JPH0253096B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a process for the preparation of gel compositions based on inert fluorocarbons or low viscosity silicone oils with gas transport capabilities. The gel produced by this method has medical uses.

[Conventional technology]

Many inert organic liquids are known that have gas carrying capacity, ie, high solubility for gases, such as gas mixtures including oxygen and air. Among the many types of inert organic liquids with such properties are water immiscible liquid fluorocarbons and low viscosity silicone oils. These types of liquids are
No. 3,850,753, issued to Chibata et al. on November 26, 1974, for culturing aerobic microorganisms. However, this patent does not mention emulsions or gel formation with emulsions.

Other perfluorocarbons and their emulsions and their properties are described in the following US patents: 4220606, REMoore, September 2, 1980; 4143079,
Arm E. Moore, March 6, 1979;
4105798, R.E. Moore et al., August 8, 1978; 4041086, Moore et al., August 9, 1977;
3911138, L. C. Clerk. Giunia (L.
C. Clark Jr.), October 7, 1975; 3962439, K.
K.Yokoyama et al., June 8, 1976
Day; 3993581, Kay. Yokoyama et al., November 23, 1976
Day; 4187252, R. J.A. Lagou (RJ
Lagow) et al., February 5, 1980; 4110474, R. J.A. Ragow et al., August 29, 1978; and
3641167, Moore et al., February 8, 1973. 1981 1
Debit, June 25, 1979, superseded by Application No. 228642, filed June 26, 1979. C. No. 52041, filed by David C.Whith, describes the application of liquid fluorocarbon to the burn directly or supported on a sponge, or in the form of a foam, spray, or gel. Treatment methods have been clarified. White's application does not disclose specific gel compositions or methods of making gel compositions.

The information contained in the above patents is incorporated herein by reference.

Techniques are known for separating various particulate materials from the aqueous medium in which they are formed or processed. For example, U.S. Pat. No. 2,107,839 describes the isolation of a dry powder therapeutic agent derived from the natural latex of the Lactuca plant, which was prepared by leaving the emulsion to separate and then The process involves filtration or centrifugation to separate the aqueous solution containing the active ingredient.

Additionally, various gels are known which are made from aqueous suspensions by sedimentation, decantation, filtration (including membrane filtration) and centrifugation. The product is commonly isolated as a dry material and appears to revert to a semi-solid, somewhat plastic or swollen state upon contact with water and is therefore termed a "gel".
It is called. They exhibit high porosity and are used for various purposes depending on their origin, porosity, and degree of swelling. Among these liquids are the gelatin-carboxymethylcellulose complex of U.S. Pat. No. 2,824,092; the soy protein hydrogel of U.S. Pat. No. 3,218,307;
A gelatinous mass obtained by fermenting natural polysaccharides and then centrifuging them as in US Pat. No. 3,096,293; hydroxy of galactomannans produced as stable dry hydrocolloids by filtration and centrifugation as in US Pat. No. 3,326,890. Lower alkyl ethers; dried agarose gels of U.S. Pat. No. 3,527,712 and U.S. Pat. Nos. 3,346,507 and
There is silica gel made as per No. 3560400.

However, none of these patents teach or suggest the concentration of emulsions associated with the formation of gelatinous materials, nor do they teach or suggest the production of gelatinous materials containing an inert, water-immiscible organic liquid gas carrier. There is nothing to teach or suggest.

[Means to solve problems]

According to the invention, a water-immiscible inert fluorocarbon or low viscosity silicone oil with gas-carrying capacity is combined with water and a suitable emulsifier;
It has been found that gel compositions can be prepared by emulsifying the combined materials, concentrating the emulsion to form a gel phase and a liquid phase, and separating the liquid from the gel. The resulting gel is a stable composition that can be used, for example, as an ointment, salve, etc., for the treatment of skin irritations and wounds, or any condition requiring gases such as enzymes. Gel-type gas transport agents have the advantage of having a much greater gas transport capacity per unit volume than emulsions. This is a result of the present invention.
This is because a large proportion of non-gas transporting material, namely water, has been removed.

