Drug delivery compositions and methods

What is claimed and sought to be secured by Letters Patent of the United States is:

1. A method of preparing a composition useful as a system to introduce and transport medically useful compositions in the body of mammals;

said composition comprising particles of a coacervate-based matrix having one or more physiologically-active compound incorporated therein and a coacervative-based encapsulating film surrounding each particle;

said method comprising forming a mixture of one or more surface active agents, water and one or more physiologically-active compounds to produce a two phase aqueous coacervate composition containing said compound, and emulsifying the composition to produce an aqueous emulsion of coacervate-based matrix particles containing the physiologically-active compound, said coacervate-based matrix comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, and said physiologically-active compound solubilized therein, said particles having an encapsulating coacervate-based film surrounding the particles.

2. The method of claim 1 further including adding an organic solvent to the mixture to form the two phase coacervate composition.

3. The method of claim 2 wherein the organic solvent comprises N-butyl alcohol or a glyceride.

4. The method of claim 1 wherein the surface active agents comprises a composition of a surface active protein and a surface active phospholipid.

5. A method of preparing a composition containing one or more physiologically-active compounds for oral, inhalation, tissue absorptive or parenteral administration to a mammal comprising emulsifying an aqueous solution of water, a polymerized or polymerizable surface active agent, a coacervating agent and a physicologically-active compound to form an aqueous emulsion of coacervate-based matrix particles containing the physiologically-active compound solubilized therein, and bound in the coacervate matrix within a coacervate-based aqueous film containing the polymerized surface active agent wherein said coacervate matrix comprises water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, and said physiologically-active compound solubilized therein.

6. The method of claim 5 further including emulsifying and microemulsifying the composition to form coacervate particles useful for oral administration having a particle size less than about 800 microns.

7. The method of claim 5 wherein the coacervate particles are microemulsified to less than about 1 micron.

8. The method of claim 5 wherein the surface active agent is a polymerized phospholipid.

9. The method of claim 8 wherein the polymerized phospholipid is polymerized lecithin.

10. The method of claim 8 wherein the phospholipid is selected from the group consisting of lecithin, cephalin, isolecithin, sphingomyelin, phosphalidyl serine, phosphatidic acid, phosphatidyl inositol, phosphatidyl choline, and mixtures thereof.

11. The method of claim 5 wherein the coacervate system includes two surface active agents, at least one of which is a polymer having a molecular weight of 300,000 or less.

12. The method of claim 11 wherein the two surface active agents comprise a phospholipid and a surface active protein.

13. The method of claim 12 wherein the two surface active agents comprise lecithin and polymerized albumin.

14. The method of claim 5 further including drying the composition to form a powder capable of being reconstituted by the addition of a physiologically-acceptable liquid.

15. The method of claim 5 wherein the surface active agent is added in monometric form and further including adding a polymerization initiator to said composition, said polymerization initiator capable of and in an amount sufficient to polymerize the surface active agent during processing of said composition.

16. The method of claim 15 wherein the polymerization initiator is 1-ethyl-3-dimethyl-aminopropylcarbodiimide.

17. The method of claim 5 wherein the physiologically-active compound is a peptide.

18. The method of claim 17 wherein the physiologically-active compound is a polypeptide.

19. The method of claim 5 including admixing with the coacervate composition a glyceride selected from the group consisting of a monoglyceride, a diglyceride, a triglyceride, and mixtures thereof; said physiologically-active compound being dissolved or dispersed in the glyceride; said aqueous coacervate-based matrix particles encapsulated in a coacervate-based film encapsulating the glyceride and the physiologically-active compound within the coacervate-based matrix particles, said coacervate-based matrix particles comprising water selected form the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, the glyceride, and the physiologically-active compound dissolved or dispersed within the matrix particles.

20. The method of claim 19 wherein the glyceride is a triglyceride having 8 to 18 carbon atoms per each substituted acid chain.

21. A method of introducing a physiologically-active compound into the circulatory system of a mammal comprising having the mammal orally ingest a composition comprising an aqueous coacervate system including water and a surface active agent, said coacervate system including an aqueous emulsion of coacervate-based matrix particles containing the compound solubilized therein; said aqueous coacervate-based matrix comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, and said physiologically-active compound solubilized therein.

22. The method of claim 21 wherein the surface active agent comprises a protein, polymerized protein, phospholipid, polymerized phospholipid, or mixtures thereof.

