Injectable dosage form, syringe and composition of lanreotide with sustained and / or controlled release

Abstract

The present invention relates to a novel injectable dosage form, a kit or a syringe comprising a composition of lanreotide or a salt thereof with sustained or controlled release. The composition of lanreotide or a salt thereof is packaged in a syringe with a diameter greater than 3.00 mm and equipped with a needle with an outer diameter not greater than 1.00 mm.

Description

Technical Field

[0001] The present invention relates to a novel injectable dosage form of a pharmaceutical composition for sustained and / or controlled release of lanreotide.

[0002] More particularly, the subject of the present invention is a novel injectable dosage form, kit or syringe comprising a composition of lanreotide or one of its salts with sustained or controlled release. Background Art

[0003] Commercially available lanreotide, usually used in the form of acetate, is an octapeptide analog of natural somatostatin. Like somatostatin, lanreotide is an inhibitor of multiple endocrine, neuroendocrine, exocrine and paracrine functions. It exhibits high affinity for human somatostatin receptors (SSTR) 2 and 5 and low affinity for human somatostatin receptors SSTR 1, 3 and 4. The main reason for the inhibition of growth hormone is this activity on SSTR 2 and 5. Lanreotide is more active than natural somatostatin and has a longer duration of action. Its significant selectivity for growth hormone secretion compared to insulin first makes it a product with a suitable composition for the treatment of acromegaly.

[0004] Today, the main area of ​​application of lanreotide is the treatment of neuroendocrine tumors (NET), first of all the symptoms of carcinoid syndrome and then the control of these tumors due to its antiproliferative activity, and so far the combinations developed for the treatment of acromegaly have been used. These combinations allow the continuous delivery of low doses for several years.

[0005] With regard to the treatment of neuroendocrine tumors, it is important to be able to adapt each treatment quickly to each development of the disease, but also to be able to easily administer higher doses, the benefits of which are known for the treatment of carcinoid syndrome, since this allows a better control of the development of these tumors over a longer period. This is easier with a product that can provide the required levels immediately and whose release can be interrupted more quickly, whether the administration period is weeks or months. It is also desirable that this objective be achieved with a product that is easier and more comfortable to inject.

[0006] Compositions of lanreotide are described in patent application WO9607398, which mentions gelable peptides including lanreotide in solid or semisolid form, which will gel to produce sustained release (or extended release) of lanreotide. Also mentioned are suspensions or semisolid compositions described as highly viscous or pasty, in which solvents are added to obtain a semisolid consistency, which automatically forms a gel after interacting with body fluids. The controlled release of lanreotide compositions is described as being highly dependent on the viscosity and volume of the injection product. These semisolids are also described as extruded rods or "strips", which are related to the importance of maintaining the shape of the injection product and the specific obligation of injecting the product with a large diameter needle. The amount of solvent (water) is specified as having to be limited to avoid any risk of solubilization of gelable lanreotide in order to preserve the resistant deposit that will gel at the injection site.

[0007] Document WO9607398 also explains the importance of the shape and volume of the deposits. It is shown that by reducing the diameter of the lanreotide deposits during injection, a more variable control of the in vitro release is observed. Overly diluted compositions are considered undesirable because they disperse after injection and do not form a gel that leads to a sustained release of the product.

[0008] Document WO2015004125 describes a pharmaceutical composition for a sustained action period of at least two months, comprising lanreotide as an active ingredient in a concentration range of 35 to 55% by weight relative to the total weight of the composition, a cosolvent and water, the cosolvent being selected from low molecular weight water-soluble polymers such as polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), propylene glycol, glycerol, polyglycol, ethanol, benzyl alcohol and mixtures thereof.

[0009] Lanreotide is commercially available and used in Somatuline LP or Depot. The 120 mg product Somatuline LP is for example in the form of a specific prefilled syringe of 0.5 mL, which includes an automatic safety system and a specific preassembled needle of 1.20 mm×20 mm. The commercial composition includes lanreotide acetate in the form of a pasty product of white translucent appearance, which must be injected into the outer upper quadrant of the buttocks by pushing the needle over its entire length (deep subcutaneous route). Subsequently and for the sake of simplicity, It should be understood as but not limited to " "Somatuline LP", or any other trade name given to the product.

[0010] The commercially available compositions have been formulated to obtain a form and amount of deposition that, after injection of lanreotide acetate, leads to in situ gelation upon contact with body fluids. To achieve this effect, a needle with an inner diameter of at least 1.00 mm must be used to obtain a dense deposit. This type of needle allows the injection of semisolid, pasty or very viscous products.

[0011] The commercial compositions that exist to date comprise a lanreotide concentration of 25% by weight. In order to be able to inject this pasty product, special syringes with a small internal diameter of about 3.00 mm and a length of 80 mm must be used. The maximum volume of product that can be injected is only 0.5 mL. However, the fineness and length of the syringe pose problems for implanting a large needle and for comfortably and accurately injecting this very viscous product.

[0012] Furthermore, it can be noted that needles with an inner diameter of at least 1 mm are also responsible for injection site pain problems or for subsequent nodule formation. Another limitation related to the pasty consistency of lanreotide is that a 25 wt.% lanreotide composition cannot be injected intramuscularly as the product, since pressure loss during injection with a needle of at least 25 mm in length would result in excessive injection forces. It is also undesirable to inject lanreotide of such a composition by a superficial subcutaneous route due to the excessively large diameter of the needle and the low local tolerance of the deposits which are not easily deformable.

[0013] The commercially available lanreotide-based compositions are intended for deep subcutaneous administration, with dosing cycles ranging from a few weeks to once a month or once every two months in certain patients for treatment that may extend over several years.

[0014] With current 20 mm long needles, this deep subcutaneous route can sometimes be intramuscular or at the border of two tissues. It is therefore useful to have injectable dosage forms and compositions that allow for a more precise selection of the injection route. In certain cases, it may also be desirable to prefer the intramuscular route, for example to avoid possible risks of local tolerance or immune responses associated with the active compound.

[0015] Therefore, there is a great need to simplify the injection, make it less painful, and be able to vary the type and location of the deposits to avoid the problem of nodules. There is also a need to improve the lanreotide release profile to meet the need at the end of the interval before reinjection in the case of acromegaly, or to increase the level and better control the release profile in the case of neuroendocrine tumors. Clearly, there is an unmet medical need and it is desirable to provide a solution by proposing a new composition, the administration of which can be based on a simple or even standard syringe type device equipped with a manually actuated piston.

[0016] Since the development of the sustained-release compositions of lanreotide currently on the market began, the compositions selected to meet the need for higher doses of lanreotide have included injections closer together or increasing the number of injections at the same time, but without satisfactorily solving the problems associated with these injections.

[0017] In fact, the use of a lanreotide composition of lower viscosity in combination with a manual device of the standard syringe type having a thinner needle has never been envisaged, since those skilled in the art have an unfavourable prejudice against such a composition.

[0018] Indeed, the person skilled in the art of pharmaceutical compositions knows that a reduction in the lanreotide concentration, even by a few percentages, will have the effect of reducing the viscosity, and thus the lanreotide composition in contact with the body fluids at the injection site will solubilize more quickly.

[0019] In view of the teachings of the prior art, in particular the teachings of application WO9607398, it could be expected that the delayed effect caused by the gelling of concentrated products would no longer occur, resulting in a rapid release of the product.

[0020] Furthermore, application WO9607398 also suggests using a needle with an inner diameter of at least 1.00 mm to inject lanreotide so that the deposit of the product maintains a release profile for at least 15 days.

[0021] Thus, it is a feature of the present invention that a lanreotide composition at a lower concentration than described in that application is administered using a needle smaller than 1.00 mm, and this runs counter to the teaching of the prior art in two fundamental respects.

[0022] Quite unexpectedly, the authors of the present invention have conducted studies and demonstrated the fact that when a lanreotide composition with a lower viscosity is injected using a needle thinner than the needle used for the commercially available composition, the composition can result in a deposit different from the aforementioned gel, but the deposit is also able to provide controlled release of lanreotide. This discovery makes it possible to produce lanreotide compositions that reduce or eliminate the disadvantages associated with the specific production and complicated use of the currently commercially available compositions.

[0023] Therefore, the improvements and simplifications of injections of the present invention can allow / realize the pre-filled preparations of the sustained-release (or extended-release) and / or controlled-release (or controlled-release) compositions of lanreotide in conventional reservoirs of standard injection devices such as syringes or conventional glass or polymer (e.g., cycloolefin polymers or COC cycloolefin copolymers) cartridges. These improvements allow the use of reservoirs of conventional sizes and diameters of these pre-filled preparations that are incompatible with the needs of extended and / or controlled injections and current compositions, while commercially available formulations of current compositions require specific techniques for filling small-diameter reservoirs combined with large-diameter needles, or require specific injection devices that can perform sustained-release or controlled-release deposit injections. Summary of the invention

[0024] The present invention therefore consists in providing novel injectable compositions based on lanreotide or one of its derivatives, such as a salt thereof, which allow:

[0025] - Reduce injection problems, such as difficulty in implanting a needle with an inner diameter of at least 1.00 mm,

[0026] - Reduce unwanted effects at the injection site, such as the appearance of nodules,

[0027] - Extending the therapeutic range by providing, for example, intramuscular, intradermal, intraocular or superficial subcutaneous administration.

