DK157060B - PROCEDURE FOR PREPARING A LIPOSOM SUSPENSION CONTAINING A MEDICINE - Google Patents
PROCEDURE FOR PREPARING A LIPOSOM SUSPENSION CONTAINING A MEDICINE Download PDFInfo
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- DK157060B DK157060B DK022380AA DK22380A DK157060B DK 157060 B DK157060 B DK 157060B DK 022380A A DK022380A A DK 022380AA DK 22380 A DK22380 A DK 22380A DK 157060 B DK157060 B DK 157060B
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- liposome suspension
- preparing
- drug
- suspension
- suspension containing
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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
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 157060 BDK 157060 B
Den foreliggende opfindelse angâr en fremgangsmâde til fremstilling af en 1iposomsuspension, der indeholder et lægemiddel, som kan være doxorubicin-hydrochlorid, aminosi-dinsulfat eller 5-fluor-uracil.The present invention relates to a process for the preparation of a liposome suspension containing a drug which may be doxorubicin hydrochloride, aminosidine sulphate or 5-fluoro-uracil.
5 Fremgangsmâden if0lge opfindelsen er ejendommelig ved, at man a) fremstiller en liposomsuspension ved opl0snng af lipid-bestanddele i et opl0sningsmiddel, tilsætter en vandig op-l0sning af lægemidlet og emulgerer ved indblæsning af en 10 indifferent gas, indtil opl0snîngsmidlet er fjernet fuld-stændigt ved fordampning, b) renser liposomsuspensionen ved behandling deraf med en polymer ionbytterharpiks eller en polymer adsorberende har-piks og eventuelt 15 c) stabiliserer den rensede suspension ved frystet0rring.The process of the invention is characterized in that: by evaporation, b) purifying the liposome suspension by treating it with a polymeric ion exchange resin or polymeric adsorbent resin and optionally c) stabilizing the purified suspension by freeze-drying.
Liposomer er pharmaceutiske saitunensætninger, hvori lægemidlet enten er dispergeret eller i anden form forekommer som smâ kugler, der bestâr af vandige koncentriske lag, der hæfter til lipide (hydrophobe) lag; lægemidlet kan forekomme 20 bâde i det vandige lag og i lipidlaget (indvendigt eller udvendigt) eller hvorsomhelst i det dishomogene, i reglen som liposomsuspension kendte System.Liposomes are pharmaceutical site compositions in which the drug is either dispersed or otherwise present as small spheres consisting of aqueous concentric layers adhering to lipid (hydrophobic) layers; the drug can be present both in the aqueous layer and in the lipid layer (inside or outside) or anywhere in the dishomogeneous system, generally known as liposome suspension.
Det hydrophobe lag indeholder i reglen, men ikke udelukkende, phospholipider sâsom lecithin og sphingomyelin, 25 steroider sâsom cholestérol, flere eller færre ionogene overfladeaktive stoffer sâsom dicetylphosphat, stearylamin eller phosphatidinsyre og/eller et andet materiale af hydro-phob karakter. Liposomernes diameter ligger i reglen mellem 15 nm og 5 jum.The hydrophobic layer usually contains, but is not limited to, phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionogenic surfactants such as dicetylphosphate, stearylamine or phosphatidic acid and / or other hydrophobic material. The diameter of the liposomes is usually between 15 nm and 5 µm.
30 Fremgangsmâden til fremstilling heraf foregâr i reglen pâ kendt mâde og omfatter to hovedtrin: 1) Fremstilling af liposomerne, hvor de lipide eller lipophile komponenter oploses i et egnet oplosningsmiddel, som derefter i reglen i vakuum afdampes til torhed.The process for its preparation is generally carried out in a known manner and comprises two main steps: 1) Preparation of the liposomes, where the lipid or lipophilic components are dissolved in a suitable solvent, which is then usually evaporated to dryness in vacuo.
