HK1204551B - Injectable compositions - Google Patents

Description

injectable composition

Description of the invention

Field and object of the invention

The subject of the present patent application is a composition useful for the treatment of cancer.

In particular, the present invention relates to a composition suitable for forming an intramuscular implant comprising a biodegradable thermoplastic polymer consisting of polylactic acid (PLA), dimethyl sulfoxide (DMSO) and an aromatase inhibitor compound, a kit suitable for the in situ preparation of the composition, and its use as a medicament in the treatment of breast cancer.

Background

There is no doubt that cancer therapy requires development, not only of new molecular entities but also of pharmacological products that can improve the quality of life of patients. In this sense, the development of extended release formulations has meant progress, as they have enabled a reduction in the total dose administered, an increase in the duration of each dose and the number of administrations, and thus have a positive effect on the emotional state of the patient.

In this sense, in the present invention we have selected the active ingredients letrozole and anastrozole as candidates for this type of extended release formulation, since they are the first-line active ingredients for the adjunctive treatment of women with menopausal hormone receptor positive advanced breast cancer, for which the alternative therapy is nothing but daily taking tablets for treatment

Letrozole (4, 4 '- (1, 2, 4-triazol-1-ylmethyl) dibenzazole) and anastrozole (2, 2' - [5- (1H-1, 2, 4-triazol-1-ylmethyl) -1-, 3-phenylene ] bis (2-methylpropanenitrile)) belong to the class of nonsteroidal inhibitors known as aromates, whose mechanism of action involves the reduction of the amount of estrogen in the body. This effect can slow or stop the growth of many types of cancer cells in the breast that require estrogen to grow.

Currently, there is no letrozole formulation on the market that can control the release of the drug over a long period of time. The pharmaceutical drug letrozole is currently available only in tablet form for daily oral administration. The letrozole formulations described herein enable therapeutic levels of drug in the blood to be obtained from the outset and last for more than three months, avoiding the need for a daily dosing regimen, thereby improving the quality of life of the patient.

In the treatment of breast cancer, as is common in cancer, the psychological state of the patient is of great importance; thus, the administration of a formulation of letrozole and/or anastrozole once every three months means a significant improvement in the quality of life of the patient, thereby reducing the effect of daily treatment. In turn, medical examinations performed during the course of monitoring the disease are usually performed at 3 and 6 months of the last years, so that the administration of the preparation can be in line with the time of consultation with the doctor.

Similar reasoning leads toThe goserelin pre-implant for subcutaneous application every three months for treating prostate cancer and method of useThe advent of such etonogestrel preformed implants for use as a contraceptive drug. However, these prefabricated implants exhibit a series of disadvantages, including:

the use of high temperatures for the preparation of implants by extrusion, which can lead to degradation of the active principle and the generation of potentially toxic impurities;

when the active ingredient is used in low doses, the product obtained is less homogeneous;

the need to implant by surgery or to inject the implant using a large gauge needle.

In addition, some disadvantages may also be found in some literature publications relating to implantable compositions of letrozole and/or anastrozole, such as:

WO 2008/041245 describes implantable compositions containing a variety of active ingredients, for example certain aromatase inhibitors including anastrozole, which use different modes of administration, from pre-formed microparticles suspended in an aqueous carrier to in situ gel-forming formulations. Although it is doubtful that this document can adequately support all active ingredient combinations and administration forms that may occur, these examples always refer to preformed microparticles, i.e. it never describes a system for forming implants directly "in situ". Finally, it should be noted that none of the examples show a duration of more than 60 days.

WO 2010/065358 a1 describes pharmaceutical compositions for administration of a relevant drug, which contain testosterone and an aromatase inhibitor for continuous administration of testosterone and to prevent its conversion into estradiol. Although the description is believed to be capable of administration in the form of an implant, the only example of administration provided is a tablet.