The term gel, as used herein, refers to an apparently homogeneous semi-solid material that is elastic and jelly-like (as in gelatin) or more or less firm. Contrary to the teachings of the patents discussed above, the "gels" of the present invention do not revert to a dry, granular, porous form and do not exhibit any appreciable degree of swelling upon contact with water. Accordingly, "gel" is used herein in its general sense rather than in its gelatinous or jelly-like nature.

As used herein, "perfluorocarbon" refers to a substantially fluorinated or fully fluorinated material that is generally, but not necessarily, a liquid at room temperature and atmospheric pressure, and that is free of oxygen and carbon dioxide. It has the ability to transport gases such as gas.

As used herein, "substantially fluorinated" means that most of the hydrogen atoms of the compound have been replaced with fluorine atoms to the extent that further substitution does not substantially increase the gas carrying capacity of the material. means. It is believed that this level is reached when at least about 80-90% of the hydrogen atoms are replaced with fluorine atoms. In the above-mentioned US Pat. No. 3,911,138 and US Pat. No. 4,105,798, oxygen carrying capacity is related to the solubility of gases such as oxygen in the material. twenty five
These patents suggest that perfluorinated materials absorb between 10 and 100 c.c. of oxygen per 100 c.c. of material at 760 mm of mercury. However, at least the hydrogen atom
Preferably 95% is substituted, more preferably at least 98% and most preferably 100%.

Fluorocarbons suitable for use in the present invention are materials broadly described as cyclic perfluorohydrocarbons, or derivatives thereof. Examples are chemically inert _C9 - _C18 polycyclic compounds,
For example, bicyclononanes (e.g. bicyclo[3.3.1]nonane, 2,6-dimethyl-bicyclo[3.3.1]nohanane or 3-methylbicyclo[3.3.1]nonane), adamantane, methyl and dimethyladamantane, ethyl and diethyladamantane , tetrahydrodicyclobentadiene, methyl and dimethylbicyclooctanes, ethylmethyladamantane, ethyldimethyladamantane, tetrahydrobinol-S, methyldiadamantane, triethyladamantane, trimethyldiadamantane, pinane, camphuan, 1,4,6,
It is a fluorinated product of 9-dimethanodecalin, bicyclo[4.3.2]undecane, bicyclo[5.3.0]decane, etc., or any mixture thereof. Other examples of perfluorocarbons are perfluorotributylamine, perfluoro-2-butyltetrahydrofuran, perfluoro-2-butylfuran, perfluoro-n-heptane, perfluoronaphthalene, perfluoro-1-methylnaphthalene, perfluoro-n-methylmorpholine, and perfluoro-n-methylnaphthalene. -1-methyldecalin and 1,2,2,2- of perfluoro(2,5,8-trimethyl-3,6,9-trioxa-1-dodecanol)
Includes perfluoroethers such as tetrafluoromethyl ether.

Some of the fluorine atoms in the above materials may be replaced with other halogen atoms such as bromine. These compounds include, for example, 1-bromopentadecafluoro-
Monobrominated compounds such as 4-isopropylcyclohexane, 1-bromotridecafluorohexane, 1-bromopentadecafluorooctane and 1-bromopentadecafluoro-3-isopropylcyclopentane or their dibrominated derivatives be.

Perfluorinated C ₈ or lower materials and materials up to and above C ₁₈ include partially brominated analogs thereof, and also include mixtures of a variety of different perfluorinated compounds. Can be used in the present invention.

The above fluorinated compounds, which are solid at room temperature, can be dissolved in a suitable solvent, such as another perfluorocarbon, which is liquid at room temperature, and the resulting mixture can be used to form the emulsions and gels of the present invention. I can do it. When describing fluorocarbons, liquid herein means:
It refers to a fluorocarbon that is liquid by itself at room temperature, or a solution of a solid fluorocarbon in a fluorocarbon solvent.

