WO2003094925A1

WO2003094925A1 - Injectable bisphosphonate formulations

Info

Publication number: WO2003094925A1
Application number: PCT/EP2003/004934
Authority: WO
Inventors: Andrea Capocchi; Rossella Musa; Annamaria Soliani Raschini
Original assignee: Chiesi Farmaceutici S.P.A.
Priority date: 2002-05-13
Filing date: 2003-05-12
Publication date: 2003-11-20
Also published as: PE20040193A1; ITTO20020406A0; AR040001A1; ITTO20020406A1; AU2003240225A1

Abstract

The present invention relates to a pharmaceutical composition in the form of an aqueous solution having a pH value within the range of from 3.5 to 5.5, comprising an alkaline salt of a bisphosphonic acid and lidocaine hydrochloride at a concentration within the range of from 0.5 to 2.0% (w/v). The composition is particularly suitable for intramuscular administration.

Description

Injectable bisphosphonate formulations

The present invention relates to pharmaceutical compositions in the form of aqueous solutions comprising an alkaline salt of a pharmacologically active bisphosphonic acid, which are useful for the treatment of affections of the skeletal system.

Bisphosphonic acids and their pharmaceutically acceptable salts are a class of drugs that is known and described in the literature for the treatment of diseases of the skeletal system.

For this purpose, the ideal administration route would be the intramuscular route since it can be performed both on hospitalized patients and on patients at home and, at the same time, it does not have the side effects i the oesophagus which are frequently associated with oral administration. However, it has been found that the administration of bisphosphonates by intramuscular injection is accompanied by pain phenomena which render it unacceptable to the patient .

To overcome this disadvantage, Italian patent application MI97A002603 proposes intramuscular pharmaceutical formulations of bisphosphonates characterized by the presence of benzyl alcohol . Benzyl alcohol is in fact a preservative with analgesic properties. However, the use of benzyl alcohol in injectable formulations may give rise to allergic side effects and, in particular, to direct toxic tissue reactions .

Italian patent application I2000A000584 on the other hand proposes pharmaceutical formulations of specific bisphosphonates of the clodronates category, in particular of disodium clodronate, which are characterized by an approximately neutral or weakly acid pH value, preferably between 4.5 and 8. However, it is known that the natural pH of disodium clodronate solutions is generally less than 4.5 and higher pH values may therefore promote precipitation of the corresponding bisphosphonic acid. The formulations described in patent application I2000A000584 are in fact preferably prepared as lyophilized preparations to be reconstituted prior to use.

International patent application WO 01/52859 describes injectable pharmaceutical formulations of a bisphosphonic acid or a salt thereof comprising one or more chelating agents. It is reported that tissue tolerance of the bisphosphonates is significantly improved by virtue of the presence of the chelating agent. However, since it is known that chelating agents such as, for example, EDTA are never completely free of metallic impurities (particularly bivalent metals) their use could cause an increase of such impurities in the solutions of the drug, with consequent partial precipitation of the salts of the bisphosphonic derivative with bivalent metals such as the alkaline-earth metals.

Patent application WO 01/52859 also proposes the addition to the above-described formulations of a local anaesthetic, for example, lidocaine hydrochloride, to reduce their algogenic effect. In particular, Example 8 describes a composition comprising, inter alia, approximately 6% lidocaine hydrochloride and ibandronate sodium salt as the active ingredient . However, the use of lidocaine hydrochloride at the concentration of 6% proposed in WO 01/52859 may bring about displacement of the bisphosphonic acid from the corresponding alkaline salt and cause total or partial precipitation thereof. It is in fact known that many unmodified bisphosphonic acids are poorly soluble in water. For example, the solubility of clodronic acid in water is about 17 mg/ml. It is not by chance that the composition indicated above, which is the only one comprising lidocaine hydrochloride that is specifically described in WO 01/52859, contains as active ingredient ibandronate sodium salt which has a high level of activity and can therefore be used at a very low concentration (about 1 mg/ml) which is below the solubility limit of the corresponding bisphosphonic acid in water, which is about 10 mg/ml.

