RU2725962C2 - Method of preparing a zoledronic acid-based pharmaceutical composition in the form of an infusion solution for the treatment of oncological diseases and a method for preparing a zoledronic acid-based pharmaceutical composition in the form of a concentrate for preparing an infusion solution for the treatment of oncological diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to oncology, and can be used to produce zoledronic acid in the form of an infusion solution. Methods according to the invention include preparation of zoledronic acid solution with continuous stirring in a stainless steel reactor, the inner surface of which has Teflon coating, with mannitol and sodium citrate at certain ratios between them and with heating of the solution while stirring them during 119–121 min with gradual increase of temperature from 60 °C to 80 °C. After that, solution sterilizing filtration is performed first through the depth filter and then through the membrane filter.

EFFECT: use of inventions enables to obtain a pharmaceutical composition exhibiting pharmacological activity at lower doses, increasing its stability during storage, increasing its sterility and manufacturing it using a simpler technology.

3 cl, 2 tbl, 3 ex

Description

The invention relates to medicine and the pharmaceutical industry, and specifically relates to a method for preparing a pharmaceutical composition in the form of a concentrate for the preparation of an infusion solution or in the form of a solution for infusion of zoledronic acid and a pharmaceutical composition, in the form of an infusion solution for the treatment of various oncological diseases.

Zoledronic acid belongs to bisphosphonates and corresponds to the chemical compound 1-hydroxy-2- (imidazol-1-yl) ethane-1,1-diphosphonic acid.

In particular, bisphosphonates are widely used to inhibit the activity of osteoclasts in various both benign and malignant diseases associated with excessive or impaired bone resorption. These pyrophosphate analogues can not only reduce the number of cases of skeletal disorders, but also improve the clinical condition of patients and increase their survival. Bisphosphonates have the ability to prevent bone resorption in vivo; The therapeutic efficacy of bisphosphonates in the treatment of osteoporosis, osteogenesis disorders, Paget's disease induced by a tumor of hypercalcemia (hereinafter referred to as JIU), and in recent years also metastases to bone tissue (hereinafter referred to as CM) and multiple myeloma (hereinafter referred to as MM) (see Fleisch review, has been proven). H. Bisphosphonates clinical (1997) in: Bisphosphonates in Bone Disease. From the Laboratory to the Patient, The Parthenon Publishing Group, New York / London cc. 68-163).

The mechanisms by which bisphosphonates inhibit bone resorption are not yet fully understood, and they probably vary with specific bisphosphonates. It was found that bisphosphonates have a high affinity for binding to hydroxyapatite bone tissue crystals, the ability to reduce bone renewal and resorption, reduce the levels of hydroxyproline or alkaline phosphatases in the blood and, in addition, inhibit the formation, recruitment, activation and activity of osteoclasts. It has now been established that farnesyl diphosphate synthase, an enzyme of the mevalonate cholesterol biosynthesis pathway, is a molecular target for nitrogen-containing bisphosphonates (see review by Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and molecular mechanisms of ofbisphosphonates Cancer 88 (app.): 2961-2978 (2000)).

Bone pain resulting from structural damage, periosteal irritation, and nerve infringement is the most common complication of both benign and metastatic bone disease and is a serious problem both in clinical practice and in the general population (Coleman, 1997, Cancer 80; 1588-1594).

