COMPOSITIONS

FIELD OF THE INVENTION

The present invention relates to the novel glass container closure systems for Lanreotide injection in a glass container comprising cerium which can withstand terminal sterilization by radiation.

BACKGROUND OF THE INVENTION

Lanreotide is a synthetic octapeptide and analogue of somatostatin that is used for its ability to suppress levels and activities of hormones (growth hormone, insulin, gastrin, secretin, glucagon) or active neuropeptides (serotonin, vasoactive intestinal polypeptide [VIP]). Natural somatostatin is produced in the hypothalamus and acts to suppress growth hormone release from the pituitary. Somatostatin is also found in other neurons throughout the body and particularly in intestinal and pancreatic neurons, where it is active in suppressing release of hormones and neuropeptides such as insulin, glucagon, gastrin, secretin, motilin, VIP, serotonin and cholecystokinin. Because its half-life is longer than somatostatin, lanreotide can be used clinically to treat neuroendocrine tumors that secrete excessive amounts of growth hormone (acromegaly) or other active hormones or neuropeptides.

Lanreotide is approved as Somatuline Autogel or Somatuline Depot (Lanreotide) injection by USFDA as 60mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL, a prolonged-release formulation in semi-solid phase having gel like appearance with viscous characteristics for deep subcutaneous injection comprising lanreotide acetate, water for injection and acetic acid. It is indicated for Acromegaly, Neuroendocrine tumors (NET)-Gastroentero- pancreatic Neuroendocrine tumors and treatment of adults with carcinoid syndrome. This depot product is supplied in a polypropylene (PP) ready-to- use prefilled syringe fitted with an automatic safety system with a bromobutyl rubber plunger stopper and a (1.2 mm x20 mm) needle covered by a plastic cap. Each ready to use pre-filled syringe is placed into a plastic tray and packed in a laminated pouch (polyethylene terephthalate/ aluminium / polyethylene laminate) and a cardboard box.

US5595760 relates to the parenteral administration of sustained- release peptide compositions and further discloses a pharmaceutical composition including a soluble, gelable salt of the peptide and up to 30 percent, by weight, of a pharmaceutically acceptable, soluble, monomeric carrier, and parenterally administering the solid composition.

US20160151447A1 discloses pharmaceutical composition for a sustained release of peptide therapeutics, in particular for a sustained release compatible with therapeutic treatments of at least two months. In an embodiment, the composition comprises lanreotide as an active agent, a hydro soluble co-solvent, and water with the p H of the composition being from 4.0 to 7.5. Further it discloses that different batches of lanreotide solution are prepared by hydrating an acetate salt of lanreotide as active pharmaceutical ingredient (API) with the corresponding mixture of water for injection (WFI) / NMP / acetic acid in a suitable container and once homogeneous media is obtained, the different formulations are aliquoted in syringes suitable for pre-filled product and preferably compatible with a terminal sterilization using gamma-irradiation.

Int. J. of Physical Sciences Vol. 5(7), pp. 960-967, July, 2010 A. Adurafimihan Abiona et al., discloses that Gamma-irradiation of polypropylene led to remarkable changes in the physico-chemical properties of the material due to chain scission, oxygen effects and crosslinking activities. These changes result in the production of the degradation products such as water vapour, carbon monoxide from hydroxyl and carbonyl groups as confirmed by Raman and UV-visible spectroscopic analyses. The absorption maximum of the second peaks have hypsochromic shift due to the formation of the carbonyl group. It was also observed that the melting temperature and crystallinity reduces as radiation doses increases. Likewise, there were losses in mechanical properties of the polymer as indicated by reduction in elongation to fracture and tensile strength of the materials as dose increases. Rad. Physics and Chemistry (2007), Athanasia T. Fintzou et al., discloses the effect of g-irradiation on mechanical, thermal, physicochemical and structural properties of polypropylene (PP) syringes was studied. Irradiation doses of 30, 60 and 120 kGy were used with non-irradiated PP syringes serving as control samples. Irradiation caused a significant deterioration in mechanical properties of samples. The compression strength of whole syringe body decreased with increasing irradiation dose. Similarly, % extension at break decreased with increasing irradiation dose i.e. it becomes brittle. Of the physicochemical properties tested, both degree of yellowness and extractable radiolysis products increased with increasing irradiation dose.

