METHOD OF PREPARING CONTROLLED-RELEASE PREPARATIONS FOR BIOLOGICALLY ACTIVE MATERIALS AND RESULTING COMPOSITIONS

Abstract: A method for preparing a controlled-release composition for biologically active materials, the composition consisting of amphiphilic substances capable of forming liquid crystalline phases, especially cubic phases, in aqueous medium. The bioactive material is either dissolved or dispersed in the liquid crystalline phase, or alternatively, coated by the liquid crystalline phase. The invention is advantageous from thermodynamical and mechanical points of view, and a rich variety of applications exists.

Description: METHOD OF PREPARING CONTROLLED-RELEASE PREPARATIONS FOR BIOLOGI¬ CALLY ACTIVE MATERIALS AND RESULTING COMPOSITIONS BACKGROUND OF THE INVENTION Amphiphilic substances, i.e. substances with both hydrophilic and hydrophobic (lipophilic) groups, spontaneously tend to self- associate in aqueous systems forming various types of aggregates. A typical example is shown in Figure 1 in "Cubic Mesomorphic Pha¬ ses" (R.R. Balmbra, J.S. Clunie and J.F. Goodman, Nature, 222, 1159 (1969)), in which an increasing amount of amphiphile in water gives rise to icellar, cubic, hexagonal and lamellar phases. The struc¬ tures of these phases are well-known, except for the cubic phases, since there are a number of cubic phases, some of which remain to be determined in detail. Several important features of the above mentioned phases are listed below: a ) Al l phases are thermodynamical ly stabl e and have therefore no tendency to phase separate with time (unl ess chemical decompo¬ si tion occurs) , and they wi l l al so form spontaneously. b) Al l phases are characterized by having distinct hydrophi l ic and hydrophobic domains , which give them the possibil i ty to dissolve (solubil ize) or disperse both water-sol ubl e and water-insol ubl e compounds . c) In general the rheology of- the phases varies from low vi scous Newtonian (di lute or moderately concentrated micel lar phases) over viscous l iquids to vi sco-elastic rigid systems (cubic pha¬ ses . d) The long-range order in the hexagonal, lamellar and cubic phases, as seen * in * t~ Λ a a in X-ray low angle diffraction, in combina ¬ tion with liquid-like properties on a molecular level, have given rise to the notation "liquid crystalline phases". The anisotropic phases, i.e. mainly the hexagonal and the lamellar phases, are birefringent and are therefore easily identified in the pola¬ rizing microscope. e) If oil, in a broad sense, is added to an amphi hile-water sys¬ tem, and the oil/water ratio is high (»1), then aggregates of the reversed type may form, i.e. reversed micellar and rever¬ sed hexagonal, or alternatively, cubic structures can be obtai¬ ned. These structures will also give rise to thermodynamical ly stable phases. f) The occurrence of the above described phases is not restricted to specific amphiphiles, but they are encountered in almost every amphi phi le-oil -water system. One or two phases may be ab¬ sent, and the location of the phases vary in the phase diagram, but it is not unjustified to state that the similarities are more pronounced than the differences. Several of the characteristics listed above make some of the phases formed in systems with amphiphilic substances interesting candidates for being used as matrices or barriers in control! ed-re- lease preparations. Perhaps the most important feature is the possi¬ bility to dissolve both water-soluble and water-insoluble compounds in the phases due to their amphiphilic character. Moreover, the highly ordered structures with distinct hydrophilic and hydrophobic domains put v restrictions on the diffusion of added compounds, a fact which may be advantageously used for control! ed-rel ease purpo¬ ses. Especially the cubic liquid crystalline phases offer many pos¬ sibilities in this context due to their rheological properties, which make them useful both as tablets and pastes. OMPI The cubic liquid crystalline phase may crudely be characteri¬ zed as being either of the water-discontinuous or oil-discontinuous droplet type, or of the bi -continuous type. The droplet structures may thus be either of a "water-soluble" or of a "water-insoluble" type. B -continuous structures