Furthermore, WO 2012/074883 a1 describes biodegradable components present during the administration of a pharmaceutical product. These compositions require the use of water-insoluble solvents, such as benzyl benzoate or benzyl alcohol, to maintain the liquid or semi-solid state of the implant. As mentioned previously, these solvents are subject to sudden release and are therefore not suitable for use in the extended release compositions of the present invention.

Finally, US 2008/0206303 a1 describes an anastrozole extended release formulation consisting of PLA or PLGA polymers which may be accompanied by various solvents; however, in the examples of the present invention, the solvents used were benzyl alcohol and n-methyl-2-pyrrolidone (NMP), such solvents being capable of producing very large burst release with almost zero subsequent release. In fact, the burst that the inventors in this document can accept is 25-30% a day, which is a very high value, since this aspect has no example for more than 60 days; particularly in dogs and animals similar to humans, the sustained release time does not exceed 35 days. Finally, this document does not mention the size of letrozole particle nor the importance of this factor in the formulation behaviour.

It is therefore expected that letrozole and/or anastrozole formulations can be obtained for once every trimester as a first-line adjunctive therapy for female menopausal hormone receptor positive breast cancer patients. For this reason, the in situ forming implant technology used in the present invention overcomes most of the disadvantages of current pre-made implant based formulations. It provides a practical and effective alternative treatment for patients, achieving a treatment profile that lasts at least 60 days.

Brief Description of Drawings

The following drawings are provided to aid in the explanation of the objects of the invention and are not meant to be limiting in any way.

FIG. 1: FIG. 1 shows the plasma content (in ng/mL) of trozole obtained after intramuscular injection of the formulation shown in example 1 into New Zealand white rabbits. The values indicated correspond to the mean plasma contents obtained in three animals of each group.

FIG. 2: FIG. 2 shows the plasma content (in ng/mL) of trazol obtained after intramuscular injection of the formulation shown in example 2 into New Zealand white rabbits. The values indicated correspond to the mean plasma contents obtained in three animals of each group.

FIG. 3: FIG. 3 shows the plasma content (in ng/mL) of trazol obtained after intramuscular injection of the formulation shown in example 3 into New Zealand white rabbits. The values indicated correspond to the mean plasma contents obtained in three animals of each group.

Detailed Description

For the compositions which are the object of the present invention, the term "initial" burst "refers to the ratio of the area under the curve of the content of active ingredient in plasma obtained in a living animal for the first 72 hours after intramuscular administration of the product to the total area under the curve (also called" AUC ") obtained after injection of a certain quantity of letrozole or anastrozole.

In order to obtain an extended release of the active ingredient suitable for the purpose of the present invention, the ratio of the area under the burst curve to the total AUC must be less than 10%, ideally less than 5%. Similarly, to obtain a balanced prolonged release profile of the aromatase inhibitor over at least 60 days, the area under the curve of the content in the plasma obtained in the first 30 days after injection must not exceed 50%. That is, for the purposes of the present invention, the preferred extended release of the active ingredient should ensure that the area under the burst curve is less than 10% of the total AUC and not more than 50% of the total AUC obtained 30 days before injection.

For the purposes of the present invention, the following terms will not be used in a distinguishing manner:

"PLA", "biodegradable thermoplastic polymer of polylactic acid", "lactic acid", and "polylactic acid".

"DMSO" and "dimethylsulfoxide".

Thus, a first aspect of the invention is a composition suitable for forming an intramuscular implant, a biodegradable thermoplastic polymer consisting of polylactic acid (PLA), DMSO and an aromatase inhibitor compound of general formula (1):

wherein:

when R is₁Is H; r₂Is thatAnd R₃Is H

When R is₁Is thatIs H and R₃Is CN

Characterized in that the aromatase inhibitor compound is suspended in a solution comprising DMSO and PLA in an amount of 15-50% by weight of the total mixture, the mixture being capable of solidifying upon administration in vivo of at least 100nmol/mL for more than 60 days, and forming a solid or gel-type implant of therapeutic value upon contact with aqueous fluid or aqueous fluid in vivo.