Silicone oils useful in the present invention, such as those described in U.S. Pat. No. 3,850,753, have a range of
It should have a viscosity of 15 centiboaz. Examples of such silicone oils include Dow Corning,
There is "DC-200-ICD" manufactured by Corporation. This has a molecular weight of 310, a specific gravity of 0.85, and an oxygen solubility of
100 ml per 100 ml of liquid at 25°C. Another silicone fluid available from Dow Corning Corporation and having utility in the present invention is generally described as "DC-200" fluid. Chemically, silicone oils are polydimethylsiloxanes, also known as liquid methylsilicones. Similar silicone fluids are available from General Electric Company.

In the first step of gel production, an inert gas-carrying liquid is emulsified in water in the presence of an emulsifier. The emulsifier is selected to produce effective emulsification and gel stability when mixed with water and the fluorocarbon or low viscosity silicone oil. The emulsifier should be compatible with the fluorocarbon or low viscosity silicone oil and should have no adverse effects when the gel is applied to, for example, human skin.

Nonionic emulsifiers are preferred because they are effective in both hard and soft water and are not PH dependent, but ionic emulsifiers, whether anionic, cationic, or amphoteric, can also be used.

Suitable nonionic emulsifiers include hebutylphenoxypolyethoxyethanol, octylphenoxypolyethoxyethanol, methyloctylphenoxypolyethoxyethanol, nonylphenoxypolyethoxyethanol, dodecylphenoxypolyethoxyethanol, etc. Alkylphenoxypolyethoxyethanols having an alkyl group of about 7 to 18 carbon atoms and 1 to 60 or more oxyethylene units; polyethoxyethanol derivatives of methylene-bonded alkylphenols; 1 to
Sulfur, such as those made by condensing 60 moles or more of ethylene oxide with nonyl, dodecyl, tetradecyl, t-dodecyl and similar mercaptans, or with alkylthiophenols having an alkyl group of 6 to 15 carbon atoms. Containing agent;
Ethylene oxide derivatives of long chain carboxylic acids such as lauric acid, myristic acid, balmitic acid, oleic acid, etc., or mixtures of acids such as those found in tall oil containing 1 to 60 oxyethylene units per molecule; octyl, Similar ethylene oxide condensates of long chain alcohols such as decyl, lauryl or cetyl alcohol; etherified or esterified with hydrophobic hydrocarbon chains such as sorbitan monostearate containing 1 to 60 oxyethylene units Ethylene oxide derivatives of polyhydroxy compounds; dodecylamine, hexadecylamine, containing 1 to 60 oxyethylene groups;
and ethylene oxide condensates of long-chain or branched-chain amines such as octadecylamine; and blocks of ethylene oxide and propylene oxide, consisting of a hydrophobic propylene oxide moiety combined with one or more hydrophilic ethylene oxide moieties. Including copolymers.

Examples of useful anionic emulsifiers include common soaps such as alkali metal, ammonium and alkanolamine salts of fatty acids, including sodium oleate, potassium palmitate, ammonium stearate, ethanolamine laurate, etc. and rosin and dehydrated rosin acid soaps, sodium lauryl sulfate, sodium cetyl sulfate, sodium salt of sulfonated paraffin oil, sodium salt of dodecane-1-sulfonic acid,
Synthetic saponifying materials, including higher aliphatic sulfates and sulfonates, such as sodium salts of octadecane-1-sulfonic acid; sodium alkylaryl sulfonates, such as sodium isopropylbenzenesulfonate, sodium isopropylnaphthalene sulfonate, etc. alkaryl sulfonates; and sodium dioctyl sulfosuccinate, sodium N-octadecyl-sulfonesuccinamide, sulfonated or sulfated alkylphenoxyethoxyethanols with 1 to 50 oxyethylene units per molecule (where the alkyl group is hexyl, n-octyl, t-octyl,
Alkali metal salts of sulfonated dicarboxylic acid esters and amides, such as those having 4 to 18 carbon atoms such as lauryl, hexadecyl and octadecyl.

