CS226002B2 - Method of stabilizing aqueous sterile platinum cis-diamine-dichloride solution - Google Patents

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 a process for stabilizing an aqueous sterile solution of cis-diamine dichloride. These solutions are suitable for the treatment of cancer.

Platinum compounds are a very special group of compounds in the field of substances used for tumor suppression. In 1965, Rosenberg and the other antibiotic effect of these compounds were found, and later it was found that animals were anti-tumor agents. (Rosenberg B., Van Camp, L. and Kigas T, Inhibition of Cell Division in Escherichia Coli by Electrolysis Products from a Valid Electrode. Nature / London / 205: 698-699, 1965, Rosenberg, B., Van Camp L, Trosko JE and Mnnoiu * V.H, Platnnum compoiunds: A new class of patent entities (Nture (London) 222: 385-386, 196 9).

As for the structure of these species, it is a complex made up of a central one. a platinum atom that is surrounded by chlorine atoms and ammonium groups in the cis or trans position according to planar relations. Two of the detailed! studied compounds have the following formula:

Cl

Cl

Cl

Cl

CL ^J MH.

Platinum diaminnetrachloride

As can be seen, the cis-diamine dichloride selected for the Naaional Ceaicer Institute clinical trials has chloride atoms and amino groups only in the horizontal plane. The cis-form of this complex was synthesized according to the following chemical equation:

nh ₄ ci

K ₂ [PtCl ₄ ] + 2HH ₃ -------- ► cis-fPtdiH.pjClg] + 2KCl

Kauffman, G. В. and J. Kleinberg (Ed.), Inorganic Synthesis, McGraw-Hill Book Co., Inc., New York, 1963.

The National Cancer Institute conducted clinical trials of chemotherapeutic efficacy against tumors with the above substance, now called the United States Adopted Name (USAN) c18platin. Some details on the chemical nature and pharmaceutical treatment of this substance are given in 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, August 1974) on pages 1 to 5 of JI to 32. The last two pages of this publication relate to the formulation of the substance into dosage forms. The compound is administered free of charge to N.C.I. for clinical evaluation to determine the chemotherapeutic effect against tumors. The two parties cited in full are set out below.

Information on pharmaceutical properties

NSC-119875 Platinum (II) -diaminoindichloride

Pharmaceutical forms

Vial containing 10 mg:

Each vial of 20 ml contains an off-white lyophilised substance. Each drug contains 10 mg of NSC-119875, 90 mg of sodium chloride, 100 mg of inannitol and hydrochloric acid to adjust the pH.

Preparation of the solution

Vial containing 10 mg of the active substance

When reconstituted with 10 ml of sterile water for injection (USP), 1 ml of the resulting solution, 1 mg of NSC-119875, 1 mg of mannitol e, 9 µg of sodium chloride at pH 3.5 will be absorbed. to 4.5.

Storage

Unopened vials with a dry content should be stored at 4 to 8 ¹ 0.

Stability

Intact dry vials have an expected stability of 1 year when stored at 4 to 8 ° C. As further testing is performed, it is possible that the stability data of the compounds may be changed. After reconstitution as described above, a pale yellow solution is formed which is stable for only 1 hour at 2 ° C in light and only 8 hours in the dark at 22 ° C. Reconstituted solutions may form a precipitate after storage for one hour at 4 to 8 ° C.

Notice

The lyophilized solutions do not contain a preservative and can be taken up to 8 hours after reconstitution.

Sppen 1974

Clinical Drug Distribution Section

Drug Development Branch

Further details of dosage forms of this substance are given, for example, in Cancer Chemotherapy Reports, Part 1, Volume 57, No. 4, pages 465-471 (1973).

Cancer JO: 1451-1456 (1972) provides the following information about the cisplatin compound:

The fabric is manufactured by Ben Venue Laboratories Inc., Bedford, Ohio. Bylg delivered Сапсез? Tjerapy Evaluation Branch, Cancer Institute in vials containing 10 mg of cis-diaoindichloride platinum, 10 mg of dry oannitol and 9 mg of dry sodium chloride. The resulting yellow-white powder is readily dissolved in 8-10 ml of sterile water and is intended for injection immediately after preparation.

In Ainnls of Interna! Copper. 86: 803-812 (1977) discloses the compound under the abbreviation DDP and describes it as follows:.

