GB2041871A - Suspensions of Drug- containing Liposomes - Google Patents
Suspensions of Drug- containing Liposomes Download PDFInfo
- Publication number
- GB2041871A GB2041871A GB8001545A GB8001545A GB2041871A GB 2041871 A GB2041871 A GB 2041871A GB 8001545 A GB8001545 A GB 8001545A GB 8001545 A GB8001545 A GB 8001545A GB 2041871 A GB2041871 A GB 2041871A
- Authority
- GB
- United Kingdom
- Prior art keywords
- resin
- drug
- suspension
- liposomic
- liposomic suspension
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1277—Preparation processes; Proliposomes
Landscapes
- 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)
Abstract
Pharmaceutical suspensions of liposomes containing a drug (e.g. doxorubicin hydrochloride, aminosidine sulphate or 5- fluorouracil) are prepared by dissolution of lipidic components in a solvent, addition of an aqueous solution of the drug, and emulsification by insufflation of an inert gas until the solvent is completely removed by evaporation, and then the liposomes are separated from non-entrapped drug by shaking the suspension with a polymeric ion exchange resin or a polymeric absorbent resin to absorb the non- entrapped drug, then filtering off the resin. The ion exchange resin may be a strong or weak, anionic or cationic resin. The resultant liposomic suspensions may be lyophilised.
Description
SPECIFICATION
Liposomic Suspensions
The invention relates to the preparation of
liposomes. Liposomes are pharmaceutical compositions in which the drug is contained in corpuscles consisting of aqueous and lipidic concentric layers. The drug can be contained both in the aqueous and in the lipidic layer. The lipidic layer generally comprises a phospholipid, such as lecithin or sphyngomyelin, a steroid, for example cholesterol, and an ionic tensioactive substance, such as dicetylphosphate, stearylamine or phosphatidic acid. Other hydrophobic materials may be present. Diameters of liposomes generally range from 1 5 nm to 5,.
The procedure usually employed for preparing liposomes comprises two main steps, preparation and separation.
A conventional preparation step comprises dissolving the lipidic components in a suitable solvent, such as chloroform, which is then evaporated off, generally under reduced pressure.
To the flask containing the residue as a thin layer, an aqueous solution of the drug is added and the whole is emulsified by submission to ultrasonic shaking for a time ranging from 10 seconds to some hours. The liposomic suspension so obtained contains an important fraction of nonentrapped drug which must be separated from the liposomes.
A conventional separation step is carried out by column chromatography with a resinous molecular sieve, for example Sepharose 2B, 4B or 6B. Sepharose is a Trade Mark. The liposomes elute first, whereas the free drug is retained by the resin. An alternative separation step, also conventional, is the ultracentrifugation at
100,000 g and subsequent washing, also by ultracentrifugation, with buffered solution. A third conventional separation step is dialysis.
British Patent Specification No. 7,838,495 (2004745A), in our former name of Societa
Farmaceutici Italia S.p.A., describes a separation step which comprises shaking the suspension with a polymeric ion exchange resin or a polymeric absorbent resin and filtering off the resin. Suitable polymeric ion exchange resins for use in this separation step include both solid and liquid synthetic organic polymers, usually but not necessarily crosslinked by functional moieties.
They may be of the weak, average or strong cationic type, cross-linked by carboxylic, phosphonic or sulphonic functions, for example.
Alternatively they may be of the strong anionic type, 1 st and 2nd type, or of weak or average anionic type, cross-linked by salified quaternary ammonium, primary, secondary or tertiary aminic or phosphinic functions, for example. Suitable matrices include phenolformaldehyde, styrenedivinylbenzol, acrylates, methacrylates, and various hydrocarbons and other condensation resins.
They may be used in salified or activated form.
