CN1213962A - Method for solubilising hydrophylic materials (E. G. proteins) in hydrophobic solvent - Google Patents
Method for solubilising hydrophylic materials (E. G. proteins) in hydrophobic solvent Download PDFInfo
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- CN1213962A CN1213962A CN97193180A CN97193180A CN1213962A CN 1213962 A CN1213962 A CN 1213962A CN 97193180 A CN97193180 A CN 97193180A CN 97193180 A CN97193180 A CN 97193180A CN 1213962 A CN1213962 A CN 1213962A
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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Abstract
Methods for the preparation of a single phase preparation comprising a hydrophilic species, e.g. a protein, solubilised in a hydrophobic phase are provided. The methods of the invention can be used in the preparation of a pharmaceutical, cosmetic, nutrient, foodstuff or food supplement composition.
Description
The present invention relates to a kind ofly with hydroaropic substance, for example protein is dissolved in the novel method in its common insoluble hydrophobic solvent.
With hydrophilic molecule for example protein and lyophobic dust for example lipoid to combine be favourable in many aspects.Hydrophilic molecule can have in the lipoid environment time advantage for example stability strengthen.In addition, this hydroaropic substance passes lipoid sexual disorders thing, and for example transporting of skin will become more easy.
Early stage hydrophobic carrier is used for the application that suggestion that protein transports comprises liposome.System afterwards is non-liposome, but still depends on the aqueous favoring prerequisite of carrying protein or other hydrophilic molecule, and this aqueous favoring forms a kind of emulsion mutually with hydrophobic.The example of these systems is disclosed in EP-A-0366277 and EP-A-0521994.
WO-A-95/13795 has disclosed a kind of system, and it is possible obtaining a kind of real monophasic preparation by it, and hydroaropic substance real " dissolving " is at thin aqueous phase herein.In the method for Jie Shiing, hydroaropic substance at first combines in liquid medium with a kind of amphiphile therein, in this liquid medium, does not have chemical interaction between amphiphile and the hydrophile.Liquid medium is removed then, stays a system of amphiphile molecules and hydroaropic substance.At last, add a kind of hydrophobic solvent and can produce a kind of monophasic preparation in system, hydroaropic substance is dissolved in the hydrophobic solvent herein.
Be surprisingly found out that now it is possible generating the monophasic preparation of a kind of hydroaropic substance in hydrophobic solvent by the common method faster after a kind of the improvement.
Therefore, on the one hand, the invention provides a kind of preparation method that contains the single-phase hydrophobic preparations of hydroaropic substance in hydrophobic solvent, this method comprises:
(ⅰ) under hydrophobic situation about existing mutually, hydroaropic substance is combined with a kind of amphiphile; And
(ⅱ) remove all hydrophilic solvents that exist;
Wherein hydrophilic solvent removal step is to carry out under the solid-state condition keeping hydrophobic mutually.
In a preferred embodiment, hydroaropic substance and amphiphile at first are dissolved in a kind of hydrophilic solvent, and for example aqueous solvent has only water usually, then this solution is combined with hydrophobic solvent.The removal step of hydrophilic solvent realizes expediently by lyophilization, and this method is solid-stately carried out under all removed temperature of all water guaranteeing that hydrophobic solvent remains on always.In some cases, oil is the possibility liquefy during lyophilizing, and this is because the result that some part (usually at surface and edge) local temperature of solid block raises is removed at these local hydrophilic solvents.The cooling effect that is produced by the distillation of hydrophilic solvent no longer exists here, will melt at these regional oil.This state will cause a kind of generation of gratifying end-product, as long as oil is once occurring its venting (otherwise the oil that gathers stops cambium layer the further removal of hydrophilic solvent) from the remainder of solid block.
Perhaps, still keep solid-state even keep the temperature during the lyophilizing so that be removed back oil at hydrophilic solvent.In this case, after the lyophilizing, then the temperature with preparation raises to generate monophasic preparation.By the preparation after the lyophilizing is elevated to room temperature, this can be realized simply that usually it also will cause the hydrophobic liquid state of getting back to mutually.Also can use other method of removing hydrophilic solvent, for example spray drying.