35 Det vandige lag, der indeholder lægemidlet, sættes til kolben, der indeholder remanensen som et tyndt lag, og 2The aqueous layer containing the drug is added to the flask containing the residue as a thin layer, and 2
DK 157060BDK 157060B
det hele underkastes derefter i et tidsrum pâ fra 10 sekun-der til nogle timer emulgering ved indblæsning af en indifferent gas. Det herved fremkomne inhomogene lag, i régien kaldet liposomsuspension, skal renses for fysisk ikke-bundet 5 lægemiddel.the whole is then subjected for a period of from 10 seconds to a few hours of emulsification by blowing in inert gas. The resulting inhomogeneous layer, in the region called liposome suspension, is to be purified from physically unbound drug.
2) Fraskillelse af liposomerne fra fysisk ikke-bundet lægemiddel: denne fremgangsmâde sker sædvanligvis ved elue-ring pâ en chromatografisk kolonne under anvendelse af har-pikser, der udelukkende har funktion som molekylarsigte, 10 sâsom "Sepharose"® 2B, 4B eller 6B og lignende.2) Separation of the liposomes from physically unbound drug: this process is usually done by eluting on a chromatographic column using resins which function exclusively as molecular sieves, such as "Sepharose" ® 2B, 4B or 6B and similar.
Liposomerne udvindes ferst, medens det frie lægemiddel holdes tilbage af harpiksen.The liposomes are recovered stiffly while the free drug is retained by the resin.
Derefter felger en ultracentrifugeringsbehandling ved 100.000 g og derefter vaskes der, stadig ved hjælp af 15 ultracentrifugering med pufret oplosning. En anden metode, der kan anvendes, er dialyse.Thereafter, an ultracentrifugation treatment is peeled at 100,000 g and then washed, still with 15 ultracentrifuged buffered solution. Another method that can be used is dialysis.
Den foreliggende opfindelse angâr sâledes en særegen fremgangsmâde til rensning af det uhomogene, som liposomsuspension kendte lag sâvel ved hjælp af flydende som faste, 20 syntetiske eller organiske, reaktionsdygtige polymère, der kan anvendes som ionbyttere, sâsom polystyren, -divinylben-zen, -acryl- eller -methacrylsyre, der er kendte ionbytter-harpikser.The present invention thus relates to a peculiar process for purifying the inhomogeneous layer known as liposome suspension by liquid as solid, synthetic or organic, reactive polymers which can be used as ion exchangers such as polystyrene, divinylbenzene, acrylic - or methacrylic acid, which are known ion exchange resins.
Den nojagtige mængde af en eller flere af de oven-25 nævnte harpikser indfores direkte i kolben, der indeholder liposomsuspensionen, der skal renses, hvorpâ der rystes i 10-60 minutter. Efter filtrering gennem et sinterglasfilter, der indeholder ionbytterharpiksen med absorberet fysisk ikke-bundet lægemiddel, fâs den rene liposomsuspension, der 30 kan frysetorres. Denne fremgangsmâde til rensning af liposomsuspensionen med ionbytterharpikser har den store fordel, at stærkt koncentrerede liposomsuspensioner (indtil 5 mg/ml doxorubicin*HCl) kan bibeholdes, hvilket ikke er tilfældet med chromatografi pâ en molekylær-sigtekolonne (maks, 0,3 35 mg/ml). Den sâledes opnâede liposomsuspension er meget stabil og har ingen tendens til sedimentering, sâledes som det erThe exact amount of one or more of the above resins is introduced directly into the flask containing the liposome suspension to be purified and shaken for 10-60 minutes. After filtration through a sinter glass filter containing the ion exchange resin with absorbed physically unbound drug, the pure liposome suspension which is freeze-dried is obtained. This method of purifying the liposome suspension with ion exchange resins has the great advantage that highly concentrated liposome suspensions (up to 5 mg / ml doxorubicin * HCl) can be maintained, which is not the case with chromatography on a molecular sieve column (max, 0.3 35 mg / ml). mL). The liposome suspension thus obtained is very stable and has no tendency to settle as it is.
