined for R_H¹ ;

R² is absent or is selected from the group consisting of fluorocarbon radicals and hydrocarbon radicals wherein said fluorocarbon radicals and said hydrocarbon radicals are independently selected from the group defined for R_F¹ and the group defined for R_H¹ ; and

p and q are independently 1-10;

provided that R_F¹ and R_F² comprise at least 4 fluorine atoms, and correspond to a hydrocarbon analogue wherein fluorine atoms replace from 50% to 100% of the hydrogen atoms.

5. A composition according to claim 4, wherein R_F¹ is CF₃ (CF₂)_t -- and wherein t=1 to 11.

6. A composition according to claim 4, wherein said lipophilic/fluorophilic compound is of the formula:

space="preserve" listing-type="equation">CF.sub.3 (CF.sub.2).sub.t1 --(CH.sub.2).sub.t2 --CH═

CH--(CH.sub.2).sub.y --CH.sub.3

wherein t₁ =2 to 11, t₂ =0 or 1 to 6 and y=1 to 15.

7. A composition according to claim 6, wherein t₂ =0;

t₁ =3, 5, or 7, and y=5, 7, 9, or 11.

8. A method for stabilizing the particle size of emulsions having an aqueous continuous phase, a fluorocarbon disperse phase and containing a hydrophilic/lipophilic surfactant, comprising the step of adding to the emulsion an effective particle size-stabilizing amount of a lipophilic/fluorophilic compound wherein the lipophilic/fluorophilic compound is different than the fluorocarbon and wherein the lipophilic/fluorophilic compound is of the formula

9. The method of claim 8, wherein the molar ratio of said lipophilic/fluorophilic compound to said surfactant is 1:

5 to 3;

1.

10. The method of claim 8 wherein the surfactant is egg yolk phospholipid (EYP) and the molar ratio of said lipophilic/fluorophilic compound to EYP is 1:

5 to 2;

1.

11. A method for adjusting the particle size in fluorocarbon emulsions, comprising the steps of:

providing an emulsion formulation comprising a fluorocarbon component, a hydrophilic/lipophilic surfactant, an aqueous component; and

0.01-10% w/v of a lipophilic/fluorophilic compound of the formula

space="preserve" listing-type="equation">R.sub.F.sup.1 --W--R.sub.H.sup.1 (I)

wherein R_F¹, W, and R_H¹ are as defined in claim 4, so that the molar ratio of said lipophilic/fluorophilic compound to said hydrophilic/lipophilic surfactant is 1;

5 to 3;

1 and wherein said lipophilic/fluorophilic compound is different than said fluorocarbon component; and

emulsifying said emulsion formulation to form a fluorocarbon emulsion.

20. A composition according to any one of claims 12-14, 1 or 4, wherein said fluorocarbon is selected from the group consisting of perfluorodecalin, perfluorooctylbromide, 1,2-bis-(F-alkyl)-ethenes, perfluoromethyldecalins, perfluorodimethyldecalins, perfluoromethyladamantanes, perfluorodimethyladamantanes, perfluoromethylbicyclo (3,3,1) nonanes, perfluorodimethylbicyclo (3,3,1) nonanes, trimethylbicyclo (3,3,1) nonanes, perfluoroperhydrophenanthrenes, ethers selected from the group consisting of (CF₃)₂ CFO(CF₂ CF₂)₂ OCF(CF₃)₂, (CF₃)₂ CFO(CF₂ CF₂)₃ OCF(CF₃)₂, (CF₃)₂ CFO(CF₂ CF₂)₂ F, (CF₃)₂ CFO(CF₂ CF₂)₃ F, F(CF(CF₃)CF₂ O)₂ CHFCF₃ and (CF₃ CF₂ CF₂ (CF₂)_u)₂ O with u=1, 3 or 5, amines selected from the group consisting of N(C₃ F₇)₃, N(C₄ F₉)₃ and N(C₅ F₁₁)₃, perfluoro-N-methylperhydroquinolines, perfluoro-N-methylperhydroisoquinolines, perfluoroalkyl hydrides, and halogenated derivatives selected from the group consisting of C₆ F₁₃ Br, C₈ F₁₇ Br, C₆ F₁₃ CBr₂ CH₂ Br, 1-bromo 4-perfluoroisopropyl cyclohexane, C₈ F₁₆ Br₂, CF₃ CF₂ CF₂ --C(CF₃)₂ --CH₂ CH₂ CH₂ --CF(CF₃)₂ and CF₃ O(CF₂ CF₂ O)_u CF₂ --CH₂ OH with u=2 or 3.