In the context of the present invention, term " hydroaropic substance " relates to any usually at hydrophilic solvent, and is for example solvable in the aqueous solvent, and in hydrophobic solvent insoluble material.The hydroaropic substance of Ying Yonging is various in the present invention, but hydrophilic macromolecule has been represented a kind of example of adaptable material.
Method of the present invention provide a kind of easily with the method that generates described monophasic preparation more fast.When relating to oil, hydroaropic substance or both stable, especially when the concentration of amphiphile is high, method be a special advantage fast.In addition, though when application examples such as triglyceride as hydrophobic phase time, also can obtain the low ratio between amphiphile and the hydroaropic substance, for example be low to moderate 7: 1, this allows preparation that higher struck capacity is arranged.
As above mentioned, in a preferred embodiment, amphiphile " appearance " is in aqueous favoring.But, if suitably, amphiphile can at first dissolve or be dispersed in the oil.When disperseing bad amphiphile in being applied in water, this is especially suitable.Another advantage of method of the present invention is that it allows the application of freeze dried amphiphile well, and for example those are liquid amphiphile under the temperature that the enforcement lyophilization is taked usually.
Various macromolecules are suitable for using in the present invention.Generally speaking, macromolecular compound will be hydrophilic or have hydrophilic region at least, seldom have any problem usually because hydrophobic polymer is dissolved in the oily solution.The example of proper polymer comprises protein and glycoprotein, low nucleic acid and polynucleic acid, and for example DNA and RNA, the supermolecule combination of polysaccharide and any of these material comprises being whole cell or organella in some cases.Also can dissolve for example vitamin and macromolecule complex of polysaccharide such as cyclodextrin be combined into for example of a micromolecule very expediently altogether.Micromolecule for example Vitamin B12 also can with the polymer chemistry conjugation, therefore and can be included in the compositions.
Can successfully comprise insulin with the dissolved concrete proteinic example of method of the present invention, calcitonin, hemoglobin, cytochrome C, horseradish peroxidase, aprotinin, gill fungus shape tryrosinase (mushroom tyrosinase), erythropoietin, growth hormone (somatotropin), growth hormone (growth hormone), somatotropin releasing factor, galanin, urokinase, factor IX, organize plasminogen activator, superoxide dismutase, catalase, peroxidase, ferritin, interferon, factor VIII, microbial toxin, peptide and proteantigen and their fragment (all above-mentioned albumen mass-energy are from any suitable source).Glucosan that other adaptable macromolecule is the FITC labelling and the RNA that from string yeast (Torulla yeast), extracts.
It seems that the molecular weight of macromolecular compound does not have the upper limit, can enough methods of the present invention dissolve easily because molecular weight is about glucosan of 1,000,000.
Except that macromolecule, method of the present invention also can be used for dissolving littler organic molecule.The example of little organic molecule comprises glucose, CF 5(6)-Carboxyfluorescein and a lot of pharmaceutical preparation, anticancer preparation for example, and still, this method can be applied to other little organic molecule equally certainly, for example on vitamin or the medicine or the active agent on the biology.In addition, for example calcium chloride and sodium phosphate also can dissolve with the method chemical compound.In fact, the present invention on the medicine and the active agent on the biology especially favourable changed because the application of anhydrous solution can make molecule enter intravital method, for example in order to improve bioavailability.
The another kind of material that can be included in the hydrophobic composition of the present invention is a for example colloidal metal of for example little inorganic molecule of inorganic matter or colloidal substance.Method of the present invention makes for example some character of aurosol, palladium, platinum or rhodium of colloidal metal, even also can be held in hydrophobic solvent, and generally microgranule can be assembled therein.This catalytic action for the reaction of carrying out in organic solvent is particularly useful.