[0028] More particularly, the present invention relates to a novel injectable presentation of a pharmaceutical composition comprising:

[0029] a) an aqueous solvent consisting of water and optionally a water-miscible organic solvent, preferably an alcohol, even more preferably ethanol,

[0030] b) lanreotide or one of its salts, in a concentration of 11-25%, preferably 18-25%, more preferably 18-22%, even more preferably 18-21% by weight of lanreotide relative to the total weight of the composition,

[0031] c) optionally, one or more amino acids, preferably arginine,

[0032] d) optionally, pharmacopoeially accepted monomeric excipients,

[0033] These new compositions are packaged in syringes having a diameter greater than 3.00 mm, preferably a diameter greater than or equal to 3.50 mm, more preferably a diameter greater than 4.00 mm and not greater than 7.00 mm, the syringe being equipped with a needle having an outer diameter equal to or less than 1.00 mm, an inner diameter equal to or less than 0.80 mm and a length preferably between 10 and 40 mm, preferably a needle length of 20 to 30 mm.

[0034] Especially when using HyPak TM or HyLok TM Type of syringe or made of COP When using a plastic syringe of the type, the inner diameter of the syringe is more preferably greater than 4.00 mm and not greater than 7.00 mm.

[0035] According to another aspect, the invention therefore relates to a prefilled syringe, characterized in that:

[0036] a. The diameter of the prefilled syringe is greater than 3.00 mm, preferably greater than or equal to 3.50 mm, more preferably greater than 4.00 mm and not greater than 7.00 mm, and the prefilled syringe is equipped with a needle, the outer diameter of the needle is equal to or less than 1.00 mm, the inner diameter is equal to or less than 0.80 mm and the length is preferably between 10 and 40 mm, preferably the length of the needle is 20 to 30 mm,

[0037] b. The pre-filled syringe comprises a pharmaceutical composition comprising:

[0038] 1) an aqueous solvent consisting of water and optionally a water-miscible organic solvent, preferably an alcohol, even more preferably ethanol,

[0039] 2) lanreotide or one of its salts, preferably lanreotide acetate, in a concentration of 11-25%, preferably 18-25%, more preferably 18-22%, even more preferably 18-21% by weight of lanreotide relative to the total weight of the composition,

[0040] 3) optionally, one or more amino acids, preferably arginine,

[0041] 4) Optionally, pharmacopoeially accepted monomeric excipients.

[0042] According to another aspect, the invention relates to an assembly consisting of a syringe prefilled with a pharmaceutical composition, characterized in that:

[0043] a) the diameter of the prefilled syringe is greater than 3.00 mm, preferably 3.50 mm, more preferably greater than 4.00 mm and not greater than 7.00 mm, and the prefilled syringe is equipped with a needle, the outer diameter of the needle is equal to or less than 1.00 mm, the inner diameter is equal to or less than 0.80 mm and the length is preferably 10-40 mm, preferably the length of the needle is 20-30 mm,

[0044] b) The pharmaceutical composition comprises or consists of:

[0045] 1) an aqueous solvent consisting of water and optionally a water-miscible organic solvent, preferably an alcohol, even more preferably ethanol,

[0046] 2) lanreotide or one of its salts, preferably lanreotide acetate, at a concentration of 11-25%, preferably 18-25%, more preferably 18-22%, more preferably 18-21% by weight of lanreotide relative to the total weight of the composition,

[0047] 3) optionally, one or more amino acids, preferably arginine,

[0048] 4) optionally, pharmacopoeially accepted monomeric excipients,

[0049] The pharmaceutical composition is included in the syringe.

[0050] According to a preferred embodiment of the present invention, the monomeric excipient is at least one compound selected from lactose, dextrose, sucrose, mannitol, sorbitol, glucose, fructose, mannose, galactose, arabinose, fucose, citric acid or a salt or ester thereof, lactic acid or a salt or ester thereof, acetic acid or a salt or ester thereof, and a mixture thereof, and the pharmaceutical composition according to the present invention does not contain a polymeric excipient, and the polymer is, for example, (d, l) polylactic acid (PLA), a copolymer of lactic acid and glycolic acid (PLGA), polyphenylene propylene, a copolymer of ethylene and vinyl acetate; fatty acid / sebacic acid copolymer, poly(erucic acid dimer-sebacic acid) copolymer, poly(fumaric acid-sebacic acid) copolymer, chitin, collagen, gelatin, monomethyl polyethylene glycol / polylactic acid, monomethyl polyethylene glycol / polylactic acid copolymer, polyethylene glycol / polylactic acid or polyethylene glycol / polylactic acid copolymer.

[0051] According to a preferred embodiment, the present invention relates to a manual syringe with a piston rod, the syringe is equipped with a standard needle of Luer lock type, the standard needle has an outer diameter of 0.80-1.00 mm, an inner diameter of 0.60-0.80 mm and a length of about 20 mm, and is pre-filled with a sustained-release pharmaceutical composition for parenteral administration, the composition comprising an aqueous solvent consisting of water and optionally 3% ethanol, a sufficient amount of lanreotide acetate so that the lanreotide concentration is preferably about 18-25% by weight of the total weight of the composition, more preferably 18-22%, even more preferably 18-21%, and optionally arginine at a concentration of 0.1-13% by weight of the total weight of the composition.

[0052] More specifically, the present invention relates to a manual syringe with a piston rod, the syringe being equipped with a standard Luer lock needle having an outer diameter of about 0.80 mm, an inner diameter of about 0.60 mm and a length of about 20 mm, prefilled with a sustained-release pharmaceutical composition or suspension for parenteral administration, the composition comprising water and a sufficient amount of lanreotide acetate, the concentration of lanreotide being about 20% by weight relative to water.

[0053] According to one embodiment of the invention, the kit comprises a pharmaceutical composition as described above and a syringe, the needle of the syringe having an outer diameter equal to or less than 1.00 mm, an inner diameter equal to or less than 0.08 mm and a length preferably of 10 to 40 mm. The injection is performed by manually actuating the plunger rod along the syringe.

[0054] According to a preferred embodiment, the present invention also relates to a prefilled syringe comprising a pharmaceutical composition as defined above, for sustained release of the active compound for at least 1 month.

[0055] According to another embodiment of the present invention, the syringe is a standard manual syringe of the Luer lock type with a standard piston rod, which is equipped with a needle that can be a standard needle with an outer diameter of 0.90 to 1.00 mm, an inner diameter of 0.70 to 0.80 mm and a length of 20 to 30 mm.

[0056] According to another preferred embodiment of the present invention, a Luer lock standard manual syringe comprises a standard piston rod, the syringe is equipped with a standard needle, the needle has an outer diameter of 0.90 mm, an inner diameter of 0.70 mm, and a length of 20 mm, and is pre-filled with a sustained-release pharmaceutical composition for parenteral administration, the composition comprising an aqueous solvent consisting of water and ethanol, the aqueous solvent being 3% by weight relative to the total weight of the composition, comprising lanreotide at a concentration of preferably 18-25%, more preferably 18-22%, and more preferably 18-21% by weight relative to the total weight of the composition, and 0.1-13% by weight of arginine relative to the total weight of the composition.

[0057] According to another preferred embodiment of the present invention, the manual syringe comprises a plunger rod having a standard Luer lock needle having an outer diameter of about 0.80 mm, an inner diameter of about 0.60 mm and a length of about 20 mm, the syringe being prefilled with a sustained-release pharmaceutical composition for parenteral administration, the composition comprising water and lanreotide acetate, the concentration of lanreotide acetate being 20% ​​by weight of lanreotide relative to the total weight of the composition.

[0058] According to a preferred embodiment, the composition of the present invention is parenterally administered to a patient by normal or deep subcutaneous injection or intramuscular injection.

[0059] According to a preferred embodiment, the composition of the present invention is administered parenterally to a patient by normal or deep subcutaneous injection or intramuscular injection using the syringe, and releases lanreotide or a salt of lanreotide over a period of at least 7 days, 7 to 14 days, 14 to 28 days, preferably at least 28 days.

[0060] According to a preferred embodiment, the composition of the present invention is in a form suitable for parenteral administration of the composition to a patient by normal or deep subcutaneous injection or intramuscular injection using the syringe to release lanreotide or a salt of lanreotide over a period of at least 7 days, 7 to 14 days, 14 to 28 days, preferably at least 28 days.

