IE48177B1 - Pharmaceutical formulations containing cis-platinum(ii)diamminedichloride - Google Patents
Pharmaceutical formulations containing cis-platinum(ii)diamminedichlorideInfo
- Publication number
- IE48177B1 IE48177B1 IE194/79A IE19479A IE48177B1 IE 48177 B1 IE48177 B1 IE 48177B1 IE 194/79 A IE194/79 A IE 194/79A IE 19479 A IE19479 A IE 19479A IE 48177 B1 IE48177 B1 IE 48177B1
- Authority
- IE
- Ireland
- Prior art keywords
- solution
- cisplatin
- concentration
- range
- mgm
- Prior art date
Links
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 title claims abstract description 49
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 239000000243 solution Substances 0.000 claims abstract description 62
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 40
- 229960004316 cisplatin Drugs 0.000 claims abstract description 37
- 239000011780 sodium chloride Substances 0.000 claims abstract description 21
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 16
- 229930195725 Mannitol Natural products 0.000 claims abstract description 16
- 239000000594 mannitol Substances 0.000 claims abstract description 16
- 235000010355 mannitol Nutrition 0.000 claims abstract description 16
- 239000007864 aqueous solution Substances 0.000 claims abstract description 14
- 239000002552 dosage form Substances 0.000 claims abstract description 12
- 238000001990 intravenous administration Methods 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 238000003860 storage Methods 0.000 claims description 9
- 241000282414 Homo sapiens Species 0.000 claims description 8
- 231100000252 nontoxic Toxicity 0.000 claims description 8
- 230000003000 nontoxic effect Effects 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000001747 exhibiting effect Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 241000282412 Homo Species 0.000 claims 1
- 239000003708 ampul Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- 229960002668 sodium chloride Drugs 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 230000036515 potency Effects 0.000 description 7
- 238000013019 agitation Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 229940090044 injection Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000005057 refrigeration Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 150000003058 platinum compounds Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 206010065553 Bone marrow failure Diseases 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 238000010268 HPLC based assay Methods 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 229940000406 drug candidate Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000008227 sterile water for injection Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 201000000274 Carcinosarcoma Diseases 0.000 description 1
- VFZRZRDOXPRTSC-UHFFFAOYSA-N DMBA Natural products COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038540 Renal tubular necrosis Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 231100000230 acceptable toxicity Toxicity 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HGAZMNJKRQFZKS-UHFFFAOYSA-N chloroethene;ethenyl acetate Chemical compound ClC=C.CC(=O)OC=C HGAZMNJKRQFZKS-UHFFFAOYSA-N 0.000 description 1
- 229940105442 cisplatin injection Drugs 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011045 prefiltration Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012859 sterile filling Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A stable, sterile aqueous solution of cis-platinum (II) diamminedichloride (cisplatin) in a sealed container such as an ampule or vial in unit dosage form suitable for intravenous administration to man has a concentration of cisplatin in the range of from 0.1 to 1.0 mgm/ml. and a pH in the range of from 2.0 to 3.0, preferably about 5.5. The solution can also contain sodium chloride and mannitol.
Description
The present invention relates to stabilized aqueous solutions of cis-platinum (11) diamminedichloride (cisplatin) which is used by injection in the chemotherapy of cancer.
The platinum compounds are a unique group of compounds in the antineoplastic group of agents. They were first noted to have an antibiotic effect by Rosenberg and his colleagues in 19^5 and have since been found to be 1 2 potent antitumor agents in animals. ’ Structurally they represent a complex formed by 3-0 a central atom of platinum and surrounded by various arrangements of chlorine atoms or ammonia groups in either a cis or trans planar relationship. Two of the more commonly studied platinum compounds are diagrammed below: Cis-Platinum (II) Diamminedichloride Cis-Platinum (TV) Diamminetetrachloride As can be seen, the platinum compound, cisplatinum (II) diamminedichloride, selected for clinical trials by the National Cancer Institute has the chloride and amino groups only in the horizontal plane. The cis form of the diamminedichloride complex has been synthesized accord ing to the following reaction:^ NHjjCl KgtPtCl^J + 2)^-—»*CiS-[Pt(NI^)2Cl23 + 2KC1 1. Rosenberg, B., VanCamp, L. and Krigas, T., Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature (London) 205: 698-699, 1965. 2. Rosenberg, B., VanCamp, L., Trosko, J.E. and Mansour, V.H., Platinum compounds: A new class of potent antitumor agents. Nature (London) 222: 385-386, 1969. 3. Kauffman, G.B. In J. Kleinberg (Ed.), lo Inorganic Synthesis, McGraw-Hill Book Co., Ine., New York, 1963.
