FI72302C - FOERFARANDE FOER FRAMSTAELLNING AV STABILT MICROCRYSTALINT CISPLATIN. - Google Patents

Description

72302

This invention relates to a process for the preparation of stable, rapidly dissolving microcrystalline cisplatin. The cisplatin-containing dry blend compositions thus prepared are used as reconstituted preparations with sterile water for injection in cancer chemotherapy.

Platinum compounds form a unique group of neoplastic agents. In 1965, Rosenberg et al. they were first found to have a single antibiotic effect (Rosenberg, B. et al., Nature (London), 205, 698-699 (1965), and later Rosenberg et al. found them to be potent antitumor agents in animals / "(Rosenberg, B. et al., Nature (London), 222, 385-386 (1969) _7.

15 In structure, these compounds are complex compounds in which the central platinum atom is surrounded by chlorine atoms and ammonia groups in different order in the cis or trans position, the two most studied platinum compounds are as follows: 20 C1 C1 NH3 Cl j NH3 zv Δ /

Cl NH, ^ lm3 25 Cl

Cis-platinum (II) diamine- Cis-platinum (IV) diamine- dichloride tetrachloride

As can be seen, all chlorine atoms and amino groups of cis-platinum (II) diamine dichloride are in the same plane.

30 This compound, which is USAN (United States Adopted Name) is cisplatin, has been synthesized as follows: NH .Cl 4 K2ZPtCl47 + 2NH3 -> cis- / Pt (NH3) 2Cl27 + 2KCl3 35 Breusova-Baidala, Y.G. et al. / Akademia Nauk USSR, no.

6, pp. 1239-1242 (June 1974) discuss the slow isomerization of cisplatin (II) diamine dichloride in aqueous solution to the trans form.

2 72302

Reishus, J.W., and Martin, D.S. [Journal of The American Chemical Society, 83, 2457-2462 (1961)} describe the acid hydrolysis of cisplatin at 25 ° C and 35 ° C. These studies were performed in aqueous solutions at concentrations of 1.5 x -3 -3 -3 5 10 -m, 2.5 x 10 -m, and 5.0 x 10 -m, corresponding to concentrations of 0.45, 0.75, and 1 .5 mg / ml. The investigators report that there was some ambiguity in locating the starting point ("zero point") of the hydrolysis curves, as it took 10-30 minutes for the samples to dissolve completely at such low concentrations.

Rozencweig, M. et al [Annals of Internal Medicine, 86, 803-812 (1977)] summarize several preclinical and clinical studies on the use of cisplatin in animals against artificially induced tumors and against different types of human tumors. They state that they have used the Qualified Researchers (edited by Investigational Drug Branch of the

Cancer Therapy Evaluation Program of the Cancer Institute) white lyophilized powder consisting of 10 mg of cispla-20 tin, 90 mg of sodium chloride, 100 mg of mannitol (U.S.P.), and hydrochloric acid to adjust the pH. Reconstruction with 10 ml of sterile water for injection (U.S.P.) gave a solution containing 1 mg cisplatin, 10 mg mannitol and 9 mg NaCl per ml.

25 Talley, R.W. et al. [Cancer Chemotherapy Reports, 57, 465-471 (1973)] describe their Phase I clinical trials in which they used cisplatin in 65 human patients with different types of cancerous tumors. As in the previous case, the drug was supplied by the National Cancer Institute in 30 vials containing 10 mg of cisplatin, 90 mg of sodium chloride, and 100 mg of mannitol, which mixture was reconstituted by adding 10 ml of sterile water.

Rossof, A.H. et al. [Cancer, 30, 1451-1456 (1972)] describe the results obtained with cisplatin in the treatment of 31 human patients with different tumor types. They report that the drug, supplied by the National Cancer Institute, was manufactured by Ben Venue Laboratories, Inc. and that it contained 10 mg of cisplatin, 10 mg (sic) of mannitol 1 per vial! 3 72302 and 9 mg (sig) NaCl and that this off-white powder readily dissolved in 8-10 ml of sterile water.

For information on the chemistry and pharmaceutical compositions of cisplatin, see "Clinical Brochure, Cis-Plati-5 num (II) diamminedichloride (NSC-119875)", H. Handelsman et al., Investigational Drug Branch, Cancer Chemotherapy Evaluation Program, Division of Cancer Treatment , National Cancer Institute (re-submitted in August 1974) on pages 1-5 and 31-32. Pages 31 and 32 discuss cisplatin free of charge for clinical trials of N.C. Irn 10 and its clinical evaluation in cancer chemotherapy as follows:

Pharmaceutical information: NSC-119875 Cis-Diammine dichloroplatinum (II)

Dosage composition 10 mg / vial: The lyophilised product in a 20 ml quartz glass bottle is an almost white cake. Each vial contains 10 mg of NSC-119875, 90 mg of NaCl, 100 mg of mannitol and hydrochloric acid to adjust the pH.

Preparation of the solution 10 mg / vial: Reconstituted with 10 ml of sterile 2t water for injections (USP), each ml of solution contains 1 mg NSC-119875, 10 mg mannitol and 9 mg NaCl and has a pH of 3.5-4 5. Storage: Dry, unopened vials should be stored at 2 ° C (4-8 ° C).

Stability: According to preliminary studies, unopened vials can be stored for 1 year at refrigerator temperature (4-8 ° C). The stability recommendations may change after the completion of the 2-year storage study. Reaction in the preferred manner gives a pale yellow solution which is stable at room temperature (22 ° C) and normal room lighting for up to one hour and protected from light at room temperature (22 ° C) for up to 8 hours. A precipitate may form in the reacted solutions during storage for one hour at refrigerator temperature (4-8 ° C).

10 Precautions; Lyophilized dosage compositions do not contain a preservative, so solutions should be discarded within 8 hours of reconstitution.