23. The method of claim 22 wherein the polymerized protein is polymerized albumin.

24. The method of claim 22 wherein the polymerized phospholipid is a polymer of a compound selected from the group consisting of lecithin, cephalin, isolecithin, sphingomyelin, phosphatidyl serine, phosphatidic acid, phosphatidyl inositol, phosphatidyl choline, and mixtures thereof.

25. The method of claim 24 wherein the polymerized phospholipid is polymerized lecithin.

26. The method of claim 21 further including the step of drying the coacervate to form a powder capable of being reconstituted by the addition of a physiologically-acceptable fluid.

27. A method of introduction a drug into the circulatory system of a mammal comprising having the mammal orally ingest a composition comprising an aqueous emulsion of coacervate-based matrix particles containing water, a surface active agent, and a drug solubilized therein; said coacervate system including a coacervate-based matrix containing the drug in aqueous solution; and a coacervate-based film encapsulating the matrix particles, said aqueous coacervate-based matrix particles comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof and the drug.

28. The method of claim 27 wherein the drug comprises insulin.

29. The method of claim 27 wherein the drug comprises an atrial peptide.

30. A method of introducing a drug into the circulatory system of a mammal comprising injecting the body of the mammal with a composition comprising an aqueous coacervate composition including water, a surface active agent, and a drug; said coacervate composition including a coacervate-based matrix containing the drug in aqueous solution or aqueous suspension and a film encapsulating the matrix particles; said aqueous matrix particles containing water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, and the drug solubilized or dispersed therein.

31. The method of claim 30 wherein the drug comprises an atrial peptide.

32. A method of preparing a composition containing one or more physiologically-active compounds for oral, tissue absorptive, inhalation, or parenteral administration to a mammal comprising mixing an aqueous solution of water, a surface active agent, a coacervating agent and a physiologically-active compound to form a two phase aqueous coacervate composition containing the physiologically-active compound in one or both of the two-phase bound as particles in a coacervate matrix and within a coacervate-based aqueous film containing the surface active agent, said coacervate-based matrix comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof and the physiologically-active compound in solution within the matrix water; separating the particles; and adding a hydrocolloid to the particles in an amount of 2-20% w/v to form a gel-like surface film surrounding the matrix particles containing the physiologically-active compound.

33. The method of claim 32 further including emulsifying and microemulsifying the composition to form coacervate particles useful for oral administration.

34. The method of claim 32 further including emulsifying and microemulsifying the composition to form coacervate particles useful for oral administration having a particle size less than about 10 microns.

35. The method of claim 32 wherein the coacervate particles are microemulsified to less than about 2 microns.

36. The method of claim 32 wherein the coacervate particles are microemulsified to less than about 1 micron.

37. The method of claim 32 wherein the surface active agent is a polymerized phospholipid.

38. The method of claim 32 further including adding an anti-oxidant to the separated particles.

39. A method of introducing a drug into the circulatory system of a mammal comprising having the mammal orally ingest a composition comprising an aqueous coacervate system including water, a surface active agent, and a drug; said coacervate system including a coacervate-based matrix containing the drug and a film encapsulating the matrix particles; said aqueous coacervate-based matrix comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, and the drug in solution within the matrix water; separating the particles; and adding a hydrocolloid to the particles in an amount of 2-20% w/v to form a gel-like surface film surrounding the matrix particles containing the drug.

40. The method of claim 39 wherein the surface active agent comprises a protein, polymerized protein, phospholipid, polymerized phospholipid, or mixtures thereof.

41. The method of claim 39 wherein the drug comprises insulin.

42. The method of claim 39 wherein the drug comprises an atrial peptide.

43. A method of preparing a composition useful as a system to introduce and transport medically useful composition in the body of mammals;

said composition comprising an aqueous emulsion of particles of a coacervate-based matrix having one or more physiologically-active compounds incorporated therein; said coacervate-based matrix comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, said matrix particles including the physiologically-active compound solubilized in the matrix water;

said method comprising forming a mixture of one or more surface active agents, water and one or more physiologically-active compounds to produce a two phase aqueous coacervate composition containing said compounds, and emulsifying the composition under conditions to produce an aqueous emulsion of the coacervate-based matrix particles containing the physiologically-active compound.