The object of the present invention is therefore to provide a pharmaceutical composition comprising an alkaline salt of a pharmacologically active bisphosphonic acid which does not have the above-mentioned disadvantages.

In particular, an object of the present invention is to provide a pharmaceutical composition for intramuscular administration comprising an alkaline salt of a bisphosphonic acid in the form of an aqueous solution which prevents or substantially reduces the algogenic effect generally associated with the intramuscular administration of this class of drugs and which at the same time remains substantially clear and free of precipitates even after storage .

This object is achieved by means of a pharmaceutical composition in the form of an aqueous solution having a pH value within the range of from 3.5 to 5.5, comprising an alkaline salt of a bisphosphonic acid and lidocaine hydrochloride at a concentration within the range of from 0.5 to 2.0% (w/v) on the total volume of the composition.

The concentration is preferably between 0.5 and 1.5% (w/v) ; even more preferably lidocaine hydrochloride is present in the compositions according to the invention at a concentration of 1% (w/v) .

As reported in the scientific literature, excipients added to parenteral formulations may produce negative effects such as loss of drug solubility, activity and/or stability in consequence of antagonist interactions.

The use of lidocaine hydrochloride at the concentrations of the invention allows to obtain formulations that are well tolerated, stable over time, and substantially isotonic. As will be illustrated in greater detail in Example 4, it has in fact been shown that, in the compositions according to the invention, the bisphosphonic acid salt and lidocaine hydrochloride are physically compatible and the solutions therefore remain clear and do not give rise to precipitates after storage either at ambient temperature or under conditions of stress (T = 5°C and T = 40°C) . Moreover, the use of lidocaine hydrochloride at the concentrations indicated above substantially reduces the algogenic effect of the bisphosphonate solutions after intramuscular administration. As shown in Examples 5 and 6, at the preferred concentration of 1% (w/v) lidocaine hydrochloride reduces the algogenic effect of the compositions according to the invention to an appreciably greater extent than the same concentrations of benzyl alcohol . According to a preferred embodiment, the compositions of the present invention comprise an alkaline salt of bisphosphonic acid selected from the group which consists of monosodium alendronate, disodium clodronate, sodium neridronate and disodium pamidronate. The concentration of the salt is preferably between 1 and 200 mg/ml, expressed as the corresponding bisphosphonic acid. Even more preferably, the concentration is above the limit of solubility in water of the corresponding bisphosphonic acid.

According to a particularly preferred embodiment of the invention, the alkaline salt is disodium clodronate tetrahydrate at a concentration of 30 mg/ml, expressed as the bisphosphonic acid present in solution (corresponding to 37.5 mg of tetrahydrate disodium salt) .

According to another particularly preferred embodiment, the alkaline salt is sodium neridronate at a concentration of 12.5 mg/ml, expressed as the bisphosphonic acid present in solution (corresponding to 13.5 mg of sodium salt) .

The compositions according to the invention have a pH value within the range of from 3.5 to 5.5, even more preferably between 4.0 and 4.5. This pH range is the natural range of aqueous solutions of disodium clodronate and there is therefore no need to correct the pH to higher values which might promote precipitation of the corresponding acid. However, according to the bisphosphonate used and the desired pH value, the pH of the composition may be adjusted with the use of a pH adjusting agent.

For example, sodium bicarbonate may be used for this purpose, and may be added to the compositions according to the invention at a concentration preferably within the range of from 0.01 to 2% (w/v) , more preferably 0.02 to 1% (w/v), even more preferably 0.05% (w/v) on the total volume of the composition.

Given the low algogenic effect, the compositions according to the present invention are particularly suitable for use as medicaments for intramuscular administration for the treatment of pathological conditions of the skeletal system. These pathological conditions of the skeletal system include, for example, osteoporosis, Paget's disease, hyperthyroidism and hypercalcemia.