The polymeric absorbent resins can be employed owing to the difference of polarity between the
hydrophobic substances forming the liposomic shell and the drugs which are hydrophilic; aliphatic, aromatic and inorganic absorbent resins can be used. Shaking is preferably carried out for
10 to 60 minutes. This purification procedure enables very concentrated liposomic suspensions to be obtained (for example, up to 5 mg/ml of doxorubicin hydrochloride). Such concentrations cannot be achieved by chromatography with a resinous molecular sieve (max 0.3 mg/ml). The liposomic suspension achieved is very stable and not inclined to sediment, unlke those obtained by ultracentrifugation.
The conventional use of ultrasonic shaking for emulsification in the preparation step, however is liable to cause titanium contamination of the liposomic suspension from the horns, tips or microtips of the sonic processor, and furthermore certain large molecules may be disrupted by the ultrasonic energy.
The invention provides a method for the preparation of a liposomic suspension, the method comprising (a) preparing the liposomic suspension by dissolution of lipidic components in a solvent, addition of an aqueous solution of a drug, and emulsification by insufflation of an inert gas until the solvent is completely removed by evaporation, and (b) the liposomic suspension by shaking the suspension with a polymeric ion exchange resin or a polymeric absorbent resin.
Definitive chemical stabilisation may be achieved by lyophilisation of the liposomic suspension.
Preferred drugs for use in the method according to the invention include doxorubicin hydrochloride, aminosidine sulphate and 5fluorouracil.
The resins used in step (b) may be as described above, specifically suitable ones being Rohm a Haas IRC-50, Dowex 50-X 4 100--200 mesh,
Amberlite IRA-400 (Cl), Dowex I 50-100 mesh and Rohm a Haas XAD-7. These resins are specified by the Trade Marks applied to them.
The invention is illustrated by the following
Examples.
Example 1
1.5 g of soya-lecithin, 0.4 g of cholesterol and 0.3 g of dicetylphosphate were dissolved in dichloromethane. A solution of aminosidine sulphate in 0.02M buffer phosphate at pH 6.5 at the concentration of 3 mg/ml was added. The two phases were emulsified under shaking, nitrogen being bubbled through at room temperature until complete removal ofthe dichloromethane.
The suspension was stood at room temperature for 4 hours and then into the flask an amount equivalent to 5 g of dry resin of Rohm and
Haas IRC-50 resin was poured. After 1 hour of shaking the liposomic suspension was filtered through a sintered glass filter to remove the resin which had retained the non-entrapped drug. The liposomic suspension was then stabilised by lyophilisation.
Example 2
Operating as described in Example 1, 2.3 g of egg lecithin, 0.65 g of cholesterol and 0.15 g of octadecylamine were dissolved in 50 ml of dichloromethane and the solution was poured into a flask containing 250 mg of mbenzoylhydratropic acid (generic name
Ketoprofen) in 1 50 ml of Na, K buffer phosphate 0.02 M at pH 7.4. Inert gas (nitrogen) was bubbled into the flask, under shaking, until complete removal of the organic solvent and resulting formation of the liposomic suspension.
10 ml of anion exchange resin IRa 400 (Cl-) manufactured by Rohm and Haas were added to the suspension. After 30 minutes of shaking, the resin was removed by filtration and the purified liposomic suspension was lyophilized.
Claims (8)
1. A method for the preparation of a liposomic suspension, the method comprising (a) preparing the liposomic suspension by dissolution of lipidic components in a solvent, addition of an aqueous solution of a drug, and emulsification by insufflation of an inert gas until the solvent is completely removed by evaporation, and (b) purifying the liposomic suspension by shaking the suspension with a polymeric ion exchange resin or a polymeric absorbent resin.
2. A method according to claim 1 in which the resin has a matrix of phenolformaldehyde, styrene-divinylbenzol, an acrylate, a methacrylate or a hydrocarbon.
3. A method according to claim 1 or claim 2 in which the resin is of the weak, average or strong cationic type, cross-linked by carboxylic, phosphonic or sulphonic functions.
4. A method according to claim 1 or claim 2 in which the resin is of the strong anionic type, 1 st or 2nd type, or of the weak or average anionic type, cross-linked by salified quaternary ammonium, primary, secondary or tertiary aminic or phosphinic functions.
5. A method according to any preceding claim in which the drug is doxorubicin hydrochloride, aminosidine sulphate or 5fluoroacil.
6. A method for the preparation of a liposomic suspension, the method being substantiaily as described herein with reference to either of the
Examples.
7. A liposomic suspension prepared by a method according to any preceding claim.
8. A liposomic suspension according to claim 7, stabilized by lyophilisation.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19434/79A IT1110989B (en) | 1979-01-19 | 1979-01-19 | PHARMACEUTICAL FORMS CONSTITUTED BY LIPOSOMES AND RELATED PROCEDURES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2041871A true GB2041871A (en) | 1980-09-17 |
| GB2041871B GB2041871B (en) | 1983-04-13 |
Family
ID=11157905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8001545A Expired GB2041871B (en) | 1979-01-19 | 1980-01-17 | Suspensions of drug-containing liposomes |
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) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3048815A1 (en) * | 1979-12-27 | 1981-09-10 | Humán Oltóanyagtermelö és Kutató Intézet, 1107 Budapest | PARTICLES FROM LIPOID-SOLUBLE SUBSTANCES, FROM THESE PARTICLES AND MIXTURES CONSTRUCTED FROM THESE BODIES, AND METHOD FOR THE PRODUCTION THEREOF |
| EP0211647A1 (en) * | 1985-08-07 | 1987-02-25 | Smithkline Beecham Corporation | Method and composition for making liposomes |
| EP0191824A4 (en) * | 1984-08-08 | 1988-04-26 | Liposome Co Inc | 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 |
| WO1994022430A1 (en) * | 1993-04-02 | 1994-10-13 | The Liposome Company, Inc. | Method of producing liposomes |
| US5380531A (en) * | 1990-07-31 | 1995-01-10 | The Liposome Company, Inc. | Accumulations of amino acids and peptides into liposomes |
| EP0707847A1 (en) * | 1994-10-20 | 1996-04-24 | Bayer Ag | Ketoprofen liposomes |
| US5736155A (en) * | 1984-08-08 | 1998-04-07 | The Liposome Company, Inc. | Encapsulation of antineoplastic agents in liposomes |
| US6406713B1 (en) * | 1987-03-05 | 2002-06-18 | The Liposome Company, Inc. | Methods of preparing low-toxicity drug-lipid complexes |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| AU733802B2 (en) * | 1997-11-10 | 2001-05-24 | Hisamitsu Pharmaceutical Co., Inc. | Sustainedly releasing agents for medicines and sustainedly released medicinal compositions containing the same |
Family Cites Families (5)
| 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 |
| AU528260B2 (en) * | 1977-09-30 | 1983-04-21 | Farmitalia Carlo Erba S.P.A. | Liposomic suspension |
-
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 JP JP219280A patent/JPS55100313A/en active Granted
- 1980-01-14 YU YU81/80A patent/YU44003B/en unknown
- 1980-01-14 AU AU54581/80A patent/AU536823B2/en not_active Ceased
- 1980-01-14 IL IL59120A patent/IL59120A/en unknown
- 1980-01-15 CS CS80309A patent/CS227010B2/en unknown
- 1980-01-15 CA CA000343663A patent/CA1148470A/en not_active Expired
- 1980-01-15 FR FR808000801A patent/FR2446635B1/en not_active Expired
- 1980-01-15 AT AT0019380A patent/AT370623B/en not_active IP Right Cessation
- 1980-01-16 ZA ZA00800269A patent/ZA80269B/en unknown