August 1974 15 Clinical Drug Distribution Section Drug Development Branch

The process according to the invention gives a stable microcrystalline form of cisplatin which is rapidly soluble in water. The permanent dry mixture of this microcrystalline form of cisplatin, s-20, is reconstituted with sterile water reconstituted for intravenous administration to humans. This dry mixture optionally contains a sterile, non-toxic, pharmaceutically acceptable inorganic source of chloride ions in an amount to provide a concentration corresponding to about 20 mg, preferably about 9 microcrystalline cisplatin per mg, added with the addition of sodium chloride; in addition, the dry mixture optionally contains a conventional, harmless, physiologically acceptable excipient, preferably mannitol, from about 2 to about 150 mg, preferably about 10 mg per mg of microcrystalline cisplatin; this dry mixture is completely soluble in sterile water within about 3 minutes (usually about 2 minutes) to a concentration of 1 mg microcrystalline cisplatin / ml sterile water.

The dry microcrystalline dry mixture of cisplatin prepared in accordance with the invention may be delivered packaged in a sterile, sealed container, such as an ampoule or vial, in a unit dosage form suitable for rapid reconstitution with sterile water and as such for intravenous administration to humans. This formulation composition is characterized in that it contains from about 0.1 to about 1 mg, preferably about 1 mg, of sterile microcrystalline cisplatin per ml of water used for reconstitution, and optionally reconstituted sterile, non-toxic, pharmaceutically acceptable inorganic chloride per ml of sterile water used. an ion source in an amount corresponding to about 1 to about 20 mg, preferably about 9 mg of sodium chloride, and that the dry mixture optionally contains about 2 to about 150 mg, preferably about 10 mg of conventional sterile water for reconstitution per ml, a harmless, physiologically acceptable excipient, preferably mannitol, and that this dry mixture is completely soluble in sterile water in about 3 to 15 minutes (usually about 2 minutes) to a concentration of 1 mg microcrystalline cisplatin / ml sterile water.

The process of the invention is characterized in that a) a first solution is prepared which contains from about 1 to about 20% by volume of aqueous hydrochloric acid in a liquid organic amide in a concentration of about 6 mol / l to about 12 mol / l, b) dissolving cisplatin in the first solution at about 10 to about 60 g per liter of the first solution to give a second solution, c) adding to the second solution with stirring about 0.5 to about 5 volumes of water or dilute aqueous hydrochloric acid having a concentration of up to about 0.2 mol / 1, at a temperature of about 10 to about 40 ° C to form 30 microcrystalline cisplatin, d) the microcrystalline cisplatin is recovered by filtration, e) the recovered microcrystalline cisplatin is washed with water or aqueous hydrochloric acid at a concentration of up to about 0.2 mol / 1.

6 72302 f) optionally further washing the microcrystalline cisplatin as an inert, water-miscible, volatile organic solvent, and g) optionally drying the washed microcrystalline cisplatin.

For practical reasons, it is important that the drug to be reconstituted with water dissolves rapidly in a suitable amount of water before administration by the physician, so that the time of the physician or his assistant is not wasted when shaking the product. Dissolution of cisplatin prepared by the conventional method in water at a concentration of 1 mg / ml typically takes 10 to 25 minutes, even if the preparation has been pre-screened to a mesh size of 200 mesh. The same time is required to dissolve cisplatin in the same concentrations in an aqueous medium containing 9 mg / ml sodium chloride and 10 mg / ml mannitol, or to dissolve a mixture of cisplatin, sodium chloride and mannitol in a weight ratio of 1: 9: 10) in water to a cisplatin concentration of 1 mg / ml. .

Cisplatin is currently commercially available for use in cancer therapy under the name “Platinoi.” It is lyophilized in unit dose powder vials containing 10 mg of cisplatin, 90 mg of sodium chloride, and 100 mg of mannitol, and is intended for reconstitution with 10 ml. Reconstitution of this product 25 may be accomplished by shaking for three minutes and is accomplished by lyophilizing aqueous solutions of cisplatin, sodium chloride, mannitol, and dilute HCl in separate vials, which is an expensive and time consuming batch process, e.g., 40,000 vials commercially. scale lyophilization takes about 4-6 days, manufacturing involves filling vials with cabinet shelves, freezing solutions, evacuating the cabinet until lyophilization is complete, adjusting the cabinet temperature above room temperature to achieve complete drying air into the cabinet, closing the bottles and emptying the cabinet. On the other hand, in a typical 7 72302 sterile dry substance filling using a single filling machine and filling 200 mg of solid powder into each vial, 40,000 vials can be filled and closed in an 8 hour shift. In addition, with a cisplatin solubility of only about 1 mg / ml, the preparation of dosage unit forms containing more than about 25 mg of cisplatin per vial is too expensive due to the large amount of water to be removed. However, such dosage unit forms can be readily prepared by sterile dry filling. In addition to the disadvantages associated with lyophilization, a possible power outage during a long manufacturing step should be mentioned, which would normally result in the rejection of the entire bisplatin batch. HCl escaping during lyophilization may also corrode the lyophilization cabinet and system.

15 The publications discussed above in N.C.I. Pharmaceutical Data

Sheet for Cisplatin and the Official Package Circular for Platinum (cisplatin) suggest that an unopened vial containing a lyophilized product should be stored at refrigerator temperature. Microcrystalline cisplatin and its dry powder compositions-20a have been found to have good stability at room temperature in stability tests. Stability tests with three different batches of cisplatin showed a loss of less than 1% after 3 months of storage at 56 ° C and 45 ° C, 4 months of storage at 37 ° C and 10 months of storage at 25 ° C. was packaged in brown glass bottles tightly closed with Teflon-coated rubber stoppers and the bottles packed in cartons. The loss of microcrystalline cisplatin was less than 1.7%, in an experiment in which cisplatin was packaged in brown glass bottles closed with Teflon-30 coated rubber stoppers and the bottles were stored in cartons exposed to light at room temperature.

Stability tests were also performed on microcrystalline dry blend compositions; the compositions contained 10 mg of microcrystalline 35 cisplatin, 90 mg of sodium chloride, and 100 mg of mannitol, and 8 72302 were packaged in brown vials closed with Teflon-coated rubber stoppers. The reduction in active substance at 2 and 3 months storage at 56 ° C and 45 ° C was less than 7%, at 4 and 6 months storage at 37 ° C less than 5 5% and at 10 and 11 months storage at 25 ° C less than 6%.