The National Cancer Institute has been conducting clinical trials in cancer chemotherapy of the chemical for which the United States Adopted Name (USAN) is now cisplatin. Certain information regarding its chemistry and Its pharmaceutical formulation are given in the publication titled Clinical Brochure, cie-platinum (il)Diamroinedichloride (NSC-H9875), H. Handelman et al., Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treat20 ment, National Cancer Institute (Revised, August, 1974), on pages 1-5 and 31-32. The last two pages of Handelman et al. concern the formulation of cisplatin supplied gratis by the N.C.I. to clinicians for their clinical evaluation in the chemotherapy of cancer and read as follows: -310 PHARMACEUTICAL DATA SHEET NSC-119875 Cis-Diamminedichloroplatlnum (II) Dosage Formulation mg./vial : The contents of each 20 ml. flint vial appears as an off-white lyophilized cake. Each vial contains 10 mg. of NSC-H9875S 90 mg. of Sodium Chloride; 100 mg. of Mannitol and Hydrochloric acid for pH adjustment.
Solution Preparation mg./vial Storage Stability When reconstituted with 10 ml. of Sterile Water for Injection, USP, each ml. of the resulting solution will contain 1 mg. of NSC-119875, 10 mg. of Mannitol, and 9 mg. of Sodium Chloride having a pH range of 3.5-4.5The dry, unopened vials should be stored at refrigeration temperatures (4-8° C.). Intact vials have a provisional stability of one year when stored at refrigeration temperature (4-8° C.). Stability recommendations may be adjusted pending completion of a two-year shelf-life study. Reconstitution as recommended results in a pale, yellow solution which is stable for not more than one hour at room temperature (22° C.) when exposed to normal room Illumination and not more than eight hours at room temperature (22° C.) when protected from light. Reconstituted so30 -448177 lutlons may form a precipitate after one hour at refrigeration temperature (4-8° C.).
Caution : The lyophilized dosage formulations contain no preservatives and therefore it is advised to discard solutions eight hours after reconstitution.
August, 1974 Clinical Drug Distribution Section Drug Development Branch Mention of this formulation and additional Information on its clinical use is given, for example, in Cancer Chemotherapy Reports, Part 1, Vol. 57, No. 4, pages 465-471 (1973).
Cancer 22.: 1451-1456 (1972) in reference to cisplatin states that The drug material used In this study was manufactured by Ben Venue Laboratories Inc., Bedford, Ohio. It was supplied by the Cancer Therapy Evaluation Branch of the National Cancer Institute in vials containing 10 mg. of cisdiamminedichloroplatinum, 10 mg. (sic) of mannitol and 9 mg, (sic) of NaCl. The resulting yellowish white powder dissolved readily in 8-10 ml. of sterile water and was injected immediately after preparation.
Annals of Internal Med. 86: 803-812 (1977) refers to cisplatin as ''DDP and states that The drug DDP Is presently available as an investigational drug only to qualified specialists through the Investigational Drug -548177 Branch of the Cancer Therapy Evaluation Program, National Cancer Institute. The product is supplied as a white lyophylized powder in vials containing 10 mg. of DDP, 90 mg. of sodium - chloride, 100 mg. of mannitol (U.S.P.), and hydrochloric acid for pH adjustment. When reconstituted with 10 ml. of sterile water for injection (U.S.P.), each ml. of the resulting solution will contain 1 mg. of DDP, 10 mg. of manni10 tol, and 9 mg. of NaCl. Ihe pH of the resulting solution will he 3.4 to 4.5« At 22° C., the reconstituted solution is stable for at least 8 h.
Thus the formulations described above are stated to require refrigeration (4-8° C.) while in vials in the solid state (i.e., before reconstitution), they are difficult to reconstitute and they have a useful life of only about twenty hours at room temperature (22° C.) following reconstitution. The very act of reconstitution can cause problems if improperly performed and is better avoided. In addition, be20 cause the aqueous solubility of cisplatin is only about mgm./ml., the cost of preparing dosage forms containing more than 25 mgm./vial by lyophilization becomes prohibitive.