Ideally, the aromatase inhibitor compound is suspended in a solution containing DMSO and PLA in an amount of 20-30% by weight of the total mixture.

More desirably, the aromatase inhibitor compound is suspended in a solution containing DMSO and PLA in an amount of 25% by weight of the total mixture.

According to another aspect, the aromatase inhibitor compound of the general formula (1) has the following particle size distribution:

particles smaller than 20 μm < 10%,

greater than 350 microns and

particles with a radius between 70 and 200 μm < 10%.

In a preferred embodiment, the aromatase inhibitor compound is letrozole or anastrozole, alone or in combination.

In another preferred embodiment, the solution formed by DMSO and PLA has 40-43% by weight PLA (100% lactic acid) and 57-60% by weight DMSO.

In a further preferred embodiment, the end groups of the PLA are replaced by carboxylic acids as esters.

In another additional preferred embodiment, the active ingredient is sterilized, for example, by gamma or beta irradiation. The active ingredient may be radiation sterilized to a maximum of 35kGy prior to being placed in the implantable composition. The active ingredient may also be sterilized by terminal irradiation of the product.

In a further preferred embodiment, the ratio of DMSO to letrozole is between 0.5 and 3.7, preferably in the range of 1.7 to 1.8.

In yet a further preferred embodiment, the viscosity of the solution containing DMSO and PLA is between 0.8 and 1.8pa.s, preferably in the range of 0.8 and 1.5pa.s, more preferably in the range of 0.8 and 1.3pa.s and 1.00 and 1.20 pa.s.

In another additional embodiment, the maximum volume is 2 ml, allowing 500 mg of letrozole to be administered by intramuscular injection.

In a second aspect of the present invention, the above composition is used as a medicament for treating breast cancer.

According to another aspect, the composition suitable for forming an intramuscular implant is characterized in that the AUC of the burst of the compound of formula (1) must be less than 10% of the total AUC and not more than 50% of the total AUC obtained 30 days before the injection.

For example, the final formulation may be prepared, including in a syringe prepared for intramuscular injection. The same formulation may form part of, for example, a dual syringe kit, which may be a male syringe and a female syringe, or two male syringes connected together by a connector, wherein the polymer solvent in DMSO is in one syringe and the aromatase inhibitor is in solid form in the second syringe.

Likewise, the final composition may be obtained by, for example, storing the solid polymer and aromatase inhibitor in one syringe and the solvent in a second syringe.

In these cases the reconstitution is carried out by directly connecting the male and female syringes or connectors, in the case of the connector, two male syringes, the product being brought together by a push-pull movement of the plunger in two directions, in such a way as to form a suspension of polymer solvent and active ingredient.

Any system that can provide the composition of the invention can be used instead of the present system, so any variant with other design of the formulation, as long as the final combination is capable of forming the desired product, for example by keeping the solvent or polymer solution in a vial separate from the active ingredient, or by keeping the polymer solution in a pre-loaded syringe, and the aromatase inhibitor in a vial, so that the polymer solution is injected into the vial to form a suspension, is considered a possible alternative for the purposes of the present invention.

Thus, according to another aspect, the invention relates to a kit suitable for the in situ preparation of the composition of the invention, wherein the aromatase inhibitor compound of general formula (1) and the polymer are present in solid form in a first container and DMSO is present in a second, separate container.

Thus, according to another aspect, the invention relates to a kit suitable for the in situ preparation of the composition of the invention, wherein the polymer is in a lyophilized state.

Thus, according to another aspect, the invention relates to a kit suitable for the in situ preparation of the composition of the invention, wherein the aromatase inhibitor compound of general formula (1) is present in solid form in a first container and the DMSO and the polymer are present in solution in a second container.