DK 157060BDK 157060B
3 tilfældet med suspensioner, der fâs ved ultracentrifugering.3 in the case of suspensions obtained by ultracentrifugation.
Det samme résultat opnâs, nâr man i stedet for ion-bytterharpikser anvendes polymère og copolymere uden nogen specifik kemisk funktion, der i reglen, men ikke udelukkende 5 reagerer pâ grund af Van der Waals-kræfter og i reglen er kendt soin adsorberende harpikser. Disse harpikser kan som f0lge af polaritetsforskellen mellem de hydrophobe stoffer, der danner liposomovertrækkene, og lægemidleme af mere eller mindre hydrophil natur anvendes ved rensningen af 10 liposomsuspensioner.The same result is obtained when, instead of ion-exchange resins, polymers and copolymers are used without any specific chemical function which usually, but not exclusively, react due to Van der Waals forces and are generally known as adsorbent resins. These resins can, as a result of the polarity difference between the hydrophobic substances forming the liposome coatings, and the drugs of more or less hydrophilic nature be used in the purification of 10 liposome suspensions.
Den endelige kemiske stabilisering opnâs ved fryse-t0rring af liposomsuspensionen.The final chemical stabilization is achieved by freeze-drying the liposome suspension.
Eksempel 1 15 1,5 g sojalecithin, 0,4 g cholestérol og 0,3 g dice- tylphosphat oploses i CH2CI2, og til denne oplesning sættes en vandig opl0sning af aminosidinsulfat i 0,02 molær phos-phatpuffer ved 6,5 i en koncentration pâ 3 mg/ml.Example 1 1.5 g of soya lecithin, 0.4 g of cholesterol and 0.3 g of diethyl phosphate are dissolved in CH 2 Cl 2, and to this solution an aqueous solution of aminosidine sulfate in 0.02 molar phosphate buffer is added at 6.5 concentration of 3 mg / ml.
Begge faser emulgeres ved indblæsning af nitrogen 20 ved stuetemperatur, indtil methylenchloridet er helt fjemet.Both phases are emulsified by blowing nitrogen 20 at room temperature until the methylene chloride is completely removed.
Suspensionen stabiliseres i 4 timer ved stuetemperatur, hvorpâ der i kolben hældes en mængde harpiks, der svarer til 5 g t0rharpiks, som fâs i handelen under betegnelsen "IRC-SO"®, en polymer kornformig harpiks, fra firmaet Rohm 25 og Haas.The suspension is stabilized for 4 hours at room temperature, to which is poured into the flask an amount of resin equivalent to 5 g of dry resin commercially available under the designation "IRC-SO" ®, a polymer granular resin, from Rohm 25 and Haas.
Efter 1 times rÿsten filtreres liposomsuspensionen gennem en glasfritte for at fjerne harpiksen, der tilbage-holder det fysisk ikke-bundne lægemiddel. Derefter stabiliseres liposomsuspensionen ved hjælp af frysetorring.After 1 hour of rest, the liposome suspension is filtered through a glass frit to remove the resin retaining the physically unbound drug. Then, the liposome suspension is stabilized by freeze drying.
3030
Eksempel 2 3,22 g lecithin, 1,13 g cholestérol, 0,956 g dicetyl-phosphat og 16 mg vitamin E-acetat oploses i en lille mængde methylenchlorid. 448 mg doxorubicin-hydrochlorid og 7,77 g 35 lactose opl0ses i en pufferoplosning med pH = 5,6 (0,066 M natriumphosphat, 0,0388 M NaCl og 0,1 mM EDTA-dinatriumsalt).Example 2 3.22 g of lecithin, 1.13 g of cholesterol, 0.956 g of dicetyl phosphate and 16 mg of vitamin E acetate are dissolved in a small amount of methylene chloride. 448 mg of doxorubicin hydrochloride and 7.77 g of lactose are dissolved in a buffer solution with pH = 5.6 (0.066 M sodium phosphate, 0.0388 M NaCl and 0.1 mM EDTA disodium salt).