We have now developed a stable, therapeutically acceptable, intravenously injectable dosage form of cisplatin which does not require lyophilization and reconstitution, which does not require refrigeration during shipment and storage,· and which can be supplied in dosages of 50 mg. or larger. -648177 According to the present invention there is provided a stable, sterile aqueous solution of cisplatin in a sealed container such, as an ampule or vial in unit dosage form suitable for intravenous administration to man, said, solution has a concentration of cisplatin in the range of from 0.1 to 1.0 mgm./ml. and preferably about l.o mgm/ml. and a pH in the range of from 2,0 to 3.0, preferably in the range of from 2.3 to 2.7 and most preferably a pH of about 2.5, the PH being caused by the presence of an appropriate amount of a nontoxic, pharmaceutically and therapeutically acceptable acid . The acid is preferably a strong mineral acid and most preferably is hydrochloric acid; the solution optionally containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions at a concentration equivalent to that produced by the presence of sodium chloride at a concentration in the range of from 1 to 20 mgm./ml. and most preferably about 9 mgm./ml.; the solution optionally also being either free of any other added chemicals or also containing a customary, harmless, physiologically acceptable excipient, which is preferably mannitol, at a concentration in the range of from 2 to 150 mgm./ml. and preferably a concentration of about 10 mgm./ml., the solution exhibiting less than 10% (and usually less than 4%) loss of potency as measured by high performance liquid chromatography (HPLC) upon the storage for one month at 560 C. Preservatives can be added if desired.
There is further provided by the present invention a method for inhibiting the growth of a malignant tumor susceptible to cisplatin which comprises intravenously administering to a non-human animal afflicted with such a malignant tumour an amount effective to inhibit the growth of said tumour of -7177 a stable, sterile aqueous solution of cisplatin in a sealed container such as an anpule or vial in unit dosage form suitable for intravenous administration to said animal, said solution having a concentration of cisplatin between about 0.1 and about 1.0 mgm./ml. and preferably of about 1.0 mgm./ml. and a pH in the range of 2.0 to 3.0 and preferably in the range of 2.3 to 2.7 and most preferably a pH of about 2.5j said pH being caused by the presence of the appropriate amount of a nontoxic, pharmaceutically and therapeutically acceptable acid, said acid preferably being a strong mineral acid and most preferably being hydrochloric acid; said solution optionally containing in addition a nontoxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml. and most preferably about 9 mgm./ml.; said solution optionally also being either free of any other added chemicals or also containing a customary, harmless, physiologically acceptable excipient, which is preferably mannitol, in a concentration in the range of 2 to 150 mgm./ml. and preferably a concentration of about 10 mgm./ml., said solution exhibiting less than 10% (and usually less than 4%) loss of potency as measured by high performance liquid chromatography (HPIC) upon storage for one month at 560 θ· -848177 EXAMPLE 1 Cisplatin Injection 1 Mg,/Ml. Γ1 Mg. Cis-diamminedichloroplatinum (II) per 1 Ml.] Formula Per Ml. Per liter Cis-diamminedichloroplatinum (II)..... . 0.0010 g.A 1.000 g.A Sodium Chloride, U.S.P.. . 0.0090 g. 9.000 g. Mannitol, U.S.P..... . 0.0100 g. 10.000 g. Hydrochloric Acid, Cone. U.S.P....... . q.s. to pH q.s. to pH 2,0-3.0® 2.0-3.0® Water for Injection, U.S.P.......... . q.s. 1.0 Ml. q.s. 1000.0 NOTES: A. 100% basis, adjust weight based on reported purity to provide 1.0 g. 100% cis-diamminedichloroplatinum (II) per liter.
B. Approximately 0.025-0-050 nil· of 37% hydrochloric acid 2o required per gram of sodium chloride to obtain a pH of approximately 2.5.
PRECAUTIONS Cis-diamminedichloroplatinum (II) is a toxic substance and is listed on page 742 in the 1976 edition of the 25 Registry of Toxic Effects of Chemical Substances. The OSHA Standard of Time Weighted Average (TWA) is 2 meg./m5. -948177 Consult the above, listed references, pertinent local publications and regulations and such publications as the National Cancer Institute Safety Standards for Research Involving Chemical Carcinogens and the National Institute of Health Specifications for a Class II type 1 Safety Cabinet. Any cis-diamminedichloroplatinum (II) weighing, the working surface of the batching vessel, the filling, stoppering, and sealing must be provided with such protection.
All personnel involved with compounding of this product must be protected with full nylon head/face cover, coveralls, rubber gloves and a respirator equivalent to the MSA Ultra Filter Respirator rated for environments contaminated with dusts, fumes and mists having a TWA rating of less than 50 mcg./m^. During the sterile liquid filling the sterile head/face cover, surgeon's gauze mask and goggles can replace the respirator. Any uniforms grossly contaminated due to spills, etc. should be stored in a closed metal container until burned.
THE IMPORTANCE OF PROTECTING PERSONNEL DURING THE HANDLING, MANUFACTURING AND ASSAYING OF THIS PRODUCT IN ACCORDANCE WITH THE ABOVE CANNOT BE OVEREMPHASIZED.
The prime bulk cis-diamminedichloroplatinum (II) must be protected from light. The processing and filling of vials described herein was conducted under diffused natural/fluorescent light.
EQUIPMENT Batching Vessel Glass-lined, agitated, pressure vessel. A 316 SS agitator is permissible. Working volume must be consistent with batch size. A dipstick and calibration curve of tank -1048177 volume is required for determining volume.
Millipore Membrane Filter Holders Jl6 SS. Filter area with necessary pre-filters and 0.22 micron final sterilizing filter. a Transfer Hoses Teflon (a Trade Mark), or Tygon.
All stainless steel contacts should meet JIG SS requirements. All other equipment should be appropriate to produce a sterile, non-pyrogenic, particulate-free product. lo Manufacturing Instructions A. These instructions are written for an eighthour batching to filling operation. Storage of this product before filling has not been investigated at this writing.
B. Maintain 27° C. ± 2° C. temperature conditions 15 throughout entire batching and filtering operations. 1. Place 80% of the batch volume of Water for Injection, U.S.P. in a suitable vessel. 2. With agitation add the sodium chloride. Agitate ten minutes or until dissolved. 3. With good agitation carefully adjust the pH of the sodium chloride solution to 2.0-3.0 (preferably 2.5) with concentrated hydrochloric acid. See estimated amount under note B on the fcemula sheet. Agitate for ten minutes after last addition. Recheck pH.
¢. With good agitation add the mannitol and agitate ten minutes or until dissolved.
, With good agitation and taking special precautions against dusting and exposure, add the cis-diamminedichloro-1148177 platinum (II). Rinse its container sufficiently with an appropriate amount of water for injection and add to the batch. 6. Agitate until completely dissolved. Approximately 5 60-90 minutes will be required for complete dissolution.
Monitor pH and add additional concentrated hydrochloric acid if required to maintain at 2.0-3.0 (optimum 2.5)· 7. Carefully adjust volume to theoretical batch volume with water for injection. Make final pH check. 8. Pass the solution through a clean, sterile 0.22 micron Millipore Filter into the sterile filling line. 9. Fill as directed below for the following products: Mg./Vial Sterile, Type I amber, 15 ml. vial, with a 10-ml. fill. 15 stopper with red, 20 mm Teflon-faced stoppers and seal with aluminum seals . Numbered as K93, 100 and 107 with nitrogen overlay and K94, 101 and 108 without nitrogen overlay.
,,Mg. Mai Sterile, Type I amber, 50 ml. vial with a 25-ml. fill.
Stopper with red, 20 mm Teflon-faced stoppers and seal with aluminum seals . Numbered as K95s 102 and 109 with nitrogen overlay and K96, 103 and 110 without nitrogen overlay. 50 Mg./Vial Sterile, Type I amber, 50 ml. vial with a 50-ml. fill. Stopper with red, 20 mm Teflon-faced stoppers and seal with aluminum seals. Numbered as K97, 104 and 111 with nitrogen overlay and Κ9θ, 105 and 112 without nitrogen 30 overlay. -1248177 These formulations were prepared in five groups (with the final pH given in parentheses) as follows: K93-96 (PH 2.4) Κ97-9θ (pH 2.5) K100-103 (pH 2.3) K104-105 (pH 2.4) K107-110 (PH 2.3) Klll-112 (pH 2.4) Original potencies by HPLC assay were in the range of 0.99 to 1.00 mgm./ml. The percentage loss in potency after storage for one or two months at the indicated temperature was found by HPLC assay to be as follows: 56'3 C. 45° C. One Two One Month Months Month K93 ttct K94 2.0 4.0 K95 0.0 -1.0* K96 1.0 4.0 0.0 K97 .3.0 K98 4.0 2.0 K100 3.0 K101 3.0 5.0 K102 3.0 K103 5.0 4.0 K104 0.0 -1.0* K105 0.0 5.0 0.0 K107 1.0 0.0 K108 2.0 5.0 1.0 K109 3.0 K110 3.0 Kill 7.0 K112 7.0 «Negative sign means assay showed 1.0% increase in potency. -1348177 The above-described solutions, with and without nitrogen cover, thus have shown 7% or less loss in potencyafter storage at 560 C. and 4-5° C. with the majority showing a loss of potency of 3% or less. The pH of the solu5 tions remained between 2.4 and 2.7.
Physically, no change is apparent at 560 C. or 45° C. after one month. Solutions remain clear and colorless. Initial Klett readings averaged 8-12; onemonth 560 C. and 45° C. readings averaged 6-15. Ho lo changes or differences are noted between samples with or without Ngt.
One sample at each temperature station for all products was tested inverted exposing the solution to the Teflon-coated plug stopper. Samples from inverted products 15 were assayed from 560 C. at one month with and without Ngf exposure. Stability was not affected at one month 5^° C. as samples showed only 1-2% loss of potency.
At two weeks 4° C. samples were observed for crystallization of cis-diamminedichloroplatinum (II). No crystals were observed until one month and it was only noted randomly, not in every sample. Only one lot of the 10 mg./vial and 25 mg./vial products show some crystals forming randomly at 4° C. Crystallization is noted throughout all lots of 50 mg./vial products but again not in all samples. One sample from 4° 0. with crystals could not be redissolved by warming the solution to 37° C. with agitation. Only partial success was obtained. It appears these products cannot be stored under refrigerated conditions as even redissolving of crystallized products was difficult. -1448177 Cis-platinum (II) diamminedichloride (NSC 119875) is an inorganic compound first noted to prevent replication of E. coli and subsequently found to possess antitumor activity. The drug exerts its effect of interfering with DNA synthesis by causing cross-linking of complementary strands of DNA. It has activity in a variety of tumour systems including L1210, Sarcoma 180, Walker 256 carcinosarcoma, DMBA induced mammary tumours and ascitic Bl6 melanosarcoma.
The compound is especially interesting in that it exhibits synergism with a large number of currently-used chemotherapeutic agents. Large animal toxicology studies showed renal tubular necrosis, enterocolitis, bone marrow hypoplasia and lymphoid atrophy. Phase I studies have demonstrated the following toxicities: myelosuppression, renal insufficiency, high frequency ototoxicity and GI Intolerance. Currently used dosages with mild to moderately acceptable toxicity are in the range of 60-100 mg/m IV as a single dose or divided over 3-5 days, to be repeated at four-week intervals. Early clinical trials show some responses to the drug in germinal cell tumours lymphomas, sarcomas, breast and head and neck carcinomas. p A dosage of 60 mgm/m Is roughly equal to 1.5 mgm/kg which in turn is roughly equal to 105 mgm/patient weighing 70 kg.
The solutions of the present invention are used in the same manner and for the same purpose as stated above and in the other publications and in the voluminous medical literature on this subject. As stated therein, frequent use is made of concurrent therapy with other chemotherapeutic agents for best results. When desired, the solutions of the present invention may be added immediately before use to a -1548177 sterile, pharmaceutically acceptable aqueous diluent such as glucose or saline. Administration is either by direct intravenous injection or by intravenous infusion. -1648177 High Perfonnanee Liquid Chromatography (HPLC) Assay for Cls-Dlammi nedichloroplatlnum.
Method Cis-diamminedichloroplatinum is chromatographed on a Water's P-Bondpak-NHg column using a loop Injection technique. Detection is achieved by monitoring the U.V. absorbance at 313 nm and quantitation is accomplished by peak height measurement with external calibration. This method is applicable to bulk powders and solid dose formulations containing NaCl and mannitol. Specificity has been demonstrated by separation of the cis and trans isomers and apparent degradations (moisture, acid, base, heat and accelerated light).
HPLC Conditions Column - Water's Micro—Bondpak-NHg (300 mm X 4.0 mm ID) 027386 or equivalent.
Mobile Phase - Ethyl acetate/methanol/dimethylformamide/ 2o distilled water (25/16/5/5). Use Burdick and Jackson distilled in glass spectroquallty reagents. Degas the water prior to use and the solution after mixing.
Detector - Water's Model 440 Absorbance Detector.
Wavelength - 313 nm (U.V.). -1748177 Sensitivity - 0·1 AUFS.
Injector - A 20 microliter loop injector.
The Loop Injector - A Valeo 7000 psi stainless steel valve (CV -6-UHPa-C20).
Injection Volume - 20 microliter.
Solvent Delivery System - Water's Model 6000A pump.
Flow - 2.0 ml./minute.
Retention - 2.8 minutes (approx.).
Recorder - Heath Model SR-255B.
Chart Speed - 0.5 inch/min.
Range - 10 millivolt.
HPLC Analysis Using the conditions above, obtain chromatograms of the standard and sample preparations in duplicate.
Reference Standard of cis-piamminedichloroplatinum (DDP): Lot No. = 78F7 (Matthey Bishop Lot No. AM7702) Assigned Purity = 99.8# Solvents - Burdick and Jackson (distilled in glass) spec20 troquallty.
Standard - Weigh accurately 25 mg· of cis-diamminedichloro platinum (DDP) into a 25-ml. volumetric flask. Dissolve in and dilute to volume with dimethylformamide, 25 Lyophilized Injection - Reconstitute vial contents with .0 ml. of dimethylformamide and mechanically shake for 5 minutes (alternately a sonic bath may be used for 2 minutes). Filter 5-0 ml. of the sample solution (Millipore Filter Kit or -18-- 48177 equivalent) discarding the first ml.
Content Uniformity - Prepare 10 vials as described above and assay.
Calculations STANDARD FACTOR (SF) = AVERA0E&tEAtf^K^STAtoARD MG. DDP/GRAM = ,S£ X AVERAGE^PE^glGCT,,SAMPLE X 2? MG. DDP/VIAL = SF X AVERAGE PEAK HEIGHT SAMPLE X 10 For assay, average results obtained for 10 vials from content uniformity test.
Method The method of assay for cisplatin described above is applied to aqueous solutions (dose formulations) containing NaCl and mannitol after making the changes indicated below.
HPLC Conditions Mobile Phase - Acetonitrile/distilled water (75/25, v/v).
Use Burdick and Jackson distilled in glass spectroquality reagents. Degas the water prior to use and the solution after mixing.
Injector - A100 microliter loop injector.
Injection Volume - 100 microliter.
Retention - 2.0 minutes (approx.).
HPLC Analysis 25 Standard - Weigh accurately 25 mg. of cis-diammlnedichloroplatinum (DDP), 225 mg- sodium chloride and 250 mg. -1948177 mannitol into a 25-®!· volumetric flask. Dissolve in and dilute to volume with distilled water.
Pipet 5-0 ml. of the resulting solution into a 25-ml. volumetric flask, add 2.0 ml. of dis5 tilled water and take to volume with acetonitrile.
Sample (1 mg./ml.) - Pipet 5-0 ol. of the sample into a -ml. volumetric flask, add 2.0 ml. of distilled water and take to volume with acetonitrile.
Calculations STANDARD FACTOR (SF) = AVERAGE PEAK HEIGHT STANDARD MG. DDP/ML. = SF X AVERAGE PEAK HEIGHT SAMPLE X 25 This invention is capable of industrial application.
Claims (28)
1. A stable, sterile aqueous solution of cisplatin in unit dosaqe form suitable for administration to man, which solution has a concentration of cisplatin in the range of from 0.1 to 1.0 mgm/mland a pH in the range of from 2.0 to 3.0.
2. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, which solution has a concentration of cisplatin in the range of from 0.1 to 1.0 mg./ml. and a pH in the range of from 2.0 to 3.0.
3. A solution as claimed in claim 2 which has a pH in the range of 2.3 to 2.7.
4. A solution as claimed in claim 2 or claim 3 which has a pH of about 2.5.
5. A solution as claimed in any one of claims 2 to 4 which has a concentration of cisplatin of 0.2 to 0.8 mqm./ml.
6. A solution as claimed in any one of claims 2 to 5 wherein the pH is caused by the presence of an appropriate amount of a nontoxic pharmaceutically acceptable acid.
7. A solution as claimed in claim 6 wherein the pharmaceutically acceptable acid is hydrochloric acid.
8. A solution as claimed in any one of claims 2 to 7 which additionally contains a nontoxic pharmaceutically acceptable inorganic source of chloride ions at a con-2148177 centration equivalent to that produced by the presence of sodium chloride at a concentration in the range of from 1 to 20 mqm/ml.
9. , A solution as claimed in claim 8 which is free from 5 any other added chemical.
10. A solution as claimed in any one of claims 1 to 8 which additionally contains a pharmacologically acceptable excipient at a concentration in the range of from 2 to 15 mgm/ml. 10
11. A solution as claimed in claim 10 wherein the excipient is mannitol.
12. A stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to man, which solution has 15 a concentration of cisplatin of from 0.1 to 1.0 mgm/ml; and pH in the range of from 2.3 to 2.7, the pH being caused by the presence of an appropriate amount of hydrochloric acid; the solution containing in addition sodium chloride at a concentration of about 9 mgm/ml and mannitol at a 20 concentration of about 10 mgm./ml. the solution exhibiting less than 10% loss of potency when measured by high performance liquid chromatography upon storage for one month at 56°C.
13. A solution as claimed in claim 1 or claim 2 sub25 stantially as hereinbefore described.
14. A solution as claimed in claim 2 substantially as hereinbefore described with reference to the Example. -2248177
15. A method for inhibiting the growth of a malignant tumor susceptible to cisplatin which comprises administering to a non-human animal afflicted with such a malignant tumor an amount effective to inhibit the growth of said tumor of a stable, sterile aqueous solution of cisplatin in unit dosage form suitable for administration to said animal, said solution having a concentration of cisplatin between 0.1 and 1.0 mgm./ml. and a pH in the range of 2.0 to 3.0.
16. A method for inhibiting the growth of a malignant tumor susceptible to cisplatin which comprises intravenously administering to a non-human animal afflicted with such a malignant tumor an amount effective to inhibit the growth of said tumor of a stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to said animal, said solution having a concentration of cisplatin between 0.1 and 1.0 mgm./ml. and a pH in the range of 2.0 to 3.0.
17. A method according to claim 16, wherein said solution has a pH in the range of 2.3 to 2.7.
18. A method according to claim 16, wherein said solution has a pH of about 2.5.
19. A method for inhibiting the growth of a malignant tumor susceptible to cisplatin which comprises intravenously administering to a non-human afflicted with such a malignant tumor an amount effective to inhibit the growth of said tumor of a stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to said animal, said solution having a concentration of cisplatin of 0.1 to 1.0 mgm./ml. and a pH in the range 5 of 2.0 to 3.0.
20. A method according to claim 19, wherein said solution has a pH in the range of 2.3 to 2.7.
21. A method according to claim 19, wherein said solution has a pH of about 2.5. 10
22. A method according to claim 19, wherein said solution has a pH in the range of 2.3 to 2.7, said pH being caused by the presence of the appropriate amount of a nontoxic, therapeutically acceptable acid; said solution containing in addition a nontoxic, pharmaceutically 15 acceptable, inorganic source of chloride ions in a concentration equivalent to that produced by the presence of sodium chloride in a concentration in the range of 1 to 20 mgm./ml.
23. A method according to claim 22, wherein 25 said pH is caused by the presence of an appropriate amount of hydrochloric acid.
24. A method according to claim 23, wherein said solution is free of any other added chemical.
25. A method according to claim 23, wherein 30 said solution also contains a customary, harmless, physiologically acceptable excipient in a concentration in the range of 2 to 150 mgm./ml. -2448177
26. A method for inhibiting the growth of a malignant tumor susceptible to cisplatin which carprises intravenously administering to a ηση-htman animal afflicted with such a malignant tumor an amount effective to 5 inhibit the growth of said tumor of a stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable far intravenous administration to said animal, said solution having a concentration of cisplatin of 0.1 to 1.0 mgm./ml. and a pH in the range of 2.3 to 2.7, said pH being caused by io the presence of the appropriate amount of hydrochloric acid; said solution containing in addition sodium chloride in a concentration of about 9 mgm./ml.; said solution also containing mannitol in a concentration of about 10 mgm./ml., said solution exhibiting less than 10% loss of 15 potency as measured by high pressure liquid chromatography upon storage for one month at 56° C.
27. A method for inhibiting the growth of a malignant tumor susceptible to cisplatin which oaiprises Intravenously administering to a non-hunan animal af20 flicted with such a malignant tumor an amount effective to inhibit the growth of said tumor of a stable, sterile aqueous solution of cisplatin in a sealed container in unit dosage form suitable for intravenous administration to said animal, said solution having a concentration of cisplatin of 0.1 to 1.0 mgm./ml. 25 and a pH in the range of 2.3 to 2.7, said pH being caused by the presence of tne appropriate amount of hydrochloric acid; said solution containing in addition sodium chloride in a concentration of about 9 mgm./ml.; said solution also containing mannitol in a concentration of about 1C 30 mgm./ml., said solution being free of any other added chemical. 2548177
28. An aqueous solution according to any one of Claims 1 - 14 as an agent for use in inhibiting the growth of a malignant tumor susceptible to cisplatin in humans and other animals.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US91032578A | 1978-05-30 | 1978-05-30 |
Publications (2)
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IE790194L IE790194L (en) | 1979-11-30 |
IE48177B1 true IE48177B1 (en) | 1984-10-17 |
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IE194/79A IE48177B1 (en) | 1978-05-30 | 1979-02-01 | Pharmaceutical formulations containing cis-platinum(ii)diamminedichloride |
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JP (1) | JPS54157817A (en) |
AR (1) | AR218134A1 (en) |
AT (1) | AT362052B (en) |
AU (1) | AU519873B2 (en) |
BE (1) | BE874596A (en) |
CA (1) | CA1119954A (en) |
CH (1) | CH619141A5 (en) |
CS (1) | CS226002B2 (en) |
CY (1) | CY1159A (en) |
DD (1) | DD142293A5 (en) |
DE (1) | DE2906700C2 (en) |
DK (1) | DK149192C (en) |
ES (1) | ES478272A1 (en) |
FI (1) | FI66121C (en) |
FR (1) | FR2427097A1 (en) |
GB (1) | GB2021946A (en) |
HK (1) | HK37982A (en) |
HU (1) | HU177557B (en) |
IE (1) | IE48177B1 (en) |
IL (1) | IL56540A (en) |
IT (1) | IT1116893B (en) |
KE (1) | KE3230A (en) |
LU (1) | LU81056A1 (en) |
MY (1) | MY8300152A (en) |
NL (1) | NL191108C (en) |
NO (1) | NO149914C (en) |
NZ (1) | NZ189556A (en) |
PH (1) | PH18056A (en) |
PT (1) | PT69207A (en) |
SE (1) | SE445172B (en) |
SU (1) | SU1192596A3 (en) |
ZA (1) | ZA79395B (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US4302446A (en) * | 1979-10-02 | 1981-11-24 | Bristol-Myers Company | Pharmaceutical compositions |
CA1162479A (en) * | 1980-03-31 | 1984-02-21 | Murray A. Kaplan | Pharmaceutical formulations containing cisplatin |
JPS5851959B2 (en) * | 1980-06-11 | 1983-11-19 | 呉羽化学工業株式会社 | Platinum compounds and their pharmaceutical compositions |
DE3046927A1 (en) | 1980-12-11 | 1982-07-15 | Josef Dipl.-Chem.Dr.rer.nat. 1000 Berlin Klosa | 8-DIALKYLAMINOALKYLAETHER-COFFEIN-PLATINUM COMPLEXES, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAME |
IT1153974B (en) * | 1982-09-23 | 1987-01-21 | Erba Farmitalia | PHARMACOLOGICAL COMPOSITIONS BASED ON CISPLATIN AND METHOD FOR THEIR OBTAINMENT |
DE3305248A1 (en) * | 1983-02-16 | 1984-08-16 | Degussa Ag, 6000 Frankfurt | METHOD FOR PRODUCING PURE CIS-PLATIN (II) DIAMMINE DICHLORIDE |
NL8303657A (en) * | 1983-10-24 | 1985-05-17 | Pharmachemie Bv | SOLUTION, STABLE, AQUEOUS, AQUEOUS, CONTAINING SOLUTION OF CISPLATINE, AND METHOD OF PREPARING THEREOF. |
GB8501354D0 (en) * | 1985-01-18 | 1985-02-20 | Ici Plc | Effecting gas-liquid contact |
IL85790A0 (en) * | 1988-03-20 | 1988-09-30 | Abic Ltd | Solution of carboplatin |
FI895340A0 (en) * | 1988-11-14 | 1989-11-09 | Bristol Myers Squibb Co | HYPERTONISK CISPLATIN-LOESNING. |
JPH04502162A (en) * | 1989-02-01 | 1992-04-16 | インスチツート、フジチェスコイ、ヒミー、イメーニ、エル、ベー、ピサルゼフスコボ、アカデミー、ナウク、ウクラインスコイ、エスエスエル | Platinum 2 derivative with polymethylsiloxane, its production method and antitumor agent based thereon |
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US4053587A (en) * | 1973-04-13 | 1977-10-11 | Research Corporation | Method of treating viral infections |
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- 1979-01-31 GB GB7903379A patent/GB2021946A/en not_active Expired - Lifetime
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- 1979-02-07 FI FI790404A patent/FI66121C/en not_active IP Right Cessation
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- 1979-02-09 JP JP1345479A patent/JPS54157817A/en active Granted
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- 1979-03-01 CH CH201479A patent/CH619141A5/de not_active IP Right Cessation
- 1979-03-01 FR FR7905349A patent/FR2427097A1/en active Granted
- 1979-03-02 BE BE0/193822A patent/BE874596A/en not_active IP Right Cessation
- 1979-03-02 ES ES478272A patent/ES478272A1/en not_active Expired
- 1979-03-05 AT AT164879A patent/AT362052B/en not_active IP Right Cessation
- 1979-03-09 DD DD79211496A patent/DD142293A5/en not_active IP Right Cessation
- 1979-03-16 LU LU81056A patent/LU81056A1/en unknown
- 1979-04-05 SU SU792747852A patent/SU1192596A3/en active
- 1979-05-16 AR AR276542A patent/AR218134A1/en active
- 1979-05-29 IT IT49215/79A patent/IT1116893B/en active
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1982
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