GB2158078A - Anthracycline-anionic polymer conjugates - Google Patents
Anthracycline-anionic polymer conjugates Download PDFInfo
- Publication number
- GB2158078A GB2158078A GB08510222A GB8510222A GB2158078A GB 2158078 A GB2158078 A GB 2158078A GB 08510222 A GB08510222 A GB 08510222A GB 8510222 A GB8510222 A GB 8510222A GB 2158078 A GB2158078 A GB 2158078A
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- GB
- United Kingdom
- Prior art keywords
- anthracycline
- doxorubicin
- anionic polymer
- drug
- polymer conjugate
- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Anthracycline-anionic polymer conjugates comprising a 1:2 regularly alternating cyclopolymer of divinyl ether and maleic anhydride in polycarboxylate form bonded to doxorubicin or an analogue thereof (particularly 4-demethoxydoxorubicin or 4'deoxydoxorubicin) by an ester linkage to the 14-C atom of the anthracycline slowly release in vivo the free form of the anthracycline drug by hydrolysis of the ester bond. The pharmacokinetic behaviour of the drug and its therapeutic efficacy are thus improved. The conjugates are prepared by reacting the polycarboxylate form of the copolymer with 14-bromodoxorubicin or a 14-bromo derivative of a doxorubicin analogue.
Description
SPECIFICATION
Anthracycline-anionic polymer conjugates
The invention relates to conjugates of doxorubicin and its analogues with anionic polymers and to a process for their preparation.
The linkage of antitumour agents to suitable water- soluble macromolecular carrier systems has been proposed as a novel approach in cancer chemotherapy in order to improve the therapeutic efficacy of the drug. Indeed, the therapeutic index of most antitumour agents (including anthracycline antibiotics) is small and host toxicity remains the main limitation in the use of available drugs.
The invention provides an anthracycline-anionic polymer conjugate comprising a 1:2 regularly alternating cyclo- polymer of divinyl ether and maleic an hydroxide in poly- carboxylate form bonded to doxorubicin or an analogue thereof by an ester linkage to the 14-C atom of the anthracycline.
The 1:2 regularly alternating cyclopolymer of divinyl ether and maleic anhydride, also known as DVE
MA or as pyran copolymer, has the formula
Divinyl Ethec-Maleic Anhydride
Copolymer (DVE-MA)
It may be converted to polycarboxylate form by hydrolysis with a strong base, preferably at a pH in excess of 12, for example with 0.2 N aqueous sodium hydroxide solution. The sodium salt of the polycarboxylate form has the formula
Polywarboxylate form The anthracycline-anionic polymer conjugate of the invention can slowly release the free form of the drug in vivo by hydrolysis of the ester bond, thus altering the pharmacokinetic behaviour of the drug.
The conjugation via the side chain (C-13,C-14) avoids modification of the drug amino sugar believed essential for optimal drug activity.
The antitumour effects in experimental tumour models in vivo indicate clear therapeutic advantages in using anthracyclines linked to the polyanionic polymer, as reflected by reduction of drug toxicity and by enhancement of effectiveness in all animal tumours used. The improvement of the therapeutic index of the polymer-bound drug may be the result of the expected alteration of the pharmacological distribution and of preferential delivery of the drug to tumour cells, which have a high endocytotic capacity.
The invention further provides a process for the preparation of an anthracycline-anionic polymer conjugate according to the invention, the process comprising hydrolysing a 1:2 regularly alternating cyclopolymer of divinyl ether and maleic anhydride with a strong base and reacting the resultant polycarboxylate form of the polymer with 14-bromodoxorubicin or a 14-bromo derivative of a doxorubicin analogue. The process is illustrated, for doxorubicin, 4-demethoxy-doxorubicin and 4'-deoxy- doxorubicin only, by the following reaction scheme.
Divinyl Etner-Mabic Anhydride Polycarboxylate torm Copolymer (DVE-MA)
The following Examples illustrate the invention.