[0061] According to a preferred embodiment, lanreotide is in the form of a salt or a free base. The salt of lanreotide that can be used in the present invention is preferably a pharmaceutically acceptable salt of an organic acid, such as acetic acid, phenylacetic acid, lactic acid, malic acid, pamoic acid, ascorbic acid, succinic acid, benzoic acid, methanesulfonic acid or toluenesulfonic acid, or a pharmaceutically acceptable salt of an inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid.

[0062] According to a preferred embodiment, lanreotide is in the form of lanreotide acetate.

[0063] According to another preferred embodiment, lanreotide is in the form of a free base.

[0064] Whatever the form of lanreotide, ie whether it is in salt or free base form, within the meaning of the present invention, the amount of lanreotide, eg expressed as a concentration or percentage in the composition, refers to lanreotide in free base form.

[0065] Advantageously, lanreotide is present in a concentration of 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5% or 25% by weight relative to the total weight of the composition.

[0066] If a composition that forms an easily manageable solid extrudate after injection is defined as an injectable semisolid, then the pharmaceutical composition of the present invention itself or the pharmaceutical composition present in a prefilled syringe is a viscous composition, not a semisolid. The composition can be injected using a standard injection device, such as a syringe with a manually operated plunger rod and equipped with a conventional needle. The preferred dimensions of the syringe and needle are as shown above.

[0067] When evaluating the administration step, the viscosity and other physical state characteristics of the composition can be evaluated as injectability. Injectability can be determined by performing simulated injection tests and by different physical methods. Injectability can be reported as injection strength or syringe injection strength (SIF).

[0068] The term "syringability" refers to the suitability of a composition for parenteral administration using an injection device such as a syringe or injector, which can be determined by measuring the injection force.

[0069] SIF can be measured using a dynamometer (L1000R, Lloyd Instruments Ltd) equipped with a calibration unit (NLC100N, Lloyd Instruments Ltd). The pharmaceutical composition of the present invention can be packaged in a syringe having a diameter greater than 3.00 mm, preferably a diameter greater than or equal to 3.50 mm, more preferably a diameter greater than 4.00 mm and not greater than 7.00 mm, the syringe being connected to a 20 mm long needle having an internal diameter of 0.60-1.00 mm comparable to existing needles, and tested for suitability for low-speed injection at 100 mm / min during simulated discharge, wherein the force and displacement thereof applied to the piston by the instrument are recorded. The simulated injection is performed vertically in air. The maximum injection force expressed in Newton (N) is derived from the data collected during discharge. These examples of injection force are described in detail in Example 9.

[0070] It is known to those skilled in the art that even with finer Type syringes, which cannot be injected manually using this thinner needle This is even more impossible with standard syringes with larger inner diameters.

[0071] According to a preferred embodiment, when tested by the above method, the pharmaceutical composition of the present invention itself or in a prefilled syringe has a syringeability within the range of 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14N as defined by SIF.

[0072] According to a preferred embodiment, when a composition comprising preferably 18-25%, more preferably 18-22%, even more preferably 18-21% lanreotide is tested using the above method and a needle with an inner diameter of 1.00 mm, the pharmaceutical composition of the present invention itself or the pharmaceutical composition present in a prefilled syringe exhibits a syringeability of 5 to 12N or 5 to 14N as defined by SIF.

[0073] Preferably, the SIF of the pharmaceutical composition according to the invention per se or present in a prefilled syringe is in the range of 5 to 6N.

[0074] According to another preferred embodiment, when a composition containing preferably 18-25%, more preferably 18-22%, even more preferably 18-21% lanreotide is tested using the above method and a needle with an inner diameter of 0.80 mm, the pharmaceutical composition of the present invention itself or the pharmaceutical composition present in a prefilled syringe has a syringeability of 7-12N or 5-14N as defined by SIF, which is always less than the SIF of a commercially available product containing 25% lanreotide.

[0075] Preferably, the SIF of the pharmaceutical composition according to the invention per se or present in a prefilled syringe is in the range of 7-9N.

[0076] According to a preferred embodiment, when testing a composition comprising preferably 18-25%, more preferably 18-22%, even more preferably 18-21% lanreotide using the above method and a needle with an inner diameter of 0.6 mm, the pharmaceutical composition of the present invention itself or the pharmaceutical composition present in the prefilled syringe has a syringeability of 9-14N as defined by SIF.

[0077] Preferably, the SIF of the pharmaceutical composition according to the invention per se or in a prefilled syringe is in the range of 9-12N.

[0078] In contrast, the commercially available composition of 25% lanreotide cannot be manually extruded from a device comprising a syringe with a diameter greater than 3.50 mm. To inject this composition, a syringe with a diameter of 3.50 mm must be used, connected to a needle 20 mm long and 1.00 mm internal diameter, and a force greater than 14 N must be applied, and the injection is very slow.

[0079] In all cases, the injection force in Newtons measured under the same conditions with an apparatus different from the commercially available apparatus was, for example, from 14.3 N (for a representative commercially available type) to 5.5N (for a composition of 19% lanreotide in water).

[0080] Knowing that there is a residual force of the order of 2N during vacuum injection related to the friction of the device, this is a reduction of more than 70% of the force required to inject these two similar compositions, demonstrating a useful threshold of exploitable properties according to the invention. Surprisingly, a relatively small reduction in concentration results in a very significant reduction in injection force.

[0081] The reduction in needle diameter results in a reduction in implantation force, which makes the decisive difference between a needle that is easily implanted (including by the patient himself) and a complex implantation procedure that requires expert experience, skill and practice.

[0082] The implantation force of a needle is proportional to the caliber or gauge of the needle. A significantly smaller difference in diameter, for example between 1.00 mm and 1.20 mm, corresponds to a 1.5 times larger impact surface or cross section.

[0083] The importance of minimizing the diameter of the injection needle to avoid pain and facilitate injection is illustrated in the article “Fracture mechanics model of needle cutting tissue” (2015) by Barnett et al., where the authors demonstrated that there is a threshold force for the needle to penetrate or insert into the skin:

[0084] - For needles with outer diameters ranging from 1.60 mm (16G) to 1.20 mm (18G), the forces are comparable and vary between 2.5 N and 3 N, which may be considered high by a person skilled in the art;

[0085] - For needles with outer diameters ranging from 0.80 mm (21G) to 0.50 mm (25G), the force decreases by a factor of two and varies between 1 N and 1.5 N.

[0086] In fact, these apparently small diameter differences correspond to a pressure drop and therefore to an increase in the injection force, which for the same product may make manual administration impossible.

[0087] Currently available formulations include Another limitation of the needles used is also related to the need to use thin-walled cannulas, for example 0.10 mm, in order not to increase the outer diameter. This reduces the possibility of having a long bevel and being sharpened, and therefore increases the risk of deformation and nucleation during implantation. All this may require unusual and complex techniques, such as pulling on the skin before implanting the needle. All these effects may complicate the insertion of the needle into the tissue and cause greater pain. Therefore, one advantage of the present invention is the ability to also revert to cannulas with thicker walls, for example, with a wall thickness ranging from 0.10 to 0.20 mm, preferably 0.15 mm.

[0088] In fact, the bevel of the needle determines how the incision is made and how the cannula penetration is achieved to inject the product. For needles with an outer diameter greater than 1.00 mm, it is preferred to have thick walls to have greater freedom in the design of its bevel: in fact, due to thin walls, it is difficult to freely shape the tip of the needle, which may complicate the incision and therefore be painful for the patient.

[0089] By using standard needles (outer diameter 1.00 mm and less) according to the present invention, the angle of the bevel can be varied to increase user comfort with needles having an outer diameter less than that of needles of currently available commercial compositions.

[0090] Finally, needles with an outer diameter of 1.00 mm and less imply less penetration force and therefore can have a bevel made on a wall thickness of only 0.10 mm, thereby reducing their outer diameter compared to the inner diameter.

[0091] In contrast, needles with an outer diameter of 1.20 mm and greater imply greater penetration and need to be made with a bevel thickness of 0.15 mm, further increasing their outer diameter compared to the inner diameter.

[0092] 1 mL BD Hypak in a Luer lock stopper TM Long syringe, or Before placing a plunger rod of, for example, butyl rubber in a 0.5 mL plastic syringe of COP of the Gerresheimer type, a composition of up to 21% or 22% or even 25% of lanreotide can be routinely loaded. The injection can be performed by fixing a 25 mm or 16 mm standard 21G needle to the Luer lock end to obtain the same curve under different injection conditions and depths, which is also due to the deposition conditions.

[0093] According to another subject of the invention, the pharmaceutical composition itself or in a prefilled syringe further comprises an alcohol, preferably ethanol. A person skilled in the art would recognize that adding organic solvents even in low concentrations of about 5-10% by weight to water would lead to stability problems.