DDP is available for research only to qualified professionals through the Investigtioin Drug Branch Cancer Therapy Evaluation Program, No. 1 Cancer Institute. The compound is administered in the form of a white lyophilized powder in vials containing 10 mg of DDP, 90 mg of sodium chloride, 100 mg of MN and nitro (U.S.P.) and hydrochloric acid to adjust the pH. When reionitized with 10 ml sterile water for injection (U.S.P.), 1 ml of the resultant solution thus obtained will contain 1 mg of DDP, 10 mg of maanntol and 9 mg of sodium chloride. The resulting solution will have a pH in the range of 3.4 to 4.5. At 22 ° C, the solution is stable for at least 8 hours after the reaction.

The above dosage forms require for storage in vials in dry form in the solid state prior rekonnsitucí storage at 4 EZ 8 ⁱⁿ C, it is difficult to reconstitute after they can be pouuít when stored at 22 ° C. for a maximum period of 12 hours.

Reconstitution may cause difficulties if carried out in an inappropriate manner. Furthermore, the water solubility of the cisplatin compound is only about 1 mg / ml, so that the costs incurred in the preparation of dosage forms containing more than 25 mg / vial of Lytfillizens are so high that their normal use cannot be considered.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a stable, therapeutically acceptable dosage form of cis-diaminedichloride for use in threads, avoiding the need for lymphoidization and reconstitution, and cooling during transport and storage at doses of 50 mg or more.

Accordingly, the present invention provides a method for stabilizing an aqueous, sterile solution of cis-diaminedichloride in a sealed container in the form of a single dose, suitable for administration to a patient, comprising: The platinum (II) cis-diamine dichloride 0.1 to 1.0 mg / ml is stabilized by the addition of chlorotriacetic acid to a pH of 2.0 to 3.0, preferably 2.3 to 2.7. in the presence of a non-toxic, pharmaceutically acceptable inorganic chloride ion source in a concentration equivalent to 1 to 20 mg / ml sodium chloride, and in the presence of a non-toxic, pharmaceutically acceptable carrier at a concentration of 2 to 150 mg / ml.

After a month of storage at 56 ° C, there is no greater effect on solution than 10%, usually less than 4% when measured by high pressure liquid Ό -manorrania. Optionally, a preservative may be added to the solution.

The use of the solutions according to the invention can inhibit the growth of malignant tumors which are sensitive to cis-diamine dichloride. The solutions are administered intravenously in an amount capable of inhibiting tumor growth, the solutions being administered as sterile aqueous solutions in a sealed or sealed container, for example, in an amine or intravenous vial, the concentration of the compound being platinum. in the solution is 0.1 to 1.0 mg / ml, preferably 1.0 mg / ml, the pH of the solution is in the range of 2.0 to 3.0, preferably in the range of 2.3 to 2.7 and especially 2 This pH is maintained in the presence of an appropriate amount of a non-toxic, pharmaceutically and therapeutically acceptable acid, preferably a strong inorganic acid, in particular hydrochloric acid.

The solution optionally comprises a non-toxic, pharmaceutically acceptable inorganic source of chloride ions in the pharmaceutical composition. a concentration which is equivalent to correction, provided by the presence of chlorine ions in an amount of 1 to 20 mJ / ml, preferably 9 m / ml. Optionally, the solution also contains other chemical substances or conventional, harmless, physiologically acceptable carriers, preferably mannitol in 2 to 150 ml / ml, preferably at a concentration of mg / ml, the solution losing at 56 ° C for 1 month less than 10%, typically less than 4%, efficiency when measured by high pressure liquid crystallography.

Description of preferred embodiments

Example 1

Injectable solution Compound ^ splatin koncceCгaci about 1 mg / mL of [1 mg c ^{* i} with ^i-CLIA cdichlsridu plstnatého 'in ¹ ml]

Ingredients in 1 ml in 1 liter cis-diamine chloride platnates (II) ^0, 0010 ^gA 1,000 ^gA sodium chloride U.S.P. 0.0090 g 9,000 g iiftCiol, U.S.P. 0.0100 g 10,000 g concentrated acid ^2, 0 to 3,0® hydrochloric acid US.P. to pH ^2, 0 ^{and 3, 0]} water to be used U.S.P. to 1.0 ml 1000.0 ml

Note:

A = 10% pure, the compound of the stated purity must be adjusted so that the solution contains 1 g of 100% pure cis-diamitdichlsaid felt in 1 liter.

B = about 0.035-0.050 ml of 37% hydrochloric acid per g of sodium chloride is required to adjust the pH to about 2.5.