The microcrystalline cis-platinum prepared in accordance with the invention has a grain size distribution in which at least about 80% of the granules are 0-5 microns in size and less than about 20% are 5-20 microns in size and there are substantially no granules in size over 20 microns. When 10 microcrystalline cisplatin is prepared according to the preferred method of preparation, it does not contain more than 10 μm of granules at all.

This particle size distribution is of the same order of magnitude as the grain size distribution of cisplatin prepared from lyophilized dilute hydrochloric acid and is significantly smaller than the typical grain size distribution of a mechanically ground drug. Table 1 below shows the microscopically determined particle size distribution of three microcrystalline bisplatin batches and the grain size distribution of one lyophilized cisplatin (from 0.07-n HCl) and a typical commercial mechanically ground benzathine cefa-20 pyrine batch.

table 1

Grain size distribution (%) 25p - η

Material un 0-5 5-10 10-20 10-730

Microcrystalline cisplatin (no. 759) 96___4__0____

Microcrystalline cisplatin (No. 315) 82 14__4____

Microcrystalline cisplatin (no. 277) 85 15___0_____

Lyophilized cisplatin (No. 276) 97__3__0 __ —- _

Mechanically ground benzathine-11.3 85.5 to 3.4 cefapirin (no. 158) il · 35 9 72302

Although grain size distribution studies show that the grain size of microcrystalline cisplatin is of the same order of magnitude as that of lyophilized cisplatin, a simple microscopic examination shows that the grain size of microcrystalline cisplatin differs markedly from that of ordinary bulk material, the crystal structure studies show the clearest difference. The X-ray powder diffraction patterns of microcrystalline cisplatin and lyophilized cisplatin show that their crystal structures are clearly different and that microcrystalline cisplatin and 10 conventional cisplatin have the same crystalline form (slight differences in the and results of X-ray powder diffraction studies of lyophilized cisplatin (CuKa radiation, 1.54051 Å).

10 72302

Table 2

X-ray studies of different forms of cisplatin Sample 2 'ty' Relative Intensity of crystal levels (degrees) distances -J .----- (Ä) ____ 13.89 100 6,370

Ordinary 15.00 49 1 ^! cisplatin. ,, ft 1 (no. 389, U · 30 24 · 10 11 3,690 26.84 40 3,319 28.37 18 3,143 38.30 3 2,348 12.51 5 7,070

Lyophilized i-j 7 <: «.

. 1 · 5 6,932 cisplatin (no. 359) 13.88 100 6,375 14.13 100 6,263 19.90 6 4,458 20.19 66 4,394 28.11 8 3,172 28.71 9 3,107 31.90 4 2,803 13.81 100 6,407

Microcrystalline ..... 14.93 84 5929 cisplatin (no. 705) 16.26 71 5.447 24.05 27 3.697 26.57 22 I 3.353 23.37 16 i 3.143 30 · 35 12 f 2.943 ___ 33.14 15 2.701 11 72302

In the preparation of microcrystalline cisplatin according to the invention, ordinary (bulk) cisplatin is first dissolved in a liquid organic amide and hydrochloric acid. A suitable amide will be apparent to one skilled in the art when the requirements imposed on it are stability and adequate solubility of cisplatin in the amide-HCl mixture. Suitable amides for use in the process include, for example, formamide, N-methylformamide, N, Ν-dimethylformamide, N-ethylformamide, N, N-diethylformamide, N, N-dimethylacetamide, Ν, Ν-diethylacetamide, N- (2-hyd roxyethyl) acetamide, N-methyl-2-pyrrolidinone and the like. Tertiary amides such as Ν, Ν-dialkylformamides and Ν, Ν-dialkylacetamides are preferred. Most preferred is N, N-dimethylformamide. It is recommended to use a high quality amide in this method. In parallel experiments using 15 (a) reagent grade DMF and (b) lower grade technical DMF, it was found that using lower grade DMF reduced the yield by about 4% and increased the dissolution rate of the product to about 5 minutes.

The composition of the amide HCl solution may range from about 1% to about 20% by volume of hydrochloric acid, and the concentration of hydrochloric acid may be from about 6 to about 12%. The most preferred amide HCl composition for a particular amide can be readily determined by standard experiments. Preferably, the amide used has an amide-HCl solution ratio of about 90% to 25% by volume of amide and about 10% by volume of about 12% HCl. It should be noted that too high a concentration of HCl causes some degradation of cisplatin.

Depending on the amide used and the composition of the amide HCl solution, cisplatin can be dissolved in about 30 to about 60 g per liter of amide HCl solution. Significantly more than 60 g of cisplatin can be dissolved in many amide HCl solutions, but it has been found that the product from over-concentrated solutions does not completely dissolve in 3 minutes. At the lower limit of concentration, it has been found that cisplatin concentrations below 35 g / l usually give lower yields and unreasonably large solutions are required.

TT

12 72302 quantities per specific product quantity. When using a preferred DMF-concentrated HCl solution (volume ratio about 9: 1), it is preferred to dissolve about 40 g of cisplatin per liter.

Crystallization can be performed at about 10 to about 35 ° C. At higher temperatures, the yield of the product is lower because of the higher solubility. The product obtained at temperatures below 10 ° C often has a dissolution time of more than 3 minutes. This is believed to be due to too rapid “shock” crystallization of the product from solution when microcrystalline cispla-10 tin crystallizes from solution slowly, increasing the crystals.This is a theory not included in the invention.Of course, crystallization is best performed at room temperature because at room temperature (20-25 ° C). C) high quality microcrystalline cisplatin is obtained in good yield, so the preferred crystallization temperature is room temperature.