Further, Kenton J et al., discloses that PP syringes if exposed to gamma irradiation for terminal sterilization, polypropylene can result in weakened container integrity, leakage, increased gas permeability and an undesirable yellowing of the container, and that gamma radiation treatment inherently causes the generation of highly reactive species. The generation of such reactive species can alter the contents of the container with respect to pH, UV absorbance levels, the presence of hydrogen peroxide (H202) and other oxidizable substances which is not desired.

The prolonged release formulation of Lanreotide acetate at higher concentration could not be terminally sterilized by aseptic filtration process because at higher concentration of Lanreotide acetate in water the hydrated peptide leads to the formation of a highly viscous supersaturated solution which is difficult to be sterilized by passing through 0.22m filter. Moist heat sterilization is not suitable for high risk of degradation of the contents inside

The lanreotide depot product is supplied in polypropylene prefilled syringes which have a lower gas barrier compared to glass syringes and thus, may not be suitable for samples that are sensitive to oxygen. Due to high permeability of plastic syringes, chances of water loss from its contents is also high.

Considering the above drawbacks of polypropylene containers, the present inventors have found an innovative and novel way to sterilize this depot product by terminal sterilization by gamma irradiation. Hence the inventors have found a novel glass container closure system comprising glass containers such as glass syringe, prefilled glass syringe, glass cartridges, with cerium oxide, which can withstand terminal sterilization by gamma irradiation or any other similar means of sterilization.

SUMMARY OF THE INVENTION

The present invention relates to a novel glass container closure system comprising an injectable composition, wherein the composition comprises of: Lanreotide acetate from about 10% to about 60% w/v with viscosity more than 5000cps filled into a glass container comprising cerium, which can withstand terminal sterilization through radiation.

The container closure system according to above aspect, wherein the concentration of Lanreotide is from about 20% to about 60% w/v.

The container closure system according to above aspect, wherein the injectable composition is a thick homogeneous solution, or gel, or gel semisolid, and the like having viscosity from about 5000 to about 20000 cps.

The container closure system according to above aspect, wherein the injectable composition is a thick homogeneous solution, or gel, or gel semisolid, and the like having viscosity from about 5000 to about 200000 cps.

The container closure system according to above aspect, wherein the container is glass syringe, prefilled glass syringe, glass cartridges and the like.

The container closure system according to above aspect, wherein the composition in glass container is subjected to terminal sterilization.

The container closure system according to above aspect, wherein terminal sterilization can be carried by irradiating or exposing the glass containers to gamma rays or electron beam or by X-rays and the like.

The container closure system according to above aspects, prevents water loss and oxidation of the composition and prevents radiation browning of glass when exposed to gamma radiation for sterilization.

The container closure system according to above aspects, wherein the composition is used to treat lanreotide related sensitive diseases or disorders. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel container closure system comprising an injectable composition of Lanreotide.

The term “Lanreotide” includes the compound, pharmaceutically acceptable salts thereof, isomers, solvates, prodrugs, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.

"Pharmaceutically-acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts, solvate, hydrate, anhydrates, enantiomers, esters, isomers, polymorphs, tautomers, complexes and the like thereof.

The terms “composition” and “formulation” and “finished product” refer to preparations comprising lanreotide or pharmaceutically acceptable salts thereof; in a form suitable for administration to a mammal.

"Carrier" or "vehicle” or “solvent” as used herein refers to pharmacologically inert materials that provide a more or less fluid matrix, suitable for topical drug administration. Carriers and vehicles useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical formulation or drug delivery system in a deleterious manner. Formulations suitable for parenteral dosage forms such as injectable like intravenous, intramuscular or subcutaneous, implants and the like. Other parenteral ingredients used in the formulation are generally those commonly used and recognized by persons skilled in the art of parenteral formulations.

The term “substantially dissolved" relates to 0.1% to 99% of total lanreotide is dissolved in the compositions.

The term "stable" or "stability" as used herein includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value and other physico-chemical parameters.

The term "physical stability" refers to compositions free from particles and that do not significantly change during storage.

The term "chemical stability" relates to a limited formation of impurities, limited decrease in potency and the like. The present invention relates to a novel glass container closure system comprising an injectable composition wherein the composition comprises of: -lanreotide acetate from about 10% to about 60% w/v with viscosity more than 5000cps filled into a glass container comprising cerium.

In one embodiment, the present invention relates to a novel glass container closure system comprising an injectable composition, wherein the composition comprises of Lanreotide acetate from about 10% to about 60% w/v with viscosity more than 5000cps filled into a glass container comprising cerium, which can withstand terminal sterilization through radiation

According to another embodiment, the present invention relates to a novel glass container closure system comprising an injectable composition wherein the composition comprises of:

-lanreotide acetate from about 10-60% w/v with viscosity more than 5000cps; -difficult to be sterilized by aseptic or moist heat sterilization; wherein the glass container comprises cerium.

