CA1148470A - Pharmaceutical compositions consisting or consisting essentially of liposomes and processes for making same - Google Patents
Pharmaceutical compositions consisting or consisting essentially of liposomes and processes for making sameInfo
- Publication number
- CA1148470A CA1148470A CA000343663A CA343663A CA1148470A CA 1148470 A CA1148470 A CA 1148470A CA 000343663 A CA000343663 A CA 000343663A CA 343663 A CA343663 A CA 343663A CA 1148470 A CA1148470 A CA 1148470A
- Authority
- CA
- Canada
- Prior art keywords
- resins
- polymers
- liposomes
- ion
- liposomic
- 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.)
- Expired
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
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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)
Abstract
ABSTRACT OF THE DISCLOSURE
A method is disclosed for purifying non-homogeneous systems, known as liposomic suspensions, from non-entrapped drugs wherein said suspensions are treated with liquid or solid polymers of synthetic and organic nature having chemical functionality, which are used as ion-exchangers. The liquid or solid polymers are based on styrene, divinylbenzene, acrylic acid, methacrylic acid, and the like, normally known as ion-exchange resins, and may include carboxylic, phosphonic, or sulphonic functions of different matrices. The ion-exchange resins may also include salified quaternary ammonium, primary, secondary and tertiary amminic or phosphinic functions or other functions with different matrices, including phenolformaldehyde, styrene-divinyl-benzene, acrylates, methacrylates, hydrocarbons and condensation-resins.
Treatment may also be carried out with polymers, copolymers, or mixtures thereof, not having any specific chemical function and which normally, but not exclusively, react according to Van der Waals' forces, commonly known as adsorbents. The invention also includes pharmaceutical compositions consisting or consisting essentially of lyophilic liposomes of doxorubicin hydrochloride, aminosidine sulphate or 5-fluoro-uracil.
A method is disclosed for purifying non-homogeneous systems, known as liposomic suspensions, from non-entrapped drugs wherein said suspensions are treated with liquid or solid polymers of synthetic and organic nature having chemical functionality, which are used as ion-exchangers. The liquid or solid polymers are based on styrene, divinylbenzene, acrylic acid, methacrylic acid, and the like, normally known as ion-exchange resins, and may include carboxylic, phosphonic, or sulphonic functions of different matrices. The ion-exchange resins may also include salified quaternary ammonium, primary, secondary and tertiary amminic or phosphinic functions or other functions with different matrices, including phenolformaldehyde, styrene-divinyl-benzene, acrylates, methacrylates, hydrocarbons and condensation-resins.
Treatment may also be carried out with polymers, copolymers, or mixtures thereof, not having any specific chemical function and which normally, but not exclusively, react according to Van der Waals' forces, commonly known as adsorbents. The invention also includes pharmaceutical compositions consisting or consisting essentially of lyophilic liposomes of doxorubicin hydrochloride, aminosidine sulphate or 5-fluoro-uracil.
Description
~ 70 1 The present invention relates to pharmaceutical com-positions (lyophilic liposomes) and to processes for their pre~
paration and purificaticn.
More particularly, the invention re~ers to a new rnethod for purifying liposomic suspensions obtained according to per se known methods and for stabilizing same by lyophilization.
Liposomes are pharmaceutical compositions in which the drug is contained either dispersed or variously present in cor-puscles consisting of aqueous concentric layers adherent to 1~ lipidic layers (hydrophobic). The drug may be present both in the aqueous layer and in the lipidic one ( inside or outside) or, in any event, in the non-homogeneous system generally known as a liposomic suspension.
The hydropho~ic layer, generally but not exclusively, comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surface active substances such as dicetylphosphate, stearylamine or phosphatidic acid, and/or other materials of a hydrophobic nature.
The diameters of the liposomes generally range from 15 nm to 5 ~.
The preparation or process generally carried out according to the known art comprises two main steps: The pre-ro~
paration of the liposomes and the purification of same ~ non-entrapped drug.
1. Preparation of the liposomes: the lipidic or lipophilic components are dissolved in a suitable solvent which is then evaporated to dryness, generally under ~acuum.
The aqueous layer containing the druy i5 added to the flask containing the residwe as a thin la~er and the whole is submitted to mechanical or ultrasonic shaking 1 for a time ranging from 10 seconds to several hours.
the non-homogeneous layer so obtained (yenerally indi-cated as a liposomic suspension), must be purified from the non-entrapped drug.
paration and purificaticn.