Have many amphiphiles can be applied to the present invention, amphion amphiphile for example phospholipid just belongs to those and has been found to be especially the amphiphile that is fit to.The phospholipid of band lecithin headgroup is especially successfully used, the example of these phospholipid comprises the derivant of lecithin (PC) itself, LYSOLECITHIN SUNLECITHIN A (lyso-PC), sphingomyelin, any of these material, for example HEXADECYL PHOSPHOCHOLINE or contain the amphipathic polymer of phosphocholine.In this application, term lecithin (PC) and the interchangeable application of lecithin (lecithin).Suitable natural phosphatidyl choline can derive from any source easily, for example egg and especially Semen sojae atricolor.In most of the cases, preferably select a kind of amphiphile that chemically is similar to selecteed hydrophobic solvent, this discusses in more detail below.
The predetermined purpose of compositions, dissolved material type and amphiphile are depended in the selection of hydrophobic solvent.Suitable solvent comprises for example preferred oleic acid of the long-chain fatty acid of being with unsaturated fatty acid and linoleic acid, alcohol, especially medium chain alcohol capryl alcohol and branched long-chain alcohol for example glycerin mono-fatty acid ester (GMO), diglyceride and triglyceride, especially medium chain triglyceride and their mixture of phytol, monoglyceride for example for example.
When hydrophobic solvent and amphiphile mate rightly, obtain optimal results usually.For example, to a kind of solvent oleic acid for example, the relative lecithin of LYSOLECITHIN SUNLECITHIN A is that a kind of of amphiphile more suitably selects, and is then opposite when hydrophobic solvent is triglyceride.
Perhaps, has under the situation of amphipathic characteristic (free fatty for example at hydrophobic solvent, as oleic acid, they can ionizing under the situation that has alkali to exist and generate enuatrol), it is just unnecessary to comprise a kind of extra amphiphile, if the part of solvent molecule before mixed process is carried out or during change into the form of amphiphile.Especially, applied alkali is for example triethylamine of a kind of volatile alkali.When dissolving calcitonin or insulin, this method is especially successful.
Therefore, second aspect the invention provides a kind of preparation method that contains the single-phase hydrophobic preparations of hydroaropic substance in hydrophobic solvent, and this method comprises:
(ⅰ) under hydrophobic situation about existing mutually, hydroaropic substance is combined with alkali; And
(ⅱ) remove all hydrophilic solvents that exist;
Wherein hydrophobic is the phase with hydrophobic property mutually, and wherein the removal step of hydrophilic solvent is to carry out under the solid-state condition keeping hydrophobic mutually.As discussed above, preferred bases is a for example triethylamine of volatile alkali.Suitable hydrophobic solvent comprises medium chain and long-chain fatty acid, and their example comprises oleic acid and linoleic acid.This method is particularly useful for dissolving calcitonin or insulin.
An advantage of preparation of the present invention is that they are anhydrous basically, is stable to hydrolysis therefore.They also are stable to freezing molten effect, and at high temperature have stronger stability, and this may be because for protein launches and degeneration, must have water to occur.This means that they can be supposed to have a longer shelf life than the aqueous compositions of hydroaropic substance.
The solution that provides with method of the present invention is extremely multiduty, and many application are arranged.They can or be used separately, perhaps combine and form a kind of emulsion or similar two-phase compositions with containing water, and this has also formed another aspect of the present invention.
An aspect can using the compositions that generates with method of the present invention is to be used for mammal, comprises the people, under normal conditions the oral administration of insoluble material in lipophilic solvent.This can be used for for example vitaminic administration of diet supplement, perhaps is used for bioactive substance, and especially protein or glycoprotein comprise the administration of insulin and growth hormone.
In Another application, might be for example by above-described method, with nutrient for example vitamin encapsulate or microcapsule encapsulate, they not only can be as human food supplement then, and can be used in agricultural and culture fishery, the latter's a example is to be used for the production that juvenile prawn is cultured feedstuff.
In addition, medicine or other preparation that said composition is used at non-intestinal, and found application in the preparation of part or ophthalmic preparation.For this application, oil solution and the emulsion that contains water that common advantageous applications is as described above.