The concentration of lanreotide is from about 10% to about 60% w/v, or for example from about 15% to about 60% w/v, or for example from about 20% w/v to about 50% w/v.

According to another embodiment, the container closure system according to above aspect, wherein the injectable composition is a thick homogenous solution, gel, or gel-like, semisolid drug product having viscosity from about 5000-20000 cps.

According to another embodiment, the container closure system according to above aspect, wherein the injectable composition is a thick homogenous solution, gel, or gel-like, semisolid drug product having viscosity from about 5000-200000 cps.

According to another embodiment, the composition in the container closure system is complex, as are the sequence of steps in the peptide selfassembly mechanisms that generate this structure and sometimes referred to as Autogel. The literature discloses lanreotide acetate is a peptide when mixed with water at the concentration range of 3-30% (w/w) spontaneously self-assembles into very long and monodisperse hollow nanotube with diameters of 24 nm and lengths up to hundreds of micrometres, these supersaturated solution are liquid crystalline gel like structure, when administered subcutaneously forms depot at the injection site due to interaction with physiologic fluid.

In another embodiment, the composition can’t be terminally sterilized by aseptic filtration process because at higher concentration of Lanreotide acetate in water the hydrated peptide leads to the formation of a highly viscous supersaturated solution which is difficult to be sterilized by passing through 0.22m filter.

Further moist heat sterilization is not suitable for high risk of degradation of the contents inside.

According to another embodiment, the container closure system, wherein the container is glass syringe, prefilled glass syringe, glass cartridges and the like or similar materials.

According to another embodiment, the container closure system, wherein the container is glass syringe, and the like or similar materials.

According to another embodiment, the container closure system, wherein the container is prefilled glass syringe and the like or similar materials.

According to another embodiment, the container closure system, wherein the container is glass cartridges and the like or similar materials.

In one embodiment the glass container closure system comprises of cerium, it helps to withstand the radiations which are used during sterilization procedure. Cerium helps to overcome the discloration due to high energy radiations and hence stabilizing the container and finished product.

According to another embodiment, the container closure system, further comprises of other ingredients used in the manufacturing of glass.

Glass containers are very common for individual units of pharmaceutical parenteral preparation which includes vials, ampoules, prefilled syringes, prefilled cartridges. Glass products typically have amorphous (i.e. non-crystalline) microscopic structures and the basic unit of the glass microscopic structure is the silica tetrahedron. As such, “glass” is particularly susceptible to radiation. The nature of the changes of the optical properties of glasses under irradiation is varied but usually consists of coloration in the visible-light region and the formation of absorption bands in the infrared and/or ultraviolet regions. The optical density of the glass is almost always increased by irradiation and this is referred to as discoloration as “radiation browning” or, simply, “browning”. Adding cerium to the glass formulation reduces the discoloration.

US6156399 discloses glass containers including injection bottle, a syringe body, and a glass cylinder that are made of glass which contains a stabilizer comprising Cerium Oxide, in the amount of 0.3-1.5% by weight, for inhibiting discolouring effects of high energy radiations during sterilization.

In another aspect, glass composition for prefilled syringe includes Cerium Oxide to provide irradiation stability with respect to coloration as described in US6027481. As such, the syringe would be sterilizable by irradiation, e.g., by gamma, electron beam, x-ray or the like, which would be advantageous over other sterilization processes where areas of difficulty to reach by the sterilization agent exist.

Other references include US9919948 that discloses silica glass composition comprising about 92 to about 99.9 wt.% S1O2 and about 0.1 to about 8 wt. % of a dopant, Ce0 ₂ , that absorbs UV radiation while exhibiting no absorption in the visible region of the spectrum, further comprising Ce as UV blocker in amount of from about 0.001 to about 0.5 wt%. Borosilicate glasses doped with CeC>2 exhibit improved irradiation resistance (Wang and Cheng, 2016). Radiation shielding is based on the principle of attenuation, which is the reduction of effect of waves or rays by blocking or bouncing particles through a barrier material.

Cerium oxide (CeC>2) has been attractive material due to catalyst, polishing agent, or potential material for ultraviolet (UV) filtration, resistant to radiation damage properties (Truffault et al., 2010). Borosilicate glasses doped with CeC>2 exhibit improved irradiation resistance (Wang and Cheng, 2016). Radiation shielding is based on the principle of attenuation, which is the reduction of effect of waves or rays by blocking or bouncing particles through a barrier material.

Further sterilization of products by radiation can be achieved by using different forms of radiation. These different forms of radiations are gamma rays or gamma irradiation, electron beams or x-rays and the like.

Radiation sterilization of parenteral products can be done through gamma radiation of high energy. This is done by utilization of the gamma rays from the radioactive isotope of cobalt, usually, cobalt-60. X-rays are another option the drugs manufacture use for sterilization of parenteral products by radiation. X-rays are produced when electron at high speed and energy hit a material. This then causes the production of the electromagnetic waves. An electron beam also emits radiation for sterilization of the parenteral products although electron beams have lower penetrative power. Out of three ways of radiation, the most commonly used way of radiation sterilization is the use of gamma rays. The radiation sterilizes the parenteral products by killing the contaminating microorganisms.

According to another aspect, the container closure system, the composition in glass container is subjected to terminal sterilization, wherein terminal sterilization is by gamma irradiation or electron beam sterilization or by X-rays.

The container closure system according to above aspect, wherein terminal sterilization is preferably done by gamma irradiation.

The container closure system according to above aspect, wherein terminal sterilization is preferably done by electron beam.

The container closure system according to above aspect, wherein terminal sterilization is preferably done by X-rays.

The container closure system according to above aspect, prevents water loss and oxidation of the composition and also prevents radiation browning of glass when exposed to gamma radiation for sterilization. As glass would not allow water to evaporate or dry from its containers and also it does not allow to enter atmospheric oxygen into the container, so prevents water loss and oxidation of the composition inside. Further it also prevents radiation browning of glass when exposed to gamma radiation for sterilization. Hence this product can be terminally sterilized by gamma irradiation without any changes to the physical and chemical properties of the container or stability of the pharmaceutical composition.

The container closure system according to above aspect, the container is a hermetically sealed container which prevents water loss and oxidation of the composition and also prevents radiation browning of glass when exposed to gamma irradiation during terminal sterilization. The composition of the present invention may comprise of lanreotide and/or its pharmaceutically acceptable salt, pharmaceutically acceptable carrier, and suitable solvent.

The composition may further comprise of other pharmaceutically acceptable excipients.

The composition automatically forms a gel after interaction with the patient's bodily fluids, and releases the lanreotide continuously within the patient over an extended period. The present invention provides sterile pharmaceutical composition of Lanreotide acetate which when administered to a patient will form a sustained-release gel. The Lanreotide acetate supersaturated solution are filled into glass syringes and terminally sterilized by radiation.

Further invention discloses the method of filling viscous supersaturated solution into glass syringes and packaged with foil-lined material to protect from moisture, further the finished product in glass syringe is terminally sterilized by gamma irradiation.

In another aspect, sterile pharmaceutical composition when administered to a patient, delivering the peptide continuously over an extended period of time by obtaining a solid pharmaceutical composition including a soluble, gelable salt of the lanreotide or its acceptable salt, soluble, monomeric carrier, e.g., water and parenterally administering the solid composition to the patient in one injection.

In another aspect the composition is administered as intramuscular, subcutaneous, intradermal, or intraperitoneal, wherein the solid composition automatically forms a gel after interaction with the patient's bodily fluids and releases the peptide continuously within the patient over an extended period.

In another aspect the present invention also discloses process of preparing the compositions and filled into the prefilled syringes.

Manufacturing process: i) Required quantity of water for batch was taken in the manufacturing vessel; ii) required quantity of lanreotide acetate was added under stirring/kneading; iii) finally make up the volume to required batch size; iv) continue stirring/kneading till homogenous product was obtained; v) the product was transferred into filling machine buffer tank and calculated volume/quantity of bulk solution filled into syringes or cartridges or vials, stoppered and sealed; vi) the filled syringes or cartridges or vials, were suitably packed into secondary packing and subjected to terminal sterilization by gamma irradiation or electron beam sterilization or by X-rays.

In one embodiment the novel container closure system comprising an injectable composition wherein the composition is used for the treatment of lanreotide sensitive diseases or disorders include but not limited to acromegaly, neuroendocrine tumors (NET)-gastroentero-pancreatic neuroendocrine tumors and treatment of adults with carcinoid syndrome.

The present methods and systems disclosed, it is to be understood that the methods and systems are not limited to specific container closure systems, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods disclosed or described herein, which are intended as illustrations of a few aspects of the claims and any containers closure system and compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and disclosed herein are intended to fall within the scope of the appended claims.