44. A method of administering a physiologically-active compound to a mammal comprising topically applying a coacervate composition containing a physiologically-active compound on the skin of a mammal; said coacervate composition comprising an aqueous emulsion of coacervate-based matrix particles, said matrix particles comprising water, selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, said matrix particles including the physiologically-active compound solubilized in the matrix water; and

applying sound waves to the topically applied coacervate composition to drive the coacervate composition into the skin.

45. A method of maintaining tissue or an organ of a mammal viable, outside of the mammal's body comprising forming a mixture of one or more surface active agents and water to form a two phase aqueous coacervate composition, and emulsifying the composition to form an aqueous emulsion of coacervate-based matrix particles comprising water selected from the group consisting of coacervate phase water, equilibrium phase water, and mixtures thereof, said matrix particles having solubilized within the matrix water, a compound capable of extending the life of the organ when in contact therewith, and contacting the tissue or organ, outside of the mammal's body, with said aqueous emulsion to maintain the visibility of the tissue or organ until said tissue organ is attached to a mammal.

Description Submit all comments and votes

FIELD OF THE INVENTION

The present invention relates to a stable drug delivery composition in oral dosage form or capable of new and unexpected stabilization, solubilization and delivery of stable drug components in parenteral form at the pH of body tissue. More particularly, the present invention is directed to a drug delivery system or composition that allows for rapid dissolution and smooth liberation of any desired drug either orally or parenterally without precipitation, and the method of preparing the drug composition. In accordance with one embodiment of the present invention, liposomes and their contents can be enveloped in a coacervate-based film to prevent disintegration of liposome vehicles.

BACKGROUND OF THE INVENTION

Drugs now in common use often require formulation compromises in order to prepare the marketed product. Thus, many parenteral compositions must be prepared using the salt of the parent compound and an excessive pH.

The instability of many useful drugs and other useful medical compositions poses other formulation problems. At present, emulsions, microemulsions and liposomes constitute the principal approaches to these problems. While such dosage forms are an advance over older forms, they are often associated with erratic bioavailability and instability of their own.

The herein disclosed invention comprises a method to prepare compositions and compositions which deliver medically useful compositions effectively. The method is based upon the use of a non-toxic aqueous coacervate; said method produces stable microemulsions comprised of particles in which one or more pharmaceutical components have been incorporated. Through the process of this invention particles are enveloped by a coacervate-based film. The compositions of this invention may be administered orally, parenterally or by tissue absorption, as required.

The disclosed method enables the preparation of particles of any desired size and any degree of particle surface film hardness, any number of coacervate-derived films of any desired thickness, or any combination of particle sizes and surface hardnesses. In preferred compositions prepared by the disclosed invention, the particle size is about 1 micron or less. The pharmaceutical component(s) may be any water soluble or water insoluble medically useful composition or combinations of such compositions.

The inventor has previously disclosed compositions based on a coacervate system using albumin and lecithin as principal components of the system. However, by polymerizing one or both of these components, the inventor has not only simplified the method but unexpectedly produced a preparation with vastly improved encapsulating capability. Details of this improvement are presented in the Experiments Section.

DESCRIPTION OF THE PRIOR ART

While there are apparent similarities to the inventor's prior art, this application differs significantly in several important aspects. Thus, encapsulation is a fundamental aspect of the inventor's prior art and the present invention. However, by polymerizing one or more of the surfactants used in the present invention, and/or by modifying the previously disclosed processes, the proportion of the pharmaceutical component incorporated in the present formulation is approximately two to six times greater than that of formulations disclosed earlier.

The intravenous delivery of many pharmaceutical preparations has been limited to the use of aqueous singular systems, as discussed, based upon the salt of a parent compound and/or the dissolution of the compound by agents such as a propylene glycol or alcohol. Other known systems which function primarily as blood substitutes, however, are able to solubilize and deliver drugs infused therein to a restricted degree. U.S. Pat. No. 4,343,797 discloses a method of preparing a synthetic blood substitute based upon a two-phase heterogeneous physico-chemical system which provides for oxygen transport and other physiological functions inherent to whole natural blood. In U.S. Pat. No. 4,439,424 a preferred synthetic blood composition comprises albumin, water, sodium chloride, urea and lecithin in the form of a two-phase coacervate system which is rendered isotonic with human blood by the addition of controlled amounts of the sodium chloride. U.S. Pat. Nos. 4,558,032, 4,539,204 and 4,596,778 relate to gelatin based synthetic blood substitutes based upon a two-phase coacervate system utilizing respectively, gelatin and acacia; two gelatins; modified fluid gelatins of different isoelectric points; and gelatin or modified gelatin and lecithin. U.S. Pat. No. 4,547,490 discloses a further coacervate synthetic blood derived from an aqueous solution containing albumin, sodium chloride and lecithin in a nonpolar or semipolar solvent.