EXAMPLE 7 Doxorubicin-pyran copolymer conjugate U) Pyran copolymer, average Mol. wt. 32000 (100 mg dissolved in 5 ml distilled water) was converted to the poly- carboxylate form by hydrolysis with 0.2 N aqueous sodium hydroxide solution (pH > 12) for at least 15 minutes. Complete hydrolysis of the maleic anhydride was confirmed by titration curve. After hydrolysis, the pH of the solution was adjusted to 8.5. 14-Bromo-daunorubicin (20-50 mg freshly dissolved in a small volume of methanol) was added to the polymer solution, under stirring. Reaction was carried out at room temperature. The acid produced during the nucleophilic substitution reaction was neutralized by addition of a dilute aqueous solution of sodium hydroxide. The reaction mixture was stirred for 2 hours and then adjusted to pH 7.0.Any free antibiotic was removed by ion-exchange chromatography on Dowex 50W-X2. Usually, the daunorubicin-polymer conjugate was diluted with water or aqueous solvent to reduce the polymer concentration. Thin layer chromatography (using chloroform:methanol:acetic acid 80:20:4 by volume for elution) and high pressure liquid chromatography on a
C-18 reverse phase column (using water:acetonitrile 66:34 by volume, adjusted to pH 3.8 with phosphoric acid, as mobile phase at a flow rate of 1.5ml/minute; fluorimetric detection, excitation, 500 nm; emission: 590 nm) were used to detect free anthracycline derivatives in the samples of the polymeric derivatives.
Samples showing residual free drug were further rechromatographed on Dowex 50W-X2. The concentration of bound drug in the polymeric derivative was estimated by absorbance at 480 nm. The polymer content in the conjugates was determined by dry weight after exhaustive dialysis of the conjugate against distilled water to remove any salt. The titration data were also used to calculate the available carboxyl groups and therefore the extent of drug substitution.This method gave identical results. Since the anhydride function could also react with the drug amino group to produce an amide linkage, this type of reaction has been excluded on the following observations: a) titration curves indicated complete hydrolysis of the anhydride under the coupling reaction conditions.
b) the presence of residual an hydroxide was also excluded by no formation of N-acyl derivatives when free aminoglycosides were mixed and incubated with alkali- huydrolyzed polymer under standard reaction conditions.
EXAMPLE 2 4-demethyoxy-doxorubicin-pyran copolymer conjugate (II). 14-Bromo-4'-deoxydoxorubicin was used in place of 14-bromo-doxorubicin in the method of Example 1 to give the title compound.
EXAMPLE 3 4'-deoxydoxorubicin-pyran copolymer conjugate (III). 14-Bromo-4'-deoxy-daunorubicin was used in place of 14-bromodoxorubicin in the method of Example 1 to give the title compound.
BIOLOGICAL ACTIVITY
Doxorubicin-pyran copolymer conjugate (I), hereinafter P-D X, was tested for cytotoxic activity and for anti- tumour activity against experimental tumours in mice and the results were compared with those of free daunorubicin (DR) and doxorubicin (DX) as reference drugs of this class of antitumour agents. The inhibition of the colony forming ability of HeLa cells was used to quantify the cytotoxic activity of the drug linked to polymers. Although an appreciable reduction of cytotoxic effect of bound drug as compared to free drug was consistently observed (Table 1), the concentration of bound drug required for 50% inhibition of colony-forming ability of HeLa cells (15 ng/ml) was only slightly higher than that required by free drug (10 ng/ml).
Comparative testing of anthracyclines was performed in both i.p. (P388 leukemia, J-744 lymphoma) and i.v. (gross leukemia) transplanted tumour systems. In these studies the route of drug administration was similar to that of tumour cell inoculation. The results of a number of experiments against P388 leukemia are summarized in Table 2. Free daunorubicin, at its optimal dose of 4 mg/kg, produced a T/C of 209%. Doxorubicin, tested at its optimal dose of 10 mg/kg, was more active (TIC = 274%) than daunorubicin. P-DX tested at various doses (expressed as doxorubicin content in the conjugate), showed a dosedependent antitumour activity. Lower doses produced antitumour effects similar to those of the free drug. However, the low toxicity of the doxorubicin-polymer conjugate allowed an increase of dose, thus improving the therapeutic effectiveness of the antitumour agents.Indeed high doses ( > 40 mgikg) were well tolerated, thus indicated marked reduction of drug toxicity in P-DX. Using the same treatment schedule, simultaneous administration of mixtures of the free drug and the polymer produced antitumour effects only slightly superior to those of the free drug alone in the range of optimal (i.e. maximally tolerated) doses. However the pyran copolymer failed to influence drug toxicity appreciably. The high activity of the macromolecular derivative of doxorubicin is also reflected in the relevant proportion of long-term (tumour- free) survivors produced by optimal doses. This curative effect was not observed with daunorubicin and only marginally observed with doxorubicin. The polymer itself had only marginal activity in this tumour system (maximum T/C = 165%).