of cubic phase have been determined by V. Luzatti et al . (Nature, 2__, 701 (1967)) and K. Larsson et al . (Chem. Phys. Li ids, 27, 321 (1980)). All the different forms of cu¬ bic phases can be used in control led-rel ease preparations which the following discussion will explain. The cubic liquid crystalline phase can also be described as erodible or non-erodible depending on its behaviour in excess water. Furthermore, the rate of erosion depends on, besides temperature and agitation, the appearance of the phase diagram for the actual amphiphile. This dependence is extremely strong and the rate of erosion may vary by several orders of magnitude. The following three examples will illustrate the erodible and non-erodible types of cu¬ bic phases at a temperature of 37 °C. In Figure 11 in "Phase Behaviour of Polyoxyethylene Surfactants with Water" (D.J. Mitchell, G.J.T. Tiddy, L. Waring, T. Bostock and M.P. McDonald, J. Chem. Soc. Faraday Trans. 1, _79, 975 (1983)) two cubic phases are found, one at low and the other at high amphi¬ phile concentration. The cubic phase at low concentration is built up by closed-packed micelles and this phase will erode fast in water giving a micellar solution. For the cubic phase at high concentra¬ tion of amphiphile, however, the rate of erosion is much slower since it, in excess water, first is converted to a hexagonal phase, then to the other type of cubic phase which finally forms a micellar phase. \ For the second case, Figure 2 in "Optically Positive, Isotro- pic and Negative Lamellar Liquid Crystalline Solutions" (J.Rogers and P.A. Winsor, Nature, 2__, 477 (1967)), the situation is in part similar to the cubic phase at high amphiphile concentration in the first example, except that now the cubic phase is converted to a lamellar phase, which then turns into a micellar solution. In this system the micelles are thermodynamically rather unstable as demonstrated by a low solubility of surfactant in aqueous solution. This will have the effect of decreasing the rate of erosion. The third example, Figure 7 (monoolein-water) in "Food Emu! si - fiers and Their Associations with Water" (N. Krog and J.B. Laurid- sen, in "Food Emulsions" (ed. S. Friberg), Marcel Dekker Inc. (1976)), shows a cubic phase which will, when in water, be in equilibrium with a monomer solution of amphiphile in water {.Q ~ ~ M) . This cubic phase will stay unchanged in excess water (at " least for extremely long times). The choice of an erodible or a non-erodible cubic phase in a control! ed-rel ease preparation depends on the required rate pro¬ file, the solubility of the compound, which rate one wants to con¬ trol etc. For example, if the active substance is an almost water- insoluble drug, an eroding cubic phase may act as a source for mo¬ lecular! y dissolved drug. Of course, the use of erodible cubic pha- ses is πot limited to water- insoluble compounds, but may also be used if a relatively fast release profile is desired, or if an ini¬ tial protection of a pharmaceutical compound ( which may be subject to chemical degradation in contact with the high acidity of the gas¬ tric juice) is required. Non-eroding cubic phases, stable in water, may be used for app¬ lications where longer release times are desirable. Both water- soluble and water-insoluble compounds can be used in this kind of cubic phase. The release rate of a bioactive substance from a non- erodible cut-vic phase may either be determined by the outer surface of the cubic phase towards the surrounding aqueous medium or the interfaces between hydrophilic and hydrophobic domain within the cubic phase, depending on whether the cubic phase is mono- or bi- continuous and the nature (hydrophilic, hydrophobic or amphiphilic) r of the bioactive compound. OMP Fine adjustments of the release rate in any kind of cub i c phase can be made by the addition of salt, glycerol , ethylene glycol , propylene glycol or any similar amphiphile of low molecular weight. Other techniques of employing amphiphilic molecules to encap¬ sulate biologically active materials for control! ed-rel ease purpo¬ ses are described in US Patents No 4,016,100; 4,145,410; 4,235,871 and 4,241,046. In these applications aggregates of other structures are involved and, furthermore, they