Cationic emulsifiers include stearamidopropyl dimethyl-beta hydroxyethylammonium dihydrodiene phosphate, stearamidopropyl dimethyl-beta hydroxyethylammonium nitrate, stearaguanamine, stearaguanamine ethylene oxide reaction product, octadecylamine of octadecylcarbamate. Includes octadecylguanamine salts of octadecylcarbamic acid reacted with salts and ethylene oxide, octadecylamine tetraethylene glycol, rosinamine ethylene oxide reaction products, and the like. Also, undecylimidazoline and reaction products of ethylene oxide and propylene oxide; oleylaminodiethylamine hydrochloride; condensation products of fatty acids and decomposed proteins; monostearylethylenediamine trimethylammonium sulfate; alkylbenzene imidazolines, cetylpyridinium bromide, octadecyl Pyridinium sulfate or chloride, octadecylmethylene pyridinium acetate; lauryl urea ethylene oxide; methyl sulfate of dimethyl octadecyl sulfonium; condensates of halohydrins and amines, polyamines and ammonia; alkylphosphonium compounds, alkylphosphonium ethylene oxide condensates, ethylene oxide and Rosin amines condensed with propylene oxide; cetyldimethylbenzylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, n-alkyldimethylbenzylammonium chloride, methyldodecylbenzyltrimethylammonium chloride, methyldodecylxylene bis(trimethylammonium chloride) ), cetyltrimethylammonium bromide, and the like.

Amphoteric emulsifiers include sodium salt of N-cocobeta aminopropionate, N-cocobeta aminopropionic acid, disodium N-lauryl beta-iminodipropionate, diethanolamine salt of coconut derivative dicarboxylate, sodium palmitic acid derivative dicarboxylate. salts, C-cetylbetaine, and N-laurylbetaine.

All types of fluorine-containing surfactants are useful, whether ionic or nonionic. Examples of the anionic type include ammonium perfluoroalkyl sulfonates, potassium perfluoroalkyl sulfonates, potassium fluorinated alkyl carboxylates, and ammonium perfluoroalkyl carboxylates. Examples of non-ionic types are fluorinated alkyl esters. These and other fluorine-containing surfactants are available from Surfactant FC, sold by 3M Company.
-93, FC-95, FC-128, FC-143, FC-430,
and commercially available products such as FC-431.

Naturally occurring emulsifiers or their derivatives are also useful. These include alginates, cellulose derivatives such as methylcellulose and carboxymethylcellulose, water-soluble gums such as acacia and tragacanth, phospholipids (such as lecithin), and sterols.

Preferred emulsifiers are the nonionic emulsifiers Bruronik F-68 and Pluronik F-108, and York phospholipids. Brulonik emulsifiers are polyoxyethylenes and polyoxypropylenes available from Wyndt BASF.
Typically an emulsifier (non-ionic or ionic)
is used in amounts up to about 10% by weight of the total emulsion composition, or up to about 5% by weight based on the water used to form the emulsion. Higher amounts can be used if desired. Emulsifiers can be used alone or in combination, provided that they are ionically compatible.

The amounts and proportions of inert, organic, gas-carrying liquid, water, and emulsifier used to form emulsions and gels can vary widely. Generally, the amounts of each ingredient will form an emulsion and can be readily determined by one skilled in the art without undue experimentation. However, preferred concentrations of inert fluorocarbon or low viscosity silicone oil range from about 1% to about 70%, more preferably from about 10 to about 50% by weight, based on the total composition.

Another aspect of the invention is that the gel can be treated to contain more enzyme than it would be untreated. One such technique is to contact the inert fluorocarbon or low viscosity silicone oil with additional oxygen before combining it with the other materials. For example, an inert fluorocarbon or low viscosity silicone oil prior to emulsification may be placed in a 100% enzyme environment at a pressure equal to or greater than 760 mm Hg. Alternatively, it can be done by placing the resulting gel in a 100% enzyme environment at a pressure equal to or greater than 760 mm Hg.

The mixture of inert fluorocarbon or low viscosity silicone oil, water and emulsifier may be prepared by any conventional agitation means, such as manual agitation, aeration, propeller agitation, turbine agitation, colloidal mixing, homogenization, radio frequency or ultrasonic oscillation (sonication). )
emulsified by etc. In most cases emulsification is effective at room temperature. However, with some of the above stirring means, excessive heat is generated during emulsion and/or gel formation and is removed by known means such as cooling jackets. The amount of mechanical energy input from the various stirring means varies substantially depending on, for example, the amount of material being processed and the equipment used.