The following examples are provided for illustrative purposes and should not be understood as limiting of the scope of the present invention.

Example 1 (comparative)

The Applicant's disodium clodronate formulations which are currently on the market for intramuscular administration consist of an injectable solution of 100 mg/ampoule (Clody® 100 mg) . These formulations have the following unitary composition:

Example 2

Disodium clodronate formulation for intramuscular administration (Clody® 100 mg + lidocaine HCl 0.6%):

Example 3

Disodium clodronate formulation for intramuscular administration (Clody® 100 mg + lidocaine HCl 1%) :

Example 4 : Stability test

Some ampoules of Clody® 300 mg/10 ml were opened and emptied into a graduated cylinder to determine their exact volume. At ambient temperature, a quantity of lidocaine hydrochloride such as to give a 1% lidocaine solution was added; the mixture was stirred until the substance had completely dissolved and stirring was continued for a further approximately 10 minutes; the solution obtained should be clear and should not have any precipitate .

Each solution obtained was shared out into the ampoules previously emptied; each ampoule should contain about 10 ml of solution. The ampoules were then re-closed with Parafilm.

Finally, some ampoules were placed in a climate-controlled chamber at 40°C/75%RH whilst others were placed in a refrigerator at T=5°C.

Before being shared out, the bulk solution (time zero) was analyzed for appearance and the pH and osmolality values were also determined.

After the solution had been shared out, the ampoules were kept for 7, 15 and 30 days at T=5°C and T=40°C/75%RH, that is, in stressful conditions which might promote more rapid precipitation and degradation of the components as well as alteration of the appearance of the solutions. The appearance, pH and osmolality of the solutions were determined after they had been kept at T=5°C and T=40°C/75%RH for 7, 15 and 30 days. Table 1 gives the results obtained. The pH and osmolality values determined on Clody® 100 mg/3.3 ml are also given in Table II for comparison. Table I

Table II

It is clear from the results that disodium clodronate and lidocaine hydrochloride are physically compatible with one another when in solution; in fact the solutions obtained were clear and there was an absence of precipitate both at time zero (bulk solution) and after storage in stressful conditions .

Moreover, the addition of lidocaine hydrochloride to the currently used Clody® formulation did not cause a change in pH; the values obtained not only conform to the data sheet of the medicament (3.5-5.5) but are also similar to its typical values (4.4-4.5).

The osmolality value of the solutions was also investigated; the currently used formulation had an osmolality value of 262 mosmol/kg whereas, for the formulation containing 1% of lidocaine hydrochloride, it was 324 mosmol/kg. It should be noted that both the currently used formulation and that containing 1% lidocaine hydrochloride had values close to isotonicity. The osmolality values were then checked over time; the results that were obtained at time zero remained unchanged when the solutions were kept at T=5°C and T=40°C/75%RH.

Example 5: "Paw lick" test

The paw lick model is a test model that is widely described and validated by the literature and which is used as an indicator of the pain induced by intramuscular administration. The injection of an irritating agent into the rear paw of a mouse in fact induces characteristic behavioural effects of licking/flinching of the paw which are displayed within the first 15 minutes after injection.

The intramuscular administration of Clody® causes a painful sensation at the moment of injection; as demonstrated below, this can be reduced by combination with a local anaesthetic such as lidocaine hydrochloride in the diluent. In particular, the tests performed had the purpose of evaluating the analgesic effect of two different concentrations of lidocaine hydrochloride (0.6% and 1%) in comparison with that of 1% benzyl alcohol in a parenteral formulation of disodium clodronate.

The tests were performed on mice housed in controlled temperature and relative-humidity conditions.

For the behavioural observations, plastics cylinders were used for containing the animal and a video recording system served to record the behavioural effect.

On the day before the test, each mouse was placed in a cylinder for 30 minutes for conditioning.