Crystallization is performed by mixing a solution of cisplatin amide HCl with water or dilute HCl (up to about 2 N) (about 0.5-5 volumes). The cisplatin solution can be added to water (or dilute aqueous HCl) or vice versa. Kum-20 is also obtained in essentially the same yield and microcrystalline cisplatin of the same quality. The most suitable volume of water (or dilute aqueous HCl) to be mixed with the cis-platinum solution depends on the amide used in each case, as well as the amide-HCl-cisplatin composition. The optimum volume 25 can be determined by routine experimentation. Generally, about 1.5 to about 2.5 volumes of water (or dilute aqueous HCl) per volume of amide-HCl-cisplatin solution are preferably used. When a preferred DMF-concentrated HCl (9: 1, v / v) solution containing about 40 g cisplatin / L is used, it is preferred to use about 2 volumes of water (or dilute aqueous HCl) per volume of DMF-HCl. cispla-tiiniliuosta. It should be noted that the use of too much water (or the amount of aqueous HCl) may cause crystallization of impurities in the starting material, such as transplatin.

72302 13

As stated above, microcrystalline cisplatin can be crystallized from its amide HCl solution by adding water or dilute aqueous HCl. It is not critical which one is used, and the amount and concentration of HCl present in the amide-HCl-cisplatin solution is preferably used as a guide. If the solution contains a relatively low amount of HCl, i.e. close to the lower limit (about 1% 6-HCl), then about 0.2-n HCl-Liu is preferably used in the crystallization. On the other hand, if the amide HCl-cisplatin solution contains 10 large amounts of HCl, i. close to the upper limit (20% 12 N HCl), water is preferably used in the crystallization. When using a preferred DMF-concentrated HCl (9: 1) solution containing about 40 g cisplatin / L, crystallization is preferably performed with about 0.1 N HCl solution.

The cisplatin prepared according to the invention can (after sterilization) be packaged as such in a sealed container such as an ampoule or vial, preferably in a dosage unit reconstituted before use with sterile water (at least 1 ml / mg microcrystalline cisplatin) to give an intravenous solution. Alternatively, microcrystalline cisplatin may be mixed with a sterile, non-toxic, pharmaceutically acceptable chloride ion source in an amount corresponding to about 1 to about 20 mg (preferably about 9 mg) of sodium chloride per 25 mg of cisplatin provided. -ionimäärää. Preferably, sodium chloride is used as the chloride ion source. In another embodiment, the microcrystalline sterile cisplatin is mixed with a sterile, conventional, harmless, physiologically acceptable excipient, preferably mannitol, in an amount of about 2 to about 150 mg (preferably about 10 mg) per mg of sterile microcrystalline cisplatin. In another embodiment, sterile microcrystalline cisplatin is mixed with both the aforementioned chloride ion source and the excipient in the aforementioned proportions. Each of these dry mixtures 35 is then packaged in hermetically sealed containers, such as ampoules or vials, preferably in unit dosage form, 14 72302 of which reconstituted sterile water (at least 1 ml / mg microcrystalline cisplatin) provides a solution suitable for intravenous administration. The above-mentioned dry blends can be prepared simply by mixing the desired ingredients dry or using wet granulation techniques, both methods of which are well known in the art. When using the wet granulation method, it is preferable to granulate all the other ingredients except cisplatin and to mix the granulated substances after drying with the desired amount of microcrystalline cisplatin.

The cisplatin prepared according to the invention and the dry mixtures containing it are readily soluble in sterile water (at least 1 ml water / mg microcrystalline cisplatin in about 3 minutes. The reconstituted solution is not used immediately; it should be stored at room temperature. When cooled below about 10 ° C, cisplatin crystallizes It is difficult to redissolve this cisplatin at room temperature, but it is made to dissolve by heating at about 35-40 ° C.

20 Cisplatin is an inorganic compound which was first found to be able to inhibit the proliferation of E. coli and which was then found to have antifungal activity. The potency of a drug is based on its effect on DNA synthesis by causing it to cross-link the complementary strands of DNA. It has 25 activities against the following tumor systems: L1210,

Sarcoma 180, Walker 256 arcinosarcoma, DMBA-induced breast tumors, and ascites B16 melanosarcoma. The compound is of particular interest because it has a synergistic effect when used in conjunction with several of your currently used chemotherapeutic agents. In extensive toxicity studies in animals, renal tubular necrosis, enetrocolitis, bone marrow hypoplasia, and lymphatic atrophy were observed. Phase I studies showed the following toxic effects: bone marrow atrophy, renal failure, high-frequency ototoxicity, and GI intolerance. The currently used doses with a mild or moderately acceptable 2 72 722 toxicity are in the range of 60-100 mg / m given intravenously as a single dose or in powdered doses over 3-5 days, which can be repeated every 4 weeks. Preliminary clinical trials demonstrate the effect of the drug on germ cell tumors, lymphoma tumors, sarcoma tumors, breast, head and neck carcinoma.

2

A dose of 60 mg / m corresponds to approximately 1.5 mg / kg, which in turn is for a patient weighing approximately 105 mg / 70 kg.

The microcrystalline cisplatin or dry mixtures thereof prepared according to the present invention are used after reconstitution in the same manner and for the same purpose as described above and reported in the extensive medical literature on the subject. As can be seen, other chemotherapeutic agents are often used concomitantly 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. The drug is administered either directly by intravenous injection or by intravenous infusion.

"Platinoi" is a registered trademark of cisplatin by Bristol-Myers Company "Darco" is a registered trademark of Atlas Chemical Industries for activated carbon.

25 "Millipore" is a registered trademark of Millipore Corporation for membrane filters.

Example 1

Preparation of microcrystalline cisplatin To a solution of 3Q HCl (0.7 mL) and dimethylformamide (DMF) (6.3 mL) was added 280 mg of cisplatin, and the mixture was stirred for 1 hour without obtaining a complete solution. An additional 2 mL of DMF and 0.7 mL of concentrated HCl were added, and the resulting solution was stirred for 1 h, then the solution was divided into two portions. (A) To another portion of the above solution (4.9 mL) was added 20 mL of 0.1 N HCl, and the resulting precipitate was stirred for 15 minutes. The solid was filtered, washed with 1.5 mL of 0.1 N HCl and 3 mL of acetone and dried in vacuo at 20 ° C for 18 hours. 93 mg (66%) of microcrystalline cisplatin were obtained. Karl Fischer analysis showed the product to be anhydrous and NMR analysis showed no DMF or acetone.

