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WO1993001806A1 - Carbones perfluoriques encapsules - Google Patents

Carbones perfluoriques encapsules Download PDF

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Publication number
WO1993001806A1
WO1993001806A1 PCT/US1992/006132 US9206132W WO9301806A1 WO 1993001806 A1 WO1993001806 A1 WO 1993001806A1 US 9206132 W US9206132 W US 9206132W WO 9301806 A1 WO9301806 A1 WO 9301806A1
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WO
WIPO (PCT)
Prior art keywords
microcapsule
acid
amine
perfluorocarbons
lewis
Prior art date
Application number
PCT/US1992/006132
Other languages
English (en)
Inventor
Tully J. Speaker
Original Assignee
Temple University Of The Commonwealth System Of Higher Education
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/734,461 external-priority patent/US5284663A/en
Application filed by Temple University Of The Commonwealth System Of Higher Education filed Critical Temple University Of The Commonwealth System Of Higher Education
Priority to US08/190,011 priority Critical patent/US5490986A/en
Priority to PCT/US1992/006132 priority patent/WO1993001806A1/fr
Publication of WO1993001806A1 publication Critical patent/WO1993001806A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • This invention relates to a microcapsule composition for the delivery of an oxygen and carbon dioxide carrying compound through the vascular system.
  • the microencapsulated composition is useful as an artificial blood substitute.
  • microcapsulant material A specific type of microcapsulant material and a method of making such material is disclosed in U.S. Patent No. 3,959,457 (of common assignment and partial common inventorship herewith) .
  • This material is comprised of the reaction product produced at the interface boundary of a finely dispersed emulsion, comprising a water immiscible solution of a Lewis base and an aqueous solution of a partially hydrophilic, partially lipophilic Lewis acid.
  • polyoxethylene-polyoxypropylene or block copolymers thereof comprise a core-forming adjuvant and/or ethylene oxide adducts of ethylenediamine (“tetronomers”) comprise a wall-forming adjuvant for use in systems of the '457 patent type.
  • titanium ethylene oxide adducts of ethylenediamine
  • Perfluorocarbons are known to be useful as blood substitutes but only in the form of dispersions or emulsions.
  • One such known prior art emulsion of perfluorocarbons is marketed under the trade name Fluosol DA. It is understood that this and similar dispersed emulsions exhibit low stability and must be stored at -40°C.
  • Microspheres containing cross-linked hemoglobin and encapsulated hemoglobin have also been prepared for use as a blood substitute. (See U.S. patents 3,875,510 - Kitajima et al., 4,133,874 - Miller et al. and 4,376,059 - Davis et al. )
  • Encapsulated fluorocarbons have previously been disclosed as tracers for use in the petroleum and petrochemical fields, but the known encapsulants (see U.S. Patents 4,520,109 - Sim onds et al. and 3,964,294 - Shair et al.) are quite different from those used in the present invention.
  • a solvent of intermediate polarity such as chloroform
  • a core material of low polarity such as light liquid petrolatum
  • solvents such as chloroform or the even less polar material light liquid petrolatum.
  • This invention comprises a microencapsulated perfluorocarbons composition.
  • the invention makes use of a Lewis acid - Lewis base salt microparticulate material similar to that of U. S. Patent No. 3,959,457, with a polyoxyalkylene adduct of an amine (POAAM) , (for example, a polyoxyalkylene adduct of a mono-, di- or poly-amine) as the Lewis base reactant or through use of a polyoxyalkylene derivative of a polymeric acid (PODPA) , for example, a polyoxyalkylene partial ester of a polymeric acid, as the Lewis acid reactant.
  • POAAM polyoxyalkylene adduct of an amine
  • PODPA polyoxyalkylene derivative of a polymeric acid
  • said Lewis base is a polyoxyalkylene adduct of an amine
  • said Lewis acid is a polyacid
  • said Lewis acid is a polyoxyalkylene derivative of a polymeric acid
  • said Lewis base is a simple amine
  • the Lewis base polyoxyalkylene adduct of an amine is a tetrapolyoxyethylene adduct of ethylenediamine, also known as a tetronomer.
  • the Lewis acid polyoxyalkylene derivative of a polymeric acid is the polyethylene glycol ester of polyacrylic acid in which nominally 30 percent of the carboxyl groups of polyacrylic acid are esterified with the glycol.
  • a perfluorocarbons (examples of which include perfluorotetralin, perfluorobutylamine and perfluorobutyl ether) is disposed in the core of the microcapsule.
  • the pendant polyethers of the POAAM or of the PODPA provide a layer of moderate polarity interposed between the ionic microcapsule wall and the encapsulated perfluorocarbon of low polarity, thus protecting the ionic wall from destabilization by the perfluorocarbons.
  • the microcapsules are of about the same size as or somewhat smaller than red blood cells (i.e. about 3 microns in diameter) so that they can circulate in the vascular system as supplements or replacements for red blood cells, either in a blood substitute or in natural blood. For such purposes, they would ordinarily be combined, in a sterile suspension, with suitable additives, such as physiologic electrolytes and macromolecules contributing to the ionic and osmotic balance required of a blood substitute.
  • the microcapsules of the invention can be associated with a compound or compounds capable of conferring stoichiometric equilibrium to the microcapsule when the microcapsule is administered to an animal.
  • the compound is a protein, and more preferably, the compound is albumin. Association of the microcapsule with such a compound may render it more compatible with the blood of the animal into which it is introduced, thereby reducing or eliminating potential adverse side-effects to the animal. This may be especially important when large volumes of suspended microcapsules are administered to the animal.
  • Lewis acid - Lewis base salt film microcapsules of the type to which this invention is directed, are made as follows:
  • a solution of a suitable Lewis base in a perfluorocarbons is dispersed in an aqueous solution of a Lewis acid to produce a momentary, finely divided emulsion of perfluorocarbon droplets in a continuous aqueous phase.
  • the perfluorocarbons may be, for example, perfluoroalkanes or perfluoroalkenes such as perfluorohexane, perfluoromethyleyclohexane, perfluorodimethylcyclohexane, perfluorotetralin, perfluoromethyltetralin, perfluoromethyldecalin, or perfluoro-5-decene, perfluoroamines such as perfluorotributylamine, perfluoroethers such as perfluorobutyl ether, or halogen substituted perfluorocarbons such as perfluorooctyl bromide.
  • perfluoroalkanes or perfluoroalkenes such as perfluorohexane, perfluoromethyleyclohexane, perfluorodimethylcyclohexane, perfluorotetralin, perfluoromethyltetralin, perfluoromethyldecalin, or perfluor
