A packaging system for delivering cysteamine formulation to improve shelf life and in-use period

Abstract

A packaging system for delivering cysteamine formulation to improve shelf life and in-use period The present invention relates to a packaging system for packaging and delivering cysteamine ophthalmic formulation to provide improved shelf life and in-use period. The present invention also relates to a method for delivering the cysteamine formulation. The present invention also relates to a cysteamine ophthalmic formulation to improve convenience, provides ease of use, and protection against microbial contamination, protection against light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

Description

[0001] A PACKAGING SYSTEM FOR DELIVERING CYSTEAMINE FORMULATION TO IMPROVE SHELF LIFE AND IN-USE PERIOD

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a packaging system for packaging and delivering cysteamine ophthalmic formulation to provide improved shelf life and in-use period. The present invention also relates to a method for delivering the cysteamine formulation. The present invention also relates to a cysteamine ophthalmic formulation to improve convenience, provides ease of use, and protection against microbial contamination, protection against light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

[0004] BACKGROUND OF THE INVENTION

[0005] Cystinosis is a rare and very serious congenital condition that could be fatal. Cystinosis is characterized by a cysteine crystal build-up, causing damage to all the organs in the body, especially the kidneys and eyes.

[0006] Cysteine is a non-essential amino acid important for making protein, and for other metabolic functions. Deposition of cystine on the eye can cause significant discomfort throughout the day and require frequent treatment with eye drops, typically every waking hour.

[0007] Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A. Cysteamine acts as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation. The result is a reduction in cystine crystals.

[0008] Several ophthalmic preparations exist for the treatment of corneal cystine crystal accumulation in patients with cystinosis. Two cysteamine topical ophthalmic preparations (Cystaran® and Cystadrops®) have been approved for the treatment of corneal cystine crystal accumulation in patients with cystinosis. Both products use cysteamine hydrochloride as the salt form in the preparation.

[0009] Cystaran® is the first approved eye-drop preparation. It is composed of a sterile solution of cysteamine hydrochloride 0.65% w / v with benzalkonium chloride and sodium chloride. The product is very unstable and therefore must be kept frozen during long term storage. Once opened, it must be kept in a refrigerated condition and must be discarded after one week. Furthermore, due to the short duration of action, Cystaran® is recommended to be administered frequently to the eye every awake hour.

[0010] Cystadrops® is a viscous eye drop solution formulation composed of a sterile solution of cysteamine hydrochloride 0.55% w / v with benzalkonium chloride, disodium edetate, carmellose sodium, and citric acid monohydrate. The product is packaged in an amber glass and purged with nitrogen gas bubbling to protect cysteamine from oxidation degradation. While this viscous eye drop solution formulation is relatively more stable in the sealed glass container, its stability quickly diminishes over time once opened and must be discarded after 7 days.

[0011] These were approved in the European Union in 2017 and in the USA in 2020 for the treatment of the ocular manifestations of cystinosis in adults and children from 2 years of age. Cystadrops® was designated an orphan drug by the European Commission with effect from November 2008.

[0012] A lyophilized cysteamine eye drop formulation was developed by Lucane Pharma with an attempt to overcome poor stability, but it failed to obtain regulatory approval for commercialization due to product contamination risk which may have occurred during assembling of the complex container system.

[0013] In view of the above, there are the following limitations in the technologies that existed in prior arts:

[0014] The process of opening the vial and attaching the dropper by patients is difficult and could lead to microbiological and particulate contamination of the product.

[0015] Dispensing drops from the assembled vial / dropper is also difficult.

[0016] The use of glass vials with stoppers and dispensing applicators as packaging material for finished products has microbiological quality and patient usability issues due to assembling issues associated with dispensing applicator.

[0017] After opening of the stopper, the product loses sterility and gets degraded by the environmental oxygen.

[0018] Dropper applicators are difficult to use, and the use of stoppers and dropper applicators also makes it challenging to fully access the product, which results in product waste.

[0019] Storage of product requires very low temperature conditions such as -20 °C for Cystaran and 2°C to 8 °C for Cystadrops which is difficult to maintain while in use period. Therefore, there is a need to develop a new packaging system for packaging and delivering the cysteamine formulation which provides better product stability, convenience to use, superior protection against microbial contamination, better protection from light and oxygen degradation, extended product shelf life, better in-use stability, and enhanced user experience.