DK 157060 BDK 157060 B
44
Den organisée og den vandige opl0sning blandes ved rystning.The organic solution and aqueous solution are mixed by shaking.
Derpâ bobles nitrogen igennem ved stuetemperatur, indtil methylenchloridet er helt fjernet. Suspensionen underkastes derefter lydbehandling ved, at den anbringes i en lydbehand-5 lingssonde, hvorpâ der i kolben hældes 80 g (vâd) ionbytter-harpiks "IRC-SO"®, en polymer kornformig harpiks, der fâs fra Rohm og Haas.Then nitrogen is bubbled through at room temperature until the methylene chloride is completely removed. The suspension is then subjected to sonication by placing it in a sonication probe to which 80 g (wet) ion exchange resin "IRC-SO" ®, a polymeric granular resin obtained from Rohm and Haas, is poured into the flask.
Efter 1 times rystning fjernes harpiksen ved filtre-ring, og liposomsuspensionen filtreres igen gennem et mem-10 branfilter med en poresitet pâ 3 μη. Liposomsuspensionen fordeles derpâ i hætteglas, anbringes i et frysetorringsap-parat og underkastes frysetorring.After 1 hour of shaking, the resin is removed by filtration and the liposome suspension is again filtered through a membrane filter with a porosity of 3 μη. The liposome suspension is then distributed into vials, placed in a freeze-drying apparatus and subjected to freeze-drying.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1943479 | 1979-01-19 | ||
| IT19434/79A IT1110989B (en) | 1979-01-19 | 1979-01-19 | PHARMACEUTICAL FORMS CONSTITUTED BY LIPOSOMES AND RELATED PROCEDURES |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK22380A DK22380A (en) | 1980-07-20 |
| DK157060B true DK157060B (en) | 1989-11-06 |
| DK157060C DK157060C (en) | 1990-04-09 |
Family
ID=11157905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK022380A DK157060C (en) | 1979-01-19 | 1980-01-18 | PROCEDURE FOR PREPARING A LIPOSOM SUSPENSION CONTAINING A MEDICINE |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS55100313A (en) |
| AT (1) | AT370623B (en) |
| AU (1) | AU536823B2 (en) |
| BE (1) | BE881225A (en) |
| CA (1) | CA1148470A (en) |
| CH (1) | CH648205A5 (en) |
| CS (1) | CS227010B2 (en) |
| DE (1) | DE3001842A1 (en) |
| DK (1) | DK157060C (en) |
| FI (1) | FI70672C (en) |
| FR (1) | FR2446635B1 (en) |
| GB (1) | GB2041871B (en) |
| HU (1) | HU184714B (en) |
| IE (1) | IE49141B1 (en) |
| IL (1) | IL59120A (en) |
| IT (1) | IT1110989B (en) |
| NL (1) | NL8000139A (en) |
| SE (1) | SE445171B (en) |
| SU (1) | SU1367839A3 (en) |
| YU (1) | YU44003B (en) |
| ZA (1) | ZA80269B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU184141B (en) * | 1979-12-27 | 1984-07-30 | Human Oltoanyagtermelo | Adjuvant particles compositions containing said particles and biologically active substances adsorbed thereon and a process for the preparation thereof |
| FR2521565B1 (en) * | 1982-02-17 | 1985-07-05 | Dior Sa Parfums Christian | PULVERULENT MIXTURE OF LIPID COMPONENTS AND HYDROPHOBIC CONSTITUENTS, METHOD FOR PREPARING SAME, HYDRATED LIPID LAMELLAR PHASES AND MANUFACTURING METHOD, PHARMACEUTICAL OR COSMETIC COMPOSITIONS COMPRISING HYDRATED LAMID PHASES |
| FR2553002B1 (en) * | 1983-10-06 | 1992-03-27 | Centre Nat Rech Scient | IMPROVED PROCESS FOR OBTAINING UNILAMELLAR LIPOSOMES OF HIGH DIAMETERS, THEIR PHARMACOLOGICAL APPLICATION FOR THE ENCAPSULATING OF AN ACTIVE INGREDIENT FOR ITS EXTEMPORANEOUS ADMINISTRATION AND CORRESPONDING DEVICE |
| US5736155A (en) * | 1984-08-08 | 1998-04-07 | The Liposome Company, Inc. | Encapsulation of antineoplastic agents in liposomes |
| CA1270198C (en) * | 1984-08-08 | 1990-06-12 | Marcel B Bally | Encapsulation of antineoplastic agents in liposomes |
| US4755388A (en) * | 1984-11-09 | 1988-07-05 | The Regents Of The University Of California | Liposome-encapsulated 5-fluoropyrimidines and methods for their use |
| IL79114A (en) * | 1985-08-07 | 1990-09-17 | Allergan Pharma | Method and composition for making liposomes |
| US6406713B1 (en) * | 1987-03-05 | 2002-06-18 | The Liposome Company, Inc. | Methods of preparing low-toxicity drug-lipid complexes |
| AU660288B2 (en) * | 1990-07-31 | 1995-06-22 | Transave, Inc. | Accumulation of amino acids and peptides into liposomes |
| DE4107152C2 (en) * | 1991-03-06 | 1994-03-24 | Gregor Cevc | Preparations for non-invasive administration of antidiabetics |
| DE4107153A1 (en) * | 1991-03-06 | 1992-09-10 | Gregor Cevc | Compsns. for application of active agents |
| JPH04127874U (en) * | 1991-05-13 | 1992-11-20 | 株式会社新潟鐵工所 | Pressure noise mitigation device for concrete pump transport pipes |
| JPH04134673U (en) * | 1991-06-07 | 1992-12-15 | 株式会社フジタ | Concrete pumping pressure fluctuation prevention device |
| CA2159596C (en) * | 1993-04-02 | 2002-06-11 | Royden Coe | Method of producing liposomes |
| IT1270678B (en) * | 1994-10-20 | 1997-05-07 | Bayer Ag | KETOPROFEN LIPOSOMES |
| DE19639811A1 (en) * | 1996-09-27 | 1998-04-02 | Artur Herzog Dr Mesmer | Use of a liposome solution to enhance the effectiveness and / or decrease the toxicity of drugs |
| CA2309597A1 (en) | 1997-11-10 | 1999-05-20 | Hiroshi Sorimachi | Sustainedly releasing agents for medicines and sustainedly released medicinal compositions containing the same |
| JP4283355B2 (en) * | 1997-11-10 | 2009-06-24 | 久光製薬株式会社 | Pharmaceutical sustained-release agent and sustained-release pharmaceutical composition containing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK425478A (en) * | 1977-09-30 | 1979-03-31 | Farmaceutici Italia | PROCEDURE FOR PREPARING INJECTIBLE LIPSOMER |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2249552A1 (en) * | 1971-10-12 | 1973-05-30 | Inchema S A | PROCESS FOR THE INCAPSULATION OF IN PARTICULAR WATER-SOLUBLE COMPOUNDS |
| JPS5126213A (en) * | 1974-08-21 | 1976-03-04 | Tanabe Seiyaku Co | JOHOSEIBIRYUSHISEIZAINO SEIHO |
| US4131815A (en) * | 1977-02-23 | 1978-12-26 | Oceanography International Corporation | Solid piezoelectric sand detection probes |