Analysis calculated from the formula PtH, N_Cl „: H 2.02 N 9.34 o Z λ

Cl 23.63

Found: H 1.89 N 9.33 10 Cl 22.59.

10 mg of the microcrystalline cisplatin obtained above was weighed into a 17 ml vial together with NaCl (90 mg) and mannitol (100 mg). To this mixture was added 9.9 ml of sterile water, whereby all the substance dissolved on shaking for 1 minute. A second 10 mg dose of the microcrystalline cisplatin prepared above was shaken in 10 ml of an aqueous solution of NaCl (90 mg) (10 ml) and mannitol (100 mg / 10 ml) to give complete dissolution in 1 minute.

(b) To another portion (4.8 mL) of the above solution li-20 was added 20 mL of 0.1 N HCl, and the resulting precipitate was stirred for 15 minutes. The precipitate was filtered, washed with 1.5 mL of 0.1 N HCl and 3 mL of acetone, and dried at 20 ° C under vacuum for 18 hours. 98 mg (70%) of microcrystalline cispplatin were obtained. 10 mg of this product was shaken in 10 ml of an aqueous solution of NaCl (90 mg / 10 ml) and 25 mannitol (100 mg / 10 ml) to give complete dissolution in 1 minute.

Example 2

Preparation of microcrystalline cisplatin 280 mg of cisplatin was dissolved in 7.0 ml of DMF-HCl solution prepared by mixing 0.7 ml of concentrated HCl and 6.3 ml of DMF. The solution was stirred for 1 h, then 14 mL of 0.1 N HCl was added. The precipitate was stirred for 15 minutes, then the precipitate was filtered, washed with 2 mL of 0.1 N HCl (0 ° C) and 4 mL of acetone and dried in vacuo at 20 ° C for 20 hours. 225 mg (80%) of microcrystalline cisplatin were obtained. 10 mg of this product was shaken in 10 ml of an aqueous solution of NaCl / 722302 (90 mg / 10 ml) and mannitol (100 mg / 10 ml), whereby dissolution was complete in 3 minutes. Another 10 mg sample was mixed with NaCl (90 mg) and mannitol (100 mg) to a dry mixture which, upon addition of 9.9 ml of water, completely dissolved in 3 minutes.

Example 3

Preparation of microcrystalline cisplatin 210 mg of cisplatin was added to 3 ml of a DMF-HCl solution prepared by mixing 0.3 ml of concentrated HCl and 2.7 ml of DMF. After stirring for 1 hour, not all of the material was dissolved, and an additional 0.1 mL of concentrated HCl and 0.9 mL of DMF were added to the mixture. The resulting solution was stirred for 1 h, then 8 mL of 0.1 N HCl was added. The resulting precipitate was stirred for 15 minutes, then the precipitate was filtered, washed with 1.5 ml of 0.1 N HCl and 2 ml of acetone, dried in vacuo at 20 ° C for 20 hours. 162 mg (77%) of microcrystalline cisplatin were obtained.

Example 4 20

Preparation of microcrystalline cisplatin 210 mg of cisplatin was dissolved in 5.25 ml of DMF-HCl solution (9: 1). the solution was stirred for 1 h, then 10.5 mL of 0.1 N HCl was added. The resulting precipitate was stirred for 25 minutes, the precipitate was filtered, washed with 1 ml of 0.1 N HCl and 2 ml of acetone and dried in vacuo at 20 ° C for 18 hours. 168 mg (80%) of microcrystalline cisplatin were obtained. 10 mg of this product was shaken in 10 ml of an aqueous solution of NaCl (90 mg / 10 ml and mannitol (100 mg / 10 ml) to complete dissolution in 2 minutes. Another 10 mg sample was mixed with NaCl (90 mg) and mannitol (100 mg)). ) to a dry mixture which, on shaking, completely dissolved in 9.9 ml of sterile water in 2 minutes.

18 72302

Example 5

Preparation of microcrystalline cisplatin 1.0 g of cisplatin was dissolved in 25 ml of DMF-HCl solution (9: 1). The clear solution was stirred for 1 h under nitrogen, then 50 mL of 0.1 N HCl was added. The resulting precipitate was stirred for 15 minutes, the precipitate was filtered and washed with 5 mL of 0.1 N HCl (4 ° C) and 10 mL of acetone.

About 1/4 of the product was dried under vacuum at 40 ° C for 18 hours to give 0.120 g of product. The remainder was dried in vacuo at 20 ° C for 18 hours to give 0.682 g of product.

The total yield of microcrystalline cisplatin was 0.802 g (80%).

A 10 mg sample was taken from each dried product batch and shaken in 10 μl of an aqueous solution of NaCl (90 mg / 10 ml) and mannitol (100 mg / ml); each sample was completely dissolved in 3 minutes. No impurities were detected in either sample by thin layer chromatography (TLC). High performance liquid chromatography (HPLC) showed a product dried at 40 ° C to be 984 μm / mg and a product dried at 20 ° C to 10 27 μg / mg.

20 Analysis calculated from the formula PtH, NOClO: H 2.02 N 9.34 O 2 2

Cl 23.63

Found (dried at 40 ° C): H 1.77 N 9.31 Cl 23.29

Found (dried at 20 ° C): H 1.79 N 9.21 Cl 23.13.

Example 6 25

Preparation of Microcontaining Cisplatin 2.5 g of cisplatin was dissolved in 62.5 ml of DMF-HCl-Liu (prepared from 15 ml of concentrated hydrochloric acid and 135 ml of DMF). The solution was stirred for 1 hour under nitrogen, then 125 ml of 0.1 N HCl was added. The resulting precipitate was stirred for 15 minutes, the precipitate was filtered, washed with 12 ml of 0.1 N HCl and 25 ml of acetone and dried in vacuo at 20 ° C for 18 hours. 2.0 g (80%) of microcrystalline cisplatin were obtained. A 10 mg sample was shaken in 10 mL of an aqueous solution of NaCl 35 (90 mg / 10 mL) and mannitol (100 mg / 10 mL) to complete dissolution in 2 minutes.

il 19 72302

A dry mixture was prepared by thoroughly mixing together 750 mg of the product prepared above (200 mesh), 6.75 g of NaCl 2 (200 mesh) and 7.5 g of mannitol (200 mesh).