21. A composition according to claim 20, wherein said fluorocarbon is perfluorooctyl bromide.

22. A composition according to claim 20, wherein said fluorocarbon is a 1,2-bis-(F-alkyl)ethene selected from the group consisting of bis(F-butyl)-1,2-ethenes, F-isopropyl-1-F-hexyl-2-ethenes and the bis(F-hexyl)-1,2-ethenes.

23. A composition according to claim 20, wherein said fluorocarbon is perfluorodecalin.

26. A composition according to any of claims 12-14, 24, 25, 1, or 4, further comprising a physiologically effective additive selected from the group consisting of mineral salts, buffering agents, osmotic agents, oncotic agents, pharmaceutical products, nutritive products, and diagnostic agents.

27. A composition according to any of claims 12-14, 24, 25, 1 or 4 wherein said hydrophilic/lipophilic surfactant is selected from the group consisting of phospholipids and polyoxyethylene-polyoxypropylene type surfactants and their mixtures.

28. A composition according to any of claims 12-14, 24, 25, 1 or 4 wherein said hydrophilic/lipophilic surfactant is egg yolk phospholipid (EYP).

29. A composition according to claim 28 wherein the ratio of said lipophilic/fluorophilic compound to EYP is between about 1:

2 and 2;

1.

12. A composition in the form of an oil-in-water emulsion, comprising:

an oily disperse phase comprising at least one fluorocarbon or highly fluorinated compound;

an aqueous phase;

a hydrophilic/lipophilic surfactant; and

0.01 to 10% w/v of a lipophilic/fluorophilic compound wherein said lipophilic/fluorophilic compound is different than said fluorocarbon or highly fluorinated compound and wherein the lipophilic/fluorophilic compound is of the formula;

space="preserve" listing-type="equation">R.sub.F.sup.1 --W--R.sub.H.sup.1 (I)

wherein

R_F¹ is a linear, branched or cyclic C_2-14 fluorocarbon group;

R_H¹ is a linear, branched or cyclic C_4-18 saturated or unsaturated hydrocarbon group; and

W is absent, a bivalent species selected from the group consisting of --O-- and --S--, or is selected from the group consisting of;

##STR7## wherein X¹, X² and X³ are absent or are independently selected from the group consisting of --O-- and --S--;

R_F² is a fluorocarbon independently selected from the group defined for R_F¹ ;

R_H² is a hydrocarbon independently selected from the group defined for R_H¹

R² is absent or is a fluorocarbon or a hydrocarbon radical independently selected from the group defined for R_F¹ or the group defined for R_H¹ ;

p and q are independently 1-10; and

R_F¹ and R_F² comprise at least 4 F atoms, and correspond to a hydrocarbon analogue wherein F atoms replace from 50% to 100% of the hydrogen atoms in the carbon chain.

15. A composition according to any of claims 12-14 or 4 wherein R_F¹ and R_F² are independently selected from the group consisting of:

CF₃ (CF₂)t-- wherein t=1 to 11;

(CF₃)₂ CF(CF₂)_v -- wherein v=0 to 8;

CF₃ --(CF₂ CF(CF₃))_w -- wherein w=1 to 4;

C₂ F₅ --(CF₂ CF(CF₃))_w -- wherein w=1 to 4;

(CF₃)₂ (CF--CF₂ CF(CF₃))_w -- wherein w=1 to 3; and

##STR10## wherein x=1 to 6; and

R_F¹ and R_F² are independently chosen from the group consisting of CF₃ --, C₂ F₅ --, n--C₃ F₇ -- and CF₃ CF₂ CF(CF₃)--;

or

R_F¹ and R_F² together form a bivalent radical chosen from the group consisting of;

--CF₂ (CF₂)₂ CF₂ --;

--CF₂ (CF₂)₃ CF₂ --; and

CF₃ CF₂ O--(CF₂ CF₂ O)_y --CF₂ --, wherein y=0 to 3; and

CF₃ (CF₂)₂ O--(CF(CF₃))(CF₂ O)_y --CF(CF₃)--, wherein y=0 to 2.

16. A composition according to any of claims 12, 13 or 4, wherein R_H¹ and R_H² are independently selected from the group consisting of:

(a) CH₃ --(CH₂)_y1 --, wherein y1=3 to 17;

(b) CH₃ (CH₂)_y2 (CH═

CH)q(CH₂)_y3 -- and CH₃ (CH₂)_y2 --S--(CH₂)_y3 -- wherein y2 and y3 are independently 1 to 16, and q=0 or 1;

(c) CH₃ (CH₂ --CH₂ --O)_y4 --CH₂ -- wherein y4=1 to 8; and

(d) CH₃ (CH(CH₃)CH₂ O)_y5 --CH--CH₃ wherein y5=1 to 5.