These known products have been found to be capable of carrying drugs, but have been designed to serve as a resuscitative fluid much in the manner of whole natural blood. One of the principal formulation problems successfully addressed by the aforementioned patents is maintenance of the structure and integrity of the microparticles (synthocytes) which comprise the composition.

The hemoglobin component of this composition (i.e., stroma-free hemoglobin, pyridoxilated-polymerized hemoglobin, liposome encapsulated hemoglobin and the like) remains functional and encapsulated within the microparticles (synthocytes) until the particles are metabolized and eliminated from the body. Encapsulation of the hemoglobin component not only preserves functionality but reduces or eliminates endotoxic reactions associated with non-encapsulated hemoglobin. The term "synthocyte" as used in this specification refers to the microparticles of this invention, the particles being about 1 micron or less in any single dimension when administered parenterally, and comprised of a coacervate-based matrix which contains the active component(s); and a coacervate-based film which envelopes the contents of the microparticle and constitutes the outer surface of the particle. The enveloping film may be comprised of one or more layers as required to prepare the desired composition. In this specification the terms "particle", "synthocyte" and "microparticle" will be used interchangeably.

Another example of a coacervate-based system is disclosed in International application No. PCT/US85/00859, published Nov. 21, 1985, relating to an oral dosage composition and method of preparation to enable the oral administration of insulin. The problems addressed by the disclosed coacervate system, however, include the need for protection of the insulin against degradation by enzymes, and factors such as the acid-base balance and other gastrointestinal conditions and processes. The coacervate-based film envelopes each individual insulin molecule to inhibit the interaction between the insulin component and the degrading conditions.

The prior art describing the liposome technology includes the following: The Ash and Hider U.S. Pat. No. 4,448,765 filed July 3, 1979 entitled LIPOSOMES AND THEIR USE IN TREATING HUMAN OR OTHER MAMMALIAN PATIENTS, describes microvesicles which are reportedly stabilized by the incorporation of a polymer having at least six atoms attached to the backbone thereof; said vesicles incorporating a physioplogically-active substance. Kelly U.S. Pat. No. 4,356,167 entitled LIPOSOME DRUG DELIVERY SYSTEMS, filed June 22, 1981, describes a liposome medicament delivery system wherein the medicament is in an aliphatic liquid-sterol-water lamellae. The lipid may be a sodium or potassium salt of a C.sub.4 to C.sub.18 fatty acid and the sterol may be cholesterol. Kao, Y. and Loo, T., Pharmacological Disposition of Negatively Charged Phospholipid Vesicles in Rats, J. of Pharm. Sci. 59;11, 1980, pp. 1338-1343 contains a report of experiments which investigated the pharmacological disposition of four negatively charged phospholipid vesicles. Gregoriadis, G., the Carrier Potential of Liposomes in Biology and Medicine; N.E. J. of Med. Vol. 295, No. 13, 1976, describes the use of liposomes to carry a large variety of biologically interesting compositions including hormones, drugs, steroids, vitamins, viruses and other compositions such as histamine. Doucet, D., et al; Oxygen Binding of Artificial Erythrocytes, in Proceedings of Int. Soc. of Artif. Organs, 5, (Supp) 1981, pp. 392-395, describes the use of liposomes to incorporate a concentrated hemoglobin solution. Gaber, B., et al; Encapsulation of Hemoglobin in Phospholipid Vesicles, FEBS Letters, Vol. 153, 2, 1983, pp. 285-287, describes a method to encapsulate hemoglobin in phospholipid vesicles. Gruner, S., Novel Multilayered Lipid Vesicles: Comparison of Physical Characteristics of Multilamellar Liposomes and Stable Plurilamellar Vesicles, Biochemistry, 24, 1985, 2833-2842, discusses the effects of osmotic compression on the production of various liposome compositions; Szebeni, J. et al.; Encapsulation of Hemoglobin in Phospholipid Liposome; Characterization and Stability; Biochemistry; 24, 1985, 2827-2832, reports the encapsulation of hemoglobin in liposomes of different lipid composition. Blood Policy and Technology; Office of Technology Assessment, U.S. Congress, U.S. Government Printing Office, 1985, pp. 146-151, reports the methods of formulation and the difficulties encountered in using liposome based blood substitutes.