Example 7 5

Preparation of sterile, pyrogen-free sodium chloride

NaCl (18.5 g) was dissolved in 62 ml of distilled water. To the solution was added 1.85 g of activated carbon (Darco KF), and the mixture was stirred for 0.5 hours. The carbon was filtered off using filter paper and the filtrate was slowly added to 62 mL of concentrated HCl with vigorous stirring. The resulting precipitate was stirred for 0.5 hours, the precipitate was filtered through a hard paper filter and dried at 100 ° C for 18 hours. 13.8 g (75%) of product were obtained.

15

Example 8

Manufacture of sterile, pyrogen-free mannitol

Mannitol (10 g) was dissolved in 67 ml of distilled water. Activated carbon (1.0 g, Darco KB) was added to the solution, and the mixture was stirred for 0.5 hours. The mixture was filtered through a hard filter paper, and the filtrate was slowly added to 335 ml of acetone with vigorous stirring. The resulting precipitate was stirred for 0.5 hours, the precipitate was filtered through hard filter paper and dried at 100 ° C for 18 hours. 8.0 g (80%) of product were obtained.

25

Example 9

Preparation of a sterile dry preparation of cisplatin for injection (10 mg cisplatin / vial) A. Preparation of sterile microcrystalline cisplatin 30 Precautions

All persons handling this product should protect themselves as follows: (a) Face shield, eye protection, gloves and protective clothing should be worn during manufacture, production and packaging.

35 (b) Contact with the medicinal product by inhalation or through the skin should be avoided.

20 72302 (C) All equipment and manufacturing facilities should be cleaned to remove any drug.

Method ^ 1. 90 ml of dimethylformamide (DMF must not contain dimethylamine and must be of the purity specified by Burdick and Jackson Laboratories for Dimethylformamide, Distilled In Glass, or Fisher Certified (ACS) Dimethylformamide, List D-119 ) is placed in a suitable glass container and protected with nitrogen gas. 10 ml of concentrated hydrochloric acid, U.S.P. The temperature is maintained at 20-27 ° C.

2. Continue stirring the solution under nitrogen; the temperature is maintained at 20-27 ° C.

Within 3.5 minutes, 4 g of cisplatin are slowly added and vigorous stirring under nitrogen is continued for one hour. All or almost all of the material is then dissolved.

4. The solution is passed through a sterile 0.22 μm Millipore-2Q filter into a sterile, pyrogen-free glass vessel using aseptic technique in a sterile room.

5. Stir the filtrate rapidly, adding 200 ml of sterile pyrogen-free 0,1 N hydrochloric acid at 20 to 27 ° C over 5 minutes. Heavy yellow microcrystals are formed. Stir for 15 minutes.

25 6. The crystals are isolated aseptically by filtration. The filter cake is sucked seemingly dry. Excess air must not be passed through it. The filtrate is stored.

7. Wash the filter cake with 10 ml of sterile, pyrogen-free 0.1 N hydrochloric acid at 20-27 ° C. The washings are added to the filtrate of step 6. The filter cake is sucked seemingly dry. Excess air must not be passed through it.

The filter cake is washed with 20 ml of sterile, pyrogen-free acetone. The washing liquid is added to the filtrate. The filter cake is sucked seemingly dry. 25 excess air must not be passed through it. (The combined filtrates are stored. Cisplatin is recovered from them according to step 9 below).

Il 21 72302 8. The microcrystalline cisplatin is removed from the filter (protected from light) aseptically and dried under high vacuum for 24 hours at 37-42 ° C. Yield: about 3.3-3.5 g (80-86%). The yellow microcrystals are stored at a controlled temperature of 5 rooms protected from light in a suitable, sterile, pyrogen-free brown container closed with a metal screw cap with a Teflon seal.

9. (a) The filtrate from step 7 is cooled to 0-4 ° C with stirring. The mixture is allowed to stand without stirring for 48 hours at 0-4 ° C.

10 It precipitates golden crystals. The crystals are filtered, washed with 20 ml of acetone and dried under high vacuum (protected from light) at 37-42 ° C for 24 hours. About 0.2 g (5%) is obtained. These crystals do not have the dissolution properties of the microcrystalline form and must be subjected to the above process to obtain microcrystalline cisplatin.

(b) The platinum compounds remaining in the filtrate can be recovered by distilling off water and dimethylformamide.

Properties of sterile microcrystalline cisplatin prepared by the above method 20 1. HPLC: Single peak at 2.8 minutes (1028 μg / mg).

2. IR: Corresponds to structure.

3. NMR: No acetone or dimethylformamide is found in TFA.

4. Elemental analysis: Corresponds to structure; the product is anhydrous.

5. Crystal Morphology: At 250x magnification in mineral oil under a polarizing microscope, microcrystals are seen as small rods with specific extinction. The cisplatin used as a starting material occurs in rather large irregular plates (they may be several hundred times the size of microcrystals) with a birefrin gene in the color spectrum.

35 B. Preparation of Sterile Sodium Chloride 1. Place 90 mL of sterile water for injection (U.S.P.) in a suitable glass container. Water is stirred at 20-26 ° C and 27 g of sodium chloride are dissolved in it.

22 7 2 3 0 2

Stirring is continued until all is dissolved.

2. 2.7 g of Darco KB activated carbon are added with further stirring. Stir for an hour.

3. Remove the carbon by filtration and wash with 5 ml of 5 sterile water for injections. The washing liquid is added to the filtrate.

4. The filtrate is aseptically pressed through nitrogen through a suitable, sterile, pyrogen-free Micropore filter (0.22 μm) into a suitable, sterile, polygen-free glass vessel.