Thus, according to another aspect, the invention relates to a kit suitable for the in situ preparation of the composition of the invention, wherein the aromatase inhibitor compound of general formula (1), the polymer and the DMSO are present in the form of a suspension in a single container.

Throughout the development of the present invention, research has been conducted in accordance with the present invention into various parameter behaviors that may affect the long-term release results of implantable composites. Such parameters are as follows:

1. rheology of polymer solutions and inherent viscosity

The behavior of both the polymer solution and the complete formulation was evaluated by rheology. Where the matrix is considered to be a letrozole carrier, they all have newtonian behavior. In this document, viscosity is used as an indirect parameter, adding to the polymer concentration of the injectable formulation behavior in terms of its ability to control the original release of the product.

From experimental work, it was determined that the minimum concentration of polymer solution should be 0.8pa.s, preferably around 1pa.s, but not more than 1.8 pa.s. The polymer solution in DMSO, measured at a temperature of 25 ℃, and obtained within this concentration range, provides the right balance between solubilization of the active ingredient and its retention capacity in the polymer matrix, thus clinically obtaining the relevant plasma concentrations of letrozole or anastrozole, avoiding excessive release of the active ingredient which could impair the useful life of the implant during the active ingredient diffusion phase. After addition of the active ingredient, the viscosity increases accordingly, but not more than the range of 3-4 pa.s.

The following table shows the apparent concentrations of the most suitable polymers in vivo and in vitro, and the concentrations of the final preferred formulations, when the polymers are present in DMSO at different concentrations at a temperature of 25 ℃.

PLA polymersThe viscosity of R203S was measured by irradiating the starting material with β rays at a dose of 10kGy,

concentration of the preferred formulation

2. Particle size of active ingredient

The active ingredient present in the solution or suspension mainly influences the release process of the active ingredient after intramuscular injection of the formulation. Thus, when letrozole is dissolved in a solution containing polymer and DMSO, the formulation for intramuscular injection results in an excessive release of the active ingredient for the first few days, due to diffusion of letrozole with water-miscible solvents during the hardening of the polymeric carrier, followed by a minimum in vivo release of the active ingredient during the incubation period, and a final release of letrozole when the polymer degrades by hydrolysis. This document describes how a formulation containing letrozole in suspension alone can control the initial release of the active ingredient and prevent release during these latent periods, where the formulation has no clinical effect. Thus, the particle size of the active ingredient has a critical role in the final behavior of the formulation, as it directly influences the release process of the formulation after injection of the formulation. The importance of this fundamental fact has not previously been described in the literature of the preparation of extended release formulations containing aromatase inhibitors.

Thus, the usage of the different fractions is evaluated to determine or minimize the appropriate and defined intervals. It is more useful to have a distribution of different crystal sizes over a specific and completely narrow size, so that the release is modulated in a staggered manner to some extent. In this manner, the smallest dimensions are not useful because they diffuse very easily with the solvent (less than 50 microns) during the formation of the implant. Medium sized particles with an average value of approximately 100-300 microns are more useful because they are retained by the matrix, take more time to dissolve, and remain in the implant during their solidification. Above this size, it is desirable to increase the degree of degradation of the polymer, leading to a new incubation period during the life of the implant, and excessive release of the active ingredient upon hydrolysis of the polymer, and it is not particularly safe to use particles in this size range at higher ratios.

In a preferred embodiment, it has been determined that not only the minimum size is eliminated, but also the medium to low size (50-100 microns) is eliminated in order to improve the product, on the one hand, to reduce the final viscosity of the reconstituted product and, on the other hand, to substantially prevent significant burst effects.

3. Degree of suspension of active ingredient in a solution containing PLA and DMSO.

One feature of the present compositions is that the aromatase inhibitor compound of formula (1) is in suspension, preferably present in a solution containing DMSO and PLA in an amount of approximately 25% by weight of the total composition, with the remaining 75% by weight of the total composition being composed of DMSO and PLA.