That many therapeutic and preventative treatment are intended to continue or the release that postpones or comprise one two component system for example comprises a kind of component that is used for discharging immediately and a kind of that be used to postpone or continue the component that discharges.Because their high stability, preparation of the present invention is particularly useful to the macromolecule preparation of release that be intended to continue or delay.
The compositions that produces by the method that discloses herein has the longer shelf life, and this is a special advantage in field of medicaments.
Hydrophile is dissolved in the preparation that generates in the oil can find application in pharmacy or similar industrial, be used for sheltering of abnormal smells from the patient.This is a special problem in pharmaceuticals industry, because many medicines have undesirable abnormal smells from the patient, therefore to patient, especially the child is out of favour.
Another application is in cosmetics industry, and the hydrophobic preparations of hydrophilic compounds can fuse in cosmetic formulations again easily.The high molecular example that can use by this way comprises the material that those have certain humidification or enzyme caloytic action.The present invention also can be used for protein for example collagen protein fuse in barrier cream and washing liquid.
Therefore, the third aspect the invention provides the application of method of the present invention in medicine, cosmetics, nutriment, feedstuff or the preparation of food supplement composition.Especially, when method of the present invention is applied to preparation of drug combination, it will be used for the part, mouth is used or the preparation of ophthalmic preparation.
At last, the present invention has many application at chemistry and biosynthesis field, and for example, anhydrous enzyme catalysis is synthetic.
Various aspects preferable feature of the present invention is with regard to after each others are done necessary improvement.
The present invention will describe further referring to following embodiment now, and this does not should be understood to and imposes any restrictions.
Embodiment 1
(ⅰ) 20 milligrams of aprotiniies are dissolved in 1 ml distilled water.
(ⅱ) 1 gram soybean lecithin is dissolved among 9 milliliters of Miglyol 818, to provide the concentration of lecithin in M818 near 100 mg/ml.
(ⅲ) vial with three threaded lids of B10 is ready to, and above-described two kinds of solution of following quantity are housed.Content mixes well.
| ????A | ????B | ????C | |
| Distilled water | 600 microlitres | 600 microlitres | 600 microlitres |
| Aprotinin (20 mg/ml) | 125 microlitres | 63 microlitres | 0 microlitre |
| M818/ lecithin (9: 1) | 1 milliliter | 1 milliliter | 1 milliliter |
| Lecithin (weight, milligram) | ?100 | ?100 | ?100 |
| Aprotinin (weight, milligram) | ?2.5 | ?1.25 | ??0 |
(ⅳ) then that bottle is freezing in liquid nitrogen, and lyophilizing two days under-45 ℃ temperature.
(ⅴ) after the lyophilizing, the content in the bottle is increased to room temperature, obtains transparent or slightly milky oil thus.
(ⅵ) measure the optical density of 200 microlitre samples in 600 nanometers, with sample C (not containing aprotinin) as blank sample.
| ????A | ????B | ????C | |
| The concentration (mg/ml) of aprotinin in oil | ????2.5 | ????1.25 | ????0 |
| Optical density 600 | ????0.330 | ????0.096 | ????0.00 |
In parallel laboratory test, only in oil, add 2.5 milligrams of aprotiniies, provide one greater than 1.0 optical density, show in this embodiment, because the result of the method that is adopted in two sample A and B dissolving has taken place.
Embodiment 2
(ⅰ) 80 milligrams of aprotiniies are dissolved in 4 ml distilled waters.
(ⅱ) 100 milligrams of salicylic acid are dissolved among 10 milliliters of Miglyol 818.
(ⅲ) with the detector sonioation method soybean lecithin is dispersed in the distilled water, concentration is 250 mg/ml.