have al! in common that the amphiphile-water preparations of these methods are thermodynamical - ly unstable (dispersions, emulsions and vesicles) and consist of at least two phases. The present invention is therefore fundamental¬ ly different from these, since the control! ed-rel ease matrices or barriers prepared by our technique will be thermodynamical ly stable one phase compositions. Because of the regular structure, with exact crystal! ographic lattices, the present invention provides a highly reproducible control! ed-rel ease system contrary to solutions in¬ volving polymers. SUMMARY OF THE INVENTION Our invention relates to a method for preparing a control led- release composition for biologically active materials, the composi¬ tion consisting of chemical substances capable of forming a cubic liquid crystalline phase, or any other type of liquid crystalline phase, and the bioactive material, the method which comprises: forming a mixture of one or more amphiphilic substances in amounts necessary to form a cubic liquid crystalline phase when placed in contact with at least one liquid selected from the group including water, glycerol, ethylene glycol and propylene glycol, adding the biologically active material to said mixture. The invention also comprises the intermediate phases formed, the product cubic phases, their use and carrier compositions including OMPI the cubic phases as the active ingredient thereof. The terms "biologically active material" and "bioactive material" as used throughout the specification and claims mean a compound or composition which, when present in an effective amount, reacts with and/or affects living cells and organisms. The term "liquid crystalline phase" as used herein denotes an intermediate state between solid crystals and isotropic liquids, cha- racterized by long-range order and short-range properties close to those of a simple liquid or solution (H. Keller and R. Hatz, in "Handbook of Liquid Crystals", Verlag Chemie, Weinheim(1980)). The terms "cubic liquid crystalline phase" and "cubic phase" as used herein mean a thermodynamical ly stable, viscous and optically isotropic phase made of at least amphiphilic substance(s) and water. The cubic phase can be unambiguously identified from the X-ray diffraction pattern. The term "any other liquid crystalline phase" as used in the claims mean thermodynamically stable optically anisotropic phases like lamellar, hexagonal and reversed hexagonal liquid crystalline phases made of at least amphiphilic substance(s) and water. The method of the invention is useful to make liquid crystalline phases, especially cubic phases, which in turn are usefully employed in a rich variety of processes. For example, the liquid crystalline phases may be used to enhance the bioavai lability of medications, oral drug delivery, rectal drug delivery, transderma! drug delivery and drug delivery through inhalation. The cubic liquid crystalline phases produced by the method of the invention may also be employed to encapsulate pesticides, feromones, compounds for sustained slow- release to effect the growth of plants and the Tike. The precursor of the cubic phase, in the form of a liquid or a OMPI solid, as described in claim 2 may also be utilized. When used in the liquid precursor form, a dispersion of the phase can be prepared, which can be utilized as a spray suitable for inhalation. DESCRIPTION OF THE EMBODIMENTS The determination of cubic phases The present invention involves the dissolution or dispersion of a bioactive material in a cubic liquid crystal composed of water and amphiphilic compound(s) or the preparation of a cubic phase in which the bioactive material occurs as an integral part. In the lat¬ ter case, the cubic phase may form only in the presence of the bio¬ active material. When the bioactive material is to be used only in small amounts, its dissolution in a known cubic phase is a more ty¬ pical procedure. In many cases, one can in the preparation of con- trolled-release compositions according to the present invention make use of existing knowledge on phase behaviour of amphiphilic systems. To have a basis for several applications we have studied in some de- tail samples composed of monoolein, egg yolk lecithin, water and