More particularly, the invention re~ers to a new rnethod for purifying liposomic suspensions obtained according to per se known methods and for stabilizing same by lyophilization.
Liposomes are pharmaceutical compositions in which the drug is contained either dispersed or variously present in cor-puscles consisting of aqueous concentric layers adherent to 1~ lipidic layers (hydrophobic). The drug may be present both in the aqueous layer and in the lipidic one ( inside or outside) or, in any event, in the non-homogeneous system generally known as a liposomic suspension.
The hydropho~ic layer, generally but not exclusively, comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surface active substances such as dicetylphosphate, stearylamine or phosphatidic acid, and/or other materials of a hydrophobic nature.
The diameters of the liposomes generally range from 15 nm to 5 ~.
The preparation or process generally carried out according to the known art comprises two main steps: The pre-ro~
paration of the liposomes and the purification of same ~ non-entrapped drug.
1. Preparation of the liposomes: the lipidic or lipophilic components are dissolved in a suitable solvent which is then evaporated to dryness, generally under ~acuum.
The aqueous layer containing the druy i5 added to the flask containing the residwe as a thin la~er and the whole is submitted to mechanical or ultrasonic shaking 1 for a time ranging from 10 seconds to several hours.
the non-homogeneous layer so obtained (yenerally indi-cated as a liposomic suspension), must be purified from the non-entrapped drug.
2. Separation of the liposomes from the non-entrapped drug: this procedure is usually carried out by elution on a chromatographic column using resins having an exclusively molecular sieve-function, such as SepharoseR, 2B, 4B or 6B, or the like.
Liposomes are first recovered, while the free drug is retained by the resin.
Another method is ultacentrifugation at 100,000 g and /ac~nf~ ?o ~!~o~l7 subsequent washing, always ~y ~ t~ u~ with a buffered solution. Still another method also used is dialysis.
The present invention relates to a new purification process for the non-homogeneous layer known as liposomic suspen-sion by both liquid and solid polymers which generally are of synthetic or organic nature with chemical functionality which can ~e used as ion-exchangers, such as for example, those based ~ on styrene, divinylbenzene, acrylic or methacrylic acid, and usually known as ion-exchange resins.
A predetermined quantity of one or more of the resins ~t~i~
above reported is introduced directly into the ~ t containing the liposomic suspension to be purified and this is submitted to shaking for 10 to 60 minutes. After filtration through a sintered glass filter able to retain the ion-exchan~e resin on which the non-entrapped drug has been adsorbed, the liposomic pure suspension is obtained, which then may be suhmitted to lyophilization.
This purification procedure of the liposomic suspensions ith ion-exchange resins shows the great advantage of maintaining highly concentrated liposomic suspensions (up to 5 mg/ml of doxorubicin HCl) which cannot be maintained by chromatography on a molecular sieve column ~max 0.3 mg/ml). The liposomic susp~n~
sion so obtained is very stable and is not inclined to sediment or settle-out, unlike those obtained by ultracentrifugation.
The same result i5 achieved by ernploying, instead of ion-exchange resins, polymers and copolymers with no speciic chemical function and which normally, but not exclusively, react according to Van der Wa~ls' forces, generally known as adsorbent resins. These resins can be employed in the purification of liposomic suspensions owing to the difference of polarity between the hydrophobic substances forming the liposomic shell and the drugs of more or less hydrophilic nature.
The final chemical stabilization is achieved by lyo-philization of the liposomic suspension.
The following examples are given for illustrative purposes in order still better to demonstrate the invention and its advantages:
~ EXAMPLE
In a saponification flask the following quantities of lipids were dissolved in chloroform and evaporated under vacuum to dryness: 1.5 g of egg lecithin, 0.4 g of cholesterol, and 0.2 g of dicetylphosphate.
A solution of doxorubicin hydrochloride ~at a concen-tration of 10 mg/ml) was poured into the flask, in buffer pho.s-- phate 0.007N, and the suspension subjected to ultrasonic ~haking for 1 minute.
lhe suspension was allowed to stand for 30 minutes a~
room temperature under nitrgen. 2 g of a resin, previously '`~' .