It is important to emphasize that liposomes differ from the coacervate preparations previously discussed and herein disclosed in mode of manufacture, and in physical and structural properties.

Coacervates are used in the preparation of the compositions of this invention. The inventor's pending U.S. patent applications based on coacervate compositions include the following: Ser. No. 591,774 filed Mar. 21, 1984 now abandoned.

The Ecanow et al application Serial No. 811,675, filed Dec. 20, 1985, now U.S. Pat. No. 4,738,952 describes a synthetic whole blood wherein the coacervate system is produced from lecithin dispersed in an aqueous solution containing albumin and sodium chloride; said system enabling a more effective use of the incorporated pyridoxilated-polymerized hemoglobin.

The Ecanow application Serial No. 835,550, filed Mar. 3, 1986, now U.S. Pat. No. 4,849,405, describes an oral dosage form of insulin based on the use of a coacervate system comprised of lecithin, albumin, and insulin.

The Ecanow application Serial No. 711,066, filed Mar. 12, 1985, now abandoned, describes an oral dosage form of atrial peptides based on a coacervate comprised of lecithin, albumin, and atrial peptides.

The Ecanow application Serial No. 896,844, filed Aug. 14, 1986, and now abandoned describes a drug delivery system based upon an albumin-lecithin coacervate system using a solvent.

The Ecanow application Serial No. 001,814, filed Jan. 8, 1987, now U.S. Pat. No. 4,794,000 describes an oral drug delivery system based on a dextran-polyethylene glycol coacervate.

The Ecanow application Serial No. 006,620, filed Jan. 14, 1987, describes a composition useful for immunoassay procedures based upon an albumin-lecithin coacervate system.

There are fundamental differences between this invention and the inventor's prior art. In some instances, e.g., the blood substitute formulations, are based on precisely opposite theoretical and functional characteristics. Thus, the blood substitute formulations are based squarely on a gas exchange system. In this instance, oxygen is absorbed by the hemoglobin component of the synthocyte and released from the hemoglobin to the tissues according to oxygen tensions. This phenomena is represented in whole blood and some blood substitutes by a sigmoid curve. In contrast, in this invention, the drug is released from encapsulation; the release can be represented by a straight line function or by an exponential rate of release.

Further, the inventor's blood substitutes are specifically formulated to maintain the hemoglobin component in an encapsulated state up to the time the synthocyte and its contents are metabolized. In the present invention, the formulations are designed to release the drug from the synthocyte promptly after administration. The present invention provides for a variety of routes of administration; the inventor's blood substitutes are restricted to intravenous injection.

SUMMARY OF THE INVENTION

The method of this invention enables the preparation of carrier vehicles useful for the delivery of medically useful compositions for man and animals. The finished products of this invention range from a red blood cell substitute (resuscitation fluid) to aqueous based formulations of water insoluble, water soluble and water sensitive drugs.

The fact that in the method of this invention, aqueous formulations successfully incorporate and deliver water insoluble and water sensitive drugs is evidence that this invention constitutes a significant advance in the state of the art.

The aqueous based compositions of this invention comprise one or more of a large variety of surface active agents, that is, molecules which are non toxic and endogenous or exogenous to the body and can include one or more polymerized or polymerizable surface active agents, particularly a polymerized form of a protein such as albumin and/or a polymerized form of a phospholipid such as lecithin and may include one or more surface active agents either in polymeric or monomeric form, including lecithin, albumin, gelatin, modified liquid gelatin, acacia gel and combinations thereof. Finished products of this invention may be administered by oral, parenteral, transdermal, transmucosal or inhalation routes, or by combinations of these routes.

Formulations prepared according to the method of this invention are stable, pharmacologically-active and will not precipitate in body tissue or fluid. Parenteral drugs now prepared to an excessive pH can be reformulated using the method of this invention. The resulting product will have improved bioavailability and absorption; said reformulation will reduce or eliminate pain and tissue damage associated with injection of drugs with an excessive pH. The physiologically-active compounds, such as a drug, may be in a concentrated form, or may be dissolved or suspended in a carrier, e.g., a liquid carrier, such as an oil, glyceride, lipid, coacervate phase(s) or within a film carrier such as a liposome. In one embodiment, a liposome is encapsulated in a coacervate-based matrix or coacervate phase and/or coacervate-based film to prevent the liposome from unravelling prematurely.