- 1980-01-16 IE IE91/80A patent/IE49141B1/en unknown
- 1980-01-17 SU SU802869298A patent/SU1367839A3/en active
- 1980-01-17 GB GB8001545A patent/GB2041871B/en not_active Expired
- 1980-01-17 CH CH370/80A patent/CH648205A5/en not_active IP Right Cessation
- 1980-01-17 HU HU8097A patent/HU184714B/en not_active IP Right Cessation
- 1980-01-17 FI FI800151A patent/FI70672C/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
- 1980-01-18 DE DE19803001842 patent/DE3001842A1/en active Granted
- 1980-01-18 SE SE8000443A patent/SE445171B/en not_active IP Right Cessation
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3048815A1 (en) * | 1979-12-27 | 1981-09-10 | Humán Oltóanyagtermelö és Kutató Intézet, 1107 Budapest | PARTICLES FROM LIPOID-SOLUBLE SUBSTANCES, FROM THESE PARTICLES AND MIXTURES CONSTRUCTED FROM THESE BODIES, AND METHOD FOR THE PRODUCTION THEREOF |
| EP0191824A4 (en) * | 1984-08-08 | 1988-04-26 | Liposome Co Inc | Encapsulation of antineoplastic agents in liposomes. |
| US5736155A (en) * | 1984-08-08 | 1998-04-07 | The Liposome Company, Inc. | 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 |
| EP0211647A1 (en) * | 1985-08-07 | 1987-02-25 | Smithkline Beecham Corporation | 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 |
| US5380531A (en) * | 1990-07-31 | 1995-01-10 | The Liposome Company, Inc. | Accumulations of amino acids and peptides into liposomes |
| WO1994022430A1 (en) * | 1993-04-02 | 1994-10-13 | The Liposome Company, Inc. | Method of producing liposomes |
| AU676906B2 (en) * | 1993-04-02 | 1997-03-27 | Transave, Inc. | Method of producing liposomes |
| EP0707847A1 (en) * | 1994-10-20 | 1996-04-24 | Bayer Ag | Ketoprofen liposomes |
| US5741515A (en) * | 1994-10-20 | 1998-04-21 | Bayer Aktiengesellschaft | Ketoprofen liposomes |
| AU698915B2 (en) * | 1994-10-20 | 1998-11-12 | Bayer Aktiengesellschaft | Ketoprofen liposomes |
Also Published As
| Publication number | Publication date |
|---|---|
| CH648205A5 (en) | 1985-03-15 |
| HU184714B (en) | 1984-10-29 |
| FI800151A7 (en) | 1980-07-20 |
| CS227010B2 (en) | 1984-04-16 |
| YU8180A (en) | 1983-12-31 |
| ATA19380A (en) | 1982-09-15 |
| IE800091L (en) | 1980-07-19 |
| FR2446635B1 (en) | 1989-03-10 |
| NL8000139A (en) | 1980-07-22 |
| IE49141B1 (en) | 1985-08-07 |
| AU5458180A (en) | 1980-07-24 |
| IL59120A0 (en) | 1980-05-30 |
| JPH0133446B2 (en) | 1989-07-13 |
| AT370623B (en) | 1983-04-25 |
| SE445171B (en) | 1986-06-09 |
| CA1148470A (en) | 1983-06-21 |
| DE3001842C2 (en) | 1990-04-26 |
| FI70672B (en) | 1986-06-26 |
| DK157060C (en) | 1990-04-09 |
| DE3001842A1 (en) | 1980-07-31 |
| IL59120A (en) | 1984-05-31 |
| YU44003B (en) | 1990-02-28 |
| SU1367839A3 (en) | 1988-01-15 |
| ZA80269B (en) | 1981-06-24 |
| AU536823B2 (en) | 1984-05-24 |
| BE881225A (en) | 1980-07-18 |
| GB2041871B (en) | 1983-04-13 |
| IT1110989B (en) | 1986-01-13 |
| JPS55100313A (en) | 1980-07-31 |
| DK157060B (en) | 1989-11-06 |
| FI70672C (en) | 1986-10-06 |
| FR2446635A1 (en) | 1980-08-14 |
| DK22380A (en) | 1980-07-20 |
| IT7919434A0 (en) | 1979-01-19 |
| SE8000443L (en) | 1980-07-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19950117 |