1 activated in sodium form, ohtained by polymerization of methyl-methacrylate properly "cross-linked~ with a chemical reagent, such as divinylbenzene, with carboxylic functionality and macroreticular structure, which allows its use also in hydro-phobic solutions, commercially known by the trademark IRC-S0 and produced by Rohm and Haas, were then added (weight refers to dry weight and is equivalent to 5 ml of in1ated or swollen resin).
rrhe flask was subjected for about 30 minutes to shaking and then the suspension was filtered through a G 1 porous sheet of filter material.
Liposomes of size varying from 0.5 to 2 ~ and containing about 60% of the starting amount of doxorubicin so obtained were sta~ilized by lyophilization.
E ~
Operating as previously described in Example 1, and with the same amounts of lipids and doxorubicin, the ultra-sonic shaking time was extended to 10 minutes in order to obtain liposomes o size less then 1 ~.
Since the liposomes were not perfectly homogeneous in size, a non-gramllar resin was used having also a sieve function.
10 ml of resin of the type known on the market as DOWEX 50-X 4 100-200 Mesh (trademark~ previously activated in sodium form were therefore added.
After filtration, a suspension was obtained containing liposomes of siæe varying from 0.2 to 0.8 ~ and comprising 75%
o the starting doxorubicin.
The liposomes were sta~ilized by lyophilization.
EX~MPLE _3 A solution o S-fluorouracil at a cGncentration of 10 mg/ml in buffer phosphate 0.00lN at pEI 8 was poured into a 1 saponification flask containing the lipidic phase prepared as above described.
The suspension was treated as in Example 1, using as filterlng resin 10 ml of the type known on the market as Amberlite IR~-400 ~Cl) previously activated as the hydrochloride.
The liposomes so obtained were stabilized by lyophil-ization.
The liposomes of S-fluorouracil were prepared operating as previously described with the following amounts of lipids:
1.5 g of egg lecithin, 0.4 g of cholesterol, and 0.2 g of stear-ylamine.
As purification system, 10 ml of a resi~ of the type ` known on the market as DOWEX 1 ~50-100 Mesh), previously act-ivated, were employed.
The liposomes so o~tained were stabilized by lyophil-iza tion .
Example 2 was repeated, except that the resin DOWEX
50~-X, 100-200 Mesh, was replaced by 15 g of adsor~ent resin Rohm ; and Haas XAD 7, and the shaking time was extended to 40 minutes.
After filtration through sintered filter glass G l, a suspension of liposomes containing a~out 50~ of the starting amount of doxorubicin was obtained.
The'liposomes were sta~ilized by lyophilization.
`~ 1.5 g of soya-lecithin, 0.4 g of cholesterol, and 0.3 - g of dicetylphosphate were dissolved in CHzCl2 and to this solution another solution of aminosidine sulphate in 0.02M buffer phosphate at pH 6.5 at the concentration of 3 mg/ml was added.
.
. , , *Trade Marks _5_ ~ ` , .,:.' , :
t The two phases were emulsified and as an emulsion subjected to shaking, and nitrogen was bubbled in at room temp-erature until the complete evaporation of the methylene chloride took place.
The suspension was stabilized at room temperature for 4 hours, then into the flask was poured an amount of resin, known commercially by the trademark "IRC-50 of Rohm and Haas", equivalent to 5 g of dry resin.
After 1 hour of shaking, the liposomic suspension was 1~ filtered on a sintered glass filter to remove the resin which had retained the non-entrapped drug.
The liposomic suspension was then stabilized by lyo-philization.
Operating as pre~iously described in Example 6, 2.3 g of lecithin ex-egg, 0.65 g of cholesterol and 0.15 g of oct-adecylamine have been dissolved in 50 ml of CH2C12 and the sol-ution has been poured into a flask containing 250 mg of m-benzoylhydratropic acid ~generic name Ketoprofen) in 150 ml of Na,K buffer phosphate 0~02M at pH 7.4.
Inert gas (N2~ has been poured into the flask kept under shaking till complete removal of the organic solvent and the resulting formation of liposomic suspension, to which 10 ml of anion exchange resin IRA 400 ~Cl ) manufactured by Rohm and Haas have been added.
After 30 minutes of shaking, the resin has been removed by filtration and the purified liposomic suspension has been lyophilized.
*Trade Marks -6-
Liposomes are first recovered, while the free drug is retained by the resin.
Another method is ultacentrifugation at 100,000 g and /ac~nf~ ?o ~!~o~l7 subsequent washing, always ~y ~ t~ u~ with a buffered solution. Still another method also used is dialysis.
The present invention relates to a new purification process for the non-homogeneous layer known as liposomic suspen-sion by both liquid and solid polymers which generally are of synthetic or organic nature with chemical functionality which can ~e used as ion-exchangers, such as for example, those based ~ on styrene, divinylbenzene, acrylic or methacrylic acid, and usually known as ion-exchange resins.
A predetermined quantity of one or more of the resins ~t~i~
above reported is introduced directly into the ~ t containing the liposomic suspension to be purified and this is submitted to shaking for 10 to 60 minutes. After filtration through a sintered glass filter able to retain the ion-exchan~e resin on which the non-entrapped drug has been adsorbed, the liposomic pure suspension is obtained, which then may be suhmitted to lyophilization.
This purification procedure of the liposomic suspensions ith ion-exchange resins shows the great advantage of maintaining highly concentrated liposomic suspensions (up to 5 mg/ml of doxorubicin HCl) which cannot be maintained by chromatography on a molecular sieve column ~max 0.3 mg/ml). The liposomic susp~n~
sion so obtained is very stable and is not inclined to sediment or settle-out, unlike those obtained by ultracentrifugation.
The same result i5 achieved by ernploying, instead of ion-exchange resins, polymers and copolymers with no speciic chemical function and which normally, but not exclusively, react according to Van der Wa~ls' forces, generally known as adsorbent resins. These resins can be employed in the purification of liposomic suspensions owing to the difference of polarity between the hydrophobic substances forming the liposomic shell and the drugs of more or less hydrophilic nature.
The final chemical stabilization is achieved by lyo-philization of the liposomic suspension.
The following examples are given for illustrative purposes in order still better to demonstrate the invention and its advantages:
~ EXAMPLE
In a saponification flask the following quantities of lipids were dissolved in chloroform and evaporated under vacuum to dryness: 1.5 g of egg lecithin, 0.4 g of cholesterol, and 0.2 g of dicetylphosphate.
A solution of doxorubicin hydrochloride ~at a concen-tration of 10 mg/ml) was poured into the flask, in buffer pho.s-- phate 0.007N, and the suspension subjected to ultrasonic ~haking for 1 minute.
lhe suspension was allowed to stand for 30 minutes a~
room temperature under nitrgen. 2 g of a resin, previously '`~' .
1 activated in sodium form, ohtained by polymerization of methyl-methacrylate properly "cross-linked~ with a chemical reagent, such as divinylbenzene, with carboxylic functionality and macroreticular structure, which allows its use also in hydro-phobic solutions, commercially known by the trademark IRC-S0 and produced by Rohm and Haas, were then added (weight refers to dry weight and is equivalent to 5 ml of in1ated or swollen resin).
rrhe flask was subjected for about 30 minutes to shaking and then the suspension was filtered through a G 1 porous sheet of filter material.
Liposomes of size varying from 0.5 to 2 ~ and containing about 60% of the starting amount of doxorubicin so obtained were sta~ilized by lyophilization.
E ~
Operating as previously described in Example 1, and with the same amounts of lipids and doxorubicin, the ultra-sonic shaking time was extended to 10 minutes in order to obtain liposomes o size less then 1 ~.
Since the liposomes were not perfectly homogeneous in size, a non-gramllar resin was used having also a sieve function.
10 ml of resin of the type known on the market as DOWEX 50-X 4 100-200 Mesh (trademark~ previously activated in sodium form were therefore added.
After filtration, a suspension was obtained containing liposomes of siæe varying from 0.2 to 0.8 ~ and comprising 75%
o the starting doxorubicin.
The liposomes were sta~ilized by lyophilization.
EX~MPLE _3 A solution o S-fluorouracil at a cGncentration of 10 mg/ml in buffer phosphate 0.00lN at pEI 8 was poured into a 1 saponification flask containing the lipidic phase prepared as above described.
The suspension was treated as in Example 1, using as filterlng resin 10 ml of the type known on the market as Amberlite IR~-400 ~Cl) previously activated as the hydrochloride.
The liposomes so obtained were stabilized by lyophil-ization.
The liposomes of S-fluorouracil were prepared operating as previously described with the following amounts of lipids:
1.5 g of egg lecithin, 0.4 g of cholesterol, and 0.2 g of stear-ylamine.
As purification system, 10 ml of a resi~ of the type ` known on the market as DOWEX 1 ~50-100 Mesh), previously act-ivated, were employed.
The liposomes so o~tained were stabilized by lyophil-iza tion .
Example 2 was repeated, except that the resin DOWEX
50~-X, 100-200 Mesh, was replaced by 15 g of adsor~ent resin Rohm ; and Haas XAD 7, and the shaking time was extended to 40 minutes.
After filtration through sintered filter glass G l, a suspension of liposomes containing a~out 50~ of the starting amount of doxorubicin was obtained.
The'liposomes were sta~ilized by lyophilization.
`~ 1.5 g of soya-lecithin, 0.4 g of cholesterol, and 0.3 - g of dicetylphosphate were dissolved in CHzCl2 and to this solution another solution of aminosidine sulphate in 0.02M buffer phosphate at pH 6.5 at the concentration of 3 mg/ml was added.
.
. , , *Trade Marks _5_ ~ ` , .,:.' , :
t The two phases were emulsified and as an emulsion subjected to shaking, and nitrogen was bubbled in at room temp-erature until the complete evaporation of the methylene chloride took place.
The suspension was stabilized at room temperature for 4 hours, then into the flask was poured an amount of resin, known commercially by the trademark "IRC-50 of Rohm and Haas", equivalent to 5 g of dry resin.
After 1 hour of shaking, the liposomic suspension was 1~ filtered on a sintered glass filter to remove the resin which had retained the non-entrapped drug.
The liposomic suspension was then stabilized by lyo-philization.
Operating as pre~iously described in Example 6, 2.3 g of lecithin ex-egg, 0.65 g of cholesterol and 0.15 g of oct-adecylamine have been dissolved in 50 ml of CH2C12 and the sol-ution has been poured into a flask containing 250 mg of m-benzoylhydratropic acid ~generic name Ketoprofen) in 150 ml of Na,K buffer phosphate 0~02M at pH 7.4.
Inert gas (N2~ has been poured into the flask kept under shaking till complete removal of the organic solvent and the resulting formation of liposomic suspension, to which 10 ml of anion exchange resin IRA 400 ~Cl ) manufactured by Rohm and Haas have been added.
After 30 minutes of shaking, the resin has been removed by filtration and the purified liposomic suspension has been lyophilized.
*Trade Marks -6-
Claims (19)
1. A method for the purification of non-homogeneous systems known as liposomic suspensions, from non-entrapped drugs, which comprises treating said suspensions with a compound selected from the group of compounds consisting of (a) liquid and solid polymers of synthetic or organic nature having chemical functionality, which are used as ion exchangers, and (b) polymers, copolymers, or mixtures thereof, not having specific chemical function and which normally, but not exclusively, react according to Van der Waal's forces.
2. A method as claimed in claim 1 wherein said compound is selected from group (a) as defined in claim 1.
3. A method as claimed in claim 2 wherein said polymers are based on styrene, divinylbenzene, acrylic acid, or methacrylate acid.
4. A method as claimed in claim 3 wherein said polymers are ion-exchange resins.
5. A method as claimed in claim 4 wherein said ion-exchange resins are of the cationic type with weak, average or strong strength generally defined, and including carboxylic, phosphonic, or sulphonic functions of different matrices.
6. A method as claimed in claim 2 wherein said polymers are selected from the class consisting of phenolformaldehyde, styrene-divinylbenzene, acrylates, methacrylates, hydrocarbon and condensation-resins.
7. A method as claimed in claim, 4 wherein said resins are of the strong anionic type, 1st and 2nd type, of weak and average strength, which may include salified quaternary ammonium, primary, secondary and tertiary amminic or phosphinic functions or other functions with different matrices, including phenolformaldehyde, styrene-divinylbenzene, acrylates, meth-acrylates, hydrocarbon and condensation-resins.
8. A method as claimed in claim 4 wherein said resins may be used in salified or activated form.
9. A method as claimed in claim 1 wherein said compound is selected from group (b) as defined in claim 1.
10. A method as claimed in claim 9 wherein said compound is an adsorbent.
11. A method as claimed in claim 10 wherein said adsorbent is of aliphatic nature.
12. A method as claimed in claim 10 wherein said adsorbent is of aromatic nature.
13. A method as claimed in claim 10 wherein said adsorbent is of inorganic natures.
14. A method as claimed in claim 1 wherein said liposomic suspensions are, prepared by injecting an inert gas in a two-phase system, emulsion-type.