10 This is solution A.

5. Using aseptic technique, add 5 volumes (approximately 550 mL) of acetone filtered through a sterile Millipore filter (0.22 μm) to mixed Millipore filtered solution A over 10 minutes. (Alternatively, solution A 15 may be added to 550 ml of vigorously stirred,

Sterile acetone filtered through a Millipore filter (0.22 μm). Crystals are formed.

6. Stirring is continued at room temperature for 0.5 hours.

20 7. The crystals are filtered aseptically.

8. Wash the crystals as filter with sterile Millipore filtered (0.22 μm) acetone (2 x 40 mL).

9. The crystals are removed aseptically by a filter and air dried at 115-125 ° C for 24 hours. Yield: about 21.5 g (80%).

10. The crystals are stored in a suitable, sterile, pyrogen-free, brown glass container closed with a screw cap with a Teflon or polyethylene seal.

Properties of Sterile Sodium Chloride Prepared by the Above Method 30 Acetone cannot be detected by NMR.

2. Water (Karl Fischer): typically about 1%.

C. Preparation of Sterile Mannitol 1. 90 ml of sterile, water for injection (U.S.P.) is placed in a suitable glass container. Water is stirred at 20-26 ° C and 13.6 g of mannitol are dissolved in it. Stirring is continued until all is dissolved.

23 72302 2. Stirring is continued and 1.4 g of Darco KB activated carbon are added to the mixture. Stir for an hour.

3. The carbon is removed by filtration and washed with 5 ml of 5 ml of sterile water for injection 5 (U.S.P.). The washings and filtrate are combined.

4. The filtrate is aseptically filtered through a suitable, sterile, pyrogen-free Millipore filter (0.22 μm) into a suitable, sterile, pyrogen-free glass vessel.

5. Aseptically add 500 ml of acetone filtered through a sterile Millipore filter (0.22 μm) over 10 minutes with vigorous stirring. Crystals are formed. (Alternatively, the filtrate can be added with vigorous stirring over 10 minutes to 500 mL of acetone filtered through a sterile Millipore filter (0.22 μm). Se-15 is continued at room temperature for 0.5 hours.

6. The crystals are aseptically filtered by a suitable method.

7. Wash the crystals as filter with sterile Millipore filtered (0.22 μm) acetone (2 x 20 mL).

8. The crystals are aseptically removed from the filter and air dried at 100-115 ° C for 24 hours. Yield: about 11.4 g (84%).

9. The crystals are stored in a suitable, sterile, pyrogen-free glass container closed with a screw cap with a Teflon seal.

Properties of Sterile Mannitol Prepared Above 1. Acetone is not detected by NMR.

2. Water (Karl Fischer): typically about 0.4-1%.

30 D. Preparation of sterile granulated mannitol and sodium chloride for use in a sterile dry microcrystalline cisplatin dry preparation for injection 24 72302

Composition 10 mg 10,000 cisplasplatin-titanium vials per vial 10 mg 5 per___

Sterile mannitol 0.1000 g 1000.00 g

Sterile sodium chloride 0.0900 g 900.00 g

Sterile Water for Injection 0.025 ml * 250.00 ml * (U.S.P.) 10 ♦ The amount of water may vary depending on the consistency obtained in wet granulation. Water is removed during the process.

Preparation Instructions ^ (Observe the safety precautions listed below) 1. Aseptically and using suitable sterile, pyrogen-free equipment, sterile, pyrogen-free mannitol and sterile, pyrogen-free sodium chloride are ground separately through a 2Q 40 mesh screen.

2. Aseptically dispense the required amounts of powdered sterile, pyrogen-free sodium chloride, and mannitol in a suitable sterile, pyrogen-free mixer. Suitable are jacketed vacuum V-mixers with a stir bar or a 2 cone mixer. Stir for an hour.

3. Gradually add small amounts of sterile, pyrogen-free water for injection (U.S.P.) suitable for injection purposes in small amounts through the mixing rod and use the mixer until a granulate of suitable consistency is obtained.

3Q after each addition of water sekoitintangon allowed to run for half an hour stirring period, 2x5 minutes.

* Note: The amounts of water shown in the compositions were obtained from small-scale laboratory experiments. Depending on the equipment used in the manufacture of large quantities of products, the amount of water required for the preparation to obtain a suitable consistency may vary within the stated limits.

25 7 2 3 0 2 4. When a suitable granulate is obtained, the mixer is allowed to rotate and the mixer rod is stopped. By heating the jacket at 50-70 ° C for 24 hours, the water content of the granules is reduced to less than 0.3% in vacuo.

Alternatively, the mixture can be removed from the mixer and dried at 50-60 ° C in a sterile Devine vacuum oven for 48 hours.

5. The aseptically dried mixture is passed through a suitable sterile pyrogen-free mill equipped with a sterile, pyrogen-free 60 mesh or similar screen.

6. The ground, sterile granulate is placed in a suitable sterile, pyrogen-free mixer and mixed with it for 0.5 hours until homogeneous. The chloride content of the powder can be analyzed to determine homogeneity.

7. The powder is stored in a suitable sterile, pyrogen-free brown glass container closed with a screw cap with a Teflon or polyethylene seal. Alternatively, the required amount of sterile mixture is left in a blender to which the required amount of microcrystalline cisplatin is added to obtain a cisplatin injectable preparation.

Preventive measures

All persons handling this product should be protected as follows: (a) Face shield, eye protection, gloves and protective clothing should be worn during manufacture, production and packaging.

(b) Contact with the drug by inhalation or dermal should be avoided.

3Q (c) All equipment and manufacturing facilities should be cleaned to remove any drug.

E. Sterile dry preparation for injection of cisplatin (10 mg cisplatin / vial [Contents to be reported as 10 mg cis-diamine dichloroplatinum (II) (cisplatin) per vial].

26 72302

Preventive measures

All persons handling this product should wear face shield, gloves and protective clothing.

(b) Contact with the drug by inhalation or dermal 5 should be avoided.

(c) All equipment and manufacturing facilities should be cleaned to remove any drug.