[0094] The inventors have found that, in the dosage form of the invention, mixtures of this type can be used in which the concentration of ethanol in water is at least 5% and at most 25%, which makes it possible to obtain stable and homogeneous lanreotide compositions.

[0095] As low percentages of alcohol do not cause pain on injection or local tolerance problems, the inventors surprisingly found that these compositions are more viscous than those obtained with water alone at the same lanreotide concentration, which may explain the stability of the active substance under these conditions.

[0096] On the other hand, the pharmaceutical composition according to the invention comprising 3 to 23% and preferably 3 to 10% ethanol, either by itself or in a prefilled syringe, makes it possible to use and more easily validate methods for ready-to-use sterile preparations without the need for gamma irradiation in terminal sterilization. They also make it possible to envisage solid preparations of lanreotide that are stable at room temperature and to prepare the product to be injected simply and quickly extemporaneously.

[0097] According to another preferred embodiment, the pharmaceutical composition of the invention per se or present in a prefilled syringe comprises ethanol in a concentration of 3-23% by weight relative to the total weight of the composition, preferably in a concentration of 3-10% by weight relative to the total weight of the composition.

[0098] According to another preferred embodiment, when tested by the above method, the pharmaceutical composition according to the present invention itself or the pharmaceutical composition present in the prefilled syringe comprises 20% by weight of lanreotide, 5-25% by weight of ethanol aqueous solution, and has a syringeability within the range of 7-9N defined by SIF.

[0099] Preferably, the SIF of the pharmaceutical composition is 7 to 8N.

[0100] For example, injection strength tests performed with pharmaceutical compositions comprising 20% ​​by weight lanreotide and 5% or 10% ethanol in water showed forces of 8.3 N and 7.3 N, respectively.

[0101] These forces are almost 50% lower than the forces of a representative mixture of 25% commercial products. If we consider that under the test conditions, a hand injection force of about 15 N represents an acceptable maximum, the reduction in force that is substantially away from this maximum value proposed by the formulation according to the invention constitutes a significant improvement.

[0102] Using these new compositions based on water-ethanol mixtures, it is also possible to prepare higher concentrations of lanreotide, for example close to 25%, comparable to the commercial products, and using a larger proportion of ethanol, but still a small amount that can be injected without problems, for example less than or equal to 25% in water. Thus, a composition with much greater fluidity than existing products is obtained (see Example 9). According to the injection force test, such a composition can be injected, for example, with a needle with an inner diameter of 0.80 mm with a force of 7.3 N, i.e. 70% less than the injection force of a representative mixture of the commercial product of 25% lanreotide.

[0103] Therefore, a subject of the present invention is also a pharmaceutical composition as such or present in a prefilled syringe comprising lanreotide in a concentration ranging from about 18% to 25% by weight and ethanol in a concentration ranging from 3 to 23%, these percentages being expressed relative to the total weight of the composition.

[0104] The results obtained from animals and the results presented in the examples show that the aqueous-ethanolic composition of the invention makes it possible to envisage a new release profile of lanreotide compared to the commercially available form, thus also making it possible, for example, to reduce the burst release or Cmax (peak concentration) by 1.5-2 times compared to the commercially available product, which also makes it possible to multiply the circulating levels of lanreotide by at least 2 times 2-4 weeks after injection.

[0105] (See Figure 2-4 )

[0106] Preferably, the composition, kit or prefilled syringe according to the invention not comprising ethanol comprises 18% to 25%, more preferably 18% to 22%, even more preferably 18% to 21% by weight of lanreotide relative to the total weight of the composition, while the composition, kit or prefilled syringe comprising ethanol comprises 18% to 25% by weight of lanreotide relative to the total weight of the composition.

[0107] According to another embodiment, the composition of the invention comprises at least one amino acid, preferably arginine, present in a concentration ranging from 0.1 to 13% by weight relative to the total weight of the composition.

[0108] We have also demonstrated that, depending on the ratio of lanreotide to at least one amino acid and the mixing conditions (type of medium, temperature and time), it is possible to obtain The release profile of current products is better than the controlled release profile of lanreotide, and the duration of action is from one week to several months.

[0109] This method of adding amino acids can generate various new compositions. For example, arginine can be added to a composition comprising lanreotide at different concentrations, for example at a concentration equal to or less than 21%, 22%, or 25% in water.

[0110] The weight of arginine may vary between 0.1% and 13% relative to the total weight of the composition.

[0111] According to another preferred embodiment, the pharmaceutical composition of the present invention itself or in a prefilled syringe is intended to release lanreotide for at least 1 month and comprises or essentially consists of the following substances:

[0112] - 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5% or 25% by weight of lanreotide;

[0113] - 0 to 23% by weight, preferably 3 to 10% by weight, of ethanol;

[0114] - 0 to 13% by weight, preferably 1 to 13% by weight, even more preferably from 2 to 13% by weight of arginine.

[0115] It is also possible, starting from the same composition, to adjust the release profile as desired by choosing the subcutaneous (SC) or intramuscular (IM) route of administration. All these advantageous and novel features also constitute further subjects of the present invention.

[0116] All these forms of dilution associated with thinner needles do not produce a deposit of controlled volume for in situ gelation, but instead lead to a greater diffusion or distribution at the injection point, or even to a flatter shaped deposit, following in situ precipitation of lanreotide.

[0117] It would have been expected that under these conditions a rapid or uncontrolled release would be obtained, for example by solubilization of lanreotide, but unexpectedly this increase in exchange surface resulted in the formation of a precipitate of smaller volume, which controlled release differently and which solved the various problems described above with respect to more conventional injections in a useful and reproducible manner.

[0118] The pharmaceutical composition of the present invention, either per se or in a pre-filled syringe, is administered parenterally.

[0119] According to a preferred embodiment, the pharmaceutical composition of the invention, as such or in a prefilled syringe, is administered by subcutaneous, intramuscular or deep subcutaneous injection, more preferably by subcutaneous injection or by intramuscular injection.

[0120] As a new composition, the inventors have found that, among other things, a more diluted composition injected subcutaneously at a lanreotide concentration of 21% or 22% or even up to 25%, injected once every 2 weeks or every 4 weeks can obtain flatter levels and higher final levels or Cmin than the current form. This type of distribution is useful, for example, in acromegaly and may also solve the problem of low efficiency at the end of the interval between each injection. The same form of intramuscular injection will make it possible to obtain higher levels and Cmin than the existing forms, with a curve that can be adapted to the needs of each patient according to the time between two injections in each case, even for those that require less than 2 weeks to meet the needs of higher doses, such as are useful in NETs (neuroendocrine tumors). These new dosage forms are also very advantageous for local regional applications of lanreotide, for example in ophthalmology, diabetes or dermatology.

[0121] All these new dosage forms are easier to inject than existing products and are necessarily less painful than existing products, both by being injected with thinner needles and by making the deposits less compact or less resistant and therefore flatter. They are therefore even compatible with closer injections. As mentioned above, we know that the injection force can be lower than on the market by a factor of, for example, more than three, which facilitates or even allows the patient himself or his companion to administer the drug using a standard syringe-type manual device.

[0122] The pharmaceutical composition of the present invention, either per se or in a pre-filled syringe, is administered parenterally.

[0123] According to a preferred embodiment, the pharmaceutical composition of the present invention itself or the pharmaceutical composition present in the prefilled syringe is administered by subcutaneous, intramuscular or deep subcutaneous injection, more preferably by subcutaneous injection or intramuscular injection. For the subcutaneous route, which is still preferred, the injection volume of the lanreotide composition is preferably not more than 2 or 1.9 or 1.8 or 1.7 or 1.6 or 1.5 or 1.4 or 1.3 or 1.2 or 1.1 or 1 mL, and the concentration range of lanreotide is 18 to 25%, more preferably 18 to 22%, even more preferably 18 to 21% by weight of lanreotide relative to the total weight of the composition.

[0124] According to a preferred embodiment, the sustained release of lanreotide in the human body is at least 2 months.

[0125] According to a preferred embodiment, the sustained release of lanreotide in the human body is at least 3 months.

[0126] The pharmaceutical composition according to the invention, by itself or in a prefilled syringe, allows sustained release for at least 7 days, from 7 to 14 days, from 14 to 28 days, 2 months or 60 days or more than 2 months or 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90 days.

[0127] According to a preferred embodiment, the pharmaceutical composition according to the invention, either as such or present in a prefilled syringe, allows a sustained release for at least 60 days.

[0128] According to another preferred embodiment, the pharmaceutical composition according to the invention, either as such or present in a prefilled syringe, allows a sustained release for at least 7 days.

[0129] According to another preferred embodiment, the pharmaceutical composition according to the invention, either as such or present in a prefilled syringe, allows a sustained release for at least 90 days.