In the second step of gel preparation of the present invention, a gel phase and a liquid phase are formed from the emulsion. For this purpose, e.g.
High-speed centrifugation (ultracentrifugation) at 10,000 to 20,000 rpm is effective. The choice of speed depends on the proportion of fluorocarbon or low viscosity silicone oil in the emulsion (the less inert fluorocarbon or low viscosity silicone oil, the higher the speed). The result is a clear supernatant liquid and a pasty solid (gel phase) that settles to the bottom of the container.

In a third step, the gel and liquid phases are separated by sedimentation, evaporation, decanting, or filtration, such as pressure filtration or vacuum filtration. Separation can be partial or complete depending on what subsequent processing is required. For example, other auxiliaries such as antibacterial agents, drugs, moisturizers, fragrances, etc.
If it is desired to mix colorants or other additives known to cosmetic chemists with the gel at this point, it may be preferable to leave some liquid in contact with the gel. On the other hand, when considering immediate packaging or use,
Complete separation of the liquids may be desirable.

The above description of the second and third stages is a sequential enrichment and separation process. These steps can be carried out simultaneously by microfiltration (also called ultrafiltration). However, microfiltration is only effective for emulsions with relatively coarse particle sizes, on the order of greater than 1 micron. This is because most commercially available microfiltration membranes have apparent pore sizes from 1 micron to about 0.002 microns. For this reason, if the emulsion particles are minute, they will not pass through the microfiltration membrane and be separated. Since many of the emulsions of the present invention have particle sizes ranging from about 0.1 to about 10 microns, microfiltration simultaneously concentrates the emulsion to form a gel and separates the gel from the resulting supernatant liquid phase. This is a practical method. Suitable microfiltration membranes are described, for example, in U.S. Pat.
No. 3,615,024 and No. 3,856,569 available from Millibore Company and Amicon Corporation.

Generally, coarse emulsion particle size is desirable when simultaneous gel formation and gel separation from the aqueous phase is desired. Such emulsions are formed when utilizing the ingredients in the following proportions:

Inert fluorocarbon or low viscosity silicone oil
10-50% by volume Surfactant 2-25% by weight Water 25-90% by weight Depending on the nature of the inert fluorocarbon or low viscosity silicone oil and surfactant, the above proportions may vary outside these ranges. .

Pressure or vacuum filtration or decanting can be used in conjunction with microfiltration if desired. Pressure filtration is preferable to vacuum filtration because foaming tends to occur during vacuum filtration.

If desired, antimicrobial materials such as antibacterial agents and/or antibiotics can be incorporated into the gels of the present invention. Antibacterial agents combat aerobic bacteria that can grow in the presence of gels because gels contain large amounts of oxygen. Examples of suitable antibacterial agents are quinoline carboxylic acid,
Includes nitrofurans and sulfonamides. Suitable agents are those that do not or are not affected by the gel. Examples of suitable antibiotic agents are aminogliosides, ansamacrolides, chloramphenicol and its analogues, lincosaminides, macrolides, nucleoxyls, oligosaccharides, peptides, phenazines, polyenes, polysaccharides, etc. Includes ethers, tetracyclines, and others.
The above drugs are listed in the Encyclopedia of Chemical Technology.
Chemical Technology), Vol. 2, pp. 752-1036 and Vol. 3, pp. 7-78 (both third editions). The agent may be added to the gel at any stage of the gel preparation, for example by addition to the liquid component prior to emulsification (e.g. by dissolution in water), by dispersion into the emulsion during or after emulsification, or into the gel after separation. Depending on the formulation, it can be incorporated into the gel.

The resulting gel can be used as an ointment applied to the skin of higher mammals, including humans, in the treatment of wounds, bruises, or irritations. The gel can also be incorporated into a dressing and applied to the skin in the dressing. As used herein, "dressing" means any suitable material for contacting and holding the gel in such contact (including at a wound), such as gauze, bandage, surgical wrapping, etc. Includes materials. The following examples illustrate some aspects of the invention and are not intended to limit its scope, except as described in the appended claims.

Example 1 4 g (2 c.c.) of F-tributylamine (perfluorotributylamine) and Bruronik F68
18 cc of water containing 5% by weight of an emulsifier (ethylene oxide-propylene oxide copolymer with an average molecular weight of 8380) was placed in the tester. The perfluorocarbon was evenly dispersed in the water by sonication. The tube containing the milky emulsion was centrifuged at 10000 rpm for 10 minutes. The result was a clear supernatant liquid and a pasty solid (gel) at the bottom. When the clear liquid was poured from the test tube, a gel remained. The gel was transferred from the test tube to another container with a spatula. The gel had the appearance of petroleum jelly and weighed 5 g.

5 c.c. of ethanol was added to the gel. Four grams of F-tributylamine, the amount originally used to form the emulsion, separated from the water-ethanol phase as a clear liquid phase, indicating that the gel had 80% by weight fluorocarbons.

Repeat the above steps except using ethanol,
The separated gel was kept in a clean wide mouth jar.
After 75 days, there were no visible changes in the physical appearance of the gel, such as separation of perfluorocarbons from water, indicating that the gel was stable.

Example 2 1.35 g of Bruronik F-68 surfactant was added to water.
Added to 25.65g. To this aqueous mixture was added 3 c.c. (6 g) of F-tributylamine. Sonication of the resulting composition resulted in a milky white emulsion with a relatively coarse particle size (average particle size of approximately 1-10 microns). Millipore (trademark) with apparent pore diameter of 0.45 microns
Pass the emulsion through the microporous membrane at a nitrogen pressure of approximately 25 psig (1.756 psig).
Kg/cm ² ). A gel formed and remained on the filter. The gel could be easily transferred to a storage container.

Example 3 The same preparative technique as Example 2 was repeated in all essential respects, except that F-trimethylbicyclononane was used in place of F-tributylamine.
Gels of essentially equivalent appearance were obtained.

Example 4 23.5 cc of water and 5 cc of water were prepared substantially as described in Example 1.
An emulsion was made by forming a liquid containing % by weight Brulonik F-68 emulsifier, adding General Electric silicone oil SF96-50 (2.5 cc), and sonicating to a milky white emulsion. Silicone oil has a viscosity of 50 cSt, a specific gravity of 0.963, a flash point of 460〓 (237.8℃), and a pour point of -67゜F (-55.0℃).
have. The emulsion was then centrifuged at 14,000 rpm for 20 minutes, and a white pasty gel was separated. The separated fluid was decanted from the gel.

Claims (1)

[Scope of Claims] 1 (a) An inert, water-immiscible fluorocarbon or low-viscosity silicone oil having gas-carrying capacity, water, and an emulsifier in a proportion effective to form an emulsion under stirring conditions. (b) forming a gel phase and a liquid phase from the emulsion; and (c) separating all or part of the liquid phase from the gel phase. Method of manufacturing the composition. 2. The manufacturing method according to claim 1, wherein the step of forming a gel phase and a liquid phase and the step of separating are performed sequentially. 3. The manufacturing method according to claim 2, wherein the step of forming the gel phase and the liquid phase is performed by centrifugation. 4. The manufacturing method according to claim 1, wherein the step of forming a gel phase and a liquid phase and the step of separating are performed simultaneously. 5. The formation step and separation step of the gel phase and the liquid phase are
The manufacturing method according to claim 4, which is carried out by passing the emulsion through a microfilter. 6. The manufacturing method according to claim 1, wherein an antibacterial agent is mixed into the gel during or after gel formation. 7. The method of claim 1, wherein the gas is oxygen and oxygen is introduced into the fluorocarbon or low viscosity silicone oil during or before any stage of gel preparation. 8. The method according to claim 1, wherein the gas is oxygen and the oxygen is introduced into the gel after separation of the liquid phase.