The mice were divided into 5 treatment groups :

- saline solution

- Clody

- Clody + lidocaine HCl 1%

- Clody + lidocaine HCl 0.6%

- Clody + benzyl alcohol 1%

The day of testing, the mice were injected into the plantar surface of the left hind rear paw with 20 μl of control solution and test solution, then each mouse was placed into a plastics cylinder for the recording of the behavioural effect. The amount of time, expressed in seconds, that the animals spent in licking and flinching the injected paw in 5 min. intervals, over a total period of 15 min., was used as measurement of intensity of pain.

During the first 5 minutes after injection, the paw licking/flinching activity was considerably greater after the administration of Clody than after the administration of the same volume of saline solution. 0.6% and 1% lidocaine and 1% benzyl alcohol significantly reduced the pain effect due to the Clody. The greatest analgesic effect was that of 1% lidocaine which was significantly greater than that of 0.6% lidocaine and also greater than that of 1% benzyl alcohol .

During the next 5-10 minutes, the acute pain due to the Clody tended to disappear and there were no notable differences between the various groups of animals.

In conclusion, the painful and irritant effect of Clody was particularly evident in the first 5 minutes. All of the analgesic formulations were effective in reducing the algogenic effect of the injections with 1% lidocaine having the greatest efficacy.

Example 6 - Tolerability and pharmacokinetic study

The tolerability and pharmacokinetic of the formulation of example 3 were investigated in comparison to a marketed formulation of disodium clodronate 100 mg containing benzyl alcohol 1% (reference A) and to a marketed formulation of disodium clodronate 100 mg without any compound added to reduce the perception of pain associated with intramuscular injection (reference B) . Thirty healthy female volunteers were treated according to a single dose, double-blind, randomised three-way cross-over design. The local tolerability was investigated by assessing reddening and hardening at the injection site, and plasma creatinine phosphokinase (CPK) levels. Pain intensity was investigated on the visual analogue scale (VAS) . Urinary clodronic acid concentrations were determined by using a validated specific GC/MS assay. CPK levels and occurrence of hardening at the injection site did not show statistically significant differences between formulations . No local redness was reported. The statistical analysis on pain assessment showed a significant reduction of pain intensity immediately and up to at least 2 hours after administration of the formulation of example 3 compared to the marketed ones. From the results reported in Table III it can be concluded that the formulation of example 3 is better tolerated than the marketed formulations .

Table III - VAS pain (mean + s.d.) experienced by subjects at various time points after injection

Test Reference Λ Reference B

Immediately 2.57 ± 2.47 2.99 + 2.73 4.75 ± 3.22

15 min 0.67 ± 1.30 2.83 + 3.25 3.42 ± 2.99

30 min 0.39 ± 0.73 2.49 + 2.78 3.05 ± 2.72

1 h 0.32 + 0.60 1.52 + 1.96 2.05 ± 2.57

2 h 0.13 + 0.24 0.61 ± 0.97 0.87 ± 1.86

4 h 0.03 + 0.08 0.08 ± 0.14 0.21 ± 0.54

6 h 0.03 ± 0.08 0.03 + 0.07 0.03 ± 0.06

8 0.03 ± 0.08 0.03 + 0.10 0.01 ± 0.03

Example 7

Sodium neridronate formulation for intramuscular administration added with lidocaine HCl 0,5%

Example 8

Sodium neridronate formulation for intramuscular administration added with lidocaine HCl 2.0°

Example 9 : Stability test

The solutions of examples 7 and 8 and the corresponding ampoules were prepared as disclosed in example 4 starting from ampoules containing 25 mg of sodium neridronate in 2 ml .

Some ampoules were placed in a climate-controlled chamber at 30°C/60% RH, whilst others were placed in a refrigerator at T=5°C. Before being shared out, the bulk solution (time zero) was analysed for appearance and the pH and osmolality values were also determined.

The appearance, pH and osmolality values of the solutions were determined after they had been stored for 7, 15 and 30 days. Tables IV and V give the results obtained. The pH and osmolality values determined on the starting solution, free from lidocaine, are also given in Table VI for comparison.

