Pharmaceutical products containing biphosphonates

FIELD: medicine.

SUBSTANCE: there is disclosed pharmaceutical product as prepared solution. The pharmaceutical product comprises a reservoir filled with dissolved zoledronic acid or its pharmaceutically acceptable salt. At least the internal surface of said reservoir contains plastic material that is polyolefin. The product is exposed to thermal sterilisation, preferentially to moist thermal sterilisation. Besides the product can contain a buffer component, preferentially the buffer organic base. Additionally, the product can contain an isotonic component, preferentially mannitol. The invention provides product sterilisation at high temperature 121°C during 150 minutes without visible deformations and damages of sealed integral reservoir, as well as decomposition of pharmaceutical substance.

EFFECT: thermal stability allows for multiple sterilisation cycle that leads to sterility assurance level at least 10^-12.

38 cl, 19 ex

The present invention relates to pharmaceutical products and processes for their preparation, in particular to pharmaceutical products containing bisphosphonates, and to methods for products bifosfonatami.

Bisphosphonates are widely used to inhibit the activity of osteoclasts in various benign and malignant diseases that cause excessive or inappropriate bone resorption. These analogues polyphosphates not only reduce the incidence of cases related to bone structure, but also provide patients clinical care and reduce mortality. Bisphosphonates are able in vivo to prevent bone resorption. Was demonstrated therapeutic effectiveness of bifosfonatami to ensure porosity of the bones, osteoporosis, deforming Ostia induced tumor hypercalcemia (IOG) and, more recently, for the treatment of bone metastasis (MK) and multiple myeloma (MM) (see Fleisch H, 1997, Bisphosphonates clinical. In Bisphosphonates in Bone Disease. From the Laboratory to the Patient. Eds: The Parthenon Publishing Group, New York/London, pp 68-163).

Conventional dosage forms of biphosphonate, for example for the treatment of IOG, MK and MM are the solutions for intravenous infusion. However, the solutions bifosfonatami though and are essentially stable, react with two - and multivalent cations, especially calcium, barium, magnie is, aluminum, boron and silicon present in the glass, the formation of insoluble precipitates, which are the causes of 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, long-term storage of the compositions of the solutions bifosfonatami in conventional glass bottles, even made of hydrolytically stable glass class I, impossible. In addition, glass bottles with this solution cannot be subjected to a final wet heat sterilization and must be filled aseptically, because the increased temperature at which there is a wet heat sterilization, accelerates the leaching of cations. It was shown that at pH values that are acceptable for parenteral delivery of mass-produced glass containers leach significant amounts of ions (Farm. Vestnik. Vol 54, p.331 (2003)). Therefore, for short-term storage solutions in glass products filling solutions must be filled, though, if you take into account the high chemical stability of solutions of bifosfonatami, their thermal sterilization is essentially possible. Such aseptic shall ispolnenie does not meet currently accepted standards of treatment, contained in document CPMP/QWP/054/98 corr., "Decision trees for the selection of sterilisation methods", issued by the European Agency for the Evaluation of Medicinal Products (European Agency for the Control and Standardization of medicinal products (EMEA). In accordance with the same document "use of non-compliant temperature-sensitive packaging materials by itself cannot be the sole reason for choosing aseptic technology".

As a consequence, the products bisphosphonates for intravenous infusion is usually produced in the form of solid liofilizatow, which do not show abilities stimulation of microbial growth compared to canned solutions bifosfonatami at physiologically acceptable pH. Before using lyophilizate with water for injection or other aqueous solvents translate into solutions for injection, such as Aredia® and Zometa®. When diluting concentrated solutions phosphonic acid because of the low solubility of sediments, formed by the divalent and multivalent cations, even small amounts of impurities of alkaline-earth metals, present in all commercially available salt solutions and solutions of sodium chloride can lead to the formation of such precipitates.

The recently proposed pharmaceutical product (WO 02/22136, F..Faulding & Co Ltd.), which includes a container containing Astor biphosphonate, in which the solution: (a) has a pH of 5 to 8 and (b) does not contain organic buffer component and the glycol and in which the container is a glass container, in which the surface in contact with the solution, pre-treated to protect against leaching of impurities from the glass solution, or in which the container contains at least one component made from a material other than glass, such as polyethylene, polypropylene and polymethylpentene. However, in WO 02/22136 not specified what to do for sterilization of the product. In addition, this link is not a method for maintaining a stable pH during storage of the formulations with low doses of potent bifosfonatami, such as zoledronate acid.

It has been found that can be prepared mortar compositions of bifosfonatami for long-term storage in tanks containing polymeric materials that do not interact chemically with the solution biphosphonate and which at the final stage can be easily sterilized.

In accordance with the present invention offers ready to use pharmaceutical product biphosphonate containing a vessel containing a solution of biphosphonate, in which at least the internal surface of the vessel contains a plastic material and in which the capacity of the can is about to be subjected to heat sterilization.

Products in accordance with the present invention are preferably solutions for parenteral application which do not require conversion freeze-dried before use. You can also easily conduct heat sterilization of the product in situ in the vessel in the retrieval process, it is preferable to moist heat sterilization (e.g. steam, the achieved level of assurance of sterility is at least 10^-6). In addition, these ready-to-use solutions do not require dilution prior to use.

Products in accordance with the present invention can be used orally, transdermally, or for injection, such as subcutaneous, arterial or intravenous. Most preferably the use of intravenous infusions.

Products in accordance with the present invention contain ready-to-use solutions in which bisphosphonates are present in a concentration suitable for direct application without dilution, and are referred to as "ready-to-use solutions".