To characterize better the differences between free anthracyclines and the macromolecular derivative, further studies were carried out in the J-744 lymphoma and Gross leukemia (Table 3). The results of comparative experiments with mice bearing J-744 lymphoma were quite similar to the results with mice bearing P388 leukemia (Table 2). The P-DX increased life span to a greater extent than either free daunorubicin or free doxorubicin. Only the P-DX produced long-term survivors.
These drugs were evaluated against Gross leukemia model using a multiple injection treatment (Table 4). Although the binding of doxorubicin to the polymer reduced drug potency, P-DX at its optimal dose was markedly more active than either daunorubicin or doxorubicin, producing a large increase in life span and a relevant number of long-term survivors.
4-Demethoxydoxorubicin-pyran copolymer conjugate (P-DmDX), when tested against Gross leukemia using a multiple treatment schedule (q 3 d x 3, i.v.) produced antitumour effects superior to those of 4demethoxydaunorubicin (DmDR) and only slightly superior to those of 4-demethoxy- doxorubicin (DmDX) (Table 5).However, as found for P-DX, only the conjugate produced an appreciable number of long-time survivors. The reduction of systemic toxicity allowed the administration of higher dose of the drug in the conjugate. The ratio between equitoxic doses of the free drug (LD 10 = 0.6 mglkg) and the polymer bound drug (LD 10 - 1.7 mg/kg) was around 3.
TABLE 1
Cytotoxic activity of daunorubicin, doxorubicin and
doxorubicin-pyran copolymer conjugate against HeLa cells.
Drug concentration Survival (O/o of control) (nglml) DR DX P-DX
3.125 94 - 100
6.25 X 75 - 55
12.5 42 45 54
25.0 3 23 35
50.0 - 1 6
Cells were exposed to the drugs for 24 hours. Survival was determined by the ability of treated cells to form colonies. After treatment, medium was removed and cells were washed and suspended in Eagle's minimal essential medium containing 10% fetal calf serum and plated. Colonies were counted after 8 days of incubation.
TABLE 2
Comparison of therapeutic effect of ip. treatment on P388 leukemia, Drug2 Dose3 TIC4 No. of toxic deaths LOTS5 mgfkg % No. of treated mice
DR 4 209 (190-240) 4138
DX 10 274 (260-288) 1/19 2/19
P-DX 4 227 0110
8 264 (250-278) 0118
16 230 (210-250) 0118
32 295 (290-300) 0119 1119
38.5 395 0110 4110
48 347 (320-374) 2119 6119
60 421 1110 4110 DR+P3 4+20 222 0110
*n8+40 255 1110
16+80 90 10110
32+160 70 10110 p6 20 140 0110 0110 40 145 0110 0110
80 165 0/10 0/10
160 150 0/10 0110 'Experiments were carried out in BDF1 mice inoculated i.p. with 1 x 10S celislmouse. The range of median survival time (MST) of control mice was 9 to 10 days in six experiments.
3Single treatment i.p. on day 1 after tumour cell transplantation. For P-DX, the dose is expressed as doxorubicin content. For DRtP the dose is expressed as daunorubicin content.
4MST of dying mice only in the treated group, divided by the MST of the control group, x 100. In parenthesis, data of single experiments or range.
SLUTS, long-term survivors ( > 60 days).
2DR+P, mixture of daunorubicin and pyran copolymer; P, pyran copolymer.
6The dose is expressed as mg of polymer; new druglpolymer molar ratio, 19 to 29 in different preparations.
TABLE 3
Activity against J-744 lymphoma'.
Drug Dose2 TIC No. of toxic deaths LOTS2 mg/kg % No. of treated mice
DR 3.3 139 0/8
5.0 71 818
DX 6.6 168 018
10.0 176 318
P-DX 30.0 302 0/8 218
45.0 265 418 118 'Experiments were carried out in BALBIc mice inoculated i.p. with 1 x 106 cellslmouse. The MST of control mice was 19 days.
2Single treatment i,p. on day 1 after tumour cell transplantation.
ALTOS, long-term survivors ( > 90 days).
TABLE 4
Effect of multiple administration of Gross leukemia1.
Drug Dose2 TIC No. of toxic deaths LTSs3
mglkg % No. of treated mice
DR 8 414 (220-608) 1117 2117
DX 7 258 (216-300) 6/17 0117
P-DX 8 171(160-183) 0117 1/17
12 768 (720-816) 0117 5117
18 426 (320-533) 9117 0117 'Experiments were carried out in C3HlHe mice inoculated i.v. with 1 x 106 cellslmouse. The MST of control mice was 5.5 days in two experiments.