H a

E--

Table VI

It is clear from the results that sodium neridronate and lidocaine hydrochloride are physically compatible with one another when in solution: in fact the solutions obtained are clear and there is an absence of precipitate both at time zero (bulk solution) and after storage in stressful conditions .

Moreover, the addition of lidocaine hydrochloride does not cause a change in the pH of the formul tions: the values obtained for both concentrations of lidocaine and in both storage conditions are similar to those of the starting formulation. As to osmolality, the solutions of the invention are isotonic or slightly hypertonic at most, and the osmolality values remain unchanged with time at the different storage conditions.

Claims

1. A pharmaceutical composition in the form of an aqueous solution having a pH value within the range of from 3.5 to 5.5, comprising an alkaline salt of a bisphosphonic acid and lidocaine hydrochloride, the lidocaine hydrochloride being present at a concentration within the range of from 0.5 to 2.0% (w/v) .

2. A pharmaceutical composition according to Claim 1, wherein the concentration of lidocaine hydrochloride is within the range of from 0.6 to 1.5% (w/v).

3. A pharmaceutical composition according to Claim 1 or Claim 2, wherein the alkaline salt of a bisphosphonic acid is selected from the group consisting of monosodium alendronate, disodium clodronate, sodium neridronate and disodium pamidronate.

4. A pharmaceutical composition according to any one of Claims 1 to 3, wherein the concentration of the alkaline salt of a bisphosphonic acid is within the range of from 1 to 200 mg/ml, expressed as the corresponding bisphosphonic acid.

5. A pharmaceutical composition according to any one of Claims 1 to 4 , wherein the concentration of the alkaline salt, expressed as the corresponding bisphosphonic acid is above the limit of solubility in water of the corresponding bisphosphonic acid.

6. A pharmaceutical composition according to any one of Claims 1 to 5, wherein the pH value is within the range of from 4.0 to 4.5.

7. A pharmaceutical composition according to any one of Claims 1 to 6, further comprising a pH adjusting agent.

8. A pharmaceutical composition according to Claim 7, wherein the pH adjusting agent is sodium bicarbonate at a concentration within the range of from 0.01 to 2% (w/v) , preferably 0.02 to 1% (w/v) .

9. A pharmaceutical composition according to any one of Claims 1 to 8, wherein the alkaline salt of a bisphosphonic acid is disodium clodronate at a concentration of 30 mg/ml, expressed as the corresponding bisphosphonic acid.

10. A pharmaceutical composition according to Claim 9, containing: 30 mg/ml disodium clodronate tetrahydrate, expressed as the corresponding bisphosphonic acid, 0.05% (w/v) sodium bicarbonate, and 0.6% (w/v) lidocaine hydrochloride .

11. A pharmaceutical composition according to Claim 9 containing: 30 mg/ml disodium clodronate tetrahydrate, expressed as the corresponding bisphosphonic acid, 0.05% (w/v) sodium bicarbonate, and 1% (w/v) lidocaine hydrochloride .

12. A pharmaceutical composition according to any one of claims 1 to 8, wherein the alkaline salt of a bisphosphonic acid is sodium neridronate at a concentration of 12.5 mg/ml, expressed as the corresponding bisphosphonic acid.

13. A pharmaceutical composition according to claim 12 containing: 12,5 mg/ml sodium neridronate, expressed as the corresponding bisphosphonic acid, and from 0,5% to 2% (w/v) lidocaine hydrochloride.

1 . A pharmaceutical composition according _^ to any one of Claims 1 to 13 for use as a medicament.

15. A pharmaceutical composition according to any one of claims 1 to 13 for use as a medicament for intramuscular administratio .

16. Use of a pharmaceutical composition according to any one of Claims 1 to 13 for the preparation of a medicament for the treatment of pathological conditions of the skeletal system.

17. Use according to Claim 16 , wherein the pathological conditions of the skeletal system are selected from the group which consists of osteoporosis, Paget's disease, hyperthyroidism and hypercalcemia.