Preferably the product is ready-to-use solution is a single dose ready-to-use solution, a dose of biphosphonate, sufficient for a single use. This single dose products ready-to-use solution for VL is there typically has a volume of from about 20 to about 500 ml, typically, from about 50 to about 250 ml, preferably 100 ml (in which these volumes can optionally contain about 20 ml, for example, preferably 2 ml, excess of these values to accommodate the liquid remaining in the tank when ready to use solution pour in the patient).

The pH values of such ready-to-use solutions are easy to bring to a physiologically acceptable value using reason. It was found that the use of organic bases capable of complexing with cations, avoids slight turbidity resulting from deposition of medicinal substance cationic impurities auxiliary substances. It was also found that in contrast to strong inorganic bases, such as sodium hydroxide, in this case, the in situ formed a weak buffer system itself biphosphonates, which makes it easy to achieve a specified pH value and provides optimum stability pH during the entire storage period. The solution preferably has a pH from about 4.5 to about 8, more preferably from about 5.5 to 7.5, such as about 6.5, or about 6.8%, or about 7.2. Examples of appropriate organic bases include sodium or potassium salts of organic acids such as acetic acid, citric acid,lactic acid, glutamic acid, tartaric acid, fumaric acid, maleic acid or malic acid. In addition, you can apply basic forms of amino acids, such as histidine or arginine. Examples of suitable inorganic bases are sodium phosphate or potassium hydroxide, sodium bicarbonate or sodium hydroxide. You can also use a mixture of the above grounds or mixture of bases with the corresponding acids. For example, the composition may contain a base, for example sodium citrate acid, such as hydrochloric. Preferably used is a salt of sodium or potassium. When using potassium salts must carefully determine the physiological tolerability and it is not recommended to exceed the physiological concentration of potassium in the blood serum, which is approximately 4 mm/l

Such ready-to-use solutions can usually also contain isotonic component. Preferably, the tonicity of the solution is from about 250 to about 400 mOsm/kg, more preferably 260 to about 350 mOsm/kg, for example about 300 mOsm/kg. Examples of appropriate isotonic components are glycerin, polyethylene glycol, propylene glycol, ethanol, cyclodextrins, amino acids, sugars and sugar alcohols: glucose, fructose, mannose, sucrose, mannitol, lactose, is regalos, maltose, sorbitol, sodium chloride, sodium nitrate, potassium chloride, urea, ammonium chloride. Preferably isotonic component is a nonionic isotonic component, more preferably a sugar, an ester, an alcohol or polyol (high alcohol). Most preferred for use in preconcentrate solutions are mannitol, 1,2-propylene glycol and sorbitol, of which particularly preferred is mannitol.

In accordance with the present invention it has been found that the use of nevinnyh isotonic components allows simple and reliable tests, for example, by ion chromatography, capillary electrophoresis and high performance liquid chromatography (HPLC). It was found that HPLC with reversed phase with UV detection using ion-pair reagent (for example, hydrosulphate of tetradecylammonium) and complexing component (for example, ethylenediaminetetraacetic acid, etc) allows to reliably detect very low concentration of biphosphonate and in particular the concentration of possible by-products and decomposition products. The possibility of determination of such by-products and decomposition products at the level of the low concentrations in which they are present in the ready-to-eat products, one is by a very important advantage. It does not require phase derivatization. In accordance with the present invention for the product ready-to-use solution can be reliable quantitative determination of the concentration level of 0.04 µg/ml, This corresponds to 0.1% of the applied dose, which is a mandatory limit that must be achieved to fulfill the international requirements.

In contrast, when using any of the normal ionic isotonic agents, for example sodium chloride, they are to such an extent interfere with the chromatographic measurements that reliable quantitative measurement of potential by-products and degradation products become impossible.

Thus, in specific embodiments of the invention described above, the product contains non-ionic isotonic component and:

(I) the product analyzed quantitatively with the detection limit of biphosphonate and its by-products and degradation products, comprising at least 0.1% of the stated dose, preferably without the use of stage derivatization and

(II) the product is analyzed by chromatography with reversed phase with a complexing component, for example add, for the quantitative measurement of biphosphonate and its by-products and degradation products with a limit of detection comprising at least 0.1% of savlon the second dose, preferably without the use of stage derivatization.

In another preferred embodiment of the invention the pharmaceutical proposed product containing a vessel containing a solution of biphosphonate in the form of ready-to-use solution, which includes:

a) a single dose of biphosphonate,

b) an organic base and

C) non-ionic isotonic component

in which at least the internal surface of the vessel contains a transparent plastic material and in which the capacity at the final stage is subjected to heat sterilization.

Ready-to-use solution can be placed in bags for infusion, for example those which are normally used for other therapeutic products for infusion, for example plastic bags for infusion made from polyvinyl chloride, polyolefin copolymers, Cryovac® M312 foil (Sealed Air Corporation), Baxter Intravia®, B.Braun PAB (polypropylene with 10% of thermoplastic-based blockcopolymer styrene, ethylene - butylene, styrene (SEBS)), or similar bags for infusion.

The product in accordance with the present invention may contain a glass container having a transparent inner plastic lining. However, preferably the container is made of plastic material and has an outer glass shell. Examples of the plastic is of materials, which can be used for this purpose include polysulfone, polycarbonate, polypropylene, polyethylene (low-density polyethylene (LDPE) or high density polyethylene (HDPE)), copolymers of ethylene/propylene, polyolefins, acrylic-kidnie copolymers, polyvinychloride (PVC), polyester (such as polyethylene terephthalate (PET), polymethyl methacrylate (TEM), and others), Teflon, Nylon, acetal (Delrin), polymethylpentene, polyvinylidenechloride (PVDC), ethylene vinyl acetate, a copolymer of Acrylonitrile and others. The plastic material used for any type of vessel, preferably is transparent, that is translucent and allows you to visually control the content.