[0130] According to a more preferred embodiment, the pharmaceutical composition according to the invention, either as such or present in a prefilled syringe, allows a sustained release for at least 14 days.

[0131] According to another more preferred embodiment, the pharmaceutical composition according to the invention, either per se or present in a prefilled syringe, allows a sustained release for at least 28 days.

[0132] As mentioned above, lanreotide is a marketed somatostatin (or somatostatin) analogue that is indicated for the treatment of acromegaly caused by pituitary and non-pituitary growth hormone-secreting tumors, for symptomatic and antiproliferative treatment of neuroendocrine tumors, particularly carcinoid tumors and vipoma, and for the treatment of thyroid adenoma.

[0133] Thus, the pharmaceutical composition of the invention, either as such or in a prefilled syringe, can be used for the treatment of acromegaly caused by growth hormone-secreting pituitary and non-pituitary tumors, for the treatment of symptoms caused by neuroendocrine tumors and their control, in particular carcinoids and vipoma, or for the treatment of thyroid adenoma.

[0134] According to a preferred embodiment, the pharmaceutical composition of the invention, per se or in a prefilled syringe, is used for the treatment of acromegaly or neuroendocrine tumors, such as functional and non-functional gastroenteropancreatic neuroendocrine tumors.

[0135] According to the present invention, a patient suffering from acromegaly or a neuroendocrine tumor can be treated by administering a therapeutically effective amount of a pharmaceutical composition as described in any of the following embodiments.

[0136] According to one embodiment, the pharmaceutical composition of the present invention itself or in a prefilled syringe is administered or injected, or prepared for administration or injection into a patient in need thereof, with a frequency not exceeding every 2 weeks or preferably every 4 or 8 or 12 or 16 weeks. Preferably, it is administered or injected every 4 weeks.

[0137] According to another preferred embodiment, the pharmaceutical composition of the invention per se or in a prefilled syringe is administered or prepared for administration as a single injection.

[0138] Preferably, the method comprises administering at least once every 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, or 16 weeks a pharmaceutical composition according to the invention, per se, or in a pre-filled syringe. More preferably, the method comprises administering at least once every 12 weeks a pharmaceutical composition according to the invention, per se, or in a pre-filled syringe.

[0139] According to another embodiment, the pharmaceutical composition according to the invention itself or in a prefilled syringe is administered by a single injection.Preferably, the pharmaceutical composition according to the invention itself or in a prefilled syringe is injected intramuscularly, subcutaneously or deep subcutaneously.

[0140] According to another embodiment, the pharmaceutical composition of the invention is administered as such or in a prefilled syringe at a dose of 60, 90, 120 or 240 or 360 mg of lanreotide. Preferably, the pharmaceutical composition of the invention is administered as such or in a prefilled syringe at a dose of 120, 240 or 360 mg of lanreotide. The advantage of the present invention is that it allows for easier injection with a thinner needle, as well as a more unobtrusive and therefore more comfortable in situ deposition, making it possible to prepare larger doses of these single injections, such as twice the dose of the commercially available product or higher doses, which corresponds to the needs of treating, for example, neuroendocrine tumors.

[0141] According to the mode of the invention, patients suffering from neuroendocrine tumors can be treated by administering a therapeutically effective amount of the pharmaceutical composition described in any of the above embodiments. Preferably, the pharmaceutical composition of the invention itself or in a prefilled syringe is administered for antiproliferative control of neuroendocrine tumors, or to avoid symptoms caused by these neuroendocrine tumors.

[0142] According to one embodiment, the symptoms are selected from the group consisting of flushing, diarrhea and abdominal cramps.

[0143] According to the present invention, a patient suffering from thyroid adenoma can be treated by administering a therapeutically effective amount of the pharmaceutical composition described in any one of the above embodiments.

[0144] According to another embodiment, the present invention allows for the formation of smaller deposits and more precise dosages because they are less concentrated and administered with thinner needles, thus making it possible to prepare smaller and less viscous doses, such as 20 mg or less or 0.1 mL or less for ophthalmic applications of lanreotide, such as for patients with glaucoma, macular edema, inflammation, diabetic retinopathy or age-related macular degeneration. These features are also suitable for product applications in dermatology, such as for the treatment of keloids.

[0145] The advantage of the syringe and the formulation according to the invention is also that these injections can be carried out very quickly with a short stroke of the piston for these small volumes.

[0146] These less viscous formulations with lower lanreotide loading according to the form of the invention also allow for more efficient preparation of combination compositions in which one or more other active ingredients are added to lanreotide, which also allow for controlled release of their combination for the same treatment, for example in ophthalmology, glucocorticoids such as dexamethasone or monoclonal antibodies or mixtures of two or more of these active compounds.

[0147] The pharmaceutical composition as described above is prepared by a method comprising the following steps:

[0148] Preparation of an aqueous solvent including water and optionally ethanol and / or an amino acid such as arginine in a syringe

[0149] · introducing lanreotide into a suitable container, such as a second syringe or a syringe-shaped container,

[0150] • Two syringes or syringe-type containers are connected with a 2-way connector, lanreotide is hydrated with an aqueous solvent, and the composition is homogenized by means of a mixing process at a temperature of 5-70° C., preferably at room temperature.

[0151] Furthermore, the entire preparation process can be controlled with equipment known to those skilled in the art with respect to key processing parameters such as temperature, pressure, cycle number and syringe-valve diameter ratio.

[0152] According to another embodiment of the present invention, the active ingredient can be pre-selected to be treated alone or with arginine in an aqueous medium in a certain ratio, and the treatment time varies according to the requirements of controlled release. Lanreotide can be freeze-dried, dried, ground, granulated, compacted, sieved, etc. before preparing the pharmaceutical composition of the present invention itself or the pharmaceutical composition present in the prefilled syringe.

[0153] Any sterilization technique used as part of the process, such as gamma irradiation, electron beam irradiation, steam or sterile filtration may be used to obtain a sterile pharmaceutical composition.

[0154] According to another embodiment of the invention, the preparation of the pharmaceutical composition according to the invention, either per se or present in a prefilled syringe, is carried out under sterile conditions.

[0155] The pharmaceutical composition of the present invention can be obtained as a prefilled and ready-to-use dosage form. It can also be obtained as a ready-to-use reconstituted dosage form, in which the lyophilized product including the active ingredient can be reconstituted extemporaneously with an aqueous solvent and other additives as required as a reconstitution solvent.

[0156] As another embodiment, the pharmaceutical composition may be packaged in a pre-filled syringe.

[0157] The present invention also relates to a kit comprising a sustained-release and / or controlled-release (controlled-release) pharmaceutical composition for parenteral administration, the composition comprising:

[0158] a) an aqueous solvent consisting of water and optionally a water-miscible organic solvent, preferably an alcohol, even more preferably ethanol,

[0159] b) lanreotide or a salt of lanreotide, preferably lanreotide acetate, in a concentration of 11-25%, preferably 18-25%, more preferably 18-22%, even more preferably 18-21% by weight of lanreotide relative to the total weight of the composition,

[0160] c) optionally, one or more amino acids, preferably arginine,

[0161] d) optionally a pharmaceutically acceptable monomeric excipient, and a syringe, the needle of which has an outer diameter equal to or less than 1.00 mm, an inner diameter equal to or less than 0.80 mm and a length preferably of 10-40 mm.

[0162] Under the novel conditions of the present invention, a deposit is obtained by precipitation of lanreotide after interaction with the patient's body tissues and fluids at the injection site. This smaller and flatter type of deposit is better tolerated.

[0163] Unexpectedly, lanreotide used in a more diluted form than the semi-solid or pasty form of the current commercially available composition can be combined with a dosage form of an injection device having a needle thinner than the existing needles with an outer diameter of at least 1.20 mm. Injection with this new dosage form results in a different deposit, which produces a controlled form with new and advantageous properties, which can be used for all therapeutic needs of the product and can solve the limitations or problems caused by the current controlled forms.

[0164] According to another preferred embodiment, the present invention relates to a pharmaceutical composition comprising:

[0165] a) an aqueous solvent consisting of water and optionally a water-miscible organic solvent, preferably an alcohol, even more preferably ethanol,

[0166] b) lanreotide or a salt of lanreotide, preferably lanreotide acetate, in a concentration of 11-25%, preferably 18-25%, more preferably 18-22%, even more preferably 18-21% by weight of lanreotide relative to the total weight of the composition,

[0167] c) optionally, one or more amino acids, preferably arginine,

[0168] d) optionally a pharmaceutically acceptable monomeric excipient, the composition being characterized in that, when it is administered to a patient by normal or deep subcutaneous injection or intramuscular injection using a syringe, it releases lanreotide or a lanreotide salt over a period of at least 7 days, preferably at least 28 days, the syringe having an inner diameter of about 3.50 mm, more preferably a diameter greater than 4.00 mm and not greater than 7.00 mm, and equipped with a needle having an outer diameter equal to or less than 1.00 mm, an inner diameter equal to or less than 0.80 mm, and a length preferably of 10 to 40 mm, preferably 20 to 30 mm.