MM is a malignant plasmacytic disease characterized by the proliferation and accumulation of malignant plasma cells in the bone marrow. Its main clinical consequences are lytic bone lesions associated with pathological fractures, and bone pain. These lesions are the result of excessive bone resorption, often leading to hypercalcemia. Bisphosphonates were included in the system of long-term treatment of MM in combination with conventional chemotherapy. It has now been found that the use of bisphosphonates such as clodronate and pamidronate can reduce the incidence of skeletal disorders, such as lytic bone lesions and pathological fractures, and can alleviate bone pain associated with these conditions and improve the quality of life of patients (Laktinen et al. . , Lancet 1992, 340, 1049-1052; McCIoskey et al. , BJ Haematol., 1998, 100, 317-325; and Berenson et al. N. Eng. J. Med. 1996, vol. 334, No.8, 488-493). Similar actions have been identified in the treatment of patients with breast cancer with bisphosphonates. When creating the present invention in experiments in vivo in animal models, it was unexpectedly found that certain bisphosphonates have pronounced and clearly directed pain-relieving (palliative) actions. For example, it was found that zolendronic acid reverses mechanical stimulus-induced hyperalgesia and neuropathic pain in rat models of chronic inflammation, exhibiting rapid action with efficacy close to 100%. In addition, when studying rat cancer-related pain tissue models in rats, it was found that zoledronic acid reduces the mechanical stimulus-induced allodynia and reduces the withdrawal (protective reaction) of the hind limbs. These results indicate that zoledronic acid and related bisphosphonates can have a direct, immediate effect, have antinociceptive and anti-allodynic effects on pain.

Zoledronic acid is prepared according to the method described, for example, in US Pat. No. 4,939,130 (see also US Pat. No. 4,777,163 and US Pat. No. 4,687,767).

In particular, from RU 2325913, 06/10/2008, it is known to use zoledronic acid, its salts, hydrates and a method for antinociceptive or anti-allodynic pain treatment, a method for treating neuropathic pain. The described group of inventions relates to methods and uses of zoledronic acid or its pharmaceutically acceptable salts or hydrates in the preparation of a medicinal product for the specified treatment. The invention provides an analgesic effect in these diseases due to previously unknown antinociceptive, antiallodynic properties of zoledronic acid.

The agents of the known invention (bisphosphonates) are preferably used in the form of pharmaceutical compositions that contain a therapeutically effective amount of an active substance, optionally in combination or in admixture with inorganic or organic, solid or liquid pharmaceutically acceptable carriers that can be used for administration.

The pharmaceutical compositions may be, for example, compositions for enteral, for example, oral, rectal administration, administration by spray or aerosol administration, nasal administration, composition for parenteral, for example, intravenous or subcutaneous administration, or composition for transdermal administration (for example, passive or ionophoretic administration )

Preferably, the pharmaceutical compositions are adapted for oral or parenteral administration (especially intravenous, intra-arterial or transdermal). The most important is intravenous and oral, but above all, and most preferably intravenous administration. Preferably, the active substance in the form of a bisphosphonate is in the form for parenteral administration, most preferably in the form for intravenous administration.

The specific route of administration and dose can be chosen by the attending physician taking into account the characteristics of the patient, especially age, weight, lifestyle, level of activity, hormonal status (for example, postmenopausal) and, if necessary, bone mineral density. However, most preferably, the bisphosphonate is administered intravenously.

The dose of the agent according to the known invention may depend on various factors, such as the effectiveness and duration of action of the active substance, route of administration, types of warm-blooded animals and / or gender, age, weight and individual condition of the warm-blooded animal.

Typically, the active substance bisphosphonate is administered to a warm-blooded animal weighing about 75 kg in a single dose of 0.002-20.0 mg / kg, preferably 0.01-10.0 mg / kg. If necessary, this dose can also be administered in the form of several, not necessarily the same, divided doses.

The term "mg / kg" refers to the amount of mg of drug per kg of body weight of a mammal, including a person who needs treatment.

The introduction of the above dose either as a single dose (which is preferable), or as several divided doses, can be repeated, for example, once a day, once a week, once a month or every three months, every six months or once once a year.

The usual dosage forms of bisphosphonate, for example, for the treatment of YOG, MK and MM, are solutions for intravenous infusion. However, bisphosphonate solutions, although substantially stable, react with bivalent and multivalent cations, in particular calcium, barium, magnesium, aluminum, boron and silicon present in the glass, and insoluble precipitates are formed which cause turbidity and possible loss of activity, which is unacceptable in a pharmaceutical product.