Additionally, the plastic material in the filled or unfilled state is able to withstand heat sterilization, preferably wet sterilization, such as steam sterilization, or irrigation of the hot water at a temperature of at least from about 110 to about 130°C. or higher, for example at a temperature of at least 121°C., for example from 121 to 124°C.

A particularly preferred plastic materials for the container are transparent cycloolefin polymers, such as polymer Daikyo CZ, thermoplastic olefinic polymers with amorphous structure (e.g. TOPAS, production Ticona). Most preferred are polymer Daikyo Z and similar cycloolefin polymers.

Ready-to-eat products can be placed in a plastic or plastic-coated flasks with a volume of from about 20 to about 500 ml, for example about 100 ml.

Solutions biphosphonate can also be used for slow intravenous infusion of more concentrated forms, such as concentrations of biphosphonate from about 0.01 to about 0.5, usually from about 0.05 to about 0.2 mg/ml For this product is placed in pre-filled syringes, which can then be sterilized by the method of moist heat sterilization, such as syringes, made of polymer Dikyo CZ or similar, or from thermoplastic olefin plastics with an amorphous structure (for example sold by Schott under the trade name Schott Top Races or similar).

In addition, commercially available plastic materials, similar to the polymer Daikyo CZ, in accordance with ASNM (American society for testing and materials) D648 have a thermal deformation temperature equal to 123°C, which limits the maximum allowable temperature sterilization value 123°C. it Was found that sterilization even at much higher temperatures, for example at 130°C, does not cause significant deformation of the tank or leakage of its closures.

Preferably bisphosphonates used in the present from which Britanie, represent a nitrogen-containing bisphosphonates, including bisphosphonates with side chains containing amino groups, or, in particular, bisphosphonates with side chains containing nitrogen-containing heterocycles, most preferably an aromatic nitrogen-containing heterocycles.

Examples of bifosfonatami, suitable for use in the present invention, may include the following compounds or their pharmaceutically acceptable salts: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronovu acid), such as pamidronate (PD); 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-PD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronate acid), such as alendronate; 1-hydroxy-ateen-diphosphonic acid, such as etidronate; 1-hydroxy-3-(methylpentylamino)-propylidene-diphosphonic acid, (ibandronate acid), such as ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, such as amino-hexylbiphenyl; 3-(N-methyl-N-n-pentylamine)-1-hydroxypropane-1,1-diphosphonic acid, for example methyl-until-PD (=VM 21,0955); 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, such as zoledronic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronate acid), e.g. risedronate, including salt-N-methylpyridine, such as iodides N-methylpyridine, such as NE-10244 and the and NE-10446; 1-(4-chlorophenylthio)methane-1,1-diphosphonic acid (tiludronic acid), such as tiludronate; 3-[N-(2-phenylthiomethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g. EB 1053 (Leo); 1-(N-phenylenecarbonyl)methane-1,1-diphosphonic acid, e.g. FR 78844 (Fujisawa); tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid, e.g. U-81581 (decision Upjohn); 1-hydroxy-2-(imidazol[1,2-a]pyridine-3-yl)ethane-1,1-diphosphonic acid, e.g. YM 529; and 1,1-dichloromethane 1,1-diphosphonic acid (clodronate acid), such as clodronate.

A particularly preferred application of the present invention is biphosphonate containing compound of the formula I

in which

Het denotes imidazole, oxazoline, isooxazolyl, oxadiazolyl, thiazole, thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole, or a benzimidazole group, optionally substituted alkyl, CNS, halogen, hydroxyl, carboxyl group, amino group, optionally substituted alkyl or alkanoyloxy group, or benzyl group, optionally substituted alkyl, nitro-, amino - or amino-alkyl group;

And denotes a saturated or unsaturated hydrocarbon group with unbranched or branched what EPU, containing from 1 to 8 carbon atoms;

X denotes a hydrogen atom, optionally substituted alkanoyloxy group, or amino group, optionally substituted alkyl or alkanoyloxy group and

R denotes a hydrogen atom or alkyl group, and its pharmaceutically acceptable salts.

Examples of compounds particularly preferred for use in the present invention are:

2-(1-Mei-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(1-benzylimidazole-2-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(1-Mei-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;

1-amino-2-(1-Mei-4-yl)ethane-1,1-diphosphonic acid;

1-amino-2-(1-benzylimidazole-4-yl)-ethane-1,1-diphosphonic acid;

2-(1-Mei-2-yl)ethane-1,1-diphosphonic acid;

2-(1-benzylimidazole-2-yl)ethane-1,1-diphosphonic acid;

2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(imidazol-1-yl)ethane-1,1-diphosphonic acid;

2-(4H-1,2,4-triazole-4-yl)-1-hydroxyethane-1,1-diphosphonic acid;

2-(thiazol-2-yl)ethane-1,1-diphosphonic acid;

2-(imidazol-2-yl)ethane-1,1-diphosphonic acid;

2-(2-Mei-4(5)-yl)ethane-1,1-diphosphonic acid;

2-(2-phenylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid;

2-(4,5-dimethylimidazole-1-yl)-1-hydroxyethane-1,1-diphosphonic acid and

2-(2-Mei-4(5)-yl)-1-guide oxetan-1,1-diphosphonic acid and their pharmaceutically acceptable salts.

More preferred for use in the present invention are disodium-3-amino-1-hydroxy-propylidene-1,1-biphosphonate pentahydrate (panikanova acid) and 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronicaa acid) or their pharmaceutically acceptable salts.

Most preferred for use in this invention is 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronicaa acid) or its pharmaceutically acceptable salt.

Particularly preferred ready-to-eat products have a single dosage form and contain from 2 to 10 mg of zoledronate acid or its pharmaceutically acceptable salt. The most preferred portions dose of the product contains the number of zoledronate equivalent of 4 to 5 mg anhydrous zoledronate acid, as described in detail in the Examples.

Pharmaceutically acceptable salts preferred are salts of bases, usually easy to get metal salts Ia, IB, IIA and IIB of the Periodic table of elements, including alkali metal salts, for example salts, especially sodium and potassium, and ammonium salts or organic amines.

Particularly preferred are pharmaceutically acceptable salts, in which one, two, three, or four, preferably two or three acidic hydrogen diphosphonic acid C is medeni pharmaceutically acceptable cation, in particular sodium, potassium or ammonium, most preferably sodium.

The most preferred group of pharmaceutically acceptable salts differs in that it has at least one acidic hydrogen and one pharmaceutically acceptable cation, in particular sodium, each of phosphonic acid groups.

All derivative diphosphonic acids listed above are described in detail in the literature. Also described receiving them (see, for example, EP-A-513760, s-48). Obtain 3-amino-1-hydroxypropane-1,1-diphosphonic acid are described, for example, in US 3962432, disodium salt in US 4639338 and BU S4711880, 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid is obtained in accordance with, for example, US 4939130. These issues are also dealt with US 4777163 and US 4687767 and EP W.

The present invention also relates to methods produce solutions which usually the final stage is heat sterilization.

In accordance with another object of the invention features a method of obtaining a pharmaceutical product, which includes a vessel containing a solution of biphosphonate, in which the solution biphosphonate placed into the vessel, in which at least the inner surface contains a transparent plastic material and in which the final stage is heat sterilization containers, soda is containing solution biphosphonate.

Thus, the container containing the solution biphosphonate, sterilized by the method of heat sterilization, preferably moist heat sterilization, for example saturated steam and mixtures of steam/air or irrigation superheated water at a temperature of at least from about 110 to about 130°C. or higher, for example at a temperature of at least 121°C or higher, for example, preferably with from about 121 to 124°C. the Effective time of sterilization depends on the value of D dispute the test cultures in the solution and has to be that to get the total level of assurance of sterility for at least 10^-6preferably at least 10^-12. The effective time of sterilization (sterilization time of exposure) may be from about 15 minutes to about 3 hours, usually from about 15 minutes to about 2 hours, for example, preferably 30 minutes. Preferably heat sterilization is the final stage of thermal sterilization, that is, this heat sterilization is conducted at the end of or after completion of the process of obtaining, after lling solution biphosphonate and preferably after stoppering containers, such as fitting lid, stopper, or other means of fastening. Can be used conventional equipment for handling glass bottles. Can be used the change the tube, low leaching of metal ions, such as calcium, magnesium, zinc or silicon in contact with aqueous solutions, for example solutions of bifosfonatami. Preferably the tube has a low ash content and is covered by the product impervious and inert barrier, made for example, of a copolymer of ethylene and tetrafluoroethylene (ETFE), Teflon or fluorinated elastomers. Such tubes are, for example, Daikyo D-777-1, Daikyo D-777-3, Daikyo D-713, Daikyo D-21-7S covered by product layer ATFT, or Helvoet FM259/0, covered with a layer of fluoropolymer (e.g proprietary material Helvoet Omniflex or Omniflex plus).

Ready-to-use solution biphosphonate can be prepared in large quantities and poured in the vessel, for example, by means known in the art methods. The bulk of the solution may be in the form of a solution of the free diphosphonic acids, such as zoledronate acid or in the form of its salts, for example sodium. A large amount of solutions bifosfonatami can be prepared by dissolving the salt in water, or can be prepared in situ in solution by means of the reaction of the free diphosphonic acid with a base, for example by neutralizing the acid with sodium hydroxide, which, depending on the need receive monosodium, disodium, trinacria the th or TETRANITRATE salt, for example distribuiton or dinitrotoluene.

In accordance with the requirements of GMP (pharmaceutical production) all materials containers used for parenteral products, you must depyrogenation to ensure a reduction in the content of endotoxins by at least 3 log units. Glass bottles are usually applied thermal depyrogenation. However, plastic containers usually cannot be processed on standard lines filling a sterile pharmaceutical product, such as the capacity to withstand thermal stress applied in a tunnel kiln for depyrogenation. Therefore, the plastic tanks are usually treated without the necessary stages of purification and depyrogenation, it introduces the risk of contamination of the drug product for parenteral use a foreign substance present in the container, as well as endotoxins, which can dissolve from the surface material of the vessel. In accordance with the present invention it was found that some plastic containers can be processed on standard lines filling glass bottles, and that the purification process allows us to reproducibly obtain a reduction in the content of endotoxins at least 1000 times.

In addition to the stage of female sterilization is the capacitance, in particular plastic containers, can be depyrogenation to fill them with a solution of biphosphonate. Found that washing plastic bottles with water under pressure provides sufficient depyrogenation, for example reduced levels of endotoxin at least 1000 times or more, for example, this reduction may be approximately 16,000 100,000 times. Preferably this stage of depyrogenation included in the methods of obtaining of the present invention.

Capacity, not containing or substantially not containing endotoxins can also be obtained from the supplier, such containers do not need depyrogenation.

In addition, the present invention relates to methods of producing products in accordance with the present invention, described above, in which to determine biphosphonate and its by-products and degradation products using chromatography with reversed phase with a complexing reagent, for example add, mainly with a detection limit of at least 0.1% of the stated dose, preferably without the use of stage derivatization.

The specific method of application and dosage of the products of the present invention can be selected by the attending physician taking into account the individual characteristics of patients, including age, weight, lifestyle, level of activity, hormonal status is I (for example, post-menopausal) and bone mineral density. Most preferably biphosphonate applied intravenously.

Usually prescribed this dosage that a single dose of active substance biphosphonate assigned warm-blooded animal weighing approximately 75 kg is from 0.002 to 20.0 mg/kg, in particular from 0.01 to 10.0 mg/kg, If necessary, this dose can be divided into several, not necessarily equal, parts.

The unit "mg/kg" denotes the number of mg of drug per kg weight of the mammal, including human in need of treatment.

Preferably bisphosphonates administered in doses that are of the same order as the dose used for the treatment of diseases for which the treatment of derivatives diphosphonic acid is a classic, such as distortive ostit, hypercalcemia induced by tumor or osteoporosis. In other words, it is preferable to appoint such doses derived diphosphonic acid, which will also be therapeutically effective for the treatment of deforming Ostia, hypercalcemia induced by tumor or osteoporosis, i.e. preferably be administered in doses that will effectively slow down bone resorption.

The following examples illustrate the invention.

EXAMPLES

Example 1: Zoledronicaa acid 4 mg/100 ml

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add excipients mannitol and sodium citrate and dissolved under stirring. Add the medicinal substance zoledronic acid and dissolved with stirring. The drug is brought to final weight with water for injection. Citrate sodium neutralized zoledronic acid to pH 6.5.

The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles sealed with sterilized stoppers Helvoet FM259/0, covered Omniflex plus, and sealed with aluminium caps. Damp heat sterilization of the bottles to obtain the level of assurance stabilnosti ^-12, that is, at 121-123°C for 30 minutes (effective time sterilization exposure).

The product is stable and shows no signs of decay even in severe stress conditions: at a temperature of 50°C./relative humidity of 75% and a temperature of 40°C/relative humidity 75%.

Example 2: Zoledronicaa acid 5 mg/100 ml

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add excipients mannitol and sodium citrate and dissolved under stirring. Add the medicinal substance zoledronic acid and dissolved with stirring. The drug is brought to final weight with water for injection. Citrate sodium neutralized zoledronic acid to pH 6.5. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles clog sterilize the data traffic Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. Damp heat sterilization of the bottles to obtain the level of assurance of sterility 10^-12, that is, at 121-123°C for 30 minutes (time sterilization exposure).

The product is stable and shows no signs of decay in severe stress conditions: at a temperature of 50°C and relative humidity of 75%and a temperature of 40°C and relative humidity of 75%.

Example 3: Regulating the pH of the compositions of zoledronate acid various reasons

533,1 mg of zoledronate acid monohydrate (equivalent to 500 mg of zoledronate acid) and 480,0 g of mannitol added to the 7520 g of water for injection and stirred to obtain a clear solution with a total weight of 8000, Every 800 g of this solution (equivalent to 50 mg C is leonovoi acid) is titrated

(a) a solution of the dihydrate of trinacria citrate in water for injection concentration 0,500 g/100 ml;

(b) a solution 0,500 g/100 ml of anhydrous sodium acetate in water for injection;

(C) solution 0,500 g/100 ml dinitrate dihydrate in water for injection;

(g) a solution 0,500 g/100 ml of trisodium phosphate uranyl in water for injection;

(d) a solution of 0.400 g/100 ml of sodium hydroxide in water for injection.

After each addition of 200 ál of solution the Foundation of the potentiometrically measured pH. Data show that since the dissociation constants pKa of zoledronate acid were 5.9 and 8,28, when using as the basis of sodium hydroxide for pH values from 6 to 7.5, most preferred from a physiological point of view, there is a stepwise increase in pH. Phosphate and sodium citrate somewhat weaken the dissociation of acid groups zoledronate acid, so the use of these bases can be easily installed in the desired value of pH is usually from 6.0 to 7.5

Example 4: Zoledronicaa acid 5 mg/100 ml in triatriatum at different pH values

Example 5: Zoledronicaa acid 5 mg/100 ml in the compounds of trisodium phosphate at different pH values

Example 6: Zoledronicaa acid 5 mg/100 ml in formulations with sodium acetate at different pH values

Example 7: Zoledronicaa acid 4 mg/100 ml

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add excipients mannitol and sodium citrate and dissolved under stirring. Add recipients who have drug zoledronic acid and dissolved with stirring. The drug is brought to final weight with water for injection. The citrate bring the pH of the solution by zoledronate acid to 6.5. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In plastic bags for infusion made from foil Cryovac® M312 (Sealed Air Corporation), Baxter Intravia®, B.Braun PAB® (foil polyethylene-based), pour 102,0 ml the mass of each solution. The bags are tightly closed. The bags are sterilized by the method of moist heat sterilization at a pressure of at least 100 mbar higher than the pressure of water vapor at a temperature chamber (irrigation superheated water or a mixture of steam/air), to obtain the level of assurance of sterility 10^-12, i.e. within 30 minutes (effective time sterilization exposure) at 121-123°C.

Example 8: Zoledronicaa acid 5 mg/100 ml

Approximately 800 g of water for injection is placed in a container for mixing. Add excipients sorbitol and sodium citrate and dissolved under stirring. Add drug zoledronic acid and dissolved with stirring. The drug is brought to final volume with water for injection. The solution is poured into the vials through a filter with a mesh size of 0.2 μm. Washed and dried plastic bottles Daikyo CZ fill with a solution. The bottles are closed sterilized tubes Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. The vials are sterilized by the method of moist heat sterilization.

As can be seen from the table below, the composition is stable even after heat treatment at 121°C for 60 minutes.

According to the analysis of any changes to the content of the component is not found, also, either before or after sterilization were not able to detect the degradation products at the level of concentrations above the limit of detection of the method used.

Example 9: Zoledronicaa acid 5 mg/100 ml

Approximately 800 g of water for injection is placed in a container for mixing. Add excipients glycerol and sodium citrate and dissolved under stirring. Add drug zoledronic acid and dissolved with stirring. The drug is brought dokoncno volume with water for injection. The solution is poured into the vials through a filter with a mesh size of 0.2 μm. Washed and dried plastic bottles Daikyo CZ fill with a solution. The bottles are closed sterilized tubes Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. The vials are sterilized by the method of moist heat sterilization.

As can be seen from the table below, the composition is stable even after heat treatment at 121°C for 60 minutes.

According to the analysis of any changes to the content of the component is not found, also, either before or after sterilization were not able to detect the degradation products at the level of concentrations above the limit of detection of the method used.

Note the p 10: Zoledronicaa acid 5 mg/100 ml

Approximately 800 g of water for injection is placed in a container for mixing. Add excipients propylene glycol and sodium citrate and dissolved under stirring. Add drug zoledronic acid and dissolved with stirring. The drug is brought to final volume with water for injection. The solution is poured into the vials through a filter with a mesh size of 0.2 μm. Washed and dried plastic bottles Daikyo CZ fill with a solution. The bottles are closed sterilized tubes Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. The vials are sterilized by the method of moist heat sterilization.

As can be seen from the table below, the composition is stable is even after heat treatment at 121°C for 60 minutes.

According to the analysis of any changes to the content of the component is not found, also, either before or after sterilization were not able to detect any degradation products at the level of concentrations above the limit of detection of the method used.

Example 11: Washing bottles / remove endotoxins

Processing of plastic bottles carried out on a standard integrated automatic processing line fill fluids. Washing is carried out on a standard rotary washing machine (for example, Bausch&Stroebel FAU 6000 or Bosch RRU 2020), which is used for glass bottles. The bottles are set on the boot tape washing machine. First, the bottles are immersed in a bath of hot water and p will gorhaut ultrasonic processing. Then the bottles move in rotary washing station and overturn. Washing is carried out using a programmable process flow of air and water through the nozzle, installed in the vials. The bottles are first washed with recirculating hot water for injections (>70°C), rinsed with filtered air, and then again washed with a fresh portion of hot water for injection and blow filtered air. After washing the bottles are returned to normal position and then transported on the conveyor tape camera hot air, where dried at 110°C. For washing machine Bausch&Stroebel FAU 6000 speed washer 84 bottles/min

For washing machines Bosch RRU 2020 the appropriate rate sinks receive during the adjustment parameters of 5.8-6.5 units of the scale.

The efficiency of this process can be estimated by comparing the content of endotoxin in bottles enriched with endotoxin, before and after a standard cleaning process. In accordance with the results of reducing the contamination with endotoxin is more than 3 log, i.e. a demand reduction of more than 3 log was performed for each object tested in the cleaning process.

Removing endotoxin from the processed bottles

Endotoxin is administered by injection in plastic vials and dried. Determination of endotoxin in five vials, is not subject m is ice, performed twice (the control input). The content of endotoxins is 8538 EU (IU, international units) per vial, which corresponds to the average value of the results of determination minus twice the standard deviation.

It was performed by three cycles of quantitative determination. In every definition 10 bottles contaminated with endotoxin, distributed in the group with clean bottles and washed in a washing machine.

The results of the allocation of endotoxin:

For all tested bottles found the reduction of endotoxin at least 1000 times.

Example 12: Sterilization zoledronate acid 5 mg/100 ml

Studies have shown that the solution for injection is stable during autoclave processing (steam sterilization). When sterilization at temperatures ≥121°C for up to 150 minutes could not find any signs of decomposition (see the results in the table below). Such resistance against the heat allows the sterilization cycle, providing the level of the HB guarantee the sterility of at least 10 ^-12.

Based on the kinetics of inactivation of spores described by a decimal value inactivation (D-value) dispute Geobacillus stearothermophilus in a solution of a medicinal product by zoledronate acid 5 mg/100 ml, it was found that the time of sterilization (sterilization time exposure)necessary to obtain the desired speed of the inactivation of spores is 30 minutes. The selected sterilization method meets the requirements of the European Pharmacopoeia and United States Pharmacopeia (Ph. Eur. and USP).

The stability of zoledronate acid 5 mg/100 ml during prolonged sterilization

In contrast to repeated sterilization of glass bottles, not detected by increasing the number of particles. The composition is stable even after 150 min sterilization at a temperature of >121°.

Example 13: Assessment of plastic bottles in case the most severe conditions of sterilization

In the process, the vials were subjected to dry heat (drying after washing) to 120°C and damp heat (during autoclave processing). To evaluate the possible risk of damage to the bottle and the integrity of the closures, investigated the resistance.

20 empty bottles as described in example 2, was subjected to dry heating at 125°C for 10 hours, which is higher than the temperature of 100-120°C, usually installed in a dry process. Before and after heat treatment was determined by the inner diameter and the ovality of the neck of the bottle, since these parameters are most critical for the integrity of the vial. It was found insignificant - 0.03 mm (0.02 to 0.05 m) reduction of the internal diameter of the neck of the bottle. The visible circle, defined as the difference of two perpendicular diameters of the inlet of the vial, divided by the sum of the diameters remained unchanged and amounts for selected samples of 0.18% (before treatment: 0.05 to 0.45%, after processing: from 0.00%to 0.5%).

The bottles of example 2 was subjected to steam sterilization in the most difficult conditions: the sterilization cycle lasted for 60 minutes at 124,5°C, which is higher than the heat distortion temperature of the vials, equal in accordance with ASTM D648) of 123°C. for sterilization do not apply excessive pressure. Determine the sizing and weight loss sterilized the unsterilized bottles, and also using the dye penetration control of leakage.

The results of the evaluation bottles for sterilization carried out in the most severe conditions

Sterilization is carried out under the most difficult conditions, no significant impact on the tightness of the LAF is she, manifested in weight loss and resistance to dye penetration. There is a very slight change in the internal diameter of the inlet of the bottle, but these changed values correspond to the technical requirements and make 22.0 +/-0.2 mm

Example 14: the Analysis of solutions by zoledronate acid 4 mg/100 ml

Example 15: the Composition pamidronic acid, ready-to-use: 100 ml of the composition in unit dose packaging is the equivalent of 101.5 g:

Proceeding from the basic structure for the unit dosage forms listed in the table above, calculate the amount needed for download. Usually this amount is approximately 5 l for the production of laboratory scale (100 l) for pilot production and 1000 l for mass production.

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add mannitol and dissolved under stirring. Add the medicinal substance disodium salt pamidronic acid pentahydrate and dissolved under stirring. Bring the pH to 6.5 with 5%solution of sodium citrate in water for injection. The drug is brought to final weight with water for injection. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles sealed with sterilized stoppers Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. Damp heat sterilization of the bottles in which the temperature > 121°C for at least 15 minutes (effective time).

Example 16: the Composition pamidronic acid, ready-to-use: 100 ml of the composition in unit dose packaging is the equivalent of 101.5 g:

Proceeding from the basic structure for the unit dosage forms listed in the table above, calculate the amount needed for download. Usually this amount is approximately 5 l for the production of laboratory scale (100 l) for pilot production and 1000 l during production.

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add mannitol and dissolved under stirring. Add the medicinal substance disodium salt pamidronic acid pentahydrate and dissolved under stirring. Bring the pH to 6.3 with a 5%aqueous solution of phosphoric acid in water for injection. The drug is brought to final weight with water for injection. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles sealed with sterilized stoppers Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. Damp heat sterilization of vials at a temperature of >121°C in ECENA at least 15 minutes (effective time).

Example 17: the Composition pamidronic acid, ready for use: 100 ml of the composition in unit dose packaging equivalent of 101.5 g:

Proceeding from the basic structure for the unit dosage forms listed in the table above, calculate the amount needed for download. Usually this amount is approximately 5 l for the production of laboratory scale (100 l) for pilot production and 1000 l for mass production.

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add mannitol and dissolved under stirring. Add the medicinal substance disodium salt pamidronic acid pentahydrate and dissolved under stirring. Bring the pH to 6.3 with a 5%aqueous solution of acetic acid in water for injection. The drug is brought to final weight with water for injection. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles sealed with sterilized stoppers Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. Damp heat sterilization of bottles p and a temperature of > 121°C for at least 15 minutes (effective time).

Example 18: the Composition pamidronic acid, ready for use: 100 ml of the composition in unit dose packaging equivalent of 101.5 g:

Proceeding from the basic structure for the unit dosage forms listed in the table above, calculate the amount needed for download. Usually this amount is about 5 l to load the laboratory scale (100 l) for pilot production and 1000 l for mass production.

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add mannitol and dissolved under stirring. Add the medicinal substance disodium salt pamidronic acid pentahydrate and dissolved under stirring. Bring the pH to 6.3 with a 5%aqueous solution of lactic acid in water for injection. The drug is brought to final weight with water for injection. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles sealed with sterilized stoppers Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. Damp heat sterilization of vials at a temperature of >121°C for at least 15 minutes (effective vimalagiri).

Example 19: Compositions pamidronic acid, ready for use: 100 ml of the composition in unit dose packaging equivalent of 101.5 g:

Proceeding from the basic structure for the unit dosage forms listed in the table above, calculate the amount needed for download. Usually this amount is about 5 l to load the laboratory scale (100 l) for pilot production and 1000 l for mass production.

Approximately 85 to 95% of the total quantity of water for injection is placed in the vessel for mixing stainless steel. Add mannitol and dissolved under stirring. Add the medicinal substance disodium salt pamidronic acid pentahydrate and dissolved under stirring. Bring the pH to 6.3 with a 5%aqueous solution of tartaric acid in water for injection. The drug is brought to final weight with water for injection. The solution is fed to the line fill and filtered to flow through the filter hole size 0.2 μm. In washed and dried 100 ml plastic bottles Daikyo CZ pour 102,0 ml. Bottles sealed with sterilized stoppers Helvoet FM259/0 coated Omniflex plus and sealed with aluminium caps. Damp heat sterilization of vials at a temperature of >121°C for at least 15 minutes (effective time).

1. Pharmaceutical product in the form of ready-to-use process is and, including the unit containing solution zoledronate acid or its pharmaceutically acceptable salts in which at least the internal surface of the vessel contains a plastic material, which is a polyolefin, and in which capacity can be subjected to heat sterilization.

2. The product according to claim 1, in which the volume of the single dosage form is from about 20 to about 500 ml.

3. The product according to claim 1 or 2, containing a buffer component, preferably the buffer base, more preferably a buffer, an organic base.

4. The product according to claim 3, in which the pH with an organic base adjusted to a physiologically acceptable value of from 5.5 to 8.0, preferably from 6.0 to 7.5, most preferably about 6.5.

5. The product according to claim 4, in which the organic base is sodium citrate.

6. The product according to claim 4, in which the organic base is sodium acetate.

7. The product according to claim 3, in which the base is sodium phosphate or potassium.

8. The product according to claim 3, in which the base is sodium hydroxide or potassium.

9. The product according to claim 1, containing isotherwise component, preferably non-ionic isotonic component, more preferably a sugar, ether or alcohol, for example, mannitol, 1,2-propylene glycol, glycerol and sorbitol, particularly preferably mannitol.

10. The product according to claim 9, where the toning component is a nonionic isotonic component, which can be analyzed with a detection limit for zoledronate acid and its by-products and degradation products, comprising at least 0.1% of the stated dose, preferably without the use of stage derivatization.

11. Product of claim 10, which is to determine zoledronate acid and its by-products and degradation products analyzed by chromatography with reversed phase with a complexing component, for example etc.

12. Pharmaceutical product containing unit containing zoledronic acid in the form of ready-to-use solution, including:
a) a single dose by zoledronate acid;
b) an organic buffer base and
C) non-ionic isotonic component
in which at least the internal surface of the vessel contains a transparent plastic material and in which the filled container at the final stage is processed by heat sterilization.

13. The product according to claim 1, in which the capacity use pre-filled plastic syringe.

14. The product according to claim 1, in which the plastic material is transparent.

15. The product according to claim 1, in which the plastic material is cycloolefine polymer.

16. The product indicated in paragraph 15, in which the plastic material is a polymer Daikio CZ or similar cycloolefinic polymer.

18. The product indicated in paragraph 15, in which the plastic material is Schott TopPac vial or syringe.

19. The product according to claim 1, in which the container comprises a bag for infusion.

20. The product according to claim 19, in which the bag for infusion is made from polypropylene, a mixture of polypropylene/Kraton, laminated bag for infusion containing propylene or polyethylene side in contact with the product.

21. The product according to claim 19, in which the bag for infusion use capacity Baxter Intravia.

22. The product according to claim 19, in which the bag for infusion use capacity Braun Ecoflac.

23. The product according to claim 19, in which the bag for infusion use capacity Braun PAB.

24. The product according to claim 19, in which the bag for infusion made from foil Cryovac M312.

25. The product according to claim 1, in which the container is made according to the technology of blow/fill/seal and material capacity is polyethylene or polypropylene.

26. Product A.25, in which the container is made according to the technology of blow/fill/seal and the material of the container is polypropylene.

27. Product A.25, in which the container is made according to the technology of blow/fill/seal and the material of the container is polypropylene Rexene 32M2.

28. The product according to claim 1, in which salt zoledronate collateralised an N-biphosphonate or its pharmacologically acceptable salt.

29. The method of obtaining ready-to-use pharmaceutical product zoledronate acid containing unit containing solution zoledronate acid, which solution zoledronate acid is placed into the vessel, in which at least the inner surface contains a transparent plastic material and in which the vessel containing the solution zoledronate acid, at the final stage is sterilized by the method of heat sterilization, preferably by the method of moist heat sterilization.

30. The method according to clause 29, in which capacity at the final stage is sterilized by the method of heat sterilization.

31. The method according to clause 29, in which heat sterilization is carried out at a temperature of from about 110 to 130°C. or higher, for example, at a temperature of at least 121°C or higher, for example, preferably at a temperature of from about 121 to 124°C.

32. The method according to clause 29, in which the exposure time is from about 15 minutes to 3 hours, usually from about 15 minutes to about 2 hours, for example, preferably about 30 minutes

33. The method according to clause 29, in which the conditions of sterilization in the autoclave provide the level of assurance of sterility for at least 10^-6for example, by autoclave treatment (exposure time) at a temperature of >121°C for at least 8-fold time corresponding to the value of D₁₂₁solution./p>

34. The method according to clause 29, in which the conditions of sterilization in the autoclave provide the level of assurance of sterility for at least 10^-12for example, by autoclave treatment (exposure time) at a temperature of >121°C for at least 14 times the time corresponding to the value of D₁₂₁solution.

35. The method according to clause 29, in which capacity depyrogenation before filling solution zoledronate acid, usually by washing with water, preferably under pressure.

36. The method according to clause 29, which receive the containers, not containing or substantially not containing endotoxin/pyrogen, and fill them with a solution of zoledronate acid.

37. The method according to clause 29, in which the product contains non-ionic isotonic component and to determine zoledronate acid and its by-products using ion chromatography, capillary electrophoresis or high performance liquid chromatography (HPLC).

38. The method according to clause 29, in which the product contains non-ionic isotonic component and to determine zoledronate acid and its by-products and decomposition products using chromatography with reversed phase, preferably with a complexing component, for example add, preferably with a limit of detection comprising at least 0.1% of the stated dose, preferably without application of the phase derivatization.