This is not a random fact but is necessary as this will be seen in example 1 which follows, for example if the formulation is in solution the in vivo response will be unsatisfactory.

Examples of the invention

The following examples are illustrative of the present invention and should not be construed as limiting.

Example 1: active ingredient impact study in physical form in formulations: suspensions and solutions

The effect of letrozole in physical form (solution and suspension of the active ingredient) in injectable solutions was evaluated using the following formulation:

preparation 1: formulations with letrozole solution

Preparation 2: formulations with letrozole suspensions

The characteristics of letrozole particle size in formulation 2 were that it was suspended in water using laser diffraction technique (Malvern Mastersizer2000, until the dullness reached 9.41%) and had the following distribution (volume percent): d (0.1) ═ 38.21 μm, d (0.5) ═ 141.35 μm, and d (0.9) ═ 312.13 μm.

In both cases, reconstitution of the product is carried out by connection of the male and female syringes, and continued movement of the plunger in both directions until a complete solution of the polymer is obtained.

In vivo release studies in New Zealand white rabbits

The in vivo release test associated with this document was performed by determining the pharmacokinetic profile of letrozole and anastrozole in plasma following intramuscular injection of the test formulation to test animals rabbits and/or dogs.

The technique used in the quantification of letrozole in dog and rabbit plasma was based on high performance liquid chromatography with a fluorescence detector HPLC-FLD equipped with a mass-mass detector, using liquid-liquid extraction with vinyl acetate as the organic solvent and resuspension used in the reverse isocratic elution analysis. Carvedilol was used as an internal standard with a treatment time of 8.5 minutes and letrozole retention time of 7.8 minutes, using wavelengths of 240 nm (lambda excitation) and 315 nm (lambda radiation). The validated concentration interval is from 5(LLOQ) to 500ng/mL, i.e., the lower limit of quantification or minimum quantifiable analyte concentration of the assay technique is 5ng/mL and the maximum validated concentration is 500 ng/mL. The calibration curve obtained is characterized by having a correlation coefficient of 0.99 or more. The precision of LLOQ and other QCs (i.e., samples of other known concentrations used as quality control in performing the analysis) and the precision of the in-day and in-day measurements were less than 20% and 15%, respectively. Three days of validation using the bioanalytical method, the results met the acceptance criteria described in the FDA guidelines: "bioassay validation".

Tests have demonstrated that letrozole samples in dog and rabbit plasma are stable for up to 6 hours at room temperature. The treated samples can be stored in the sampler at a temperature of 4 ℃ for 24 hours without noticing any change in the accuracy and precision of the analysis. The freeze/thaw cycles performed did not affect the stability of letrozole in dog and rabbit plasma. Tests have shown that the long-term stability of samples stored at a temperature of-80 ℃ can reach 132 days.

In the present example used for formulations 1 and 2, intramuscular injection was performed at the gluteus muscle site of a New Zealand white rabbit weighing about 3 kg. Three animals were used per group, corresponding to an injection of 5.4mg/kg for formulation 1 and 10.8mg/kg for formulation 2. Following injection, plasma samples were collected from white rabbits at the previously established sampling time of up to 231 days post-injection. The results obtained are shown in figure 1. In FIG. 1 it is shown that the initial plasma levels are similar after injection of double dose of formulation 2 in New Zealand white rabbits compared to single dose of formulation 1. Given that formulation 1 uses half the dose of formulation 2, it can be seen that there is significant importance in controlling the physical form of the active ingredient in the formulation. The extent of diffusion of letrozole solution with the solvent in formulation 1 was greater than that of letrozole in formulation 2. It can also be seen that in the case of formulation 1, the plasma level rapidly drops and does not begin to recover until day 154 after injection, at which point the release of the active ingredient begins due to hydrolytic degradation of the polymer holding the active ingredient. Formulation 2 was able to maintain high levels of letrozole in rabbit plasma for longer than 4 months.