Composition Vials 100 Vials 10 Ingredients * 2ϋ £ ί per

Sterile, pyrogen-free * 0.0100 g 1.00 g microcrystalline, cisplatin

Sterile, pyrogen-free NaCl (40 mesh) 0.0900 g 9.00 g

Sterile, pyrogen-free mannitol 0.1000 g 10.00 g 15 (40 mesh) 0.2000 g 20.00 g.

♦ A prerequisite for this amount of cisplatin is that it is 1000 yug / mg. The following formula is used to calculate the appropriate amount of cisplatin.

20 1000 x 0.0100 q ...............

--- a = g) cisplatne vials of cisplatin butter,,,.

per sweetness ^ / μg / mg

For instructions on preparation; 1. Aseptically and in a suitable sterile, pyrogen-free apparatus, sterile, pyrogen-free mannitol and sterile, pyrogen-free sodium chloride are ground separately through a 40 mesh screen.

2. The required amounts of screened, sterile, pyrogen-free sodium chloride and mannitol are mixed in a suitable sterile, pyrogen-free mixer for one hour. A V-blender or conical mixer with a stir bar is suitable.

27 7 2 3 0 2 3. Microcrystalline cisplatin is sieved through a 40 mesh screen to break up any lumps. To the mixture in the mixer obtained in the previous step (or to the granulate of step D previously described) is added the required amount of sterile, pyrogen-free microcrystalline cis-platinum in three separate equal amounts. Stir for 30 minutes after each addition. The mixture is screened with a sterile 40 mesh screen and returned to the mixer. Stir for 30 minutes or longer until a uniform mixture is obtained.

4. The mixture is filled into suitable, sterile, pyrogen-free brown containers closed with screw caps with Teflon seal. The product is stored in the dark.

15 5. The required amount of mixture is filled into suitable, sterile, pyrogen-free brown glass vials.

They are hermetically sealed with suitable sterile, pyrogen-free Teflon-coated rubber stoppers and encapsulated in aluminum capsules. The vials are stored in the dark.

6. 10 mg of cisplatin is reconstituted by the addition of at least 10 mL of 22-30 ° C sterile water for injection (U.S.P.). The clear solution is obtained by shaking for 3 minutes at a pH of 4.0-5.5. Cisplatin solution with a concentration greater than 0.5 mg / ml must not be stored at refrigerator temperature, as cisplatin will crystallize from solution.

Claims (5)

28 72302 A process for preparing a stable microcrystalline cisplatin having a particle size distribution such that at least about 80% of the granules are less than 5 μm, less than about 20% are 5-20 μm and substantially no granules are more than 20 μm, and which is easily distinguishable from lyophilized cisplatin by X-ray powder diffraction, which is essentially as follows: 1 0 λΓ \ Process according to Claim 1, characterized in that the liquid organic amide is a tertiary amide. 2 Relative Intensity of crystal planes (degrees) distances (A) 13.81 100 6.407 14.93 84 5.929 15 16.26 71 5.477 24.05 27 3.677 26.57 22 3.352 28.37 16 3.143 30.35 13 2.943 20 33, 14 15 2,701 and which cisplatin is completely soluble in water at a concentration of 1 mg / ml in about 3 minutes, characterized in that a) a first solution is prepared containing in the liquid organic amide about 1 to about 20% by volume of aqueous hydrochloric acid at a concentration of is from about 6 mol / l to about 12 mol / l, b) dissolving cisplatin in the first solution at about 10 to about 60 g per liter of the first solution to give a second solution, c) adding about 0.5 to about 0.5 g per liter of the first solution. 5 volumes of water or dilute aqueous hydrochloric acid at a concentration of up to about 0.2 mol / l at a temperature of about 10 ° C to about 40 ° C to form 35 microcrystalline cisplatin, 29 72302 d) the microcrystalline cisplatin is recovered by filtration, e) recovered u the microcrystalline cisplatin is washed with water or aqueous hydrochloric acid at a concentration of up to about 0.2 mol / l, f) the microcrystalline cisplatin is optionally further washed as an inert, water-miscible, volatile organic solvent, and g) the washed microcrystalline cisplatin is optionally dried. 10 watts. Process for the preparation of microcrystalline cisplatin according to Claim 1 or 2, characterized in that a) a first solution is prepared which contains about 5 to about 15% by volume of aqueous hydrochloric acid in a liquid organic tertiary amide at a concentration of about 12 mol / l, b) dissolving cisplatin in the first solution at about 40 g per liter of the first solution to give a second solution, c) adding about 0.75 to about 2.5 volumes of water or dilute aqueous hydrochloric acid to the second solution at about room temperature with stirring. , at a concentration of up to about 0.2 mol / l to form microcrystalline cisplatin, d) recovering the microcrystalline cisplatin by filtration, e) washing the recovered microcrystalline cisplatin with aqueous hydrochloric acid at a concentration of up to about 0.2 mol / l, f) microcrystalline cisplatin is optionally washed with li-35 intert, mixed with water as a volatile organic solvent, and 72 722 g) the washed microcrystalline cisplatin is optionally dried. Process according to Claim 3, characterized in that the liquid tertiary organic amide is N, N-dialkylformamide, Ν, Ν-dialkylacetamide or N-methyl-2-pyrrolidinone. Process for the preparation of microcrystalline cisplatin according to one of Claims 1 to 4, characterized in that a first solution is prepared which contains about 10% by volume of aqueous hydrochloric acid in dimethylformamide at a concentration of about 12 mol / l, b) dissolving cisplatin in the first solution at about 40 g per liter of the first solution to give a second solution, c) adding to the second solution at about room temperature with stirring about 2 volumes of dilute aqueous hydrochloric acid having a concentration of up to about 0.1 mol / l, to form microcrystalline cisplatin, d) recovering the microcrystalline cisplatin by filtration, e) washing the recovered microcrystalline cisplatin with aqueous hydrochloric acid at a concentration of about 0.1 mol / L, 25 f) washing the microcrystalline cisplatin with any additional inert, water-miscible material, as a volatile organic solvent which is a lower alkanol t ai di (lower alkyl) ketone, and g) optionally drying the washed microcrystalline cisplatin. li 3i 72302