| GB1575343A (en) * | 1977-05-10 | 1980-09-17 | Ici Ltd | Method for preparing liposome compositions containing biologically active compounds |
-
1979
- 1979-01-19 IT IT19434/79A patent/IT1110989B/en active
-
1980
- 1980-01-09 NL NL8000139A patent/NL8000139A/en not_active Application Discontinuation
- 1980-01-14 IL IL59120A patent/IL59120A/en unknown
- 1980-01-14 YU YU81/80A patent/YU44003B/en unknown
- 1980-01-14 JP JP219280A patent/JPS55100313A/en active Granted
- 1980-01-14 AU AU54581/80A patent/AU536823B2/en not_active Ceased
- 1980-01-15 FR FR808000801A patent/FR2446635B1/en not_active Expired
- 1980-01-15 AT AT0019380A patent/AT370623B/en not_active IP Right Cessation
- 1980-01-15 CS CS80309A patent/CS227010B2/en unknown
- 1980-01-15 CA CA000343663A patent/CA1148470A/en not_active Expired
- 1980-01-16 ZA ZA00800269A patent/ZA80269B/en unknown
- 1980-01-16 IE IE91/80A patent/IE49141B1/en unknown
- 1980-01-17 HU HU8097A patent/HU184714B/en not_active IP Right Cessation
- 1980-01-17 SU SU802869298A patent/SU1367839A3/en active
- 1980-01-17 CH CH370/80A patent/CH648205A5/en not_active IP Right Cessation
- 1980-01-17 FI FI800151A patent/FI70672C/en not_active IP Right Cessation
- 1980-01-17 GB GB8001545A patent/GB2041871B/en not_active Expired
- 1980-01-18 DE DE19803001842 patent/DE3001842A1/en active Granted
- 1980-01-18 SE SE8000443A patent/SE445171B/en not_active IP Right Cessation
- 1980-01-18 BE BE0/199021A patent/BE881225A/en not_active IP Right Cessation
- 1980-01-18 DK DK022380A patent/DK157060C/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK425478A (en) * | 1977-09-30 | 1979-03-31 | Farmaceutici Italia | PROCEDURE FOR PREPARING INJECTIBLE LIPSOMER |
Also Published As
| Publication number | Publication date |
|---|---|
| ATA19380A (en) | 1982-09-15 |
| FI70672B (en) | 1986-06-26 |
| CS227010B2 (en) | 1984-04-16 |
| YU8180A (en) | 1983-12-31 |
| ZA80269B (en) | 1981-06-24 |
| SU1367839A3 (en) | 1988-01-15 |
| IL59120A (en) | 1984-05-31 |
| JPH0133446B2 (en) | 1989-07-13 |
| DK157060C (en) | 1990-04-09 |
| AU5458180A (en) | 1980-07-24 |
| JPS55100313A (en) | 1980-07-31 |
| FR2446635B1 (en) | 1989-03-10 |
| SE8000443L (en) | 1980-07-20 |
| DK22380A (en) | 1980-07-20 |
| SE445171B (en) | 1986-06-09 |
| AU536823B2 (en) | 1984-05-24 |
| DE3001842C2 (en) | 1990-04-26 |
| GB2041871A (en) | 1980-09-17 |
| IT7919434A0 (en) | 1979-01-19 |
| FI70672C (en) | 1986-10-06 |
| CA1148470A (en) | 1983-06-21 |
| CH648205A5 (en) | 1985-03-15 |
| IL59120A0 (en) | 1980-05-30 |
| HU184714B (en) | 1984-10-29 |
| IE800091L (en) | 1980-07-19 |
| DE3001842A1 (en) | 1980-07-31 |
| GB2041871B (en) | 1983-04-13 |
| BE881225A (en) | 1980-07-18 |
| AT370623B (en) | 1983-04-25 |
| NL8000139A (en) | 1980-07-22 |
| FI800151A (en) | 1980-07-20 |
| IT1110989B (en) | 1986-01-13 |
| IE49141B1 (en) | 1985-08-07 |
| FR2446635A1 (en) | 1980-08-14 |
| YU44003B (en) | 1990-02-28 |
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| PBP | Patent lapsed |