Example 2: polymer end group Effect study

In evaluating the effect of the carboxyl end groups or ester (N-terminated) groups of the polymer, the following formulations were used:

preparation 1: lactic acid polymer formulations terminating in carboxyl groups

Preparation 2: lactic acid polymer formulations terminated by an ester group

The characteristics of the letrozole particle size in formulations 1 and 2 were that it was suspended in water using laser diffraction technique (malvern mastersizer2000, until the dullness reached 9.41%) and had the following distribution (in volume%): d (0.1) ═ 38.21 μm, d (0.5) ═ 141.35 μm, and d (0.9) ═ 312.13 μm.

In both cases, reconstitution of the product is carried out by connection of the male and female syringes, and continued movement of the plunger in both directions until a complete solution of the polymer is obtained.

The viscosity of the solution containing the male syringe components was evaluated in parallel using a rotational viscometer (Haake) at a temperature of 25 c in an amount proportionately equivalent to the amount of the solution (41.5% polymer by weight of solution). The viscosity results obtained are shown in the following table:

in vivo release studies in New Zealand white rabbits

In the present example used for formulations 1 and 2, intramuscular injection was performed at the gluteus muscle site of a New Zealand white rabbit weighing about 3 kg. Three animals were used per group, and each formulation was injected at a dose corresponding to 10.8mg/kg of the formulation. Following injection, plasma samples were collected from white rabbits at the previously identified sampling time of up to 175 days post-injection. The results obtained are shown in fig. 2.

In figure 2 it is shown that very high levels of initial letrozole plasma are achieved in rabbits following injection of formulation 1. However, the level value was gradually decreased until no level was detected on day 119. On the other hand, formulation 2 was able to remain at a significantly high level for a significantly longer period. The hydrophilicity of the carboxyl-terminated polymers and their wettability were higher than that of the ester-terminated polymers, probably due to the higher degree of release of the active ingredient at the early stage of the study. However, formulation 2 was able to modulate the release of letrozole to a level higher than formulation 1 to a level more sustainable for a period of time. The percentage of the area under the letrozole plasma content curve relative to the total area under the curve in each formulation is shown in the following table:

example 3: polymer end group Effect study in beagle dogs

In evaluating the effect of the carboxyl end groups or ester (N-terminated) groups of the polymer, the following formulations were used:

preparation 1: lactic acid polymer formulations terminating in carboxyl groups

Preparation 2: lactic acid polymer formulations terminated by an ester group

The characteristics of the letrozole particle size in formulations 1 and 2 were that it was suspended in water using laser diffraction technique (malvern mastersizer2000, until the dullness reached 9.41%) and had the following distribution (in volume%): d (0.1) ═ 38.21 μm, d (0.5) ═ 141.35 μm, and d (0.9) ═ 312.13 μm.

In both cases, reconstitution of the product is carried out by connection of the male and female syringes, and continued movement of the plunger in both directions until a complete solution of the polymer is obtained.

The apparent viscosity of fully reconstituted formulation 2 at 25 ℃ was 2.865 pa.s.

The viscosity of the solution containing the male syringe components was evaluated in parallel using a rotational viscometer (Haake) at a temperature of 25 c in an amount proportionately equivalent to the amount of the solution (41.5% polymer by weight of solution). The viscosity results obtained are shown in the following table:

beagle in vivo Release study

In the present example used for formulations 1 and 2, intramuscular injection was performed at the gluteus muscle site of beagle dogs weighing about 10 kg. Three animals were used per group and each formulation was injected at a dose corresponding to 86.5mg/kg of the formulation. Following injection, plasma samples were collected from dogs at the previously identified sampling time of up to 472 days post-injection. The results obtained are shown in fig. 3.