Moreover, these sediments can cause blockage of blood vessels and thus can lead to thrombosis, which significantly complicates the treatment. Thus, the long-term storage of the compositions of solutions of bisphosphonates in ordinary glass bottles, even made of hydrolytically stable glass of class I, is impossible. In addition, glass bottles with such a solution cannot be subjected to final wet heat sterilization and must be filled aseptically, since the elevated temperature at which wet heat sterilization is carried out accelerates the leaching of cations.

It has been shown that at pH values acceptable for parenteral delivery, significant quantities of ions are leached from commercially available glass containers (Farm. Vestnik. Vol 54, p. ZZ1 (2003)). Therefore, for short-term storage of solutions in glass products, filling with solutions must be carried out aseptically, although, given the high chemical stability of bisphosphonate solutions, their thermal sterilization is essentially possible. Such aseptic filling does not comply with the currently accepted processing standards given in document CPMP / QWP / 054 / 98corr., "Decision trees for the selection of sterilization methods" issued by the European Agency for the Evaluation of Medicinal Products Drug Standardization) (EMEA). In accordance with the same document, "the use of inappropriate thermolabile packaging materials in itself cannot be the only reason for choosing aseptic technology."

In particular, in the document US 2013040915, A1, 02/14/2013, a method for preparing a pharmaceutical composition based on zoledronic acid is described, according to which water for injection is placed in a stainless steel container and sodium citrate is added at a temperature of 35 ° C, for example, 3 6 g and 32.6 g of mannitol. It is stirred until complete dissolution for 30 minutes, cooled to room temperature and 633 mg of zoledronic acid (monohydrate) is added, dispersed with constant stirring for 30 minutes under nitrogen until dissolved, the pH is 6.3. Add the required amount of water for injection. Next, the solution is filtered through a 0.22 μm membrane in order to sterilize it, freeing the solution from the presence of any foreign substance. The sterile solution is metered into vials made of improved glass (borosilicate glass), which, after filling with the solution, are sealed with glass stoppers and autoclaved for 40 minutes at 121 ° C. However, the temperature range from 121 ° C to 136 ° C, the pressure range from 2 to 3 atm and the sterilization time interval from 20 to 45 minutes, does not exclude its incompatibility with borsilicate, as it reacts with divalent alkaline earth metals (calcium, magnesium, iron etc.).

In order to avoid this, the said patent provides that the vials containing this pharmaceutical composition based on zoledronic acid are made of improved glass, type 1 borosilicate glass, on the inner surface of which there is a thin film of silicon dioxide, obtained as a result of the chemical deposition of silicon dioxide from gas phase onto glass to form a thin layer of silicon dioxide. The resulting thin film of deposited silicon dioxide on the surface of glass vials prevents the diffusion of alkali and alkaline earth metals into a solution of a pharmaceutical preparation based on zoledronic acid, which leads to an increase in the stability and sterility of the pharmaceutical composition under autoclaving conditions, since the presence of alkali and alkaline earth metals on the walls of the bottles decreases, in contact with a solution of zoledronic acid for a long time (period) of storage.

However, this known method for the preparation of a pharmaceutical composition based on zoledronic acid, as follows from its description, is characterized by a rather complex technology, including its multi-stage nature, as well as the need for preliminary rather complex and lengthy preparation of vials in which a pharmaceutical composition based on zoledronic acid is packaged.

From another document RU 2358739, 04/18/2006, another method for preparing a pharmaceutical composition based on zoledronic acid is known.

The method consists in the following: water for injection is placed in a vessel for preparing a mixture of stainless steel. Auxiliary substances mannitol and sodium citrate are added and dissolved with stirring. The medicinal substance zoledronic acid is added and dissolved with stirring. The drug is adjusted to the final weight with water for injection. Sodium citrate neutralized zoledronic acid to a pH of 6.5.

The solution is fed to the filling line and filtered in a stream using a filter with a hole size of 0.2 μm. In washed and dried 100 ml plastic bottles of Daikyo CZ pour 102.0 ml of solution. Vials are sealed with sterilized Helvoet FM259 / 0 stoppers coated with Omniflex plus and sealed with aluminum caps. Wet thermal sterilization of the vials is carried out in order to obtain a sterility guarantee level of 10 ^-12 , i.e., at 121-123 ° C for 30 minutes (effective sterilization exposure time).