[0020] OBJECTIVE OF THE INVENTION

[0021] Main objective of the present disclosure is to provide a packaging system for packaging and delivering ophthalmic formulation comprising cysteamine or a pharmaceutically acceptable salt thereof to provide improved shelf life and in-use period stability.

[0022] Another objective of the present disclosure is to provide a packaging system which minimizes the headspace oxygen available which causes degradation of the cysteamine or a pharmaceutically acceptable salt thereof by oxidation.

[0023] Yet another objective of the present disclosure is to provide a method for delivering the cysteamine formulation.

[0024] Still another objective of the present disclosure is to provide a cysteamine ophthalmic formulation to improve convenience, provides ease of use, and protection against microbial contamination, protection against light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

[0025] Yet another objective of the present disclosure is to provide packaging system for packaging and delivering ophthalmic formulation comprising cysteamine or a pharmaceutically acceptable salt thereof which are in the form of multilayered bottles, lami tubes, and aluminium tubes.

[0026] SUMMARY OF THE INVENTION

[0027] Main aspect of the present disclosure provides a packaging system for packaging and delivering ophthalmic formulation comprising cysteamine or a pharmaceutically acceptable salt thereof to provide improved shelf life and in-use period stability. Another aspect of the present disclosure provides a packaging system which minimizes the headspace oxygen available which causes degradation of the cysteamine or a pharmaceutically acceptable salt thereof by oxidation.

[0028] Still another aspect of the present disclosure provides a packaging system for packaging and delivering cysteamine formulation comprising: a primary container; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the primary container; one or more layers selected from metallic layer, plastic barrier layer, and sealing layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulation

[0029] Wherein,

[0030] The primary container has no or minimal head space reducing the availability of free oxygen;

[0031] The container is made up of a material that is compatible and does not interact with the cysteamine or a pharmaceutically acceptable salt thereof during storage;

[0032] One or more layers do not allow oxygen transmission.

[0033] Yet another aspect of the present disclosure provides a packaging system for packaging and delivering cysteamine formulation comprising: an Aluminium container having no or minimal head space reducing availability of free oxygen; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the Aluminium container; aluminium metallic layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulation.

[0034] Still another aspect of the present disclosure provides a method for delivering the cysteamine formulation, method comprising the following steps: removing the resealable closure mechanism; dispensing the desired amount of cysteamine formulation, and securely resealing the container after each use to prevent environmental oxygen exposure and maintain formulation stability.

[0035] Still another embodiment of the present disclosure provides the packaging system, wherein the container with a resealable closure mechanism allows for easy dispensing and protects the formulation from environmental oxygen and light degradation. Container is made of material that is compatible with the formulation and does not react or interact with the formulation during storage. The container is opaque, preventing light exposure and protecting the formulation from light-induced degradation. The container has a small footprint, making it easy to store and transport.

[0036] Yet another aspect of the present disclosure provides a cysteamine ophthalmic formulation to improve convenience, provides ease of use, and protection against microbial contamination, protection against light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

[0037] Still another aspect of the present disclosure provides a packaging system for packaging and delivering ophthalmic formulation comprising cysteamine or a pharmaceutically acceptable salt thereof which are in the form of multilayered bottles, lami tubes, and aluminium tubes. DETAILED DESCRIPTION OF THE INVENTION

[0038] At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is an only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is understood as an exemplary embodiment and teaching of invention and is not intended to be taken restrictively.

[0039] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. Further, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.

[0040] Main embodiment of the present disclosure provides a packaging system for packaging and delivering cysteamine formulation comprising: a primary container; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the primary container; one or more layers selected from metallic layer, plastic barrier layer, and sealing layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulation

[0041] Wherein,

[0042] The primary container has no or minimal head space reducing the availability of free oxygen;

[0043] The container is made up of a material that is compatible and does not interact with the cysteamine or a pharmaceutically acceptable salt thereof during storage;

[0044] One or more layers do not allow oxygen transmission. In certain embodiments, the cysteamine ophthalmic formulation is in the form of a free base or a pharmaceutically acceptable salt, a solvate, a hydrate, a polymorph, a prodrug, an isomer, or a solvate of a pharmaceutically acceptable salt thereof. Examples of cysteamine salt include, but are not limited to, hydrochloride, bitartrate, phosphate and tartrate. In some embodiments, the ophthalmic formulation comprises cysteamine, benzalkonium chloride, disodium edetate, carmellose sodium, citric acid monohydrate and optionally sodium metabisulfite. In other embodiments, the ophthalmic formulation further comprises one or more pharmaceutically acceptable carriers or excipients. Examples of carriers or excipients / include, but are not limited to, antioxidants, buffering agents, polymers, chelating agents, preservatives, tonicity agents, viscosifying agents, surfactants, dispersing agents and / or combination thereof.