[0169] Animal experiments were conducted to demonstrate that the deposits obtained, even though different, maintained the controlled-release or delayed effect of lanreotide.

[0170] Depending on the purpose, many different new products of lanreotide compositions and possible kits or pre-filled syringes according to the invention can be produced.

[0171] Without limiting, the following different types of possibilities may be mentioned by way of example:

[0172] - For a composition comprising 20% ​​lanreotide in water for subcutaneous administration in a 3.50 mm diameter syringe equipped with a needle of 0.80 mm outer diameter and 20 mm length, up to 120 mg, within 4 weeks with a The release profile of the currently marketed form is similar to the release profile of lanreotide.

[0173] - For a composition comprising 20% ​​lanreotide in water, at a dose of 240 mg or more, for subcutaneous administration in a syringe with an inner diameter of 3.50 mm equipped with a needle with an outer diameter of 1.00 mm and a length of 20 mm, the effect of the composition on the efficacy of the composition is less than that of the composition of the composition of the present invention within 4 weeks. The current form has a higher lanreotide release profile.

[0174] - For a composition comprising 20% ​​lanreotide in water for intramuscular administration in a dose of up to 120 mg in a syringe of 3.50 mm diameter equipped with a needle of 0.80 mm outer diameter and 40 mm length, the effect of the drug on the intramuscular ... The current form has a higher lanreotide release profile.

[0175] - For a composition comprising 20% ​​lanreotide in water for subcutaneous administration in a 3.00 mm diameter syringe equipped with a needle of 0.60 mm outer diameter and 20 mm length, up to 100 mg, within 4 weeks with a The release profile of lanreotide is similar to that of the current form.

[0176] - For a composition comprising 20% ​​lanreotide in water in a dose of 20 mg or less in a syringe of 3.00 mm diameter equipped with a needle of 0.60 mm or less outer diameter, over a period of 4 weeks or more, such as The release profile of lanreotide is similar to that of the current form.

[0177] - For a composition comprising 20% ​​lanreotide in water for intramuscular administration in a dose of up to 100 mg in a 3.00 mm diameter syringe equipped with a needle of 0.70 mm outer diameter and 30 mm length, the effect of the above treatments on the efficacy of the composition is not significantly different from that of the above treatments in 2 weeks. The current form has a higher lanreotide release profile.

[0178] - For a 20% composition in water at a dose of up to more than 120 mg in a conventional pre-filled standard syringe attached to a 21 or 20G short subcutaneous or long intramuscular Luer lock needle, within 4 or 2 weeks with a The lanreotide release profile is similar to or higher than the current form.

[0179] - For compositions comprising 20% ​​lanreotide in a 5:95 alcohol / water mixture, prepared extemporaneously in a sterile manufactured standard syringe and stable at room temperature, for subcutaneous or intramuscular administration, at doses up to more than 120 mg, within 4 or 2 weeks with The lanreotide release profile is similar to or higher than the current form.

[0180] - For compositions comprising 25% lanreotide in a 25:75 alcohol / water mixture, prepared extemporaneously and stable at room temperature in a sterile manufactured standard syringe for subcutaneous or intramuscular administration at doses up to more than 120 mg, within 4 or 8 weeks compared to compositions such as The current form has a flatter lanreotide release profile.

[0181] - For a composition comprising 20% ​​lanreotide and 12% arginine in water at a dose of up to more than 120 mg in a conventional standard prefilled syringe attached to a short subcutaneous or long intramuscular Luer lock needle, the effect of the composition on the efficacy of the composition is comparable to that of the composition of the present invention within 2, 4, 8 or 12 weeks. The current form of lanreotide has a flatter release profile. BRIEF DESCRIPTION OF THE DRAWINGS

[0182] Figure 1 Comparative lanreotide acetate extrudates obtained after injection into air of compositions comprising 19% and 25% by weight of lanreotide in a 3.50 mm diameter syringe equipped with a 1.00 mm internal diameter needle are shown.

[0183] Figure 2 The changes in plasma concentration of lanreotide over time for two compositions A and B prepared according to Example 13 are shown.

[0184] Figure 3 The changes in plasma concentration of lanreotide over time for the composition prepared according to Example 14 are shown.

[0185] Figure 4 The changes in plasma concentration of lanreotide over time for the composition prepared according to Example 15 are shown.

[0186] Figure 5 The changes in plasma concentration of lanreotide over time for the composition prepared according to Example 17 are shown. DETAILED DESCRIPTION

[0187] The present invention may be described in more detail by illustrating in detail some examples of embodiments according to the present invention.

[0188] Example 1

[0189] Preparation of a composition in which 18-21% or 22% or even 25% of lanreotide is in the form of lanreotide acetate in two types of solvents: water and a 95:5% water / ethanol mixture

[0190] The preparation is carried out by a reciprocating technique between 2 syringe-type reservoirs, closed on one side by a piston and opened on the other side by a part connected to a valve, to allow conditioning of the lanreotide acetate powder, optionally under vacuum, hydration of the powder with a solvent and reciprocating mixing of the product by regulating the connected opening of the valve, optionally by measuring the force applied to control the type of mixture to be prepared.

[0191] By comparing the methods for preparing these mixtures with the methods for preparing 25% lanreotide compositions comparable to the commercial product, we see that it is easier and faster to prepare these 18-22% formulations and that less mixing force is required. This type of mixture can then also be extrapolated to much larger volumes or produced by techniques other than those particularly suitable for semi-solid or pasty mixtures.

[0192] Mixing is simplified in such a way that the syringes can also be filled as is done with liquid form according to protocols known to those skilled in the art, or the required dose is packaged in each syringe in powder or lyophilized form so that it can be hydrated first and then mixed manually at the time of use.

[0193] This other dosage form of lanreotide according to the invention makes it possible, for example, to envisage compositions with sustained and / or controlled release that are stable at room temperature, or even compositions of different concentrations from the same dose of lanreotide, in order to obtain profiles adapted to different therapeutic needs.

[0194] Example 2

[0195] Composition comprising 19.0% lanreotide in water

[0196] Batch prepared from 1.88 g lanreotide acetate and purified water.

[0197] The formulations were prepared using 2 plastic syringes connected to a connector that allowed mixing after hydration of the lanreotide acetate powder and water by the reciprocating technique described in Example 1. The obtained compositions were distributed in different injection systems to evaluate injection force and other parameters such as peptide content and chromatographic purity.

[0198] Embodiment 3:

[0199] Composition comprising 19.5% lanreotide in water and ethanol

[0200] Batch prepared from 0.36 g lanreotide acetate and a 95:5 mixture of purified water and ethanol. A 95:5 water-alcohol mixture was prepared by mixing 1.906 g purified water with 0.103 g 96% ethanol.

[0201] The preparation was carried out using 2 plastic syringes connected to a connector that allowed mixing after hydration of the lanreotide acetate powder with the water / ethanol mixture by the reciprocating technique described in Example 1. The obtained composition was distributed in different injection systems to evaluate the injection force and other parameters such as peptide content and chromatographic purity.

[0202] Example 4

[0203] Description of injection force measurement

[0204] The injection force measurements of the compositions prepared as described in Example 1 were performed using a dynamometer (L1000R, Lloyd Instruments Ltd) with a calibrated force capture unit (NLC100N, Lloyd Instruments Ltd), which was connected to a computer system for data acquisition and processing. For each measurement, the injection system (syringe + needle) comprising the composition was placed on a support in a vertical position (needle facing downward), and the plunger rod in the syringe was moved using a dynamometer to simulate injection. The measurements were performed at a constant displacement speed of 100 mm / min, recording the force detected by the unit as a function of piston displacement. The compositions discharged during each test can be recovered in a volumetric flask to complete physicochemical analysis, e.g., the peptide content of the samples described in Example 5.

[0205] Example 5

[0206] Description of the method for determination of peptide content and chromatographic purity

[0207] The compositions prepared as described in Examples 1, 2 and 3 were analyzed by liquid chromatography in RP-HPLC mode (standing for reversed phase high pressure liquid chromatography). To determine the chromatographic purity, the area of ​​the main peak corresponding to lanreotide was compared in % relative to the area of ​​all detected peaks. To determine the peptide content, the area of ​​the main peak corresponding to lanreotide was used to calculate the concentration of the injected composition, taking into account the response (area) obtained for the composition injected with the lanreotide reference standard. From the concentration of the injected composition, the mass of the analyzed sample and the dissolved volume, the peptide content (mass %) of the composition can be calculated.