2Treatment i.v. on days 1, 4 and 7 after tumour transplantation.
3LTS, long term survivors ( > 60 days).
TABLE 5
Effect of4-demethoxy-daunorubicin (DmDR), 4Demethoxy-doxorubicin (DmDX) and 4-demethoxy-doxorubicin-pyran copolymer conjugate (P-DmDX) on gross leukemia7
Dose or Toxic
Drug optimal dose2 TIC o/o3 deaths LTS' (m glkg) DmDR 0.75 143 1/10 0/10
DmDX 0.50 288 (285-291) 0/20 1/20
0.75 229 (200-258) 12/20 1/20
P-DmX 1.13 350 1/10 0/10
1.70 286 (272-300) 3/20 3120
Experiments were carried out in C3HIHe mice inoculated i.v. with 1 x 106 cellslmouse. The MST of control
mice was 6.5 days in two experiments.
2 Treatment i.v. on days 1,4 and 7 after tumour transplantation.
3 In parenthesis, range.
4 LTS, long term survivors ( > 60 days).
Claims (12)
1. An anthracycline-anionic polymer conjugate comprising a 1:2 regularly alternating cyclopolymer of divinyl ether and maleic anhydride in polycarboxylate form bonded to doxorubicin or an analogue thereof by an ester linkage to the 14-C atom or the anthracycline.
2. An anthracycline-anionic polymer conjugate according to claim 1 in which the anthracycline is doxorubicin.
3. An anthracycline-anionic polymer conjugate according to claim 1 in which the anthracycline is 4demethoxy- doxorubicin.
4. An anthracycline-anionic polymer conjugate according to claim 1 in which the anthracycline is 4'deoxy- doxorubicin.
5. A doxorubicin-pyran copolymer conjugate having the formula I herein.
6. A 4-demethoxydoxorubicin-pyran copolymer conjugate having the formula II herein.
7. A 4'-deoxydoxorubicin-pyran copolymer conjugate having the formula Ill herein.
8. A process for the preparation of an anthracycline- anionic polymer conjugate according to claim 1, the process comprising hydrolysing a 1:2 regularly alternating cyclopolymer of divinyl ether and maleic anhydride with a strong base and reacting the resultant polycarboxylate form of the polymer with 14bromodoxorubicin or a 14- bromo derivative of a doxorubicin analogue.
9. A process according to claim 5 in which the strong base is aqueous sodium hydroxide solution.
10. A process according to claim 8 or claim 9 in which the polycarboxylate form of the polymer is reacted with the 14-bromo-anthracycline in aqueous methanolic solution at ambient temperature for from 2 to 3 hours, keeping the solution neutral by addition of a base.
11. A process for the preparation of an anthracycline- anionic polymer conjugate, the process being substantially as described herein with reference to any of the Examples.
12. A pharmaceutical composition comprising an anthracycline-anionic polymer conjugate according to any of claims 1 to 7 or an anthracycline-anionic polymer conjugate prepared by a process according to any of claims 8 to 11 in admixture with a pharmaceutically acceptable diluent or carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848413464A GB8413464D0 (en) | 1984-05-25 | 1984-05-25 | Anthracycline-anionic polymer conjugates |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8510222D0 GB8510222D0 (en) | 1985-05-30 |
| GB2158078A true GB2158078A (en) | 1985-11-06 |
| GB2158078B GB2158078B (en) | 1987-09-16 |
Family
ID=10561522
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB848413464A Pending GB8413464D0 (en) | 1984-05-25 | 1984-05-25 | Anthracycline-anionic polymer conjugates |
| GB08510222A Expired GB2158078B (en) | 1984-05-25 | 1985-04-22 | Anthracycline-anionic polymer conjugates |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB848413464A Pending GB8413464D0 (en) | 1984-05-25 | 1984-05-25 | Anthracycline-anionic polymer conjugates |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS6156128A (en) |
| BE (1) | BE902344A (en) |
| DE (1) | DE3515178A1 (en) |
| GB (2) | GB8413464D0 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2612074A1 (en) * | 1987-03-11 | 1988-09-16 | Erba Carlo Spa | IDARUBICIN CONTAINING IMMUNOGLOBULIN CONJUGATE, MEDICAMENT CONTAINING THE SAME, AND METHOD FOR IN VITRO DEPLETION OF A T-LYMPHOCYTE SUB-GROUP OF A CELL POPULATION USING THE CONJUGATE |