15. A method as claimed in claim 1 wherein said liposomic suspension is prepared by the co-presence of non-miscible solvents.
16. A method as claimed in claim 14 wherein said gas is nitrogen.
17. A method for the purification and stabilization of liposomic suspensions which comprises the process of claim 1 further including subjecting the purified suspension to lyophilization.
18. A pharmaceutical composition consisting of purified liposomes of a material selected from the group consisting of doxorubicin hydrochloride, aminosidine sulphate and 5-fluoro-uracil, whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
19. A pharmaceutical composition consisting of purified and lyophilic liposomes of a material selected from the group consisting of doxorubicin hydrochloride, aminosidine, sulphate and 5-fluoro-uracil, whenever prepared by a process as claimed in claim 17 or an obvious chemical equilvalent thereof.
Applications Claiming Priority (2)
| 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 |
| IT19434A/79 | 1979-01-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1148470A true CA1148470A (en) | 1983-06-21 |
Family
ID=11157905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000343663A Expired CA1148470A (en) | 1979-01-19 | 1980-01-15 | Pharmaceutical compositions consisting or consisting essentially of liposomes and processes for making same |
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 |
| CA1270198A (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 |
| ATE138803T1 (en) * | 1990-07-31 | 1996-06-15 | Liposome Co Inc | ACCUMULATION OF AMINO ACIDS AND PEPTIDES IN LIPOSOMES |
| DE4107153A1 (en) * | 1991-03-06 | 1992-09-10 | Gregor Cevc | Compsns. for application of active agents |
| DE4107152C2 (en) * | 1991-03-06 | 1994-03-24 | Gregor Cevc | Preparations for non-invasive administration of antidiabetics |
| 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 |
| 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 |
| 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 |
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 IL IL59120A patent/IL59120A/en unknown
- 1980-01-14 AU AU54581/80A patent/AU536823B2/en not_active Ceased
- 1980-01-14 JP JP219280A patent/JPS55100313A/en active Granted
- 1980-01-14 YU YU81/80A patent/YU44003B/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 CS CS80309A patent/CS227010B2/en unknown
- 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 FI FI800151A patent/FI70672C/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 HU HU8097A patent/HU184714B/en not_active IP Right Cessation
- 1980-01-17 GB GB8001545A patent/GB2041871B/en not_active Expired
- 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 BE BE0/199021A patent/BE881225A/en not_active IP Right Cessation
- 1980-01-18 SE SE8000443A patent/SE445171B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IT1110989B (en) | 1986-01-13 |
| SU1367839A3 (en) | 1988-01-15 |
| DK157060C (en) | 1990-04-09 |
| SE8000443L (en) | 1980-07-20 |
| GB2041871A (en) | 1980-09-17 |
| DK157060B (en) | 1989-11-06 |
| ZA80269B (en) | 1981-06-24 |
| JPH0133446B2 (en) | 1989-07-13 |
| DK22380A (en) | 1980-07-20 |
| FR2446635B1 (en) | 1989-03-10 |
| FI70672C (en) | 1986-10-06 |
| HU184714B (en) | 1984-10-29 |
| IE49141B1 (en) | 1985-08-07 |
| CS227010B2 (en) | 1984-04-16 |
| IT7919434A0 (en) | 1979-01-19 |
| YU44003B (en) | 1990-02-28 |
| IL59120A (en) | 1984-05-31 |
| FR2446635A1 (en) | 1980-08-14 |
| FI70672B (en) | 1986-06-26 |
| DE3001842C2 (en) | 1990-04-26 |
| GB2041871B (en) | 1983-04-13 |
| SE445171B (en) | 1986-06-09 |
| IE800091L (en) | 1980-07-19 |
| BE881225A (en) | 1980-07-18 |
| YU8180A (en) | 1983-12-31 |
| DE3001842A1 (en) | 1980-07-31 |
| AU536823B2 (en) | 1984-05-24 |
| FI800151A (en) | 1980-07-20 |
| IL59120A0 (en) | 1980-05-30 |
| AU5458180A (en) | 1980-07-24 |
| AT370623B (en) | 1983-04-25 |
| NL8000139A (en) | 1980-07-22 |
| JPS55100313A (en) | 1980-07-31 |
| CH648205A5 (en) | 1985-03-15 |
| ATA19380A (en) | 1982-09-15 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |