Pharmaceutical parenteral composition containing a biphosphonate

Description of the invention

The invention relates to a composition for parenteral administration containing a bisphosphonate, a method of its preparation and its use. The compositions according to the invention are particularly useful for increasing the local tolerance to the active ingredient when administered parenterally, especially by the subcutaneous route.

The bisphosphonates, i.e., the bisphosphonic acids, or their pharmaceutically acceptable salts, are synthetic analogues of the naturally occurring pyrophosphate. Due to their high affinity for calcium phosphate, the essentially compact bisphosphonates bind strongly to bone minerals. Pharmacologically active bisphosphonates are well known to be potent bone resorption inhibitors and are therefore useful in the treatment and prevention of diseases associated with abnormal bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metabolic bone diseases.

Bisphosphonates as pharmaceuticals are described e.g. in EP-A-170228, EP-A-197478, EP-A-22751; EP-A-252504, EP-A-252505, EP-A-258618, EP-A-350002, EP-A-273190, WO-A-90/00798 etc.

Commercially available pharmaceutical forms of bisphosphonates are oral preparations (tablets or capsules) or solutions for intravenous injection or infusion. When administered in therapeutic doses, they are well tolerated by the system. However, bisphosphonates as a class of compounds are irritating to the skin and mucous membranes, causing gastrointestinal side effects, e.g., deleterious side effects in the esophagus or gastrointestinal disturbances. Thus, oral administration is associated with a number of inconvenient recommendations for patients. Intravenous administration with improper administration of the drug has adverse effects. Inaccurate hit to the vein or inadvertent injection next to the vein causes severe local tissue reactions, including necrosis. Therefore, it is necessary to improve the pharmaceutical form of the bisphosphonate to reduce or avoid tissue damage when administered parenterally, especially by the subcutaneous route.

The pathophysiological mechanism of bisphosphonate-induced tissue damage is unknown. Since the local reactions are similar for different types of bisphosphonates, and at least for nitrogen-containing bisphosphonates (aminobisphosphonates), a common mechanism should be assumed. A delay in the onset and development of a local reaction may indicate a non-specific immune system activity.

Attempts to increase tissue tolerance to bisphosphonates have involved the preparation of suspensions of insoluble or poorly soluble bisphosphonate salts capable of sustained local release of the active ingredient, as described e.g. in EP-A-449405, DE-A-4244422 and DE-A-4244423. This approach only slightly improved local tolerance.

The essence of the invention is to provide a composition which reduces or prevents the above drawbacks.

It has been surprisingly found that the administration of a bisphosphonate in a composition containing a pharmaceutically acceptable chelating agent selected from the group consisting of EDTA and DTPA and a pharmaceutically acceptable salt thereof significantly influences the duration, frequency and intensity of the side effects. The presence of an additional divalent cation chelating agent, selected from EDTA and DTPA, significantly alleviates adverse local reactions at the sites of drug administration compared to the performance of a corresponding formulation without the addition of a divalent cation chelating agent.

Thus, the invention relates to a composition for parenteral administration comprising a bisphosphonate, a pharmaceutically acceptable chelating agent and a pharmaceutically acceptable excipient, the feature of which is that the bisphosphonate comprises a compound selected from the group consisting of

a) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,

b) 4- (N, N-dimethylamino) -1-hydroxybutylidene-1,1-bisphosphonic acid,

c) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate),

d) 3- (N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid),

e) 3- (N-Methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid monosodium salt monohydrate (ibandronate)

f) 1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid,

g) 1-hydroxy-2- [3-pyridinyl] ethylidene-1,1-bisphosphonic acid (risedronate),

h) 1- (4-piperidinyl) -1-hydroxymethylene-1,1-bisphosphonic acid,

i) cycloheptylaminomethylene-1,1-bisphosphonic acid (cimadronate)

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j) 1,1-dichloromethylene-1,1-diphosphonic acid and its disodium salt (clodronate),

k) 1-hydroxy-3- (1-pyrrolidinyl) propylidene-1,1-bisphosphonic acid (EB-1053),

l) 1-hydroxyethane-1,1-diphosphonic acid (ethidronic acid),

m) 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate),

n) 3- (dimethylamino) -1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate)

o) [2- (2-pyridinyl) ethylidene] -1,1-bisphosphonic acid (pyridronate),

p) (4-chlorophenyl) thiomethane-1,1-diphosphonic acid (tiludronate) and / or

q) 1-hydroxy-2- (1H-imidazol-1-yl) ethylidene-1,1-bisphosphonic acid (zolendronate),

r) [(cycloheptylamino) methylene] bisphosphonic acid (icadronate) and / or

s) [1-hydroxy-2-imidazo- (1,2-a) pyridin-3-yl-ethylidene] bisphosphonic acid, and pharmaceutically acceptable salts thereof, and as a pharmaceutically acceptable chelating agent a compound selected from the group consisting of EDTA and DTPA and a pharmaceutically acceptable salt thereof.

Unless otherwise stated, the following definitions will illustrate and define the meaning and scope of the terms used to describe the present invention.

The term "bisphosphonate" means a compound containing two C-PC3 bonds^2-. Compounds in which two such bonds occur on the same carbon atom are called geminal bisphosphonates. It should be noted that the term "bisphosphonate" as used herein with respect to the medicaments of the invention also includes diphosphonates, bisphosphonic and diphosphonic acids as well as salts and derivatives thereof. The use of specific nomenclature for bisphosphonates or bisphosphonates does not limit the scope of the invention, unless otherwise stated.

The term "chelating agent" or "chelator" denotes an organic or inorganic compound which, through its two or more functional groups, forms stable ring complexes with metal cations. It should be noted that bisphosphonates also have chelating abilities. Thus, the term "chelating agent" means a metal ion binder that is competitive with the bisphosphonate active ingredient of the pharmaceutical composition.

The term "pharmaceutically acceptable" as used herein means those salts or chelating agents which are toxicologically acceptable forms.

The term "pharmaceutically acceptable salt" denotes ammonium salts, alkali metal salts such as potassium and preferably sodium salts (including mono-, di- and trisodium salts), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as salts with dicyclohexylamine and N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc.

The term "diluent" means a component of a medicinal preparation that has no pharmacological activity but is necessary or desirable from a pharmaceutical point of view. The diluent can be, for example, a liquid used to dissolve the drug or drugs for injection, for example, water.

The term "solvent" denotes a liquid that contains another substance in solution and is therefore capable of dissolving it, such as, for example, water.

The term "preservatives" means substances added to a medicament to prevent the growth of bacteria.

The term "device" means an instrument for use for a specific purpose. As used herein, the purpose is to enable, promote or facilitate the administration of a drug by the parenteral route.

The term "local anesthetic" denotes a compound that reversibly reduces the function of neurons at the site of administration, and suppresses the ability to feel pain and other sensations, such as lidocaine hydrochloride.

In particular, the invention relates to a composition for parenteral administration, comprising a bisphosphonate and a pharmaceutically acceptable chelating agent. The composition for parenteral administration may take the form of a liquid, e.g. an aqueous solution, or a sterile powder and / or lyophilisate. A liquid, e.g. water, is added to a sterile powder and / or lyophilisate to prepare an administration solution.

In a more preferred embodiment of the invention, the above composition is a liquid, preferably an aqueous solution.

Bisphosphonates pharmaceutical agents are described e.g. in US 4,666,895, US 4,719,203, EP-A-252504, EP-A-252505, US 4777163, US 5002937 and US 4,971,958.

Methods for producing bisphosphonic acids can be found e.g. Org. Chem. 32 4111 (1967) and in EP-A-252504. The invention also includes the use of pharmaceutically acceptable salts of the bisphosphonic acids. Examples of the basic salts of bisphosphonic acids are ammonium salts, alkali metal salts such as potassium and preferably sodium salts (including mono-, di- and trisodium salts), alkaline earth metal salts,

Such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine salts, and salts with amino acids such as arginine, lysine, and the like are preferred are non-toxic, physiologically acceptable salts. . These salts are obtained by known methods such as those described in European patent publication 252504 or in US 4,922,077.

Bisphosphonates, i.e., bisphosphonic acids, and their pharmaceutically acceptable salts, which can be used as active ingredients in the compositions of the invention, include the following compounds:

a) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,

b) 4- (N, N-dimethylamino) -1-hydroxybutylidene-1,1-bisphosphonic acid,

c) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate),

d) 3- (N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid),

e) [3- (N-Methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid] monosodium salt monohydrate (ibandronate)

f) 1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid,

g) 1-hydroxy-2- [3-pyridinyl] ethylidene-1,1-bisphosphonic acid (risedronate),

h) 1- (4-piperidinyl) -1-hydroxymethylene-1,1-bisphosphonic acid,

i) cycloheptylaminomethylene-1,1-bisphosphonic acid (cimadronate),

j) 1,1-dichloromethylene-1,1-diphosphonic acid and its disodium salt (clodronate),

k) 1-hydroxy-3- (1-pyrrolidinyl) propylidene-1,1-bisphosphonic acid (EB-1053),

l) 1-hydroxyethane-1,1-diphosphonic acid (ethidronic acid),

m) 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate),

n) 3- (dimethylamino) -1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate)

o) [2- (2-pyridinyl) ethylidene] -1,1-bisphosphonic acid (pyridronate),

p) (4-chlorophenyl) thiomethane-1,1-diphosphonic acid (tiludronate),

q) 1-hydroxy-2- (1H-imidazol-1-yl) ethylidene-1,1-bisphosphonic acid (zolendronate),

r) [(cycloheptylamino) methylene] bisphosphonic acid (icadronate) and / or

s) [1-Hydroxy-2-imidazo- (1,2-a) pyridin-3-ylethylidene] bisphosphonic acid and pharmaceutically acceptable salts thereof.

Preferably the composition according to the invention comprises a bisphosphonate compound selected from the group consisting of cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, pyridronate, parnidronate, zolendronate and pharmaceutically acceptable salts thereof.

The above-defined composition of the invention more preferably comprises 3- (N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid) or a pharmaceutically acceptable salt thereof as the bisphosphonate; or even more preferably it comprises 3- (N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid monosodium salt monohydrate.

A pharmaceutically acceptable chelating agent or a pharmaceutically acceptable salt thereof according to the invention is a compound that forms, through its two or more functional groups, stable ring complexes with metal cations selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) or a pharmaceutically acceptable thereof. salt. Chelating agents are complexes which, unlike simple ligands such as e.g. ferrocyanide (Fe (CN) 6^4-), forming complex salts through a single bond formed by one pair of electrons, exhibit the ability to form more than one bond. For example, ethylenediamine is bifunctional (forms two bonds), tripyridyl is three-functional (three bonds), and ethylenediaminetetraacetic acid (EDTA) is six-functional (six bonds), which makes it extremely effective as a pharmaceutical chelating agent. One of the effects of chelation is the formation of a cyclic structure with high thermodynamic and thermal stability, analogous to aromatic rings. Furthermore, the chelate complex is generally more stable than the ligand since two bonds would have to be broken, but while one may break, it may regrow before the second bond breaks. This effect is called the chelation effect.

In the compositions of the invention, the molar ratio of bisphosphonate to pharmaceutically acceptable chelating agent is preferably about 1: 0.01-1: 500, more preferably about 1: 0.1-1:50, and more preferably about 1:10.

For example, to a solution containing 1 mg ibandronate / ml of saline at pH 7.4, EDTA was added at a concentration of 0.1 to 10 mg / ml, which corresponds to the molar ratio of ibandronate to EDTA of about 1: 0.1 up to 1:10. The beneficial effects of EDTA turned out to be dose dependent. Some beneficial effects were observed at the lowest molar ratio of 1: 0.1, and at the highest

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1:10 there were still some adverse local reactions. It is therefore expected that also at the higher and lower molar ratios the local tolerance to parenterally administered bisphosphonate compositions will improve. Moreover, it allowed the observation of the effect of EDTA on the local reaction induced by the action of alendronate as well as the effectiveness of DTPA as a chelating agent.

The above-defined composition of the invention preferably comprises one or more additional pharmaceutically acceptable chelating agents mentioned above.

The above-defined composition according to the invention preferably contains excipients selected from diluents, solvents and / or preservatives, e.g. water, alcohol, polyols, glycerin and vegetable oils.

The composition of the invention may contain one or more pharmaceutically acceptable excipients.

The above-defined composition of the invention preferably comprises a bisphosphonate or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable chelating agent, a tonic (tonicity agent as described below), a pH adjusting agent (e.g. an acid, base or buffer as described below) and a solvent.

The above-defined composition according to the invention may advantageously additionally contain a local anesthetic.

Preferably, the pH of the above-described solution of the composition according to the invention is in the range of 2-10, more preferably 4-9, more preferably 6-8, most preferably 7-8 and especially about 7.4.

A preferred example of a composition of the invention described above is a parenteral composition comprising:

a) 0.1-10 mg of 3- (N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid monosodium salt monohydrate, and

b) 0.5-50 mg EDTA-Na2 ^ 2H2O.

Another preferred example of a composition of the invention described above is a parenteral composition comprising:

a) 0.1-10 mg of 3- (N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphene acid monosodium salt monohydrate;

b) 0.5-50 mg EDTA-Na2N2O2;

c) about 9.0 mg of sodium chloride;

d) an amount of sodium hydroxide necessary to obtain a pH of about 7.4;

(e) water for injection to bring the volume up to 0.5 or 1.0 ml.

A further preferred example of a composition of the invention described above is a parenteral composition containing: about 1.125 mg of ibandronate sodium, about 10 mg

EDTA-Nay2H₂About 9.0 mg of sodium chloride, sodium hydroxide as needed to bring the pH to about 7.4, and water for injection to bring the volume up to 1.0 ml.

Yet another preferred example of a composition of the invention described above is a parenteral composition comprising: about 1.125 mg of ibandronate sodium, about 10 mg of EDTA-Nay2H₂About 5.78 mg of lidocaine hydrochloride, about 9.0 mg of sodium chloride, sufficient sodium hydroxide to obtain a pH of about 7.4, and water for injection to bring the volume up to 1.0 ml.

Furthermore, the invention relates to a process for the preparation of the above-defined composition, characterized in that at least one bisphosphonate is mixed with at least one pharmaceutically acceptable chelating agent and a pharmaceutically acceptable excipient.

Preferably, the invention also relates to a process for the preparation of the above-defined composition, characterized in that at least one bisphosphonate is mixed with at least one pharmaceutically acceptable chelating agent and a local anesthetic.

Furthermore, the invention relates to the use of the above-defined composition for the preparation of medicaments useful in the treatment and prophylaxis of diseases related to bone resorption, in particular osteoporosis, Paget's disease, malignant hypercalcemia and bone diseases of metabolic origin.

The invention also relates to the use of the above defined composition for the preparation of medicaments for the prevention of tissue damage following parenteral administration of bisphosphonates, preferably by administration in the form of an aqueous solution.

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The compositions according to the invention are useful in the treatment and prophylaxis of diseases related to bone resorption, in particular osteoporosis, Paget's disease, malignant hypercalcemia and bone diseases of metabolic origin.

In particular, the composition according to the invention described above may contain additional excipients selected from among solvents and co-solvents (water for injection, ethanol, glycerin, propylene glycol, polyethylene glycol, various oils), solubilizers, wetting, suspending, emulsifying or thickening agents (carboxymethylcellulose, Cremophore EL, sodium deoxycholate, gelatin, lecithin, polysorbate 20 and 80, poloxamer), antioxidants and reducing agents (ascorbic acid, sodium bisulfite, sodium metabisulfite), antimicrobial preservatives (benzyl alcohol, propylparaben, methylparaben), buffering and pH adjusting agents (acetates, citrates, lactates, hydrochloric acid, sodium hydroxide), volumizing agents, preservatives and tonicity agents ( sodium chloride, glucose, mannitol) and local anesthetics (lidocaine, benzocaine, buvicaine, procaine, tetracaine).

In a preferred embodiment, a composition of the invention for parenteral administration preferably comprises a bisphosphonate and a pharmaceutically acceptable chelating agent (s) as described above.

The parenteral route of administration of the compositions of the invention includes subcutaneous, intramuscular, intravenous, transdermal, intradermal, intranasal, intraarterial and intraperitoneal injection or infusion. Preferably, parenteral administration comprises subcutaneous, intramuscular and intravenous injection or infusion, preferably subcutaneous.

A device may be used that enables the local, sustained release of the composition described above. Such a device may include, for example, osmotic, implantable or external pumps and portable infusion pumps connected to a supply line and / or to a cannula placed under the skin.

In addition, a device may be used to permit, facilitate or support the parenteral administration of the compositions of the invention. For example, a device enabling local, sustained release of the active ingredient may be used, consisting of portable infusion pumps connected to a supply line and / or to a subcutaneous cannula (e.g. Portable Injection Appliance in US Patent No. 4,886,499) or for local injection pain relief using a needleless injection injector (e.g. MicroPor ™, Medi-jector ™).

The invention further relates to injectable formulations for sustained release of the compositions of the invention and for topically reducing pain caused by injection. For example, a sustained-release composition may contain compounds that enable sustained action such as various pharmaceutically acceptable oils, thickeners (carboxymethylcellulose, poloxamer, gelatin), biodegradable microparticle releasing polymers (lactide / glycolide derivative polymers, polymeric anhydrides, chitosan) or pharmaceutically acceptable polyelectrolytes ( Albumin, Protamin).

The following examples and figures illustrate the invention in detail.

Examples

Example 1: Local Tolerance Test I

Groups of rats each consisting of 3 animals were administered test preparations containing 1 mg ibandronate / ml of physiological saline, buffered pH 7.4. One group of rats was administered the test composition without any additives, and the other group was administered the test solution with the addition of 1 mg EDTA / 1 ml. One day prior to treatment, the rats had their backs shaved. Each of them was injected subcutaneously with 0.5 ml of the preparation in three different places on the right side of the shaved back. The corresponding ibandronate-free solution (placebo) is shown on the left. Local reactions were scored for swelling: 0 = no reaction, 0.5 = very little visible swelling, 1 = slight swelling, 2 = moderate swelling, 3 = marked swelling, 4 = very marked swelling. The animals were observed for 9 days and then necropsied. During the autopsy, the diameter of the subcutaneous lesions, mainly reddened or swollen, was measured. The results are shown in Figures 1 and 2.