The product is stable and does not show any signs of decomposition even under severe stress conditions: at a temperature of 50 ° C / relative humidity of 75% and a temperature of 40 ° C / relative humidity of 75%.

In particular, in the table below, the consumption of the starting components is indicated, and as a result, a pharmaceutical composition containing zoledronic acid 4 mg / 100 ml is obtained.

Thus, a plastic container, or a coated container, if it is made of glass containing a bisphosphonate solution, is sterilized by heat sterilization, preferably wet heat sterilization, for example, saturated steam, steam / air mixtures or irrigation with superheated water, at a temperature of at least from about 110 ° C to about 130 ° C or higher, for example, at a temperature of at least 121 ° C or higher, for example, preferably at about 121 ° C to 124 ° C. The effective sterilization time depends on the D value of the spores of the test cultures in solution and should be such as to obtain a total sterility guarantee of at least 10 ^-6 , preferably at least 10 ^-12 . The effective sterilization time (sterilization exposure time) can be from about 15 minutes to about 3 hours, usually from about 15 minutes to about 2 hours, for example, preferably 30 minutes. Thermal sterilization is the final stage of thermal sterilization, that is, this thermal sterilization is carried out at the end or after completion of the preparation process, after filling the container with a bisphosphonate solution and after sealing the container, for example, with a suitable lid, cork or other closure. Conventional glass bottle processing equipment may be used. Plugs can be used, characterized by a slight leaching of metal ions, such as calcium, magnesium, zinc or silicon in contact with aqueous solutions, for example, solutions of bisphosphonates. Preferably, the corks have a low ash content and are coated on the product side with an impenetrable and inert barrier made, for example, from a copolymer of ethylene and tetrafluoroethylene (ETFE), teflon or fluorinated elastomers. Such plugs are, for example, Daikyo D-777-1, Daikyo D-777-3, Daikyo D-713, Daikyo D-21-7S, coated on the product side with an ETFT layer, or Helvoet FM259 / 0, coated with a fluoropolymer layer (e.g. , proprietary Helvoet Omniflex or Omniflex plus).

Plastic containers can usually not be processed on standard filling lines of a sterile pharmaceutical drug product, since such containers cannot withstand the thermal stress used in a tunnel furnace for depyrogenation. Therefore, plastic containers are usually treated without the necessary stages of cleaning and depyrogenation, thus introducing the risk of contamination of the drug product for parenteral use with an extraneous substance present in the container, as well as endotoxins that can be dissolved from the surface material of the container. In accordance with this known method, it was found that some plastic containers can be processed on standard glass bottle filling lines, and that the cleaning process can reproducibly produce a reduction in endotoxin content of at least 1000 times.

In addition to the sterilization step, containers, in particular plastic containers, can be depyrogenated before filling with a bisphosphonate solution. It was found that washing plastic bottles with water under pressure provides sufficient depyrogenation, for example, reducing the content of endotoxins by at least 1000 or more times, for example, this decrease can be from about 16,000 to 100,000 times. Preferably, such a depyrogenation step is included in methods for preparing this known method.

Zoledronic Acid 4 mg / 100 ml

Component Amount [kg] per 1000 L Zoledronic Acid Monohydrate
Corresponds to 0,0400kg anhydrous
zoledronic acid 0.04264 kg Mannitol 51.00 kg Sodium citrate 0.240 kg Water for injections Up to 1015 kg = 1000 l

Bisphosphonate solutions, as described in the known method, can also be used for slow intravenous infusion of more concentrated forms, for example, bisphosphonate concentrations from about 0.01 to about 0.5, usually from about 0.05 to about 0.2 mg / ml.

However, the known method, therefore, firstly, has a rather complex technology, an indispensable condition of which, in particular, is the use of a special type of packaging of the specified preparation, namely containers, the inner surface of which contains plastic material, and the container can be subjected to heat sterilization with special conditions: autoclaving of vials containing a pharmaceutical product based on bisphosphonate (for example, zoledronic acid) at a holding time> 121 ° C. Secondly, the pharmaceutical composition according to the known patent is only active at high concentrations of bisphosphonate, in particular, zoledronic acid.

It is widely known drugs (pharmaceuticals), produced, for example, by the company "Bel honey products", 2014, information on which is contained on the Pharmaceutical information portal of RUE "Belmedpreparaty". This portal describes the powder, lyophilized for the preparation of an infusion solution, containing one bottle: zoledronic acid (as zoledronic acid monohydrate) - 4 mg, mannitol - 220 mg, sodium citrate 5.5-aqueous - 24 mg.

Thus, as follows from the above known sources (patents US 2013040915 and RU 2358739) for the preparation of a pharmaceutical composition containing zoledronic acid as bisphosphonates in combination with additives such as mannitol (an isotonizing component), sodium citrate (organic buffer base) with stable characteristics which is sterile to the extent necessary for the dosage form, not contaminated with decomposition products and other by-products released upon contact of zoledronic acid in the container in which it is stored, it is necessary to pre-treat these containers containing this drug in a special way.

And only after the special preparation of these bottles (containers) for a preparation based on zoledronic acid can you put this drug in them and then process these bottles in a special way already with the pharmaceutical product: either use a glass container having an internal plastic lining, or use a container made of plastic material, which are then subjected to heat sterilization under the conditions specified in RU 2358739, or use bottles of special glass coated (on the inside) with a thin film of silicon dioxide (patent US 2013040915).

In both known methods, a rather complicated and time-consuming technology for the preparation of a pharmaceutical preparation based on zoledronic acid is used.

Therefore, the technical task of the claimed invention is the development of a simpler technology for producing a pharmaceutical composition (pharmaceutical preparation) based on bisphosphonate - zoledronic acid, which is sufficiently sterile and stable under the conditions of storage and use, which does not lose its activity during storage and use, and the ability to use it even lower concentrations in a solution of zoledronic acid.

The technical problem and the technical result obtained are achieved by the claimed group of inventions, which includes methods of preparing a pharmaceutical composition based on zoledronic acid, obtained in the form of a solution for infusion (one of the inventions of the claimed group), and in the form of a concentrate for the preparation of a solution for infusion (second invention of the claimed groups).

So, the task and the technical result are achieved by the method of preparing a pharmaceutical composition based on zoledronic acid for the treatment of cancer, including dissolving in a stainless steel reactor with teflon coating on its inner surface the substance of zoledronic acid in water for injection containing mannitol and sodium citrate in the ratio between zoledronic acid, mannitol, sodium citrate and water for injection from 1: 990: 6: 20,000 to 1: 1275: 6: 25000 wt. hours, subsequent heating of the solution with stirring for 119-121 minutes at a temperature of 60 ° C with a gradual increase in temperature to 80 ° C and subsequent sterilizing pressure filtration (or vacuum filtration) to obtain an infusion solution at final concentrations in zoledronic water acids in the range of 0.036-0.055 mg / ml, mannitol 4.4-5.6 mg / ml, sodium citrate 0.22-0.33 mg / ml, dosing the resulting solution in 100 ml polypropylene bottles and corking the bottles with stoppers, having low ash content and coated with an inert barrier polymer, while sterilizing filtration (or vacuum filtration) is carried out first through a depth filter with an excess pressure of 0.11 MPa and a filtration rate of 1-3 l / min, and then through a membrane filter under a residual vacuum a pressure of 0.01-0.02 MPa and a filtration rate of 1-2 l / min.

Another variant of the claimed group of inventions, which solves the problem and achieves the technical result, is a method for preparing a pharmaceutical composition based on zoledronic acid for the treatment of cancer, including dissolving in a stainless steel reactor with a teflon coating on its inner surface the substance of zoledronic acid in water for injections containing mannitol and sodium citrate in the ratio between zoledronic acid, mannitol, sodium citrate and water for injection from 1: 55: 6: 1250, subsequent heating of the solution with stirring for 119-121 minutes at a temperature of 60 ° C with gradual raising the temperature to 80 ° C and subsequent sterilizing pressure filtration (or vacuum filtration) to obtain a concentrate for the preparation of an infusion solution at final concentrations in the water of zoledronic acid in the range of 0.72-0.88 mg / ml, mannitol 4.4- 5.6 mg / ml, sodium citrate 0.22-0.33 mg / ml, dosing received solution in 100 ml polypropylene bottles and corking the bottles with stoppers having a low ash content and covered with an inert barrier polymer, while sterilizing filtration (or vacuum filtration) is carried out first through a depth filter with an overpressure of 0.11 MPa and a filtration rate of 1- 3 l / min, and then through a membrane filter under vacuum with a residual pressure of 0.01-0.02 MPa and a filtration rate of 1-2 l / min.

Using a dispenser, the resulting concentrate is dosed at 5.0 - 6.25 ml.

The following are specific examples of the implementation of the claimed method (variants thereof), to illustrate the invention, which do not limit it.

Example 1. Preparation of a solution containing zoledronic acid as a bisphosphonate used as an injection for 100 vials.

The preparation of the pharmaceutical composition is as follows.

Prepared water for injection (100 g) is transferred to a Teflon-coated stainless steel reactor (container), mannitol (510 g) is added with constant stirring, after its dissolution sodium citrate (2.4 g) is added to the reactor, and then with constant stirring add the substance of zoledronic acid (0.4 g), which corresponds to their ratio of 25000: 1275: 6: 1 wt.h (corresponds to the ratio between zoledronic acid, mannitol, sodium citrate and water 1: 1275: 6: 25000). Continuous stirring is carried out continuously for 120 minutes while gradually raising the temperature from 60 ° C to 80 ° C until the solution is homogenized. After that, check the pH of the solution, the permissible value of which should be in the range of 5.7 - 6.7.

Further, subsequent sterilizing pressure filtration and vacuum filtration are carried out to obtain an infusion solution at final concentrations of zoledronic acid in water in the range of 0.036-0.055 mg / ml, mannitol 4.4-5.6 mg / ml, sodium citrate 0.22-0 , 33 mg / ml, dosing the resulting solution in 100 ml polypropylene vials and corking the vials with cinders having a low ash content and coated with an inert barrier polymer, while sterilizing filtration (or vacuum filtration) is carried out first through a depth filter with an overpressure of 0, 11 MPa and a filtration rate of 1-3 l / min, and then through a membrane filter under vacuum with a residual pressure of 0.01-0.02 MPa and a filtration rate of 1-2 l / min.

Example 2. Preparation of an injection for 100 vials.

The method is carried out analogously to example 1, but in this case, mannitol (495 g) is added to the prepared water for injection (1000 g) in a prepared Teflon-coated stainless steel reactor with stirring, after dissolving mannitol, sodium citrate (3 g) is added to the reactor with constant stirring and then add the substance of zoledronic acid (0.5 g), dissolving it with stirring for 121 minutes while gradually raising the temperature from 60 ° C to 80 ° C until the solution is homogenized. The ratio of the components correspond to 20,000: 990: 6: 1 parts by weight (the ratio between zoledronic acid, mannitol, sodium citrate and water is 1: 990: 6: 20,000). The pH of the solution is 5.7 - 6.7. Sterilization filtration is then carried out as described in Example 1. The concentration of zoledronic acid in the solution is in the range of 0.045-0.055 mg / ml, the concentration of mannitol in the solution is 4.45-5.45 mg / ml, and sodium citrate is 0.27-0.33 mg. / ml

Example 3. Preparation of a pharmaceutical composition in the form of a concentrate for the preparation of a solution for injection.

The method is carried out analogously to example 1 under the following conditions: the prepared water for injection (500 g) is transferred for stirring to a stainless steel reactor with a Teflon coating on its inner surface, mannitol (22 g) is added, after dissolving mannitol, sodium citrate is added to the reactor (2.4 g), then add the substance of zoledronic acid (0.4 g), which corresponds to 1250: 55: 6: 1 wt.h. The pH of the solution is 5.7-6.7. The resulting concentrate of the solution is dosed through a dosing device in 10 ml plastic bottles, 5 ml of solution per bottle.

The concentration of zoledronic acid in the solution is in the range of 0.72 - 0.88 mg / ml, the concentration of mannitol in the solution is 40-48 mg / ml, and sodium citrate is 4.4 - 5.2 mg / ml.

Obtained in examples 1-3, the pharmaceutical composition according to the invention after testing has the following properties.

Storage conditions:

at 50 ° C, humidity 95% or

- at 40 ° C, humidity 75% or others.

Characteristics of a pharmaceutical product after testing:

- appearance (transparent, colorless)

- extracting components: heavy metals Ca, Mg, Al, Cd, Cr, Cu, Fe, Ti, Zn as in RU 2358739,

- decomposition products (total),

-RN ... (optimal values), from 5.5 to 7.5

The table below meets the storage conditions for:

- at 50 ° C, humidity 75% storage for 1 month

- at 40 ° C, humidity 75% storage for 3 months.

Test Start the end Quantitative analysis one hundred% one hundred% Decomposition products,
in total <0.1% <0.1% pH 6.6 6.6 Appearance Transparent, colorless solution without foreign particles Transparent, colorless solution without foreign particles Extractable components <0.05 mcg / ml <0.05 mcg / ml Heavy metals Ca <50 mcg / l <50 mcg / l Mg <50 mcg / l <50 mcg / l Cr <100 mcg / kg <100 mcg / kg Cu <100 mcg / kg <100 mcg / kg Fe <100 mcg / kg <100 mcg / kg Ti <100 mcg / kg <100 mcg / kg Zn <100 mcg / kg <100 mcg / kg Al <100 mcg / kg <100 mcg / kg Cd <100 mcg / kg <100 mcg / kg

As follows from the presented examples 1-3 and the above data, the claimed group of inventions compared with the known methods described in documents RU 2358739 and US 2013040915, has such obvious advantages as:

- the ability to ensure the effectiveness of the pharmaceutical product and at lower concentrations of zoledronic acid,

- increased sterility (absence of heavy metal ions in the final product: Ca, Mg, Zn, etc.),

- stability during long-term storage,

- simplification of the method.

All this is achieved by the totality of features characterizing the claimed group of inventions related to the preparation of a pharmaceutical composition based on zoledronic acid, including preparation of the composition in a stainless steel reactor (vessel) with its inner lining made of Teflon (fluoroplast), followed by sterilizing filtration of the obtained composition with the indicated the selected conditions of its conduct prior to packaging the pharmaceutical composition in medical bottles (plastic) for its subsequent use, as well as the quantitative ratios of the starting components between the substance of zoledronic acid, mannitol, sodium citrate and water, selected as a result of numerous experiments, to obtain the pharmaceutical product in the form (form) of a solution for infusions and in the form of a concentrate for the preparation of a solution for infusions with different concentrations of zoledronic acid, which involves the use of a pharmaceutical product and at a lower concentration than known similar pharmaceutical preparations.

The pharmacological effect of the zoledronic acid-based pharmaceutical compositions obtained according to the invention is described below, which is similar to known preparations, for example, Aklast, Zomet and Resorb based on zoledronic acid.

Zoledronic acid, as noted above, refers to highly effective bisphosphonates with a selective effect on bone. The preparation according to the invention inhibits bone resorption by acting on osteoclasts.

The selective effect of bisphosphonates on bone tissue is based on a high affinity for mineralized bone tissue. The exact molecular mechanism providing inhibition of osteoclast activity is still unclear. Zoledronic acid does not adversely affect bone formation, mineralization, and mechanical properties. In addition to the inhibitory effect on bone resorption, zoledronic acid has antitumor properties that ensure the effectiveness of the drug in bone metastases: in vivo: inhibition of osteoclastic bone resorption, which changes the microenvironment of bone marrow, leading to a decrease in the growth of tumor cells; antiangiogenic activity. Suppression of bone resorption is also clinically accompanied by a marked reduction in pain.

a) in vitro: inhibition of osteoblast proliferation, direct cytotoxic and proapoptotic activity, synergistic cytostatic effect with antitumor drugs; anti-adhesive / anti-invasive activity.

b) preparations prepared on the basis of pharmaceutical compositions declared as inventions can be used in the treatment of the following diseases: bone metastases of common malignant tumors (prostate cancer, breast cancer) and myeloma, including to reduce the risk of pathological fractures, compression of the spinal cord, tumor-caused hypercalcemia, and a decrease in the need for radiation therapy or bone surgery: hypercalcemia due to a malignant tumor.

Thus, as follows from the description and illustrated by specific examples, the claimed method according to the invention produces a pharmacological agent in a simpler way, but it is shown that pharmaceutical preparations based on a solution of zoledronic acid for infusion or on the basis of a concentrate for the preparation of a solution for infusion activity and at lower concentrations of zoledronic acid, which avoids the undesirable effects of drugs based on these compositions on the formation, mineralization and mechanical properties of bone tissue, and other negative side effects during prolonged action of the drugs.

Claims (3)

1. A method of preparing a pharmaceutical composition based on zoledronic acid in the form of an infusion solution for the treatment of cancer, comprising dissolving the substance of zoledronic acid in water for injection containing mannitol and sodium citrate in a stainless steel reactor with a teflon coating in the ratio between zoledronic acid, mannitol, sodium citrate and water for injection from 1: 990: 6: 20,000 to 1: 1275: 6: 25000 parts by weight, subsequent heating of the solution with stirring for 119-121 min at a temperature of 60 ° C with a gradual increase in temperature to 80 ° C and subsequent sterilizing pressure filtration and vacuum filtration to obtain an infusion solution at a final concentration in water of zoledronic acid in the range of 0.036-0.055 mg / ml, mannitol 4.4-5.6 mg / ml, sodium citrate 0.22-0.33 mg / ml, dosing the resulting solution in 100 ml polypropylene bottles and corking the bottles with stoppers having a low ash content spine and coated with an inert barrier polymer, while sterilizing filtration and vacuum filtration are carried out first through a depth filter with an overpressure of 0.11 MPa and at a filtration rate of 1-3 l / min, and then through a membrane filter under vacuum with a residual pressure of 0, 01-0.02 MPa and at a filtration rate of 1-2 l / min. 2. A method of obtaining a pharmaceutical composition based on zoledronic acid in the form of a concentrate for the preparation of an infusion solution for the treatment of cancer, comprising dissolving in a stainless steel reactor with Teflon coating on its inner surface the substance of zoledronic acid in water for injection containing mannitol and sodium citrate , with the ratio between zoledronic acid, mannitol, sodium citrate and water for injection 1: 55: 6: 1250, subsequent heating of the solution with stirring for 119-121 min at a temperature of 60 ° C with a gradual increase in temperature to 80 ° C and the subsequent sterilized pressure filtration and vacuum filtration to obtain a concentrate for the preparation of an infusion solution at final concentrations in the water of zoledronic acid in the range of 0.72-0.88 mg / ml, mannitol 4.4-5.6 mg / ml, sodium citrate 0 , 22-0.33 mg / ml, dosing the resulting solution in 100 ml polypropylene bottles and corking the bottles and having a low ash content and coated with an inert barrier polymer, while sterilizing filtration and vacuum filtration are carried out first through a depth filter with an excess pressure of 0.11 MPa and at a filtration rate of 1-3 l / min, and then through a membrane filter under vacuum with residual pressure of 0.01-0.02 MPa and at a filtration rate of 1-2 l / min. 3. The method of preparing the pharmaceutical composition according to claim 2, characterized in that the resulting concentrate is dosed in 5.0-6.25 ml using a dispenser.