IE49141B1 - Liposomic suspensions - Google Patents
Liposomic suspensionsInfo
- Publication number
- IE49141B1 IE49141B1 IE91/80A IE9180A IE49141B1 IE 49141 B1 IE49141 B1 IE 49141B1 IE 91/80 A IE91/80 A IE 91/80A IE 9180 A IE9180 A IE 9180A IE 49141 B1 IE49141 B1 IE 49141B1
- Authority
- IE
- Ireland
- Prior art keywords
- resin
- suspension
- drug
- liposomic
- liposomic suspension
- Prior art date
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—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
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
DESCRIPTION
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 15 nm to 5p.
The procedure usually employed for preparing liposomes comprises two main steps, preparation and separation.
(5 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 non-entrapped drug which must be separated from the liposomes.
- 3 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 Hark. 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. 7838495 (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 adsorbent 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, io phosphonic or sulphonic functions, for example.
Alternatively they may be of the strong anionic type,
1st and 2nd type (see Applebaum, the Demineralizition by Ion-exchange in water treatment chemical processing of other liquids. Academic Press 1968); or of weak or average anionic type, cross-linked by salified quaternary ammonium, primary, secondary or teritiary aminic or phosphinic functions, for example. Suitable matrices include phenolformaldehyde, styrene-divinylbenzol, acrylates, methacrylates, and various hydrocarbons and other condensation resins.
They may be used in salified or activated form. The polymeric adsorbent 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 adsorbent 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, unlike those obtained by ultracentrifugation .
The conventional use of ultra sonic 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 and purification 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.
48141
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, aminosidlne sulphate and 5-fluorouracil.
The resins used in step (b) may be as described above, specifically suitable ones being Rohm & Haas IRC-5O, Dowex 50-X 4 100-200 mesh, Amberlite IRA-400 (Cl),
Dowex 1 50-100 mesh and Rohm t Haas XAD-7. These resins •IO 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 of the dichloromethane.
The suspension was stood at room temperature for 4 hours and then into the flask an amount equivalent to 5 g of
141 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 lo solution was poured into a flask containing 250 mg of m-benzoylhydratropic acid (generic name Ketoprofen) in 150 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, 5 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 10 polymeric absorbent resin.
2. A method according to claim 1 in which the resin has a matrix of phenolformaldehyde, gtyrene-divinylbenzol, an acrylate, a methacrylate or a hydrocarbon.
3. A method according to claim 1 or claim 2 in which 15 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, 1st or 2nd type, 20 (see reference herein), 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 25 the drug is doxorubicin hydrochloride, aminosidine sulphate or 5-fluorouracil.
6. A method for the preparation of a liposomic suspension, the method being substantially as described herein with reference to either of the Examples.
7. A liposomic suspension prepared by a method according 5 to any preceding claim,
8. A liposomic suspension according to claim 7, stabilised 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 |
|---|---|
| IE800091L IE800091L (en) | 1980-07-19 |
| IE49141B1 true IE49141B1 (en) | 1985-08-07 |
Family
ID=11157905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE91/80A IE49141B1 (en) | 1979-01-19 | 1980-01-16 | Liposomic suspensions |
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 |
| CA1270198A (en) * | 1984-08-08 | 1990-06-12 | Marcel B. Bally | 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 |
| 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 |
| CA2087965A1 (en) * | 1990-07-30 | 1992-02-01 | Ajoy Chakrabarti | 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 |
| JPH09502700A (en) * | 1993-04-02 | 1997-03-18 | ザ リポソーム カンパニー、インコーポレーテッド | Method for producing liposome |
| 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 |
| 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 |
| CN1278738A (en) * | 1997-11-10 | 2001-01-03 | 久光制药株式会社 | Release-sustaining agent for drugs and sustained-release pharmaceutical composition containing 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 |
| NL7809709A (en) * | 1977-09-30 | 1979-04-03 | Farmaceutici Italia | METHOD FOR PREPARING INJECTABLE LIPOSOMES |
-
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 JP JP219280A patent/JPS55100313A/en active Granted
- 1980-01-14 AU AU54581/80A patent/AU536823B2/en not_active Ceased
- 1980-01-14 YU YU81/80A patent/YU44003B/en unknown
- 1980-01-15 CS CS80309A patent/CS227010B2/en unknown
- 1980-01-15 AT AT0019380A patent/AT370623B/en not_active IP Right Cessation
- 1980-01-15 FR FR808000801A patent/FR2446635B1/en not_active Expired
- 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 SU SU802869298A patent/SU1367839A3/en active
- 1980-01-17 FI FI800151A patent/FI70672C/en not_active IP Right Cessation
- 1980-01-17 CH CH370/80A patent/CH648205A5/en not_active IP Right Cessation
- 1980-01-17 GB GB8001545A patent/GB2041871B/en not_active Expired
- 1980-01-17 HU HU8097A patent/HU184714B/en not_active IP Right Cessation
- 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 DE DE19803001842 patent/DE3001842A1/en active Granted
- 1980-01-18 DK DK022380A patent/DK157060C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK157060B (en) | 1989-11-06 |
| FI70672B (en) | 1986-06-26 |
| IL59120A0 (en) | 1980-05-30 |
| CS227010B2 (en) | 1984-04-16 |
| FR2446635B1 (en) | 1989-03-10 |
| IT1110989B (en) | 1986-01-13 |
| BE881225A (en) | 1980-07-18 |
| FI70672C (en) | 1986-10-06 |
| FI800151A (en) | 1980-07-20 |
| IL59120A (en) | 1984-05-31 |
| NL8000139A (en) | 1980-07-22 |
| DK157060C (en) | 1990-04-09 |
| AU536823B2 (en) | 1984-05-24 |
| DE3001842C2 (en) | 1990-04-26 |
| CA1148470A (en) | 1983-06-21 |
| IE800091L (en) | 1980-07-19 |
| YU8180A (en) | 1983-12-31 |
| SE8000443L (en) | 1980-07-20 |
| AT370623B (en) | 1983-04-25 |
| JPS55100313A (en) | 1980-07-31 |
| SE445171B (en) | 1986-06-09 |
| FR2446635A1 (en) | 1980-08-14 |
| ATA19380A (en) | 1982-09-15 |
| ZA80269B (en) | 1981-06-24 |
| CH648205A5 (en) | 1985-03-15 |
| DE3001842A1 (en) | 1980-07-31 |
| DK22380A (en) | 1980-07-20 |
| JPH0133446B2 (en) | 1989-07-13 |
| YU44003B (en) | 1990-02-28 |
| GB2041871B (en) | 1983-04-13 |
| HU184714B (en) | 1984-10-29 |
| AU5458180A (en) | 1980-07-24 |
| IT7919434A0 (en) | 1979-01-19 |
| SU1367839A3 (en) | 1988-01-15 |
| GB2041871A (en) | 1980-09-17 |
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