(ⅳ) above-mentioned ready solution according to the form below is dispersed in the vial of the threaded lid of B10.
| A | ?B | ?C | ?D | ?E | ?A′ | B′ | C′ | D′ | E′ | |
| Aprotinin (20 mg/ml) | 0 | ?250 | ?375 | ?500 | ?750 | ?0 | ?250 | ?350 | ?500 | ?750 |
| Distilled water | 600 | ?350 | ?- | ?- | ?- | ?600 | ?350 | ?- | ?- | ?- |
| Lecithin (250 mg/ml) | 400 | ?400 | ?400 | ?400 | ?400 | ?400 | ?400 | ?400 | ?400 | ?400 |
| ????M818 | 1 | ?1 | ?1 | ?1 | ?1 | ?- | ?- | ?- | ?- | ?- |
| The M818+ salicylic acid | ?- | ?- | ?- | ?- | ?- | ?1 | ?1 | ?1 | ?1 | ?1 |
| Aprotinin (milligram) | 0 | ?5 | ?7.5 | ?10 | ?15 | ?0 | ?5 | ?7.5 | ?10 | ?15 |
(ⅴ) mixture is all carried out 10 seconds of eddying motion, freezing in liquid nitrogen, and-45 ℃ of following lyophilizing two days.
(ⅵ) after the lyophilizing, bottle was heated 15 minutes down at 37 ℃.
(ⅶ) transparency of solution or other character are estimated in the optical density of 600 nanometers by measuring oil.
The result provides in following table.
| ????A | ????B | ????C | ????D | ????E | |
| Aprotinin (mg/ml) | ????0 | ????5 | ????7.5 | ????10 | ????15 |
| M818 is only arranged | ?0.009 | ?0.191 | ?0.566 | ?0.390 | ?1.576 |
| The M818+ salicylic acid | ?0.000 | ?0.006 | ?0.000 | ?0.012 | ?0.021 |
The result shows, uses method described herein, can obtain protein effectively dissolving in oil, especially promoter for example (being described among International Patent Application PCT/GB95/02891) under the salicylic acid situation about existing is being arranged.
Embodiment 3
(1) in three 7 milliliters of vials, 1 milliliter of salmon (salmon) calcitonin solution is dispersed in the distilled water, concentration is 1 mg/ml.
(2) to a bottle, be labeled as " A ", add 0.4 milliliter of oleic acid dropwise, carry out eddying motion simultaneously from (1).Freezing dispersion liquid in liquid nitrogen immediately.
(3) to a bottle, be labeled as " B ", add 5 microlitre glacial acetic acid, add 0.4 milliliter of oleic acid then dropwise, carry out eddying motion simultaneously from (1).Freezing dispersion liquid in liquid nitrogen immediately.
(4) to a bottle, be labeled as " C ", add 5 microlitre triethylamines, add 0.4 milliliter of oleic acid then dropwise, carry out eddying motion simultaneously from (1).Freezing dispersion liquid in liquid nitrogen immediately.
(5) in a lyophil apparatus, it is+4 ℃ of following lyophilizing a whole nights at storage temperature with all bottles.
(6) second days, the heating bottle was in liquid oil to obtain all, measures the optical density of every kind of oil in 600 nanometers.
The result
| ????A | ????B | ????C | |
| Optical density 600 nanometers | ????0.096 | ????0.096 | ????0.005 |
Obtained a transparent solution.
Embodiment 4
(1) in one 7 milliliters vial, allocates 1 milligram of bovine insulin into, and add 1 ml distilled water.
(2) in from the bottle of (1), add 5 microlitre triethylamines, then, add 0.4 milliliter of oleic acid dropwise, carry out eddying motion simultaneously.Freezing dispersion liquid in liquid nitrogen immediately.
(3) in a lyophil apparatus, it is+4 ℃ of following lyophilizing a whole nights at storage temperature with bottle.
(4) second days, the heating bottle to be to obtain to be in liquid oil, wherein, with top embodiment 3 in the same mode of the relevant calcitonin described, insulin is dissolved into a clear solution.
Claims (22)
1. preparation method that in hydrophobic solvent, contains the single-phase hydrophobic preparations of hydroaropic substance, this method comprises:
(ⅰ) under hydrophobic situation about existing mutually, hydroaropic substance is combined with a kind of amphiphile; And
(ⅱ) remove all hydrophilic solvents that exist;
Wherein the removal step of hydrophilic solvent is to carry out under the solid-state condition keeping hydrophobic mutually.