Uppoornění

Cis-diafluoric acid is a heavy substance and is listed on page 942 of the Reegstric Effects of Chemical Substance of 1976. The OSHA standard TWA (Time Wei ^g htcd Inversion) is 2 based on the above publications and the regulations that apply to that substance in Natona! Cancer Institute Safety Standards in the case of chemicals, Keré may cause serious damage to health, and very strict safety devices must be maintained with this substance in accordance with the National Institute of Health Specifications for Class II Safety CeCi-net. Any weighing of Celsius-diaiCrdichlsaid cane, filling into vials, capping and similar procedures must be carried out with the use of protective equipment.

All persons who come into contact with this substance must be protected by a full head and face mask, full protective suit, rubber gloves and breathing apparatus, such as NSA Ultra FUter eecsirator, designed for dust, vapor and ma em ^of the ΓΥΑ ^less thee ^from 5 ° / ^ / ^. The ^{p ga} fiddle with rilního ^ n ^ i ^ jc respirator may replace conventional surgical gauze mask. Any fabrics or aids into which the cloths. it must be stored in a closed metal container until it is burnt.

It is by no means possible to impose the above-mentioned regulations in the manufacture, processing of this compound has been exaggerated.

cis-diamine dichloride · must be protected from light. Production and filling:! to vials as described above should always be performed in diffuse light, which is natural and fluorescent illumination.

Establishment

Reaction vessels

Pressure vessels lined with glass should be used. Stirrers A 316 no. A safe working volume must be maintained, which must be monitored by an integral part of each reaction vessel.

Membrane-type filter devices

316 čč. If necessary, pre-filtration standard filters and a final sterilizing filter of 0.2 ^ 2 _< am must be included.

Compound transfer vessels

Not the best one is a typhoon or a tygon.

Requirements 316 čč can also be provided when using stainless steel. Also, all other devices must be selected so as to obtain a sterile, pyrogen-free, particulate-free product.

Production instructions

These instructions were modified for production and filling within 8 hours. product loading prior to filling was not taken into account.

A temperature of 27 - 2 ° C was maintained during production and filtration.

Water is injected into a suitable container for injection (U.P. in the amount of 80% of the final batch volume).

Sodium chloride is added with stirring. The mixture is stirred for 10 minutes - or until completely dissolved.

While stirring, the pH of the sodium chloride solution is carefully adjusted to a value of 2.0 to 3.0, preferably 2.5 by adding concentrated hydrochloric acid. An approximate amount of this acid has been mentioned above. After the last addition, the resulting mixture was stirred for a further 10 minutes, then the resulting pH was checked again.

Mannitol is added with vigorous stirring and the mixture is stirred for 10 minutes or until complete dissolution.

Platinum (II) platinum (II) is added under vigorous stirring while maintaining all the above safety precautions. The vessel from which the compound was added is rinsed with plenty of water for injection and added to the reaction vessel.

the mixture is stirred until completely dissolved, which takes about 60 to 90 minutes. The pH is then rechecked and, if necessary, further concentrated hydrochloric acid is added to a pH of 2.0 to 3.0, the optimum pH being 2.5.

Make up to volume with water for injection. Pre-calculated charge volume. The pH is then adjusted again.

The solution was passed through a clean 0.22 µm sterile filter (Millipore FLter) for sterilization.

The resulting mixture is divided into vials as follows:

Drug containing 10 mg of active substance

A 15 ml sterile Type I dark glass vial is filled with 10 ml of the solution. It is then stoppered with red 20 mm diaphragm stoppers with a telephone coating and sealed with aluminum foil. It will turn back. as K93, 100 and 107 with a nitrogen blanket and as K94, 101 and 108 without a nitrogen blanket.

Vial of 25 mg Active ingredient

Enjoy. In a 50 ml sterile dark glass vial of I type, fill 25 ml of the above solution into the vial. The vial is closed with a 20 mm Teflon coated red stopper and covered with planer foil. They are treated as K95, 102 and 109 with nitrogen overlay and K96, 103 and 110 without nitrogen overlay.

Vial containing 50 mg of the active substance

Use sterile Type I dark glass vials of 50 ml, place 50 ml of the above solution in a vial. The vial was stoppered with a red stopper 20 mm in diameter with a teflon coating and covered with aluminum foil. It is denoted as K97, 104 and 111 with nitrogen overlap and K98, 105 and 112 without nitrogen overlap.

Said dosage forms were prepared in the following 5 groups, the resulting pH being shown in parentheses.

K93-96 (ph 2.4) K97-98 (pH 2.5) K100-403 (pH 2,3) K104-105 (pH 2,4) K107-110 (pH 2,3) K111-112 (pH 2,4)

Initial efficacy in high pressure liquid chromatography monitoring ranged from 0.99 to 1.00 mg / ml.

The loss of efficacy in% when stored for 1 or 2 months at the indicated temperature is summarized in the following table;

High: 55 ° C 1 month 2 months High: 32 ° C 1 month K93 4.0 K94 2,0 4.0 K95 0.0 -1,0 * K96 », 0 4.0 0.0 K97 3.0 K98 4.0 2,0 K100 3.0

High: 55 ° C 1 mmmonth 2 m High: 32 ° C 1 mmmonth K101 3.0 5.0 K102 3.0 K103 5.0. 4.0 K104 o, o -1,0 * K1C5 o, o 5.0 0.0 K107 1.0 0.0 K108 2,0 5.0 1.0 K109 3.0 K110 3.0 K1 1 t 7.0 K112 7.0

μ A negative number indicates that the efficiency increases.

It can be seen from the table that said solutions, with or without nitrogen supersaturation, lose only 7% of their activity or less after storage at 56 ° C or 45 ° C, with most samples losing only 3% effective or less. The solutions maintained a pH of 2.4 to 2.7.

After 1 month no physical grain was observed at 56 or 45 ° C. The solutions remain clear and colorless. The Klett values are on average 8 to 12, after 1 month at 56 or 45 ° C, 6 to 15. No differences were observed between the overlapped and non-overlapped nitrogen samples.

One sample at each of these temperatures was stored so that the vial was turned downward so that the solution had been consumed. in contact with the Tefoon plug. Samples from these vials were monitored after storage at 56 ° C for 1 month with or without nitrogen overlay. Stability was not affected after 1 month storage at 56 ° C and samples lost only 1-2% of their original potency.

When stored for 2 weeks at 4 ° C, the samples were examined for possible crystallization of felt di-diamine dichloride. Up to 1 month, crystal formation could not be detected and crystals were still observed only randomly, not in each sample. Only 1 batch of 10 mg vials and 1 batch of 25 mg vials formed crystals at 4 ° C. A measure of 50 mg of active ingredient per vial was crystallized in all batches, but not in all samples. In one sample containing crystals formed at 4 ° C, crystals could not be dissolved even by heating the solution to 37 ° C with stirring. From these observations, it can be concluded that the product cannot be stored at lower temperatures because even the re-dissolution of the crystallized product was very difficult.

cis-Platinum (II) chloride (NSC 119875) is an inorganic substance which was first shown to have the ability to 'inhibit the reproduction of Escherichia coli and later to produce its efficacy'. The effect of this compound appears to be that it interferes with DNA synthesis by forming cross-bridges between the complementary DNA strands. The compound is active against a variety of tumor systems including L1210, sarcoma 180, Waaer carcinosaccom 256, mammary gland tumors induced by DMBA and ascites mmlanosarcoma B16. The compound is of particular interest because it is synertic with a large mtoostomy of substances which are commonly used as cheotherapeutics.

Widespread animal toxicology experiments have shown that the compound can cause renal duct necrosis, inflammation of the small and large intestine mucosa, suppression of bone marrow activity, and lymphoid tissue atrophy. Thus, the experiments have shown toxicity in the following directions:

В

Bone marrow suppression, renal insufficiency, intestinal intolerance and, in addition, toxicity to the auditory system. Commonly used doses of low to moderate toxicity range from 60 to 100 mg / m 2 in a single dose or dose divided into 3-5 days, which may be repeated after 4 weeks. In clinical trials, the substance has been shown to be useful in germ cell tumors, lymphons, sarcomas and breast carcinomas as well as skin cancers on the head and neck.

The 60 mg / t dose is approximately equal to 1.5 mg / kg, which is approximately 105 mg in a 70 kg patient.

The solutions of the invention are used in the same manner and for the same purpose as other antitumor agents. As already mentioned, they can also be used in conjunction with other chemotherapeutic agents with very good results. If desired, the solutions of the invention may be added immediately prior to use to a sterile, pharmaceutically acceptable diluent in an aqueous solution, such as an aqueous solution of glucose or sodium chloride. The solution is administered as an intravenous injection or as an intravenous infusion.

High pressure liquid chromatography (HPLC) of cis-diamine dichloride

The cis-diamdichichium dichloride method was column chromatographed using Mater * with Micro-Bondapak-NHg using an injection technique. Detection is performed by determining ultraviolet adsorption at 313 nm, calculated according to the height of the peak obtained by external calibration. In this way, it is possible to determine the substance in a pulverulent composition which also contains sodium chloride and mannitol. The specificity of the method can be demonstrated by separating the cia-isomer and the trans-isomer as well as the apparent impurities and, moreover, water, acid and base. Both isomers can be represented by the following formulas:

Cis- (NH _{3) 2} II ClgPt

Trans- (NH ₃ ) ₂ Cl ₂ Pt II

HPLC conditions

Column - Water's Micro-Bondapak-NH ₂ (300 x 4.0 mm ID) 027386 or equivalent

Mobile phase - 25: 16: 5: 5 mixture of ethyl acetate, methanol, dimethylformamide and distilled water. Spectromiatric purity reagents (Burdick and Jackson) should be used. The water before use and the resulting solution after mixing must be degassed.