glycerol. By choosing a suitable composition in this system, it has been found feasible to include in the cubic phase appropriate amounts of a large number of bioactive materials and also to control the re¬ lease rate. However, it- is also useful in a number of contexts to apply cubic phases in other systems. If, in such a case, the phase dia¬ gram is not available or, in the case mentioned above, where the existence of a cubic phase may be dependent on the bioactive material used, then s-ome phase studies are a prerequisite to the application of the invention. In particular, the approximate region of existen¬ ce of the cubic phase (concentrations and temperature) and the pha¬ ses existing at higher (and depending on mode of employment occasio¬ nally also lower) water contents must be determined. Such studies involve visual observations but in particular observations in a po- OMPI " * larizing microscope and other techniques. Low angle X-ray diffraction work- s needed for the differentiation between different types of cu¬ bic phases. During the work on this invention it was found particu¬ larly useful to apply nucelar magnetic resonance (NMR) spectrosco- py to rapidly scan the phase behaviour of a novel system. Especially H NMR, working with deuter ted water, could very effectively distin¬ guish between single- and different multiphase regions and also cha¬ racterize the degree of anisotropy of a liquid crystalline phase and thus give structural information. Diffusion rates The rates of release of bioactive materials according to the present invention can as described above be determined either by an erosion process or a molecular diffusion process or a combination of both. In the case a molecular diffusion process is rate-limiting, useful information on the factors determining the release rate can be obtained in self-diffusion studies. Such self-diffusion measure¬ ments are very useful in predicitng how and which factors should be modified to obtain a required release rate. Self-diffusion studies in connection with the present invention have been made both using the classical pulsed field-gradient nuclear magnetic resonance spin- echo method (E.O. Stejskal and J.E. Tanner, J. Chem. Phys., ^ , 288 (1965)) and the novel Fourier transform pulsed-gradient spin-echo technique (P. Stubs, J. Colloid Interface Sci., 8_7, 385 (1982)). To illustrate the types of effects encountered some of these results may be mentioned. For a cubic phase of the oil-in-water droplet type in a cationic surfactant-water system consisting of ca. 50% cationic surfactant and ca. 50% water, the self-diffusion of hydrophilic com- ponent is ca\.70 times more rapid than the self-diffusion of hydro¬ phobic component. For another cubic phase, of the network bi-conti- nuous type, in the same system and consisting of ca. 80% cationic surfactant and ca. 20% water, the self-diffusion of hydrophilic com¬ ponent is ca. eight times as fast as that of hydrophobic component. For a number of cubic phases built up of anionic surfactant, diffe- rent hydrocarbons or derivatives thereof and water, self-diffusion coefficients of the order of 10 "12 m 2 s~ can be achieved and control led. The monoolein-egg yolk lecithin-water system The examples below describe the control! ed-rel ease properties of the system monoolein-egg yolk !eci thin-water using a water-sol u- ble dye (methylene blue) as a model for the bioactive material, re¬ ference being made to the accompanying drawings, in which: Figure 1 shows the phase diagram of the ternary system monoolein- egg yolk lecithin-water at about 40 C, Figure 2 shows the amount of dye released versus square root of time for the system monoolein-water (including dye) at 37 °C, Figure 3 shows the amount of dye released versus square root of time for the system monoolein-egg yolk lecithin-water (including dye) at 37 °C and Figure 4 shows the amount of dye released versus square root of time for the system monoolein-glycerol -water (including dye) at 37 °C. An, in many respects, excellent example of an amphiphilic sys¬ tem which shows the advantages of the present invention is the three- component system monoolein-egg yolk lecithin-water. Its phase dia¬ gram is not completely known, but the cubic phase is wel! established, as