  • the Lewis base reactant is selected from a simple amine capable of reacting with a polyoxyalkylene derivative of a polymeric acid and a polyoxyalkylene adduct of a mono-, di-, or poly-amine (POAAM).
  • the POAAM has the following generic structure:
  • R 2 -CH2-0-R ! or CH 2 -N-(R ! ) 2
  • the Lewis acid reactant is selected from a polyacid capable of reacting with a polyoxyalkylene adduct of an amine and a polyoxyalkylene derivative of a polymeric acid (PODPA) .
  • the PODPA has the following generic structure:
  • R - (CH- -O-) - ( H-CH-O) f H
  • the general class of POAAM as the Lewis base and the general class of PODPA as the Lewis acid are not well adapted for concurrent use. However, there may be specific compounds having the PODPA and POAAM structures which are capable of producing the microcapsule of the claimed invention.
  • the Lewis base reactant is a POAAM
  • the Lewis acid is a polymeric acid capable of reacting with a polyoxyalkylene adduct of an amine, such as acacia, Arabic acid, carboxymethylcellulose, ghatti gum, guar gum, polyacrylic acid and the like.
  • the polyacid is not likely to include the polyoxyalkylene derivative of a polymeric acid (PODPA) .
  • the preferred concentration range for the Lewis acid is 1%-10% w/v.
  • the Lewis acid reactant is a PODPA
  • the Lewis base is a simple amine capable of reacting with a polyoxyalkylene derivative of a polymeric acid, a sufficiently strongly basic mono-, di- or poly- amine such as n-hexylamine, octadecylamine, ethylenediamine, piperazine, 2,4- imethyIpentylamine, tetraethylenetriamine, polyethylenei ine and the like.
  • the simple amine is not likely to include the POAAM.
  • the preferred concentration range of the Lewis base is restricted by the limiting solubility of the Lewis base in the perfluorocarbons employed as core material.
  • the concentration of amine is in the range 0.1 to 10%. While the exact concentration of the solution of amine serving as Lewis base is not critical, it is important to use a total amount of base stoichiometrically equivalent to the non-esterified ionizable carboxylate functions of the PODPA.
  • the Lewis base is dissolved in the perfluorocarbons (PFC) resulting in a PFC-Lewis Base (PFC-LB) phase.
  • the Lewis acid is dissolved in the aqueous solution, prior to combining the aqueous solution with the PFC-LB phase.
  • a momentary, finely dispersed emulsion of PFC droplets in a continuous aqueous phase is produced with rapid stirring.
  • the Lewis acid and Lewis base must be substantially soluble in the appropriate phase.
  • the Lewis base, a POAAM is dissolved in the PFC phase, and Arabic acid is dissolved in the aqueous phase.
  • the Lewis base 2,4-dimethylpentylamine is dissolved in the PFC phase and the Lewis acid, a PODPA, is dissolved in the aqueous phase.
  • perfluorocarbons encapsulation efficiencies near 60% are easily achieved with a 1:1 ratio of aqueous (Lewis acid-containing) phase to non-aqueous (Lewis base-PFC-containing) phase, essentially 100% of the perfluorocarbons may be encapsulated if the initial nonaqueous to aqueous phase ratio is adjusted to 2:5.
  • b vigorously mixing the solution with a multi-orifice axial turbine (such as a Brinkmann homogenizer PT10/35 and generator PST/10, Brinkmann Instruments, Westbury, N.Y.) at a nominal setting of 5; or c. vigorously agitating the solutions with an ultrasonic probe (such a Heat Systems model W185D, Ultrasonics, Inc., Plainview, N.Y.) at a nominal output of 100 watts.
  • a multi-orifice axial turbine such as a Brinkmann homogenizer PT10/35 and generator PST/10, Brinkmann Instruments, Westbury, N.Y.
  • an ultrasonic probe such a Heat Systems model W185D, Ultrasonics, Inc., Plainview, N.Y.
  • a 10 ml volume of a 10% w/v aqueous solution of Arabic acid was mixed with a stoichiometrically equivalent solution of a tetronomer, (i.e., ca 2.2g), such as Tetronic 702, a product of BASF-Wyandotte Corp., Wyandotte, IL, in 5 ml of perfluorotetralin.
  • a tetronomer i.e., ca 2.2g
  • Tetronic 702 a product of BASF-Wyandotte Corp., Wyandotte, IL
  • the mixture was insonated at 20 kilohertz for 1-5 minutes at a power output of about 100 watts.
  • the sonic energy dispersed the perfluorocarbons phase into small droplets which had the momentary characteristic of an emulsion stabilized in part by the surfactant properties of Arabic acid.
  • Studies with small volume (2-5 ml) formulations show that longer msonation produces finer dispersions but does not
  • the reaction mixture was centrifuged (10,000 gravity minutes) and the supernatant removed. Distilled water was added and the pellet of microcapsules was resuspended by vortexing. The suspension was allowed to stand a few minutes to permit unencapsulated perfluorocarbons phase to separate, and the microcapsular suspension was harvested. The microcapsules were resuspended in distilled water and centrifuged as needed to remove unreacted manufacturing components. The washed product was rendered as a flowable concentrate by a final centrifugation. The resulting preparation of microencapsulated perfluorocarbons is stable at 20°C for about one month. Similar experiments were conducted to compare the encapsulation of perfluorocarbons with different Lewis acids.
  • control 1 polyethylene glycol alone is not capable of encapsulating perfluorocarbons nor does control 2, polyacrylic acid alone, or control 3, the simple non- esterified combination of polyethylene glycol mixed with polyacrylic acid encapsulate perfluorocarbons, in an attempted wall forming reaction using 2,4- dimethylpentamine as Lewis base.
  • experiment 4 using polyacrylic acid (ca 30%) esterified with polyethylene glycol as the Lewis acid and the same 2,4-dimethylpentamine as Lewis base does effectively 100% encapsulate perfluorocarbons.
  • PODPA polyethylene glycol 600 polyacrylate
  • mice were administered suspensions of perfluorocarbons microcapsules (or an equal volume of sterile saline as a control) intravenously into the tail vein.
  • the microcapsules contained the polyethylene glycol poly-acrylate macromolecule and were prepared as described above.
  • Each mouse received 0.05 mL of suspension which is approximately 5 to 7% of the total blood volume of the animals.
  • the animals were sacrificed in groups of five at logarithmically incrementing times of 3, 10, 30, 100, 300, 1000 and 3000 minutes. Importantly, all of the test and control mice lived until sacrificed and none displayed any indication of toxicity except for transient quiescence.
  • perfluorocarbons encapsulation is tolerated by these animals without undue or remarkable distress.
  • Additives such as physiologic electrolytes and macromolecules may be incorporated in the microencapsulated perfluorocarbons suspensions. These additives contribute to and adjust for the ionic and osmotic balance required of a blood substitute, whose serum specifications are well known, or a perfusion fluid.
  • Additives may be especially important when encapsulated perfluorocarbons are used as a means to replace larger volume fractions of blood.
  • Blood not only carries oxygen, but also contains nutrients, ions and colloids, the most abundant of which is albumin.
  • Such compounds when dissolved in blood plasma, contribute to the osmotic tension of blood and are vital to maintaining fluid balance in all perfused tissues.
  • perfluorocarbons emulsions exert a "protein stripping" action on blood. The general phenomenon of aggregration of proteins with perfluorocarbons is described in Biro et al. (CRC Critical Reviews in Oncology Hematology, Vol. 6, No.
  • Protein stripping is understood to be the association of protein which no- ⁇ tially exists in solution in plasma with microparticulate material to form a bound complex comprising the microparticle (emulsion droplet) , the adherent protein, and possibly other macromolecules.
  • microparticle emulsion droplet
  • adherent protein emulsion droplet
  • macromolecules emulsion droplet
  • replacement of large volume fractions of blood with encapsulated perfluorocarbons may result in dilution of ions and colloids, in "protein stripping", and in subsequent hypo-osmolarity of blood.
  • the microencapsulated perfluorocarbons suspension can be combined with, or be treated with, a compound or compounds which when associated with microcapsules, may reduce or eliminate depletion of blood components, in particular albumin, which are essential for maintaining normal osmolarity of blood. Larger volumes of microcapsules when so treated, can then be administered to an animal without inducing potentially adverse side- effects. Elimination or reduction of potentially adverse effects may be accomplished by simply administering microcapsules to animals in conjunction with a sufficient quantity of a compound, without prior treatment of the microcapsule with that compound. Alternatively, the microcapsule of the invention may be pretreated with such a compound. An example of such pretreatment is now described below.
  • mice To explore whether treatment of microcapsules with such a compound could be tolerated in mice, a microcapsule suspension prepared as described above, was treated with albumin prior to administration of the suspension to mice.
  • Albumin treated microcapsules were separated from unreacted albumin by centrifugation and resuspended in 2 mL of sterile saline. Five mice were inoculated with 0.2 L aliquots of treated perfluorocarbons microcapsules into the tail vein.
  • This volume represents approximately 20-28% of the total blood volume of a mouse. All five animals remained viable for more than 300 minutes following inoculation. One animal died within one day and another died within two days following inoculation. The remaining animals survived and appeared healthy for a least one week. Because the sterility of the suspension could not be guaranteed and because the large volume of the injection represents a substantial fluid stress to the animals, the death of the two animals was not surprising. Notwithstanding, the fact that three of the animals survived and remained healthy for greater than one week is evidence that pretreatment of microcapsules with albumin can be tolerated by the animals. Furthermore, these data demonstrate that this treatment has potential use when circumstances necessitate that large volumes of microcapsules be administered to an animal.
  • mice represent excellent models for therapies and treatments of other animals and humans. Because mice which had received either albumin-treated or untreated perfluorocarbons microcapsules not only survived but also appeared to be healthy, such microcapsules may also be tolerated and provide useful therapies to other animals and to humans. It is not necessary to limit pretreatment of microcapsules to albumin alone. Conceivably, perfluorocarbons microcapsules can be pretreated with any protein, colloids, or even inorganic ion components of blood such that they are adjusted to stoichiometric equilibrium with that of the blood of the animal or human to whom they will be administered.
  • microcapsules are to be administered to an animal in - conjunction with a compound, the invention need not be limited to albumin alone.
  • Other compounds such as those described above, are also suitable for administration in conjunction with microcapsules.
  • albumin When albumin is the blood component of choice, the type of albumin used should be compatible with the species of animal being treated. Many species specific preparations of albumin, including human albumin, are available commercially.
  • albumin when albumin is administered to the animal in conjunction with the microcapsule of the invention, preferably the suspension of microcapsules and albumin should contain up to 5% weight by volume of albumin, which is the approximate maximal concentration of albumin in blood. Higher concentrations of albumin may be used if medical conditions so indicate.
  • the microencapsulated perfluorocarbons of the present invention is stable at room temperature. It should be capable of circulating freely in the vascular system; taking up, carrying and releasing dissolved oxygen to tissues; and capturing carbon dioxide from tissues and releases it in the lungs.
  • the material of the present invention will be useful as (or in) perfusion fluids in hospital surgical suites, and as (or in) a temporary substitute or replacement for human blood, for example, when supplies of real human blood are limited or unavailable, when inadequate time or facility is available to determine the blood type of the intended recipient, such as at sites of accidents, disasters, catastrophe scenes, battlefields and hospital emergency rooms; when there is concern for transmission of blood- borne diseases, such as AIDS and hepatitis, from donor to recipient; when the use of human blood is rejected for religious or ethical reasons.
  • the microencapsulated perfluorocarbons of this invention may also benefit athletes, marathon runners for example, anemics, and animals, such as race horses, by providing a means to improve the oxygen and carbon dioxide exchange capacity of the vascular system of such subjects.
  • microencapsulated perfluorocarbons used as artificial blood are overcome by the present invention, including stability problems, as the microencapsulated perfluorocarbons of the present invention are stable, and do not coalesce, at 20°C for about one month.
  • the microencapsulated perfluorocarbons of the present invention eliminates the need for thawing the blood substitute and oxygenating the perfluorocarbons prior to administration. Furthermore, the microencapsulated perfluorocarbons of the invention eliminates the need for blood typing prior to use. Accordingly, the microencapsulated perfluorocarbons of the claimed invention may be used more rapidly than conventional blood substitutes.
  • the microencapsulated perfluorocarbons of the present invention also has utility in other applications in which stable compositions including perfluorocarbons have been shown to be useful, such as a contrast agent in medical imaging.
  • Perfluorocarbon- containing perfusion fluid may also be used during surgery and for wound healing to increase oxygen carrying capacity to damaged and surrounding tissues.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

L'invention concerne un substitut de sang artificiel composé d'une microcapsule filmogène d'un sel d'acide de Lewis-base de Lewis comportant des carbones perfluoriques encapsulés. La base de Lewis peut être un produit d'addition polyoxyalkylène d'une amine, ayant la structure (I) dans laquelle, indépendamment, R1=(II), a=7-26, R2=-CH2-O-R1 ou CH2-N(R1)2, R3=(III), b=7-26 et R4=H, CH3 ou alkyle, et ledit acide de Lewis peut être un dérivé de polyoxyalkylène d'un acide polymérique ayant la structure (IV) dans laquelle des unités répétitives du type c et d sont aléatoirement réparties dans le polymère, c=70 à 3150, des unités répétitives du type c comprennent de 50 à 90 % du polymère total, d=70-1750, la somme de c+d étant comprise entre environ 140 et environ 3500 et dans laquelle R=(V) où R' et R'' indépendamment sont égaux à H ou CH3 et e=7-75, f=7-75, et la somme de e+f est comprise entre 14 et 85.
PCT/US1992/006132 1991-07-23 1992-07-23 Carbones perfluoriques encapsules WO1993001806A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US08/190,011 US5490986A (en) 1992-07-23 1992-07-23 Encapsulated perfluorocarbons
PCT/US1992/006132 WO1993001806A1 (fr) 1991-07-23 1992-07-23 Carbones perfluoriques encapsules