Detector - Weters Model 440 Abrosbance Detector.

Wavelength - 313 nm (ultraviolet light).

Sensitivity - 0.1 AUPS.

Injector - 20 microlitres.

Injector type - Valco of 49,000 kPa in stainless steel (CV -6-UHPa-C20).

Injection volume - 20 microlitres.

Wáter's Model 6000A Pump for Solvent Drive.

Flow rate - 2.0 mL / minute.

Retention - approximately 2.8 minutes.

Recording Equipment - Heath Model SR-255B.

Paper speed - 1.25 cm / minute.

Voltage - range 10 millivolts.

HPLC Analysis ·

Under the above conditions, it is necessary to obtain chromatograms of the standard and the sample in duplicate.

Platinum cis-diamine dichloride (DDP) is used as standard:

Batch δ. = 78F7 (Mtthey Bishop Batch AM7702.

Labeled clean = 99.8%.

Solvent - Spectromeer quality, destiolated in glass (Bnurdick and Jackson).

Standard - Weigh accurately 25 mg ois-diamindic Platinum Moride (PPP) into a 25 ml volumetric flask. After dilution, make up the volume with dimethylformamide.

Injection material into the chromraograllic device - reconstitute the contents of the vial by adding 10.0 ml of dimethylformamide. and shake mechanically for 5 minutes or shake. mix the ultrasonication to '2' = minute.- · ‘5,> mwArku is then filtered (Millipore ter Kit or equavaleelS) .. green ώ. the material obtained is discarded.

in each case in the same manner before carrying out the assay. _O

Preserving uniformity of sample - prepare individual

Calculations .o

Standard factor (SF) mg stendard / ml

, ........... ... .. II average peak height for standard

SF x average peak height for · sample x 25 mg DDP / g sample in ^g · ^7: “mg DDP / vial = SF x average peak height. for sample x 10

To obtain uniform results, the average for each is calculated. · 10 pre-made vials. .

Method

The above determinations of the compound of the platinum are made in aqueous solutions containing sodium chloride and rannStol.

HPLC conditions

Mooile bath - a mixture of acetonitrile and distilled water (75:25 by volume). It is necessary to use Solvents in spectrometric purity, distilled in glass (Burdick and Jackson). The iodine before use and the resulting solution after mixing all the components must be removed from the gas.

yssMaking device - A100 micrroit loop injector.

Injection volume - 100 microlitres of the ticket - approximately 2.0 minutes.

HPLC analysis

226002. 10

Standard - Weigh accurately - 25 mg of cis-diaminedicyl chloride (DDP), 225 mg of sodium chloride and 250 mg of mmnitol in a 25 ml volumetric flask. The material is dissolved and made up to volume with distilled water. Pipette 5.0 mL of the resulting solution into a 25 mL volumetric flask, add 2.0 mL of distilled water and make up to volume with acetonitrile

Sample (1 mg / ml) - Pipette 5.0 mL of the sample into a 25 mL volumetric flask, add 2.0 mL of distilled water and make up to volume with acetone.

Calculations of mg standard / ml, Factor for standard (SF) = ..........

mean peak height for standard mg DDP / ml = SF x mean peak height for sample x 25

The visor is sbhopen industrial use.

Claims (4)

SUBJECT OF THE INVENTION A method for stabilizing an aqueous sterile solution of cis-diamine dichloride in a sealed container in the form of a single dose, suitable for intravenous administration to a patient, characterized in that from 0.1 to 1, by weight, from 0.1 to 1 The 0 kg / ml solution is stabilized by the addition of hydrochloric acid to a pH of 2.0 to 3.0, preferably 2.3 to 2.7, in the presence of a non-toxic, pharmaceutically acceptable inorganic chloride ion source, equivalent to 1-20 mg / ml chloride sodium, and in the presence of a nontoxic, pharmaceutically acceptable carrier at the end of 2 to 150 v / m, 2. The process of claim 1, wherein the solution is stabilized to a pH of 2.5. 3. The process of claim 2, wherein 1.0 mg / ml of cis-diamine dichloride is used. 4. The method according to claims 1 to 3, characterized in that the carrier is used in an amount of 10 m / m.