17. A composition according to any of claims 12 or 4, wherein:

R_H¹ is R⁴ --CH═

CH--(CH₂)_p --, wherein R⁴ is a C_4-12 alkyl group, and p=0 or 1 to 8, provided however R⁴ and (CH₂)_p comprise 16 or less carbon atoms, and W is absent.

18. A composition according to any of claims 12 or 4, wherein:

R_H¹ is a straight chain C_4-14 alkyl group, and

W is absent.

19. A composition according to claim 12 or 4, wherein:

R_H¹ is a, straight chain C_4-12 alkyl group, and

W is a group of formula;

##STR11## wherein X¹, X², X³ are absent or are independently selected from the group consisting of --O-- and --S--, R² is absent and R_H² is a hydrocarbon independently selected from the group defined for R_H¹.

13. A composition in the form of an oil-in-water, emulsion, comprising:

an oily disperse phase comprising at least one fluorocarbon or highly fluorinated compound;

a continuous aqueous phase;

a hydrophilic/lipophilic surfactant; and

0.01 to 50% w/v of a lipophilic/fluorophilic compound wherein said lipophilic/fluorophilic compound is different than said fluorocarbon or highly fluorinated compound and wherein the lipophilic/fluorophilic compound is of the formula;

##STR8## wherein X⁴ is --O--, --S-- or --S--S--; and

a1 and a2 are independently from 0 to 11;

or a mixture of said compounds;

R_F¹ is a linear, branched or cyclic C_2-14 fluorocarbon group;

R_H¹ is a linear, branched or cyclic C_1-18 saturated or unsaturated hydrocarbon group;

R_F² is a fluorocarbon independently selected from the group defined for R_F¹ ;

R_H² is a hydrocarbon independently selected from the group defined for R_H¹ ;

provided that R_F¹ and R_F² comprise at least 4 F atoms, and correspond to a hydrocarbon analogue wherein F atoms replace from 50% to 100% of the hydrogen atoms in the carbon chain.

14. A composition in the form of an oil-in-water emulsion, comprising:

an oily disperse phase comprising at least one fluorocarbon or highly fluorinated compound;

a continuous aqueous phase;

a hydrophilic/lipophilic surfactant; and

0.01 to 50% of a lipophilic/fluorophilic compound wherein said lipophilic/fluorophilic compound is different than said fluorocarbon or highly fluorinated compound and wherein said lipophilic/fluorophilic compound is of the formula ##STR9## wherein X⁵ is --O--, --S--, or --S--S--;

p and q are independently from 1 to 10;

R_F¹ and R_F² are independently selected from a group of perfluoroalkylated radicals having from 2 to 10 carbon atoms, and R_H³ is selected from the group of consisting of hydrocarbon radicals having from 2 to 16 carbon atoms and a mixture of said compounds.

24. A composition in the form of an oil-in-water emulsion, comprising:

a disperse oily phase comprising at least one fluorocarbon or highly fluorinated compound;

a continuous aqueous phase;

a hydrophilic/lipophilic surfactant; and

0.01-50% of a lipophilic/fluorophilic compound, wherein said lipophilic/fluorophilic compound is different than said fluorocarbon or highly fluorinated compound, and wherein the lipophilic-fluorophilic compound is of the formula;

space="preserve" listing-type="equation">R.sub.F.sup.1 --W--R.sub.H.sup.1 (I)

wherein

R_F¹ is a linear, branched or cyclic C_2-14 fluorocarbon group

R_H¹ is a straight chain C_4-12 alkyl group, and

W is O or S or a mixture of said compounds.

25. A composition in the form of an oil-in-water, emulsion, comprising:

an oily disperse phase comprising at least one fluorocarbon or highly fluorinated compound;

a continuous aqueous phase;

a surfactant; and

0.01-50% of a lipophilic/fluorophilic compound, wherein said lipophilic/fluorophilic compound is different than said fluorocarbon or highly fluorinated compound, and wherein the lipophilic-fluorophilic compound is of the formula;

space="preserve" listing-type="equation">R.sub.F.sup.1 --W--R.sub.H.sup.1 (I)

wherein

R_F¹ is a linear, branched or cyclic C_2-14 fluorocarbon group;

R_H¹ is a straight chain C_4-12 alkyl group, and

W is a group of formula;

##STR12## wherein X¹, X², X³ are absent or are independently selected from the group consisting of --O-- or --S--; and

R_F² is a fluorocarbon independently selected from the group defined for R_F¹.