Example 2: Local tolerance test II

According to the scheme described in Example 1, the dependence of the effects of drug administration on the concentration of EDTA was investigated. EDTA was added at concentrations of 0.1, 1.0 and 10 mg / ml. The results are shown in Figures 3 and 4.

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Example 3: Local tolerance test III

According to the scheme described in Example 1, the efficacy of DTPA was tested with subcutaneous administration of ibandronate. DTPA was added at a concentration of 10 mg / ml. The results are shown in Figures 5 and 6.

Example 4: Local Tolerance Test IV

Following the scheme described in Example 1, the efficacy of DTPA was tested with subcutaneous administration of alendronate. The test solutions contained 3 mg alendronate / ml of saline, buffered at a pH value of 7.4. EDTA was added at a concentration of 10 mg / ml. The results are shown in Figures 7 and 8.

In conclusion, strong evidence has been obtained that the presence of a chelating agent such as EDTA or DTPA in the injectable bisphosphonate, alendronate or ibandronate solutions reduces both the intensity and duration of local swelling at the injection site and the size of the lesions. subcutaneous samples measured at 9 days necropsy.

Example 5: Composition for parenteral administration I

<td>Ibandronate sodium salt</td><td>1.125 mg</td>

<td>EDTA-W2H2O</td><td>10.0 mg</td>

<td>Sodium chloride</td><td>9.0 mg</td>

<td>Sodium hydroxide in the amount necessary to obtain the reaction</td><td>pH 7.4</td>

<td>Water for injection, to make up the volume</td><td>1.0 ml</td>

Example 6: Composition for parenteral administration II

<td>Ibandronate sodium salt</td><td>1.125 mg</td>

<td>DTPA</td><td>10.0 mg</td>

<td>Sodium chloride</td><td>9.0 mg</td>

<td>Sodium hydroxide in the amount necessary to obtain the reaction</td><td>pH 7.4</td>

<td>Water for injection, to make up the volume</td><td>1.0 ml</td>

Example 7: Composition for parenteral administration III

<td>Alendronate</td><td>3.0 mg</td>

<td>EDTA-W2H2O</td><td>10.0 mg</td>

<td>Sodium chloride</td><td>9.0 mg</td>

<td>Sodium hydroxide in the amount necessary to obtain the reaction</td><td>pH 7.4</td>

<td>Water for injection, to make up the volume</td><td>1.0 ml</td>

Example 8: Composition for Parenteral Administration IV

<td>Ibandronate sodium salt</td><td>1.125 mg</td>

<td>EDTA-W2H2O</td><td>10.0 mg</td>

<td>Lidocaine hydrochloride</td><td>5.78 mg</td>

<td>Sodium chloride</td><td>9.0 mg</td>

<td>Sodium hydroxide in the amount necessary to obtain the reaction</td><td>pH 7.4</td>

<td>Water for injection, to make up the volume</td><td>1.0 ml</td>

Figures:

Figure 1: Mean degree of swelling after subcutaneous injection of ibandronate solution, pH 7.4, with 0.1% EDTA and no EDTA addition (n = 9);

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Figure 2: Mean diameter of subcutaneous lesions 9 days after subcutaneous injection of ibandronate solution, pH 7.4, with 0.1% EDTA and no EDTA addition (n = 9);

Figure 3: Mean degree of swelling after subcutaneous injection of ibandronate solution, pH 7.4, with and without EDTA (n = 9). The data obtained for 0.1% EDTA was combined with the results of the first run (n = 18);

Figure 4: Mean diameter of subcutaneous lesions 9 days after subcutaneous injection of ibandronate solution, pH 7.4, with and without EDTA (n = 9). The data obtained for 0.1% EDTA was combined with the results of the first run (n = 18);

Figure 5: Mean degree of swelling after subcutaneous injection of ibandronate solution, pH 7.4, with 1% DTPA and no DTPA addition (n = 12);

Figure 6: Mean diameter of subcutaneous lesions 9 days after subcutaneous injection of ibandronate solution, pH 7.4, with and without DTPA (n = 12);

Figure 7: Mean degree of swelling after subcutaneous injection of alendronate solution, pH 7.4, with 1% EDTA and no EDTA addition (n = 9);

Figure 8: Mean diameter of subcutaneous lesions 9 days after subcutaneous injection of alendronate solution, pH 7.4, with and without EDTA (n = 9).