| EP0292964A2 (en) * | 1987-05-28 | 1988-11-30 | Hiroshi Maeda | Superoxide dismutase derivatives a method of producing the same and medicinal use of the same |
| EP0363604A2 (en) * | 1988-10-11 | 1990-04-18 | Sicor Societa' Italiana Corticosteroidi S.P.A. | Improved process for the conversion of daunorubicin into doxorubicin |
| EP0408019A2 (en) * | 1989-07-12 | 1991-01-16 | Union Carbide Chemicals And Plastics Company, Inc. | Pharmaceutical active derivative delivery systems |
| EP0616813A2 (en) * | 1993-03-25 | 1994-09-28 | American Cyanamid Company | Antitumor mitoxantrone polymeric compositions |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5609867A (en) | 1994-11-01 | 1997-03-11 | American Cyanamid Company | Polymeric antitumor agents |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1602967A (en) * | 1977-07-16 | 1981-11-18 | Hercules Inc | Reaction prodcut of methotrexate with divinyl ether and maleic anhydride copolymer |
-
1984
- 1984-05-25 GB GB848413464A patent/GB8413464D0/en active Pending
-
1985
- 1985-04-22 GB GB08510222A patent/GB2158078B/en not_active Expired
- 1985-04-26 DE DE19853515178 patent/DE3515178A1/en not_active Withdrawn
- 1985-05-03 BE BE0/214956A patent/BE902344A/en not_active IP Right Cessation
- 1985-05-24 JP JP60110620A patent/JPS6156128A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1602967A (en) * | 1977-07-16 | 1981-11-18 | Hercules Inc | Reaction prodcut of methotrexate with divinyl ether and maleic anhydride copolymer |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2612074A1 (en) * | 1987-03-11 | 1988-09-16 | Erba Carlo Spa | IDARUBICIN CONTAINING IMMUNOGLOBULIN CONJUGATE, MEDICAMENT CONTAINING THE SAME, AND METHOD FOR IN VITRO DEPLETION OF A T-LYMPHOCYTE SUB-GROUP OF A CELL POPULATION USING THE CONJUGATE |
| DE3808166A1 (en) * | 1987-03-11 | 1988-09-22 | Erba Carlo Spa | IMMUNGLOBULIN CONJUGATES, METHOD FOR THE PRODUCTION AND USE THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
| BE1001051A4 (en) * | 1987-03-11 | 1989-06-20 | Erba Carlo Spa | Immunoglobulin conjugate containing idarubicin, drugs containing the depletion and method for in vitro a sub-group t cell of a cell population using conjugate. |
| US5798097A (en) * | 1987-03-11 | 1998-08-25 | Pharmacia & Upjohn S.P.A. | Immunogobulin conjugates |
| EP0292964A2 (en) * | 1987-05-28 | 1988-11-30 | Hiroshi Maeda | Superoxide dismutase derivatives a method of producing the same and medicinal use of the same |
| EP0292964A3 (en) * | 1987-05-28 | 1990-06-13 | Hiroshi Maeda | Superoxide dismutase derivatives a method of producing the same and medicinal use of the same |
| EP0363604A2 (en) * | 1988-10-11 | 1990-04-18 | Sicor Societa' Italiana Corticosteroidi S.P.A. | Improved process for the conversion of daunorubicin into doxorubicin |
| EP0363604A3 (en) * | 1988-10-11 | 1990-07-25 | Sicor Societa' Italiana Corticosteroidi S.P.A. | Improved process for the conversion of daunorubicin into doxorubicin |
| EP0408019A2 (en) * | 1989-07-12 | 1991-01-16 | Union Carbide Chemicals And Plastics Company, Inc. | Pharmaceutical active derivative delivery systems |
| EP0408019A3 (en) * | 1989-07-12 | 1992-10-14 | Union Carbide Chemicals And Plastics Company, Inc. | Pharmaceutical active derivative delivery systems |
| EP0616813A2 (en) * | 1993-03-25 | 1994-09-28 | American Cyanamid Company | Antitumor mitoxantrone polymeric compositions |
| EP0616813A3 (en) * | 1993-03-25 | 1995-03-29 | American Cyanamid Co | Antitumor mitoxantrone polymeric compositions. |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2158078B (en) | 1987-09-16 |
| JPS6156128A (en) | 1986-03-20 |
| GB8510222D0 (en) | 1985-05-30 |
| BE902344A (en) | 1985-09-02 |
| DE3515178A1 (en) | 1985-11-28 |
| GB8413464D0 (en) | 1984-07-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |