SE445172B - STABLE, STERILE WATER DISPOSAL OF CISPLATIN IN UNIT DOSAGE FORM - Google Patents

Description

7900774-6 Cl cl NH3 Cl NH3 Cl NH; Cl fl à Cis-platinum (II) - Cis-platinum (IV) - diamine dichloride 1 diamine tetrachloride As can be seen, the platinum compound cis-platinum- (II) -diammine dichloride, S, n has been selected for clinical testing by the National Cancer Institute, the amino groups only in the horizontal plane. The cis form of the diamine dichloride complex has been synthesized according to the following reaction: NH 4 Cl K PtCl 4- N --- ü> '- Qi 4] 2 I. cis §P.§ (mf3) 2c12} + 2Kc1 (Kauffman, GB in J Kleinberg (Ed.): "Inorganic Synthesis", McGraw-Hill Book Co., Inc., New York, 1963).

The National Cancer Institute has performed clinical trials in cancer chemotherapy with the aforementioned platinum compound, which goes by the name of cisplatin. Some information regarding its chemistry and its pharmaceutical preparation is given in the publication Clinical Brochure, CIS-PLATINUM (II) DIAMMINEDICHLORIDE (NSC--119875), H. Handelman et al., Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute (revised, mrmsti 1974), on p. 1-5 and 31-32. The last two pages of this publication relate to the preparation of cisplatin, which is provided free of charge by the National Cancer Institute to clinics for clinical evaluation in cancer chemotherapy, and is translated as follows: NSC-ll9875 Dosage preparation 10 mg / ampoule: Preparation of 10 mg / ampoule: Storage: Stability: Warning: -7900774-6 PHARMACEUTICAL DATA Cis-diamine dichloroplatinum (II) The contents of each 20 ml flint glass ampoule are shown as an off-white lyophilized cake.

Each ampoule contains 10 mg NSC-119875; 90 mg sodium chloride; 100 mg mannitol and hydrochloric acid for pH control. solution for reconstitution with 10 ml of sterile water for injection, USP, each ml of the solution obtained will contain 1 mg of NSC-119875, 10 mg of mannitol and 9 mg of sodium chloride with a pH of 3.5-4.5.

The dry, unopened ampoules should be stored at a refrigerator temperature (4 ° C). intact ampoules have a temporary stability of 1 year when stored at refrigerator temperature (4-8 ° C). The stability recommendations may change pending the completion of a two-year sustainability review. Recommended reconstitution results in a pale yellow solution, which is not stable for more than 1 hour at room temperature (22oC) when exposed to normal room lighting and not more than 8 hours at room temperature (22oC) when protected from light. . Reconstituted solutions may form a precipitate after 1 hour at refrigerator temperature (4-8 ° C).

The lyophilized dosage formulations do not contain any preservative and it is therefore recommended to discard solutions 8 hours after reconstitution.

August 1974 'f Clinical Drug Distribution Section E Drug Development Branch É Reference to these pharmaceutical data and further information on the clinical use of the compound is given, for example, in Cancer Chemotherapy Reports, Part 1, Vol. 57, no. 4, p. 465-471 (1973).

With reference to cisplatin, Cancer Year (l972) l451- -1456 states in translation that “The drug used in this study has been manufactured by Ben Venue Laboratories Inc., Bedford, Ohio. It has been provided by the Cancer Therapy Evaluation Branch of the National Cancer Institute in ampoules containing 10 mg of cis-dLammine dichloroplatinum, 10 mg (sic) mannitol and 9 mg (sic) NaCl. The resulting yellow-white powder was rapidly dissolved in 8-10 ml of sterile water and injected immediately after preparation. "Ånnals of Internal Med. §§ (1977) 803-812 refers to cisplatin as" DDP "and states in translation that "The medicinal product DDP is currently only available to qualified specialists for research purposes 2. and is provided by the Investigational Drug Branch of the Cancer Therapy Evaluation Program, National Cancer Institute. The product is supplied as a white lyophilized powder in ampoules containing 10 mg DDP, 90 mg sodium chloride, 100 mg mannitol (USP) and hydrochloric acid for pH control. When reconstituted with 10 ml of sterile water for injection (USP), each ml of the solution obtained will contain 1 mg of DDP, 10 mg of mannitol and 0 mg of Naul. The pH of the resulting solution 7900774-6 is 3.4-4.5. At 2200, the reconstituted solution is stable for at least 8 hours. "The preparations described above are thus required to require a refrigerator temperature (4-8 ° C), as they are difficult to reconstitute in ampoules in a solid state (ie before reconstitution) and have a useful life of only about 20 hours at room temperature (22oC) after reconstitution.The reconstitution step itself can cause problems if not performed properly and should be avoided if possible.Because in addition the water solubility of cisplatin is only about 1 mg / ml, the costs for position of dosage forms containing more than 25 mg / ampoule by lyophilization deterrent.

An object of the present invention is to provide a stable, therapeutically acceptable, intravenously injectable dosage form of cisplatin which does not require lyophilization and reconstitution and which does not require refrigerated storage during transport and storage and which can be provided in doses of 50 mg or more. .

This object is achieved according to the present invention.

The invention relates to a stable, sterile aqueous solution of cisplatin in a closed container, such as an ampoule, in unit dosage form suitable for intravenous administration to humans, the solution having a concentration of cisplatin between 0.1 and 1.0 mg / ml, preferably 1.0 mg / ml, and a pH of 2.0-3.0, preferably 2.3-2.7 and in the vicinity of 2.5, this pH is obtained by the presence of a suitable amount of hydrochloric acid, and wherein the solution in addition, it contains a non-toxic, pharmaceutically acceptable, inorganic source of chloride ions in a concentration corresponding to that present in the presence of sodium chloride in a concentration of 1-20 mg / ml and in particular 9 mg / ml. The solution is either free of other added chemicals or it optionally contains a customary, harmless, physiologically acceptable excipient, which is preferably mannitol, in a concentration of 2-150 mg / ml and preferably a concentration of 10 mg / ml. Furthermore, the solution exhibits less than 10% (and usually less than 4%) potency loss, as measured by high performance liquid chromatography (HPLC), when stored for 1 month at 56 ° C. Preservatives can be added, if desired.

The invention is further illustrated by the following embodiments.

Example 1 Injection solution of cisplatin 1 mg / ml (1 mg cis-diamine dichloroplatinum (II) per 1 ml) Composition Per ml Per liter of cis-diamineichloroplatinum (II) 0.0010 gf * 1,000 gf * Sodium chloride, U.s.P. 0.0090 g. 9,000 g.

Mannitol, U.s.1>. - 0.0100 g. 10,000 g.

Hydrochloric acid, conc. U.S.P. q.s.to pH q.s. to pH 2.0-0.0B 2.0-3.0B Water for Injection, U.S.P. q, s, 1.0 ml q.s. 1000.0 ml.

NOTES: A. The amount adjusted on the basis of the stated purity to obtain 1.0 g of 100% cis-diamine dichloroplatinum (II) per liter.

B. About 0.035-0.050 ml of 37% hydrochloric acid is required per g of sodium chloride to obtain a pH of about 2.5. 7900774-6 SAFETY INSTRUCTIONS Cis-diamine dichloroplatinum (II) is a toxic substance, which is listed on p. 942 of the 1976 edition of the "Registry of Toxic Effects of Chemical Substances." The OSHA standard for Time Weighted Average (TWA) is 2 pg / m3. The above references, local publications and regulations, and publications such 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 should be consulted. When weighing cis-diamine dichloroplatinum (II), the working surface, filling, sealing and sealing of the weight vessel must be subjected to such protective measures.

All personnel involved in the compounding of this product must be provided with nylon covers for complete protection of the head and face, overalls, rubber gloves and a breathing mask equivalent to the MSA Ultra Filter Respirator used in environments contaminated with dust, fumes and mists with a TWA value of less than 50 pg / m3. During the step of filling with sterile fluid, a sterile head and face cover, a surgical gauze mask and goggles may replace the respirator. Any work clothes, which have been heavily contaminated as a result of spills, etc., should be stored in a closed metal container until they are burned. The importance of protecting personnel during the handling, manufacture and analysis of this product in accordance with the above safety regulations cannot be overemphasized.

The raw material cis-diamine dichloroplatinum (II) must be protected from light.

The preparation and filling of the ampoules given below were performed under diffuse natural / fluorescent light.

APPARATUS Production vessel The vessel was a glass-lined pressure vessel equipped with a stirrer. A suitable stirrer was 316 SS. The working volume was 7900774-6 in accordance with the size of the batch. A dipstick and calibration curve regarding the tank volume were required to determine the volume.

Millipore membrane filter holder 3l6 SS. The filter area was equipped with the necessary pre-filters and 0.22 micron final sterilization filter. Transmission hoses Made of Teflon or tygon. All stainless steel contact surfaces met the 3l6 SS standard. All other equipment was adapted for the production of a sterile, non-pyrogenic, particle-free product.

Preparation procedure A. The preparation procedure described below relates to a preparation procedure which takes 8 hours from batch to ampoule filling. Storage of the product before ampoule filling has not yet been studied.

B. The temperature was maintained at 270 ° C throughout the manufacturing process. l. 80% of the batch volume of water for injection, U.S.P., was introduced into a suitable vessel. 2. The sodium chloride was added with stirring. The mixture was stirred for 10 minutes or until the sodium chloride had dissolved. With good stirring, the pH of the sodium chloride solution was carefully adjusted to 2.0-3.0 (preferably 2.5) with concentrated hydrochloric acid. For the quantities required, see Note B above. After the last addition, the mixture was stirred for 10 minutes and the pH was checked again. 4. The mannitol was added with good stirring and the mixture was stirred for 10 minutes or until the mannitol had dissolved. 7900774-6 5. Cis-diamine dichloroplatinum (II) was added with good stirring and observing special precautions regarding dusting and exposure. Its container was carefully rinsed with an appropriate amount of water for injection and the rinse was added to the rest of the batch. 6. The mixture was stirred until all material had completely dissolved. This required about 60-90 minutes. The pH was monitored and additional concentrated hydrochloric acid was added, if required, to maintain the pH 2.0-3.0 (optimally 2.5). 7. The volume was carefully adjusted to the theoretical batch volume with water for injection purposes. The pH value was checked one last time. 8. The solution was passed through a clean, sterile, 0.22 micron Millipore filter to the sterile filling section. 9. Ampoules were filled with the solution as follows: 10 mg / ampoule The ampoules used were sterile type I, amber, with a volume of 15 ml and filled to 10 ml. The ampoules were fitted with 20 mm red Teflon-coated plugs and an aluminum seal. These ampoules were numbered K93, 100 and 107 with a nitrogen atmosphere and K94, 101 and 108 without a nitrogen atmosphere. 25 mg / ampoule The ampoules used were sterile type I amber, with a volume of 50 ml and filled to 25 ml. The ampoules were fitted with 20 mm red Teflon-coated plugs and an aluminum seal. They were numbered K95, l02 and 109 with a nitrogen atmosphere and K96, 103 and ll0 without a nitrogen atmosphere. The 50 mg / ampoule Do ampoules used were sterile type I, amber, with a volume of 50 ml and filled to 50 ml. The ampoules 7900774-6 10 were fitted with 20 mm red Teflon-coated plugs and an aluminum seal. They were numbered K97, 104 and III with nitrogen atmosphere 0Ch K98, 105 and III without nitrogen atmosphere.

The preparations were prepared in five groups as follows (with the final pH in brackets): K93-96 (pH 2.4) K97-98 (pH 2.5) K1010-103 (pH 2.3) K104-105 (pH 2.4) K107 ~ 110 (PH 2.3) K lll-ll2 (pH 2.4) The potencies of these preparations, determined by HPLC analysis, were originally 0.99-1.00 mg / ml.

The percentage loss of potency after storage for one or two months at the specified temperature was found by HPLC analysis to be as follows: 56 ° c 45 ° c one month two months one month K93 K94 K95 K96 K97 K98 Kl00 KlOl KlO2 Kl03 Kl04 Kl05 Kl07 Kl08 Kl09 Kll0 Klll Kll2 -1.0 * 4.0 o, o <~ 4uJw | o »4o <3u1wL» uJ @ L »+ ~ c> Ns fifi \ ~ ä fi Nä fi ä fi * ä § \ § \\ o <: c > o <: c> o <: c> o <: c> o <: c> o: o <: ß _ c X Negative value indicates that the analysis showed 1.0% power increase.

The solutions described above, with and without a nitrogen atmosphere, thus showed a potency loss of 7% or less after storage at 560 and 450, respectively, with most solutions showing a potency loss of 3% or less. The pH of the solutions was maintained at 2.4-2.7.

Physically, no change could be detected after 1 month at 560 and 450, respectively. The solutions remained clear and colorless. The original Klett values averaged 8-12, while the same values after 1 month at 560 and 45O, respectively, averaged 6-15. No changes or differences between samples with and without a nitrogen atmosphere could be noted.

A sample at each temperature station for all products was tested by turning the ampoule upside down and bringing the solution into contact with the Teflon-coated stopper. These samples were analyzed after storage for 1 month at 560 with and without a nitrogen atmosphere. The stability was not affected during one month of storage at 56 °, as the samples only showed a power loss of 1-2%.

Samples stored for two weeks at 40 were examined for crystallization of cis-diamine dichloroplatinum (II). No crystals could be observed until after one month and then only randomly. Only one batch of the products 10 mg / ampoule and 25 mg / ampoule showed some random crystallization formation at 40. Crystallization could be found consistently in all batches of the products 50 mg / ampoule but not in this case in all samples. A sample stored at 40 with crystal bond could not be redissolved by heating the solution to 37 ° with stirring. Only partial redissolution could be achieved. It is obvious that these products can not be stored in the cold, as redissolution of crystallized products is difficult to carry out.

Cis-platinum (II) diamine dichloride (NSC 119875) is an inorganic compound which was first found to prevent reproduction of E. coli and was subsequently found to exhibit antitumor activity. The compound exerts its action by interfering with DNA synthesis by cross-linking complementary strands of DNA.

The compound has activity against a variety of tumor systems including L1210, sarcoma 180, Walker 256 carcinosarcoma, DMBA- -induced mammary tumors and ascitic B16 melanosarcoma. The association is particularly interesting in that it exercises synergism with a large number of chemotherapeutic agents currently used. Extensive toxicological studies in animals have shown renal tubular necrosis, enterocolitis, bone marrow hypoplasia and lymphoid atropy. Phase I studies have shown the following toxicities: mß fl psupmäæion, renal insufficiency, high frequency toxicity and GI fi ümnlææms. Currently used doses with mild to moderately acceptable toxicity are 60-100 mg / m2 IV as a single dose or spread over 3-5 days and repeated at 4-week intervals. Early clinical trials have shown some response to the drug in germinal cell tumors, lymphoma, sarcoma, breast, head and neck carcinomas.

A dose of 60 mg / m2 roughly corresponds to 1.5 mg / kg, which in turn roughly corresponds to 105 mg / patient weighing 70 kg.

The solutions of the present invention are used in the same manner and for the same purposes as set forth above and in the other publications and extensive medical literature available in the art. As can be seen from the literature, concomitant therapy with other chemotherapeutic agents is often used for best results. If desired, the solutions of the present invention may be added to a sterile, pharmaceutically acceptable aqueous diluent, such as glucose or saline, immediately before use. Administration is either by direct intravenous injection or by intravenous infusion.

High performance liquid chromatography (HPLC) analysis of cis-diamine dichloroplatinum Analysis method Cis-diamine dichloroplatinum is chromatographed on a Water's / l-Bondapak-NH2 column using loop injection technique. Detection takes place by monitoring the U.V. absorbance at 313 nm and quantization is performed by measuring the peak height with external calibration. This method is applicable to bulk powders and solid dosage formulations containing NaCl and mannitol. Specificity has been established by separation of the cis and trans isomers and significant decomposition (humidity, acid, base, heat and accelerated light). i K .ft N15 / \ Clu m3 / \ c1 Cis- (NH3) 2 C12 Pt II Trans- (NH3) 2 C12 pt II §PLC conditions Column - Water's Micro-Bondapak-NH2 (300 MM X 4.0 MM ID) 027386 or equivalent.

Mobile phase - ethyl acetate / methanol / dimethylformamide / distilled water (25/16/5/5). Burdick and Jackson glass-distilled reagents of spectroqual quality are used. The water is degassed before use and the solution after mixing.

Detector - Water's Model 440 Absorbance Detector. wavelength - 313 nm (U.V.).

Sensitivity - 0.1 AUFS.

Injector - and 20 microliter loop ~ injector.

LOOP injector - a Valco 492 kg / cmz stainless steel valve (CV-6 ~ UHPa-C20).

Injection volume - 20 microliters Solvent supply system ~ Water's Model 6000A pump.

Flow - 2.0 ml / min.

Retention - 2.8 minutes (approximate).

Registering instruments - Heath Model SR-255B. 7900774-6 14 Paper speed - 12.7 mm / min.

Range - 10 millivolts.

HPLC analysis Using the conditions above, chromatograms of standard and sample preparations are taken up in duplicate.

Reference standard of cis-diamine dichloroplatinum (DDP): Kit no. = 78F7 (Matthey Bishop Lot No. AM7702) Specified purity = 99.8% _ Solvent - Burdick and Jackson (glass distilled) spectro quality.

Standard - Carefully weigh 25 mg of cis-diamine dichloroplatinum (DDP) in a 25 ml flask. Dissolution and dilution to the indicated volume is done with dimethylformamide.

Lyophilized injection - the ampoule contents are reconstituted with 10.0 ml dimethylformamide and the whole is shaken mechanically for 5 minutes (alternatively ultrasound can be used for 2 minutes). 5.0 ml of the sample solution is filtered (Millipore filter or equivalent), the first milliliter being discarded.

Content uniformity - 10 ampoules are prepared as above and analyzed.

Calculations _ MG. STANDARD / ML.

STANDARD FACTOR (SF) _ AVERAGE HEAD FOR STANDARD SF X AVERAGE HEIGHT FOR SAMPLE X 25 MG 'DD? / GRAM = WEIGHT OF THE SAMPLE (GRAM) MG. DDP / AMPULL = SF X AVERAGE HEIGHT FOR SAMPLE X 10 For analysis, average results obtained for 10 ampoules from content uniformity tests are used.

Method The above analysis method with respect to cisplatin is applied to aqueous solutions (dosage formulations) containing NaCl and mannitol after the following changes in the method description above. §§§§; conditions Variable phase ~ acetonitrile / distilled water (75 parts by volume / 25 parts by volume). Burdick and Jackson glass-distilled reagents of spectroqual quality are used. The water is degassed before use and the solution after mixing.

Injector - a l00-microliter-l00p injector.

Injection volume - 100 microliters.

Retention - 2.0 minutes (approximate).

HPLC Assay Standard - 25 mg of cis-diamine dichloroplatinum (DDP), 225 mg of sodium chloride and 250 mg of mannitol are carefully weighed into a 25 ml flask.

The whole is dissolved and diluted to the specified volume with distilled water. 5/0 ml of the resulting solution Pipette into a 25 ml flask, add 2.0 ml of distilled water and dilute the whole with acetonitrile to the indicated volume.

Sample (1 mg / ml) - 5.0 ml of the sample pipetted in a 25 ml flask, add 2.0 ml of distilled water and dilute the whole with acetonitrile to the indicated volume.

Calculations s-I-SECOND FACTQR (SF) = MG 'STANDARD / ML' AVERAGE TOP HEAD FOR STANDARB MG. DDP / ML. SF X AVERAGE HEIGHT FOR SAMPLE X The present invention can be applied industrially.

Claims (4)

7900774-6 16 Patent claims Stable, sterile aqueous solution of cisplatin (cis-platinum (II) -diamine dichloride) in unit dosage form suitable for administration to humans, characterized in that it has a concentration of cisplatin of 0.1-1, 0 mg / ml, a pH of 2.0-3.0, this pH being adjusted by the presence of an appropriate amount of hydrochloric acid, and containing a non-toxic, pharmaceutically acceptable source of chloride ions in a concentration corresponding to that present in the presence of sodium chloride at a concentration of 1-20 mg / ml. > 2. Stable, sterile cisplatin aqueous solution according to claim 1, characterized in that it has a concentration of cisplatin of 1.0 mg / ml and a pH of 2,3- 2.7, preferably a pH of 2.5. Stable, sterile aqueous solution of cisplatin according to claim 1 or 2, characterized in that the solution further contains a customary, harmless, physiologically acceptable excipient in a concentration of 2-150 mg / ml, preferably mannitol. A stable, sterile aqueous solution of cisplatin according to claim 3, characterized in that it contains sodium chloride in a concentration of 9 mg / ml and mannitol in a concentration of 10 mg / ml.