2. a basis the process of claim 1 wherein and at first hydroaropic substance and amphiphile is dissolved in a kind of hydrophilic solvent, then this solution is combined mutually with hydrophobic.
3. a basis the process of claim 1 wherein hydrophobic with before hydroaropic substance combines, and amphiphile is dissolved or combine mutually with hydrophobic.
4. one kind according to each the method in the claim 1～3, and wherein the removal step of hydrophilic solvent realizes with lyophilization.
5. one kind according to each the method in the claim 1～3, and wherein hydroaropic substance comprises macromolecule, little organic or inorganic molecule or colloidal substance.
6. method according to claim 5, wherein macromolecule comprises protein, glycoprotein, low nucleic acid or polynucleic acid, polysaccharide or the combination of their supermolecule.
7. method according to claim 6, wherein protein is insulin, calcitonin, hemoglobin, cytochrome C, horseradish peroxidase, aprotinin, gill fungus shape tryrosinase, erythropoietin, growth hormone, growth hormone, somatotropin releasing factor, galanin, urokinase, factor IX, organizes plasminogen activator, superoxide dismutase, catalase, peroxidase, ferritin, interferon, factor VIII, microbial toxin, peptide and proteantigen and their fragment.
8. one kind according to each the method in the claim 1～7, and wherein amphiphile is a phospholipid.
9. a method according to Claim 8, wherein phospholipid band lecithin headgroup.
10. method according to claim 9, wherein phospholipid is for example HEXADECYL PHOSPHOCHOLINE or contain the amphipathic polymer of phosphocholine of lecithin (PC), LYSOLECITHIN SUNLECITHIN A (lyso-PC), sphingomyelin, above-mentioned a certain derivant.
11. one kind according to each the method in the claim 1～10, wherein hydrophobic long-chain fatty acid, medium chain alcohol, branched long-chain alcohol, monoglyceride or the medium chain triglyceride of comprising mutually.
12. one kind according to each the method in the claim 1～11, wherein amphiphile comprises lecithin, and hydrophobic is triglyceride mutually, and perhaps wherein amphiphile comprises LYSOLECITHIN SUNLECITHIN A, and hydrophobic is oleic acid mutually.
13. one kind according to each the method in the claim 2～12, wherein hydrophilic solvent is an aqueous solvent, preferred water.
14. a preparation method that contains the single-phase hydrophobic preparations of hydroaropic substance in hydrophobic solvent, this method comprises:
(ⅰ) under hydrophobic situation about existing mutually, hydroaropic substance is combined with a kind of alkali; And
(ⅱ) remove all hydrophilic solvents that exist;
Wherein hydrophobic is the phase with hydrophobic property mutually, and wherein the removal step of hydrophilic solvent is to carry out under the solid-state condition keeping hydrophobic mutually.
15. the method according to claim 14, wherein alkali is a kind of volatile alkali.
16. the method according to claim 15, wherein alkali is triethylamine.
17. one kind according to each the method in the claim 14～16, wherein hydrophobic solvent is this or the sort of mixture of medium chain or long-chain fatty acid or these materials.
18. one kind according to each the method in the claim 14～17, improves by any one or multinomial feature in the claim 4～7.
19. one kind according to each the method in the claim 14～18, wherein hydroaropic substance is a calcitonin.
20. one kind according to each the method in the claim 14～18, wherein hydroaropic substance is an insulin.
21. the method that defines in each in claim 1～20 is applied in the preparation of medicine, cosmetics, nutriment, feedstuff or food supplement composition.
22. according to the application of claim 21, wherein pharmaceutical composition is used for part, oral or eye usefulness.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9605709.6A GB9605709D0 (en) | 1996-03-19 | 1996-03-19 | Method |
| GB9605709.6 | 1996-03-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1213962A true CN1213962A (en) | 1999-04-14 |
Family
ID=10790620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97193180A Pending CN1213962A (en) | 1996-03-19 | 1997-03-18 | Method for solubilising hydrophylic materials (E. G. proteins) in hydrophobic solvent |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0891184A1 (en) |
| JP (1) | JP2000507935A (en) |
| KR (1) | KR20000064684A (en) |
| CN (1) | CN1213962A (en) |
| AU (1) | AU1936497A (en) |
| BR (1) | BR9708089A (en) |
| CA (1) | CA2248351A1 (en) |
| GB (1) | GB9605709D0 (en) |
| NO (1) | NO984351L (en) |
| WO (1) | WO1997034581A1 (en) |
| ZA (1) | ZA972353B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103861090A (en) * | 2012-12-18 | 2014-06-18 | 美迪思生物科技(北京)有限公司 | Protein or peptide containing hydrophobic solution, preparation method and application thereof |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9613858D0 (en) | 1996-07-02 | 1996-09-04 | Cortecs Ltd | Hydrophobic preparations |
| WO2010113177A2 (en) | 2009-03-31 | 2010-10-07 | Reliance Life Sciences Pvt. Ltd. | Oral insulin delivery systems for controlling diabetes |
| JP5954856B2 (en) | 2011-02-01 | 2016-07-20 | ルネサスエレクトロニクス株式会社 | Manufacturing method of vertical channel type normally-off power JFET |
| GB201107629D0 (en) * | 2011-05-06 | 2011-06-22 | Proxima Concepts Ltd | Hydrophobic preparations |
| GB201107630D0 (en) * | 2011-05-06 | 2011-06-22 | Proxima Concepts Ltd | Microemulsions |
| US20180153989A1 (en) * | 2016-12-02 | 2018-06-07 | Rubius Therapeutics, Inc. | Compositions and methods related to cell systems for penetrating solid tumors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9323588D0 (en) * | 1993-11-16 | 1994-01-05 | Cortecs Ltd | Hydrophobic preparation |
| US5553924A (en) * | 1994-11-15 | 1996-09-10 | The Board Of Trustees Of The University Of Alabama For Its Division, The University Of Alabama At Birmingham | Vehicle safety seat system |
| GB9521805D0 (en) * | 1995-10-25 | 1996-01-03 | Cortecs Ltd | Solubilisation methods |
-
1996
- 1996-03-19 GB GBGB9605709.6A patent/GB9605709D0/en active Pending
-
1997
- 1997-03-18 CA CA002248351A patent/CA2248351A1/en not_active Abandoned
- 1997-03-18 JP JP9533251A patent/JP2000507935A/en active Pending
- 1997-03-18 WO PCT/GB1997/000749 patent/WO1997034581A1/en not_active Application Discontinuation
- 1997-03-18 CN CN97193180A patent/CN1213962A/en active Pending
- 1997-03-18 AU AU19364/97A patent/AU1936497A/en not_active Abandoned
- 1997-03-18 ZA ZA972353A patent/ZA972353B/en unknown
- 1997-03-18 KR KR1019980707401A patent/KR20000064684A/en not_active Application Discontinuation
- 1997-03-18 EP EP97907228A patent/EP0891184A1/en not_active Ceased
- 1997-03-18 BR BR9708089A patent/BR9708089A/en not_active Application Discontinuation
-
1998
- 1998-09-18 NO NO984351A patent/NO984351L/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103861090A (en) * | 2012-12-18 | 2014-06-18 | 美迪思生物科技(北京)有限公司 | Protein or peptide containing hydrophobic solution, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000064684A (en) | 2000-11-06 |
| AU1936497A (en) | 1997-10-10 |
| ZA972353B (en) | 1998-10-26 |
| JP2000507935A (en) | 2000-06-27 |
| GB9605709D0 (en) | 1996-05-22 |
| BR9708089A (en) | 1999-07-27 |
| NO984351D0 (en) | 1998-09-18 |
| CA2248351A1 (en) | 1997-09-25 |
| EP0891184A1 (en) | 1999-01-20 |
| WO1997034581A1 (en) | 1997-09-25 |
| NO984351L (en) | 1998-09-18 |
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