[0045] Another embodiment of the present disclosure provides the packaging system, wherein the primary container is made up of oxygen-impermeable material.

[0046] Yet another embodiment of the present disclosure provides the packaging system, wherein the oxygen-impermeable material is selected from metals such as Aluminium, tin, lead, and steal, preferably Aluminium. In some embodiments, oxygen-impermeable materials also comprise plastic, glass, fiberglass, rubber.

[0047] Yet another embodiment of the present disclosure provides the packaging system, wherein the metallic barrier layer is made up of one or more metals such as aluminium, tin, lead, and steel.

[0048] Yet another embodiment of the present disclosure provides the packaging system, wherein the metallic barrier layer further comprises a protective or non-reactive lacquer contacting the cysteamine formulation.

[0049] Yet another embodiment of the present disclosure provides the packaging system, wherein the protective or non-reactive lacquer is made up of material selected from Resins, Epoxy Phenolic Lacquers, Epoxy-Polyester Lacquers, Phenolic Lacquers, Acrylic Lacquers, Polyamide Lacquers, Vinyl-based Lacquers, BPA-free Lacquers, Polyester Lacquers, Polyurethane Lacquers, and a combination thereof.

[0050] Yet another embodiment of the present disclosure provides the packaging system, further comprises a secondary container to enclose the primary container. In some embodiments, both the primary container and secondary container are made up of a material that is compatible with the formulation and does not react or interact with the formulation during storage.

[0051] Yet another embodiment of the present disclosure provides the packaging system, wherein the secondary container comprises an oxygen scavenger selected from Activated carbon, Sodium sulfite, Silica gel, Iron powder, Ascorbic acid, Citric acid, Zinc powder, zinc oxide, Glucose oxidase and Catalase.

[0052] Yet another embodiment of the present disclosure provides the packaging system which further comprises a nozzle configured to control dispensing the formulation. In some embodiments, nozzle is configured to control dispensing of the formulation, while the dispenser is configured to dispense the formulation in a controlled manner i.e., the dispenser ensures that only the precise amount of the formulation needed is dispensed, thereby minimizing the possibility of overuse or waste.

[0053] Yet another embodiment of the present disclosure provides the packaging system which further comprises a shoulder and a neck for precise dispensing of the formulation.

[0054] Yet another embodiment of the present disclosure provides the packaging system which optionally comprises a sealed laminated pouch to keep the packaging system.

[0055] Yet another embodiment of the present disclosure provides the packaging system, wherein the sealed laminated pouch further comprises an oxygen scavenger.

[0056] Yet another embodiment of the present disclosure provides the packaging system, wherein the resealable closure system is selected from a lid, a twist-off cap, and a screw cap.

[0057] Yet another embodiment of the present disclosure provides the packaging system, wherein the packaging system is in the form of a multilayered bottle, or a tube selected from an Aluminium tube or laminated tube.

[0058] Yet another embodiment of the present disclosure provides the packaging system, wherein the tube is Aluminium tube.

[0059] Yet another embodiment of the present disclosure provides the packaging system, wherein the oxygen-impermeable material of primary containers is a poly foil laminate. Yet another embodiment of the present disclosure provides the packaging system, wherein the metallic layer is sandwiched between plastic barrier layers in poly foil laminate.

[0060] Yet another embodiment of the present disclosure provides the packaging system, wherein the plastic barrier layer is made up of material selected from Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE), Polypropylene (PP), Ethylene Vinyl Acetate (EVA), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof.

[0061] Yet another embodiment of the present disclosure provides the packaging system, wherein the laminated tube is selected from Polyethylene (PE) laminated tube, Polyethylene terephthalate (PET) laminated tube, Polypropylene (PP) laminated tube, Ethylene vinyl alcohol (EVOH) laminated tube, Nylon laminated tube.

[0062] Yet another embodiment of the present disclosure provides the packaging system, optionally comprises a special lining of sealing layer that prevents the metal from reacting with the formulation inside.

[0063] Yet another embodiment of the present disclosure provides the packaging system, wherein the sealing layer is made of a polymer material that is compatible with the formulation.

[0064] Yet another embodiment of the present disclosure provides the packaging system, wherein the polymer material is selected from Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE) Polypropylene (PP), Ethylene Vinyl Acetate (EVA), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof

[0065] Yet another embodiment of the present disclosure provides the packaging system, wherein the packaging system provides better product stability, convenience, superior protection against microbial contamination, superior protection against light and oxygen degradation, extended product shelf life and enhanced user experience.

[0066] Yet another embodiment of the present disclosure provides the packaging system, for use in ophthalmic disease therapy in an individual. Yet another embodiment of the present disclosure provides a packaging system for packaging and delivering cysteamine formulation comprising: an Aluminium container having no or minimal head space reducing availability of free oxygen; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the Aluminium container; aluminium metallic layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulation.

[0067] In some embodiments, the primary container comprises an administration port for administering the ophthalmic formulation to a subject or patient in need thereof. The administration port can be made of any suitable material. In certain embodiments, the administration port may be made or manufactured with may be made or manufactured with materials include, but are not limited to, metal, plastic and a combination thereof. Metal including but not limited Aluminium, Tin, steel etc. and a combination thereof. The plastic material is made up of material selected from a group comprising Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE) Polypropylene (PP), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof.

[0068] Yet another embodiment of the present disclosure provides the packaging system, wherein the nozzle provides minimum or no head space due to which oxygen is not availability during both storage and in-use.

[0069] Yet another embodiment of the present disclosure provides the packaging system, wherein the packaging system consists of a layer of aluminum foil sandwiched between layers of plastic film.

[0070] Yet another embodiment of the present disclosure provides the packaging system, wherein the metallic layer provides a barrier to oxygen. Yet another embodiment of the present disclosure provides the packaging system, wherein the aluminum layer provides a barrier to oxygen.

[0071] Yet another embodiment of the present disclosure provides the packaging system, wherein the plastic layers provide a protective outer layer.

[0072] Yet another embodiment of the present disclosure provides the packaging system, which is made up of thin, flexible material that is lightweight and easy to handle.

[0073] Yet another embodiment of the present disclosure provides the packaging system, wherein the packaging system provides excellent protection against light and air, which can degrade the quality of the product.

[0074] Yet another embodiment of the present disclosure provides a method for delivering the cysteamine formulation, method comprising the following steps: removing the resealable closure mechanism; dispensing the desired amount of cysteamine formulation, and securely resealing the container after each use to prevent environmental oxygen exposure and maintain formulation stability.

[0075] Yet another embodiment of the present disclosure provides the method for dispensing cysteamine formulation for use in ophthalmic disease therapy in an individual.

[0076] Yet another embodiment of the present disclosure provides the method for dispensing the cysteamine ophthalmic formulation to improve convenience, provides ease of use, and protection against microbial contamination, protection against light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

[0077] Yet another embodiment of the present disclosure provides a method for delivering the formulation, which comprises the following steps: unscrewing the cap; squeezing the gently the packaging system to dispense the desired amount of formulation; screwing back the cap on to protect the remaining gel from light and air.

[0078] Yet another embodiment of the present disclosure provides an Aluminium tube for packaging and delivering a cysteamine formulation, comprising: an Aluminium container having no or minimal head space reducing availability of free oxygen; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the Aluminium container; aluminium metallic layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulation.

[0079] Yet another aspect of the present disclosure provides the tube wherein the container has a small footprint which makes it easy to store and transport.

[0080] Yet another embodiment of the present disclosure provides the tube, wherein the tube optionally comprises of a shoulder and a neck that allows for precise dispensing of the formulation.

[0081] Yet another embodiment of the present disclosure provides the tube, wherein nozzle provides minimum or no head space.

[0082] Yet another embodiment of the present disclosure provides the tube, which optionally comprises sealed laminated pouch with or without oxygen scavengers in which said packaging system can be kept.

[0083] Yet another embodiment of the present disclosure provides the tube which is laminated tube.

[0084] Yet another embodiment of the present disclosure provides the tube, wherein the laminated tube can be a poly foil laminated tube.

[0085] Yet another embodiment of the present disclosure provides the tube for packaging and delivering ophthalmic formulations. Yet another embodiment of the present disclosure provides the tube, wherein the ophthalmic formulations can be selected from ophthalmic viscous solutions, gels, ointments and creams.

[0086] Yet another embodiment of the present disclosure provides the tube, wherein ophthalmic formulation is oxygen sensitive formulation.

[0087] Yet another embodiment of the present disclosure provides the tube, wherein the plastic barrier layer is made up of material selected from Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE), Polypropylene (PP), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof.

[0088] Yet another embodiment of the present disclosure provides the tube, wherein the metallic barrier layer is made up of a metal selected from Aluminium, Tin, steel etc., and / or a combination thereof.

[0089] Yet another embodiment of the present disclosure provides the tube, wherein the tube optionally comprises a special lining of sealing layer that prevents the metal from reacting with the formulation inside.

[0090] Yet another embodiment of the present disclosure provides the tube, wherein the tube optionally comprises a special lining of sealing layer that prevents the aluminium from reacting with the formulation inside.

[0091] Yet another embodiment of the present disclosure provides the tube, wherein the sealing layer is made of a polymer material that is compatible with the formulation.

[0092] Yet another embodiment of the present disclosure provides the tube, wherein the sealing layer is made of a polymer material that is compatible with the ophthalmic formulation.

[0093] Yet another embodiment of the present disclosure provides the tube, wherein the tube consists of a layer of aluminum foil sandwiched between layers of plastic film.

[0094] Yet another embodiment of the present disclosure provides the tube, wherein the metallic layer provides a barrier to oxygen. Yet another embodiment of the present disclosure provides the tube, wherein the aluminum layer provides a barrier to oxygen.

[0095] Yet another embodiment of the present disclosure provides the tube, wherein the plastic layers provide a protective outer layer.

[0096] Yet another embodiment of the present disclosure provides the tube, wherein the tube provides excellent protection against light and air, which can degrade the quality of the product.

[0097] Yet another embodiment of the present disclosure provides tube for packaging and delivering a therapeutic formulation, for use in ophthalmic disease therapy in an individual.

[0098] Yet another embodiment of the present disclosure provides tube for packaging and delivering a therapeutic formulation to improve convenience, provides ease of use, and protection against microbial contamination, light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

[0099] Yet another embodiment of the present disclosure provides the tube, which is poly foil laminated tube.

[0100] Yet another embodiment of the present disclosure provides laminated tubes which are made by bonding multiple layers of materials together, typically including a plastic barrier layer, a metallic layer, and a sealing layer.

[0101] Yet another embodiment of the present disclosure provides the following types of laminated tubes:

[0102] 1. Polyethylene (PE) laminated tubes: These tubes are made of a layer of PE bonded to a layer of aluminum foil. They provide excellent protection against light and air.

[0103] 2. Polyethylene terephthalate (PET) laminated tubes: These tubes are made of a layer of PET bonded to a layer of aluminum foil. They provide a higher barrier against light and air than PE laminated tubes can provide.

[0104] 3. Polypropylene (PP) laminated tubes: These tubes are made of a layer of PP bonded to a layer of aluminum foil. They provide higher temperature resistance than PE or PET laminated tubes can provide. 4. Ethylene vinyl alcohol (EVOH) laminated tubes: These tubes are made of a layer of EVOH bonded to a layer of aluminum foil. They provide a high barrier against oxygen.

[0105] 5. Nylon laminated tubes: These tubes are made of a layer of nylon bonded to a layer of aluminum foil. They provide a high barrier against oxygen and moisture.

[0106] In abovementioned laminated tubes a layer is provided which is made up of material selected from Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE), Polypropylene (PP), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof.

[0107] Yet another embodiment of the present disclosure provides packaging and delivering solution comprises improved therapeutic formulation and a packaging system for packaging and delivering the therapeutic formulation to provide improved shelf life and in-use period.

[0108] Yet another embodiment of the present disclosure provides packaging and delivering solution comprises improved ophthalmic formulation and a packaging system for packaging and delivering the ophthalmic formulation to provide improved shelf life and in-use period.

[0109] Yet another embodiment of the present disclosure provides packaging and delivering solution comprises improved Cysteamine therapeutic formulation and a packaging system for packaging and delivering the Cysteamine ophthalmic formulation to provide improved shelf life and in-use period.

[0110] Yet another embodiment of the present disclosure provides the packaging and delivering solution, wherein the formulation comprises pharmaceutically active agent or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient, wherein pharmaceutically active agent or pharmaceutically acceptable salt thereof is present in the form of gel or solution.

[0111] Yet another embodiment of the present disclosure provides the packaging and delivering solution, wherein the ophthalmic formulation comprising pharmaceutically active agent or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient, wherein pharmaceutically active agent or pharmaceutically acceptable salt thereof is present in the form of ophthalmic gel or ophthalmic solution. Yet another embodiment of the present disclosure provides the packaging and delivering solution, wherein the formulation is in the form of Gel or solution.

[0112] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein in the ophthalmic formulation the pharmaceutically active agent is selected from cysteamine, Cysteamine bitartrate, Cysteamine hydrochloride, Cysteamine phosphate, Cysteamine tartrate and / or pharmaceutically acceptable salt thereof.

[0113] Yet another embodiment of the present disclosure provides the packaging and delivering solution, wherein in the ophthalmic formulation the polymer can be mucoadhesive.

[0114] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein in the ophthalmic formulation the pharmaceutically acceptable excipients include but are not limited to, antioxidants, buffering agents, polymers, chelating agents, preservatives, tonicity agents, viscosifying agents, surfactants, dispersing agents and / or combination thereof.

[0115] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein ophthalmic formulation comprising pharmaceutically active agent or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient, wherein active agent or pharmaceutically acceptable salt thereof is present in the form of ophthalmic gel or ophthalmic solution, for use in an ophthalmic disease therapy in an individual.

[0116] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein ophthalmic formulation comprising pharmaceutically active agent or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient, wherein active agent or pharmaceutically acceptable salt thereof is present in the form of ophthalmic gel or solution, for use in an ophthalmic disease therapy in an individual.

[0117] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein ophthalmic formulation comprising cysteamine or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient, wherein active agent or pharmaceutically acceptable salt thereof is present in the form of ophthalmic gel or ophthalmic solution, for use in an ophthalmic disease therapy in an individual. Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein ophthalmic formulation comprising cysteamine or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient, wherein active agent or pharmaceutically acceptable salt thereof is present in the form of ophthalmic gel, for use in an ophthalmic disease therapy in an individual.

[0118] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein the ophthalmic formulation comprising pharmaceutically active agent or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient which can offer improved convenience, ease of use, and protection against microbial contamination, light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period for the ophthalmic formulation.

[0119] Yet another embodiment of the present disclosure provides packaging and delivering solution, wherein the ophthalmic formulation comprising cysteamine or pharmaceutically acceptable salt thereof, polymers, antioxidants and / or pharmaceutically acceptable excipient which can offer improved convenience, ease of use, and protection against microbial contamination, light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period for the ophthalmic formulation.

[0120] Yet another embodiment of the present disclosure provides a packaging system which minimizes the headspace oxygen available which causes degradation of the therapeutically active agent by oxidation.

[0121] Yet another embodiment of the present disclosure provides a packaging system which packs the primary packaging inside a sealed pouch with or without oxygen scavengers.

[0122] Yet another embodiment of the present disclosure provides a packaging system which packs the primary packaging inside a sealed laminated pouch with or without oxygen scavengers.

[0123] Yet another embodiment of the present disclosure provides an oxygen barrier / impermeable container closure systems including but not limited to multilayered bottles, lami tubes, metal tubes. While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.

[0124] EXAMPLES

[0125] Step 1: Collect Water for Injection; purge with nitrogen gas to achieve dissolved oxygen level less than 1 ppm.

[0126] Step 2: Separate 50% batch size Water for injection in another manufacturing vessel.

[0127] Step 3: Add & dissolve weighed quantity of citric acid in step 2 Water for injection.

[0128] Step 4: Add & dissolve weighed quantity of sodium hydroxide in step 3 solution.

[0129] Step 5: Add & mix measured quantity of 0.1 N hydrochloric acid solution in step 4 solution.

[0130] Step 6: Adjust the pH of step 5 solution to pH 4.4 with IN sodium hydroxide solution.