seen in Figure 1. One advantage with this system is the fact that all components occur as natural parts in both animals and plants, which among other things make them attractive for pharmaceutical use. Furthermore, the system offers many possibilities for controlled- release preparations with various properties. For example, by vary¬ ing the relative amounts of onoolein and egg yolk lecithin, cubic phases of the non-erodible (low lecithin content) or erodible (high lecithin content) type may be formed. The system also allows glyce¬ rol, ethylene glycol or propylene glycol to be incorporated to app¬ reciable amounts without destroying the cubic structure. Glycerol is preferred for toxicological reasons and it acts as a highly effec- tive release rate modulator. When water is replaced by glycerol the cubic phase is stil! formed, with only a minor increase in swel¬ ling. Example 1: A cubic liquid crystalline phase is formed by mixing 0.6 g of monoolein (Nu-chek-prep Inc., USA) and 0.4 g of a 2.8 mM aqueous solution of methylene blue. The re¬ lease of the dye in 100 ml water was studied at 37 C by monitoring the increasing absorbance at 664 nm. The resulting release curve is shown in Figure 2, which gi- ves the amount of dye released versus square root of time. As seen in the figure the curve is linear between about 20 in to 24 h, which is to be expected for a re¬ lease preparation of the matrix type ("Sustained and Con¬ trolled Release Drug Delivery Systems", Marcel Dekker Inc. (1978)). As an alternative to the monoolein mentioned above, an industrially distilled product was used. Example 2: Figure 3 shows the release profile for one cubic phase where egg yolk lecithin was incorporated. The composition of the cubic phase was (monoolein/egg yolk lecithin/dye- solution) (48.0/12.0/40.0) (w/w). The figure clearly re¬ veals that the release profile may be altered by the addi¬ tion of egg yolk lecithin. Example 3:^igure 4 shows corresponding release curves for cubic phase where some water were replaced by glycerol. The compositions of the two cubic phases are (monoolein/ glycerol/dye-solution) (w/w): A=(60.0/4.0/36.0) B=(60.0/10.0/30.0) It is evident from Figure 4 that even a small amount of glycerol has a large effect on the release rate of methy- lene blue. The following three examples describe how to make cubic liquid crystalline phases with pharmaceutical compounds, either dissolved or dispersed: Example 4: 0.6 g of monoolein was mixed with 0.4 g of a 7.5 % (w/w) aqueous solution of terbutaline sulphate (other names are Bricanyl and Fϋair ; used for the treatment of asthma) in an ampoule, which was sealed. After 24 h at 40 °C a glass-clear cubic liquid crystalline phase was obtained. It is also possible to replace up to 15 % (w/w) of the water by glycerol, and still obtain the cubic phase. Example 5: 0.6 g of monoolein was mixed with 0.4 g water and 0.5 g of oestrio! (other names are Ovesterin , Triodurin and Triovex ; used for the treatment of vaginal desease). The ampoule was sealed and after about 24 h at 40 C a glass-clear cubic liquid crystalline phase was obtained. Example 6: 0.6 g of monoolein was mixed with 0.4 g of water and 0.2 g of 2-amino-l-phenylpropano! hydrochloride (other names Lunerin and Rinomar ; used for treatment of desea- ses in the nose). The mixture was placed at 40 C for about 24 h, and the saturated cubic phase obtained (with respect to 2-amino-1-phenylpropano! hydrochloride) was ^heated to 100 °C for about ten minutes, and then shaked extensively during cooling, in order to disperse the rest of the drug in the cubic phase. Transderma! application of cubic phases The following example describes a method to make a mixture of monoolein and egg yolk lecithin on a molecular level, and how to use c this mixture together with nitroglycerin and water to make a cubic phase suitable for transderma! control! ed-rel ease. Example 7: A mixture of 90 g monoolein and 30 g egg yolk lecithin is dissolved in 800 g of ethanol , 95% (v/v). The solvent is ^ Q evaporated in order to get a molecular mixture of the li- pids. 6% (w/w) nitroglycerin is solved in a glycerol - water 1:1 (w/w) mixture and 80 g of this solution is added to the 120 g lipid mixture obtained above. Equilibrium has been reached when a glass-clear gel -like phase has been ■ ζ obtained. This phase is suitable for transderma! control - 1 ed-rel ease of nitroglycerin from a depot-plaster in the range of 0.1 - 5 mg nitroglycerin absorbed per hour. Coating with cubic phases for protection 0 The example below describes how the cubic liquid crystalline phase precursor may be used to protect a patient against bad taste and to protect the drug against degradation in the stomach. The drug is benzylpenicillin. 5 Example 8: Benzylpenicillin is pressed into tablets of 0.3 g accor¬ ding to conventional techniques. The tablets are coated with monoolein in an ethanol solution using a fluidized bed, and then covered with a thin film of sugar. Such a 0 Goating will also give a total protection against taste disturbance due to the penicillin in the mouth, and a control!ed-release function so that the benzylpenicill in is protected against acidic degradation in the stomach, whereas it is exposed for absorbtion in the small intes- 5 tine due to the solubilization of the coat by bile acids ΪΩ OMPI from the bile. Reversed hexagonal liquid crystalline phase preparation Galactoyl-diglycerides can be isolated from plants or prepared synthetically, and monogalactoyl-diglycerides form reversed hexago¬ nal phases with any amount of water above 5% (w/w). The example be¬ low describes a method to prepare reversed hexagonal liquid crystal¬ line phase from galactoyl-diglycerides. Example 9: Saturate water with acetylsalicyl ic acid and add 20 g of this solution to 80 g of monogalactoyl-diglyceride isola¬ ted from wheat ϋpids by column chromatography. The wheat lipids are easily obtained by ethanol extraction of wheat flour or wheat gluten. After a few days equilibrium has been reached as seen by the homogeneous appearance in the polarizing microscope. Spray inhalator in the form of a precursor of a cubic phase The final example describes a method to make a precursor of the cubic phase in liquid form, which is suitable for spray inhalation of insul in. Example 10: A saturated solution of insulin in water is prepared. 10% (w/w) of this solution is added to 90% (w/w) of li¬ quid monoliπolein. The resulting liquid is atomized to an aerosol by conventional spray technique for inhala¬ tion. The above described system provides a possibility for absorption of native insulin for diabetes. Insulin keeps its native conformation both in the liquid phase used to give the aerosol as well as in the cubic phase-formed at contact between droplets and water in the mu- cous layer where absorption takes place.

Claims: CLAIMS 1. A method for preparing a control!ed-release composition for bio¬ logically active materials, the composition consisting of chemi¬ cal substances capable of forming a cubic liquid crystalline phase, or any other type of liquid crystalline phase, and the bioactive material, the method which comprises: forming a mixture of one or more amphiphilic substances in amounts necessary to form a cubic liquid crystalline phase when placed in contact with at least one liquid selected from the group including water, glycerol, ethylene glycol and pro¬ pylene glycol, adding the biologically active material to said mixture. 2. The method of claim 1 wherein the biologically active material is either dissolved or dispersed in said mixture, or alternati¬ vely, the bioactive material being coated by said mixture. 3. The method of claim 1 wherein said mixture comprises at least one liquid selected from the group including water, glycerol, ethy¬ lene glycol and propylene glycol, and wherein the biologically active material is added either before or after the formation of the cubic liquid crystalline phase, the bioactive material being either dissolved or dispersed, depending on its solubility in the cubic phase, or alternatively, coated by the cubic " liqάid'crys ' tal- line phase. 4. The method of claim 1 wherein the amphiphilic substances are li- pids, preferably selected from the group consisting of monoglyce- rides, phospholipids and galactolipids. 5. The method of claim 4 wherein the monoglyceride is selected from the group consisting of monoolein and monoϋnolein. 6. The method of claim 4 wherein the phospholipid is selected from the group consisting of phosphatidylcho! ines, preferably egg yolk. 7. The method of claim 1 wherein the weight ratio of phosphol ipids to monoglycerides ranges from 0/1 to about 3/1. 8. The method of claim 3 wherein the water content of the preproduced cubic liquid crystalline phase ranges from about 5% (w/w) to about 50% (w/w). 9. The method of claim 3 wherein the glycerol content in the cubic liquid crystalline phase ranges from 0% to about 50% (w/w). 10. The method of claim 1 wherein the amphiphilic substance is a non- ionic surfactant. 11. The method of claim 10 wherein the polar part of the non-ionic surfactant is built up of polyoxyethylene groups and the non- polar part is alkyl or alkylaryl. 12. The method of claim 11 wherein the non-ionic alkylpolyoxyethylene surfactant is selected from the group consisting of triethylene- glycol hexadecy! ether and dodecaethylene glycol hexadecyl ether. 13. The method of claim 1 wherein the amphiphilic susbstance is an anionic surfactant. 14. The method of claim 13 wherein the anionic surfactant is selected from the group consisting of alkali alkylsulfates, alkali alky!- carboxyϊates, alkali alkylarylsulfonates, alkali alkylsulfonates, alkali dialkylsulfosuccinates, alkaline earth dialkylsulfosucci- nates, conjugated bile saltsand non-conjugated bile salts. 15. The method of claim 14 wherein the alkali dialkylsulfosuccinate is sodium diethylhexylsulfosuccinate, the alakaline earth dial- kylsulfosuccinate is selected from the group consisting of cal ¬ cium diethylhexylsulfosuccinate and magnesium diethylhexylsulfo- succinate and non-conjugated bile salt is sodium cholate. 16. The method of claim 1 wherein the amphiphilic substance is a cationic surfactant. 17. The method of claim 16 wherein the cationic surfactant is selec¬ ted from the group consisting of alkylammonium halides, alkyl- pyridinium ha! ides and alkyl trimethylammonium halides. 18. The method fo claim 17 wherein the alkyltrimethylammonium halide is dodecyltrimethylammonium chloride. 19. The method of claim 1 wherein the amphiphilic substance is a zwitterionic surfactant. 20. The method of claim 19 wherein the zwitterionic surfactant is an alkylbetaine. 21. The method of claim 1 wherein the amphiphilic substances are a mixture of the ionic and non-ionic types. 22. The method of claim 1 wherein the liquid crystalline phase is selected from the group consisting of hexagonal liquid crystal¬ line phase, lamellar liquid crystalline phase and reversed hexa¬ gonal liquid crystalline phase. 23. The method of claim 22 wherein the reversed hexagonal liquid cry¬ stalline phase is formed by galactoyl-diglycerides. 24. The method of claim 2 wherein the precursor of the cubic phase is a fluid reversed micellar phase consisting of monolinolsπn and water, the water content ranging from 0% to about 10% (w/w). iURJE4 OMPI 25. The method of claim 24 wherein the liquid precursor of the cubic phase is utilized as a spray suitable for inhalation. 26. The method of claim 1 wherein the biologically active material is a pharmaceutical compound. 27. The control! ed-rel ease composition prepared- by the method of claim 26. 23. The method of claim 26 wherein the pharmaceutical compound is selected from the group consisting of antibiotics, proteins, steroids, vitamins and nucleic acids. 29. The method of claim 28 wherein the antibiotic is penicillin. 30. The method of claim 28 wherein the protein is insulin. 31. The method of claim 28 wherein the steroid is selected from the group consisting of oestriol and prostaglandin. 32. The method of claim 27 wherein the control! ed-rel ease composi¬ tion is suitable for oral, rectal or transdermal administartion, or suitable for inhalation. 33. The method of claim 1 wherein the biologically active material is a compound for agricultural use such as pesticides, fertili¬ zers and trace elements. 34. The control! ed-rel ease composition prepared by the method of claim 33. 35. The method of claim 1 wherein the biologically active material is a feromone. 36. The controlled release composition prepared by the method of claim 35.

Inventors: ENGSTROEM SVEN, LARSSON KAORE, LINDMAN BJOERN, ENGSTROEM, SVEN, LARSSON, KAORE, LINDMAN, BJOERN
Applicants: FLUIDCARBON INTERNATIONAL AB
Application year: 1983
Main classification: A61K9
IPC codes: A61K9