[0208] RP-HPLC conditions and methods used by the inventors:

[0209] - Solvents for sample preparation: 0.1% acetic acid in HPLC grade water or a 85:15 mixture of acetic acid (0.1%) and acetonitrile in HPLC grade water.

[0210] -Column: C18 XBridge 150×4.6mm

[0211] - Column temperature: 35℃

[0212] -Mobile phase A: 0.1% trifluoroacetic acid (TFA) in HPLC grade water

[0213] - Mobile phase B: 0.1% trifluoroacetic acid (TFA) in a 80:20 mixture of acetonitrile / HPLC grade water

[0214] -Flow rate: 0.9mL / min

[0215] - Elution: Gradient of B in A (from 15% to 53.7% in 21.5 min, then 70% in 22.5 min, then 85.0% in 23.5 min)

[0216] -Injection volume: 10 to 100 μL

[0217] -Concentration of the composition: 80-800 μg / mL lanreotide

[0218] -Detection: UV at 280nm

[0219] Example 6

[0220] Packaging of the preparation in a commercially available insulin type fine syringe and in a conventional prefillable syringe or container

[0221] The inventors have realized that filling a syringe with a composition prepared as described in Example 1 is easier, quicker and less problematic than with a mixture corresponding to 25% of a commercial product. The difference is so great that a syringe-type reservoir can also be filled in the conventional manner like an injection liquid, and standard containers of larger diameter can be used, such as glass or plastic cartridges or commercially available prefillable syringes. For example, it is also possible to fill a syringe with a composition such as a HyPak TM 、HyLok TM Standard glass syringe or Pre-filled doses are prepared in plastic COP syringes.

[0222] Example 7

[0223] Description of the "19% composition" dispensed in a "thin" insulin-type syringe

[0224] The batch comprising 19% lanreotide in water prepared as described in Example 2 was filled into thin plastic syringes of the insulin type with an inner diameter of 3.50 mm. The syringe was filled from the front by connecting the thin syringe to the end of one of the large syringes used to prepare the composition. The charge of the composition moved the plunger rod of the thin syringe backwards during its introduction.

[0225] For the subsequently reported 30 mg lanreotide dose injected with a 1.00 (OD) x 0.80 (ID) x 20 mm (L) needle, 162 mg of the composition was loaded into each plastic syringe. The needle was then attached to the syringe and protected with a standard butyl rubber stopper.

[0226] Example 8

[0227] Description of the "19% composition" dispensed in a commercially available prefillable syringe

[0228] A 1.0 mL glass syringe was filled with a batch comprising 19% lanreotide in water prepared as in Example 2. The glass syringe was back filled as in industry, using a plastic cannula with an inner diameter of 3.50 mm and an outer diameter smaller than the inner diameter of the glass syringe.

[0229] For an injection dose of 30 mg lanreotide, a 21G needle (16 or 25 mm long) was then added to load approximately 225 mg of the composition into the bottom of each glass syringe. A bromobutyl rubber plunger was then placed to minimize the volume of air trapped between the composition and the plunger as much as possible.

[0230] Example 9

[0231] Example of injection force measurement

[0232] The injection force test was performed according to the calibrated and validated protocol described in Example 4.

[0233] The maximum injection force in Newtons (N) was derived from the data collected during expulsion.

[0234] In this example, a representative needle of the commercial product Somatuline (1.20 mm outer diameter, 1.00 mm inner diameter) was compared with a needle of smaller diameter, and the injection force of the compositions prepared according to Examples 1, 2 and 3 was compared through the same needle and different injection systems (syringe + needle).

[0235] The results obtained are reported in the following table:

[0236]

[0237]

[0238] By using a more dilute composition, a reduction in injection force of at least 3 or 4 was observed under the conditions of the present invention, despite the needles selected being thinner and longer than those of commercial products for deep subcutaneous injections.

[0239] Example 10

[0240] Visual appearance and comparison of extrudates obtained by injection with different needles

[0241] To demonstrate the importance of a large diameter needle according to known methods before insertion, it can be demonstrated that, with a needle having a lumen or inner diameter of at least 1 mm, a commercial product of 25% lanreotide and one of the more dilute compositions obtained extrudates or columns of the same diameter after in vitro injection. Using a thinner needle with a more dilute composition, the inventors succeeded in obtaining a product that did not retain this shape after in vitro injection, demonstrating the ability of this new presentation of a thinner needle and a more dilute composition to control the release of lanreotide independently of the deposit.

[0242] Tests were performed through different needles to evaluate the visual appearance and extrudate geometry of the two lanreotide compositions prepared as in Example 1 .

[0243] The results are Figure 1 Visible in:

[0244] - On the left, extrudate of a composition comprising 25% lanreotide through a needle with an inner diameter of 1.00 mm

[0245] - In the middle, extrudate of a composition comprising 19% lanreotide passed through a needle with an inner diameter of 1.00 mm

[0246] - On the right, extrudate of a composition comprising 19% lanreotide through a needle with an inner diameter of 0.60 mm

[0247] The results obtained with a needle with an internal diameter of 1.00 mm gave similar extrudates. It was not possible to make the same comparison with a 0.60 mm needle: only the composition with 19% lanreotide could be manually extruded and the extrudates were significantly different.

[0248] Embodiment 11

[0249] Manual syringe

[0250] It was demonstrated that manual injections can be performed using a 25 mm 21G standard hypodermic needle for the composition dose of 19% lanreotide prefilled in a standard 1.00 mL glass syringe prepared according to Example 2. These manual injections were performed using a standard finger rest that can be obtained from a standard commercial syringe.

[0251] The test was performed using standard needles temporarily attached to various syringes, allowing for normal or deep subcutaneous injections depending on the needle length from 10 to 20 mm, such as intramuscular injections using long needles from 25 to 40 mm.

[0252] The combination of less force to implant the needle and deliver the product, the choice of injection site, a less sticky deposit that retains its shape less or spreads more, and the reduced volume due to precipitation of lanreotide are all factors that help make these treatments easier, more comfortable, less painful to administer, and better tolerated at the site of deposition by avoiding sensitive nodules.

[0253] Example 12

[0254] Stability studies of compositions comprising 20% ​​lanreotide in water and in a water-ethanol mixture.

[0255] The stability of compositions of 25% lanreotide with purified water and with a 75:25 ethanol mixture prepared as described in Example 1 were tested at 5°C and 25°C / 60% humidity. After 1 month storage under these conditions, the purity of the peptide determined by RP-HPLC was compared to the initial purity.

[0256] The results are reported in the table below.

[0257]

[0258] The stability of different compositions was studied according to the protocol, allowing the feasibility of ready-to-use dosage forms to be predicted under different manufacturing conditions, either aseptically or under terminal sterilization. It has been shown that the composition of 20% lanreotide is stable.

[0259] Surprisingly, when considering other data with low percentages of organic solvents, it was found that compositions with water mixtures containing 10% or less ethanol were also stable.

[0260] Therefore, the use of these two types of less viscous sustained- and / or controlled-release compositions can provide a ready-to-use injectable product dosage form without the need for a reconstitution step of the product prior to injection.

[0261] Embodiment 13

[0262] Pharmacokinetic (PK) profiles obtained in rats

[0263] To verify the functionality and feasibility of new injectable products based on these novel dosage forms, pharmacokinetic studies were performed in rats and dogs.

[0264] The following two compositions prepared according to Example 1 based on lanreotide acetate were tested on rats:

[0265] - Formulation A: 24.6% lanreotide in a mixture of purified water and ethanol in a ratio of 75:25,

[0266] - Formulation B: 27.9% lanreotide in purified water.

[0267] A dose of approximately 15 mg was injected subcutaneously and blood samples were collected throughout the study. Various plasma samples from the blood samples were analyzed by LC-MS to determine the plasma concentration of lanreotide.

[0268] Results Figure 2 , on which the lanreotide plasma concentrations are plotted over time for the two compositions A and B. In both cases, a sustained release of lanreotide can be observed. However, it is clearly visible that composition A, despite comprising a lower percentage of lanreotide, is improved in terms of the release profile: the initial burst or Cmax is reduced, which makes it possible to almost double the level of lanreotide at 4 weeks.

[0269] This new dosage form can be tested with, for example, a needle of 1.00 mm diameter and a composition comprising 20% ​​lanreotide and compared to a known reference of a 25% commercial composition injected with a needle of 1.20 mm diameter.

[0270] The results obtained in this example show that a comparable or even better controlled release profile can be obtained with the novel formulation of the invention, due to the arrangement of the deposits in their sedimentary manner. It can then be estimated that a novel dosage form of this type with an appropriate needle could allow, for example, subcutaneous dosing every 28 days in the case of acromegaly, where the release profile presents less burst release and higher levels at the end of the interval, or, for example, intramuscular dosing every 14 days for the treatment of neuroendocrine tumors, where the release profile has lanreotide levels that are higher at all points and then rapidly decline.

[0271] In order to verify the functionality of the new controlled form, this new formulation could also be tested under extreme conditions with much lower viscosities, such as a formulation comprising 20% ​​lanreotide in a mixture of water and ethanol in a ratio of 95:5%. In this case, it could be shown that we maintain a controlled release towards these limits and could therefore also have new more favorable profiles, such as the possibility of obtaining higher release levels that are better adapted to certain treatments such as in the case of NET.

[0272] Embodiment 14

[0273] Example of Pharmacokinetic Profile (PK) Obtained in Dogs

[0274] In general, the formulations of the invention are able to give a higher dose curve in dogs than in rats and are therefore more easily compared to doses used in humans in the clinic.

[0275] A batch of lanreotide prepared from lanreotide acetate in purified water according to Example 1 at a concentration of 20.2% was tested in dogs. A dose of 60 mg (lanreotide) was injected intramuscularly and blood samples were collected throughout the study. The doses were packaged in syringes with a diameter of 3.0 mm, which were connected to needles of 0.8×0.6×19 mm. Intramuscular administration did not cause problems with these small diameter needles.

[0276] Various plasma samples from the blood samples were analyzed by LC-MS to determine the plasma concentration of lanreotide.

[0277] Sustained release (or extended release) of lanreotide was observed over a period of at least 1 month. Figure 3 As can be seen in FIG. 1 , a curve of the change in plasma concentration of lanreotide over time is plotted thereon.

[0278] Embodiment 15

[0279] Pharmacokinetic characterization (PK) in dogs

[0280] A 20.7% lanreotide formulation prepared from lanreotide acetate and a 93:7% mixture of purified water and ethanol according to Example 1 was tested in dogs. A 60 mg dose of lanreotide was injected intramuscularly, and blood samples were collected throughout the study. Various plasma samples from the blood samples were analyzed by LC-MS to determine the plasma concentration of lanreotide.

[0281] The results are Figure 4 As can be seen in FIG. 1 , a curve of the change in plasma concentration of lanreotide over time is plotted thereon.

[0282] Sustained release of lanreotide was observed for a period of at least 1 month.

[0283] Example 16

[0284] Preparation of an aqueous composition of lanreotide including arginine and analytical results of purity

[0285] A novel composition is prepared from a purified aqueous solution of 0.40 g of lanreotide acetate and 0.072 g / g of L-arginine. The composition is obtained by mixing lanreotide acetate with 2.67 g of arginine solution. The two components are weighed in a 5 mL plastic syringe.

[0286] Mixing was performed by moving back and forth between two syringes connected by a connector as described in Example 1. At the end of the mixing phase, the composition was dispensed into 1.0 ml plastic syringes (approximately 530 mg of composition per syringe). The composition can be injected as is, or can be lyophilized to obtain a form that is easily reconstituted before injection. RP-HPLC analysis of the product as described in Example 5 showed that the purity of the peptide remained above 95% (98.6%).

[0287] Embodiment 17

[0288] Pharmacokinetic properties (PK) obtained in rats with arginine-containing compositions

[0289] A solid composition of lanreotide acetate and L-arginine was tested on rats. The composition was prepared from an aqueous composition containing 11% lanreotide, and the final lanreotide content was 57.9% w / w, containing approximately 0.57 g arginine per gram of lanreotide.

[0290] A dose of approximately 3.5 mg was injected subcutaneously and blood samples were collected throughout the study. Various plasma samples from the blood samples were analyzed by LC-MS to determine the plasma concentration of lanreotide.

[0291] The results are Figure 5 As can be seen in the figure, a curve of lanreotide plasma concentration over time is drawn on it. It is observed that the sustained release of lanreotide lasts for at least 4 weeks. By comparison, it is found that the PK curve of the equivalent form without arginine is improved on the curve.

[0292] Embodiment 18

[0293] Determination of deposit forms, findings and possible inferences by palpation and temporary sampling of different compositions injected subcutaneously into rabbits

[0294] Solutions of different concentrations were prepared as described in Example 1.

[0295] Formulation A: Formulation containing 20% ​​lanreotide in water

[0296] Formulation B: Formulation comprising 20% ​​lanreotide in a 95:5% water / ethanol mixture

[0297] Reference formulation: A formulation comprising 25% lanreotide in water which reproduces the conditions of the currently marketed product.

[0298] These formulations were injected into rabbits according to the following model:

[0299] The first model was to inject 30 mg of Formulation A and 30 mg of the reference formulation at two different injection sites at t=0; 30 mg of Formulation A was injected at a third injection site at t=7 days, and 30 mg of Formulation A was injected at a fourth injection site at t=11 days, i.e., a total of 4 injections;

[0300] The second model was to inject 30 mg of Formulation B and 30 mg of the reference formulation at two different injection sites at t=0; 30 mg of Formulation B was injected at a third injection site at t=7 days, and 30 mg of Formulation B was injected at a fourth injection site at t=11 days, i.e., a total of 4 injections;

[0301] The various deposits can be felt through the skin by touch in order to follow the evolution of their shape and their consistency, and their properties can be verified by immediate sampling after two weeks.

[0302] Note that for these same low doses of 30 mg injected lanreotide, the deposits prepared from the reference formulation, although smaller in volume, were more palpable or tactile than those from Formulations A or B. The less viscous precipitates were produced by the water mixture. Alcohol Formulation B was the least tactile.

[0303] The animals were sacrificed after 2 weeks and it was noted that 20% of all the sediments of formulation A or formulation B showed more or less solid white material corresponding to the precipitation of lanreotide after 3, 7 or 14 days. These sediments were analyzed for their lanreotide content and it was found that the remaining amount of the peptide was inversely proportional to the time after injection and was comparable to that obtained with the sediments of the reference formulation at 2 weeks.

[0304] This demonstrates the possibility of obtaining controlled compositions of lanreotide over a week or even longer according to different release profiles by using these new dosage forms combining thinner needles and more dilute compositions.

Claims

1. A prefilled syringe, characterized in that: a) the diameter of the syringe is greater than 3.00 mm and not greater than 7.00 mm, and the syringe is equipped with a needle with an outer diameter equal to or less than 1.00 mm and an inner diameter equal to or less than 0.80 mm, and a length of 10 to 40 mm, b) The syringe comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises the following: 1) an aqueous solvent consisting of water, 2) Lanreotide or lanreotide acetate at a concentration of 11-25% by weight of lanreotide relative to the total weight of the composition.

2. The prefilled syringe according to claim 1, characterized in that The syringe is used to parenterally administer to a patient by subcutaneous injection or intramuscular injection of the composition contained in the syringe, and the composition releases lanreotide or lanreotide acetate over a period of at least 7 days.

3. The prefilled syringe according to claim 1, characterized in that The composition includes pharmacopoeia-accepted monomeric excipients.

4. The prefilled syringe according to any one of claims 1 to 3, characterized in that The syringe is a manual syringe with a piston rod, provided with a Luer lock type standard needle, wherein the Luer lock type standard needle has an outer diameter of 0.80 to 1.00 mm, an inner diameter of 0.60 to 0.80 mm and a length of 20 to 30 mm.

5. The prefilled syringe according to any one of claims 1 to 3, characterized in that The syringe has a piston rod and is equipped with a standard Luer lock needle with an outer diameter of 0.80-1.00 mm, an inner diameter of 0.60-0.80 mm and a length of 20 mm. The syringe is pre-filled with a sustained-release pharmaceutical composition for parenteral administration, wherein the composition comprises an aqueous solvent consisting of water and lanreotide acetate, and the concentration of the lanreotide acetate is 18%-25% by weight of the lanreotide relative to the total weight of the composition.

6. The prefilled syringe according to any one of claims 1 to 3, characterized in that The syringe has a piston rod and is equipped with a standard Luer lock needle with an outer diameter of 0.80 mm, an inner diameter of 0.60 mm and a length of 20 mm. The syringe is prefilled with a sustained-release pharmaceutical composition for parenteral administration, the composition comprising water and lanreotide acetate, wherein the concentration of lanreotide acetate is 20% by weight of lanreotide relative to the weight of water.

7. A kit comprising a sustained-release or controlled-release pharmaceutical composition for parenteral administration, the composition comprising: a) an aqueous solvent consisting of water, b) lanreotide or lanreotide acetate at a concentration of 11-25% by weight of lanreotide relative to the total weight of the composition, and a syringe, wherein the needle of the syringe has an outer diameter equal to or less than 1.00 mm, an inner diameter equal to or less than 0.80 mm and a length between 10 and 40 mm.

8. The kit according to claim 7, characterized in that The composition includes a pharmaceutically acceptable monomeric excipient.

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