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US734,461 1991-07-23
US07/734,461 US5284663A (en) 1991-07-23 1991-07-23 Salt film encapsulated perfluorocarbons
PCT/US1992/006132 WO1993001806A1 (fr) 1991-07-23 1992-07-23 Carbones perfluoriques encapsules

Publications (1)

Publication Number Publication Date
WO1993001806A1 true WO1993001806A1 (fr) 1993-02-04

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0804283A4 (fr) * 1994-04-15 1997-11-12
US6531156B1 (en) 1994-04-15 2003-03-11 Temple University Aqueous solven encapsulation method, apparatus and microcapsules
DE102008045152A1 (de) * 2008-07-09 2010-01-14 Universität Duisburg-Essen Künstliche Sauerstoffträger und ihre Verwendung
CN102949709A (zh) * 2011-08-18 2013-03-06 中国科学院大连化学物理研究所 一种治疗糖尿病足的外用凝胶剂及制备和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3959457A (en) * 1970-06-05 1976-05-25 Temple University Microparticulate material and method of making such material
US3964294A (en) * 1972-03-13 1976-06-22 California Institute Of Technology Technique and system for coding and identifying materials

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3959457A (en) * 1970-06-05 1976-05-25 Temple University Microparticulate material and method of making such material
US3964294A (en) * 1972-03-13 1976-06-22 California Institute Of Technology Technique and system for coding and identifying materials

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIRD et al., (1987), "Perfluorocarbon Blood Substitutes", Volume 6; issue 4, pages 311-374. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0804283A4 (fr) * 1994-04-15 1997-11-12
US6531156B1 (en) 1994-04-15 2003-03-11 Temple University Aqueous solven encapsulation method, apparatus and microcapsules
DE102008045152A1 (de) * 2008-07-09 2010-01-14 Universität Duisburg-Essen Künstliche Sauerstoffträger und ihre Verwendung
CN102949709A (zh) * 2011-08-18 2013-03-06 中国科学院大连化学物理研究所 一种治疗糖尿病足的外用凝胶剂及制备和应用
CN102949709B (zh) * 2011-08-18 2014-02-26 中国科学院大连化学物理研究所 一种治疗糖尿病足的外用凝胶剂及制备和应用

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