Figure 3 shows that in the previous example, the difference observed between the two polymers was significantly higher in beagle dogs than in new zealand white rabbits. Lower body temperature beagle dogs (approximately 2.4 ℃ lower than New Zealand white rabbits) slowed the diffusion process, probably due to the slower rate of polymer hydrolysis at lower temperatures, while the diffusion of the active ingredient throughout the matrix was also slowed by the lower animal body temperature, a combination of both effects. In this case, where the diffusion and degradation rates were reduced, a greater effect of the hydrophilic polymer on the letrozole kinetic profile was observed. We observed a continuous increase in plasma letrozole levels from the first 14 to 21 days, indicating the presence of a gastrointestinal circulation phenomenon that has been previously confirmed in the population pharmacokinetic analysis data obtained (non-human). It is also possible that this phenomenon of the gastrointestinal circulation of letrozole is observed in humans. The percentage of the area under the plasma content curve of letrozole in each formulation relative to the total area under the curve is shown in the following table:

Claims (18)

1. A composition suitable for forming an in situ intramuscular implant comprising a biodegradable thermoplastic polymer polylactic acid (PLA), DMSO and an aromatase inhibitor compound of the general formula (1):

wherein:

when R is₁When is H, R₂Is thatAnd R is₃Is H;

when R is₁Is thatWhen R is₂Is H and R₃Is a CN group, and the CN group,

characterized in that the aromatase inhibitor compound is suspended in a solution comprising DMSO and PLA and represents 15-50% by weight of the total composition, said composition forming a solid or gel type in situ implant upon contact with an aqueous fluid or an in vivo aqueous fluid.

2. A composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the aromatase inhibitor compound is suspended in a solution comprising DMSO and PLA and represents 20-30% by weight of the total composition.

3. A composition suitable for forming an in situ intramuscular implant according to any of claims 1 or 2 wherein the aromatase inhibitor compound is suspended in a solution comprising DMSO and PLA and represents 25% by weight of the total composition.

4. The composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the aromatase inhibitor compound of general formula (1) has the following particle size distribution:

< 10% of particles smaller than 20 microns,

particles greater than 350 microns < 10%, and

d0.5 is between 70 and 200. mu.m.

5. The composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the aromatase inhibitor compound is letrozole or anastrozole used alone or in combination.

6. The composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the solution containing DMSO and PLA consists of PLA in a weight ratio of 40-43% and DMSO in a weight ratio of 57-60%.

7. The composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the end group of the PLA is an ester.

8. A composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the formulation is irradiated at a dose of maximum 35 kGy.

9. Composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the ratio between DMSO and the aromatase inhibitor compound of general formula (1) is between 0.5 and 3.7.

10. Composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the ratio between DMSO and the aromatase inhibitor compound of general formula (1) is between 1.7 and 1.8.

11. The composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the viscosity of the solution containing DMSO and PLA is between 0.8 and 1.8 Pa.s.

12. The composition suitable for forming an in situ intramuscular implant of claim 1 wherein the composition has a maximum volume of 2 ml containing 500 mg of letrozole for intramuscular injection.

13. A composition suitable for forming an in situ intramuscular implant according to claim 1 wherein the AUC for burst release of the compound of formula (1) must be less than 10% of the total AUC and not more than 50% of the total AUC obtained 30 days before injection.

14. Use of a composition according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of breast cancer.

15. A kit suitable for the in situ preparation of a composition according to any one of claims 1 to 13, wherein the aromatase inhibitor compound of general formula (1) and the polymer are present in solid form in a first container and DMSO is present in a second, separate container.

16. A kit suitable for the in situ preparation of a composition as claimed in claim 15 wherein the polymer is in a lyophilised state.

17. A kit suitable for the in situ preparation of a composition according to any one of claims 1 to 13, wherein the aromatase inhibitor compound of general formula (1) is present in solid form in a first container and the DMSO and the polymer are present in solution in a second container.

18. A kit suitable for the in situ preparation of a composition according to any one of claims 1 to 13, wherein the aromatase inhibitor compound of general formula (1), the polymer and the DMSO are present in suspension in a single container.