Either prompt or sustained release characteristics or mixtures thereof, can be manufactured by the method of the present invention. The method of the present invention using a polymerized or polymerizable surface active agent constitutes an improvement in incorporating ability ranging from two to six times greater than that of the inventor's previously disclosed methods.

The delivery systems of this invention encompass emulsions, microemulsions, encapsulated liposomes, suspensions, gels and microsuspensions. The size of the coacervate-based encapsulated particles which comprise the finished products of this invention extend from the nanogram range to about one micron when administered parenterally. Larger size particles may be made by the disclosed method if required. Filtering procedures may be used to insure appropriate particle size. This invention envisages compositions in which particles 1 micron or less are mixed with particles 2 microns or more.

In this invention, the pharmacologically-active component is bound to or embedded in the coacervate matrix comprising the pharmacologically-active compounds held in a coacervate matrix of the equilibrium water phase and/or the coacervate phase forming a particle; and the particle, including the pharmacologically-active component and equilibrium water and/or coacervate phase (forming the coacervate matrix) is then encapsulated by a coacervate-based film. The coacervate-based film can contain one or more pharmacologically-active component(s), and layered films can contain no, or different, pharmacologically-active components. The film can be prepared to any degree of structure (hardness) ranging from soft (semi-gel like) to rigid. The method provides for a mixture of particle sizes if desired, and for any degree of surface film hardness, any number of surface films with or without an active compound, or combinations thereof.

OBJECTS OF THE PRESENT INVENTION

Accordingly, an object of the present invention is to provide a composition and a method of making the composition wherein one or more physiologically-active compounds are encapsulated by an aqueous coacervate-based film containing at least one polymerized surface active compound to provide unexpected stability to the composition.

Another object of the present invention is to provide a composition and a method of making the composition wherein one or more physiologically-active compounds is dissolved or dispersed in a liquid carrier and the carrier and compound are encased in an aqueous coacervate-based matrix containing at least one polymerized surface active compound, the composition including an aqueous colloid-rich phase or an aqueous colloid-poor phase or a combination of both phases from a two-phase coacervate system.

Another object of the present invention is to provide a composition and a method of making the composition wherein one or more physiologically-active compounds is dissolved or dispersed in a liquid carrier, such as a glyceride, and the carrier and compound are encased in an aqueous coacervate-based matrix containing at least one polymerized surface active compound including an aqueous colloid-rich phase or an aqueous colloid-poor phase or a combination of both phases from a two-phase coacervate system, thereby preventing the compound from diffusing out of the composition prematurely, and to prevent degradation of the compound by body fluids.

Another object of the present invention is to provide a method of administering a physiologically-active compound to a mammal wherein the composition includes one or more physiologically-active compounds in concentrated form or in a solid or liquid carrier, held in an aqueous coacervate-based matrix containing at least one polymerized surface active compound, surrounded or encapsulated with a film containing an aqueous colloid-rich coacervate phase.

Still another object of the present invention is to provide a composition and a method of making the composition wherein previously encapsulated physiologically-active compounds, such as compounds encapsulated in a liposome, are further stabilized by encapsulation in an aqueous coacervate-based matrix containing at least one polymerized surface active compound to prevent the compound from leaking by preventing the liposome from unravelling prematurely.

A further object of the present invention is to provide a composition and a method of making the composition wherein one or more physiologically-active compounds are encapsulated in an aqueous coacervate-based matrix containing at least one polymerized surface active compound, the matrix including a colloid-rich or a colloid-poor phase, or a combination of a colloid-rich and a colloid-poor phase to stabilize the physiologically-active compound and prevent the compound from prematurely leaking out of the matrix and to prevent compound-degenerative materials, such as enzymes, or digestive fluids, from reaching and degenerating the compound.

Another object of the present invention is to provide a composition and method of making the composition wherein one or more physiologically-active compounds are encapsulated by an aqueous coacervate-based matrix containing a polymer of lecithin to substantially and unexpectedly increase the yield or amount of physiologically-active compound capable of being carried in the composition.

Another object of the present invention is to provide a coacervate matrix enveloping one or more physiologically-active compounds wherein the coacervate matrix includes a plurality of surface active compounds one of which is polymerized albumin or polymerized lecithin.

The above and other objects and advantages of the present invention will become apparent from the following detailed de