[0131] Step 7: Make up the batch quantity to 90% with previously nitrogen purged Water for Injection.

[0132] Step 8: Divide the step 7 solution into two parts as below.

[0133] Part 1: Divide 80% solution from step 7 solution for polymer phase preparation.

[0134] Part 2: Divide 10% solution from step 7 solution for drug phase preparation.

[0135] Preparation of Polymer Phase Solution:

[0136] Step 9: To part 1 solution of step 8, add slowly and disperse sodium carboxymethyl cellulose.

[0137] Step 10: Autoclave the step 9 polymer phase solution at 121 °C for 20 mins and after autoclaving cool down the polymer phase solution to 2 - 8°C temperature condition.

[0138] Preparation of Drug Phase Solution:

[0139] Step 11: To part solution of step 8, add and dissolve weighed quantity of edetate disodium.

[0140] Step 12: Add and dissolve weighed quantity of BKC 50% solution in step 11 solution. Step 13: Add and dissolve weighed quantity of cysteamine hydrochloride in step 12 solution.

[0141] Step 14: Aseptically filter the drug phase solution of step 13 through 0.22 pm filter.

[0142] Step 15: Aseptically mix the step 10 polymer phase and step 14 dug phase to get uniform viscous solution. Step 16: Aseptically make up the step 15 solution batch size to 100% with previously nitrogen purged Water for Injection through 0.22 pm filter.

[0143] Step 17: Aseptically fill the sterilized bulk into amber color USP Type-1 glass vials, maintain the pre & post nitrogen environment in the glass vials and stopper with 20 mm butylated rubber stopper and seal with 20 mm aluminum flip-off seals. Step 18: Label the filled and sealed vials.

[0144] The ingredients and amount thereof for the preparation of Example 1 are summarized in Table 1 below.

[0145] Table 1: Ingredients and amount thereof used in Example 1.

[0146] Example -2 Manufacturing Process (Filled in aluminium tubes of the present invention):

[0147] Step 1: Collect Water for Injection; purge with nitrogen gas to achieve dissolved oxygen level less than 1 ppm.

[0148] Step 2: Separate 50% batch size Water for injection in another manufacturing vessel. Step 3: Add & dissolve weighed quantity of citric acid in step 2 Water for injection.

[0149] Step 4: Add & dissolve weighed quantity of sodium hydroxide in step 3 solution.

[0150] Step 5: Add & mix measured quantity of 0.1 N hydrochloric acid solution in step 4 solution.

[0151] Step 6: Adjust the pH of step 5 solution to pH 4.4 with IN sodium hydroxide solution.

[0152] Step 7: Make up the batch quantity to 90% with previously nitrogen purged Water for Injection. Step 8: Divide the step 7 solution into two parts as below.

[0153] Part 1 : Divide 80% solution from step 7 solution for polymer phase preparation.

[0154] Part 2: Divide 10% solution from step 7 solution for drug phase preparation.

[0155] Preparation of Polymer Phase Solution: Step 9: To part 1 solution of step 8, add slowly and disperse sodium carboxymethyl cellulose.

[0156] Step 10: Autoclave the step 9 polymer phase solution at 121 °C for 20 mins and after autoclaving cool down the polymer phase solution to 2 - 8°C temperature condition.

[0157] Preparation of Drug Phase Solution: Step 11: To part solution of step 8, add and dissolve weighed quantity of edetate disodium.

[0158] Step 12: Add and dissolve weighed quantity of BKC 50% solution in step 11 solution.

[0159] Step 13: Add and dissolve weighed quantity of cysteamine hydrochloride in step 12 solution.

[0160] Step 14: Aseptically filter the drug phase solution of step 13 through 0.22 pm filter.

[0161] Step 15: Aseptically mix the step 10 polymer phase and step 14 dug phase to get uniform viscous solution.

[0162] Step 16: Aseptically make up the step 15 solution batch size to 100% with previously nitrogen purged Water for Injection through 0.22 pm filter.

[0163] Step 17: Aseptically fill the sterilized bulk into aluminium tubes and sealed the filled aluminium tubes. Step 18: Label the filled and sealed aluminium tubes.

[0164] The ingredients and amount thereof for the preparation of Example 2 are summarized in Table 2 below.

[0165] Table 2: Ingredients and amount thereof used in Example 2.

[0166] After preparing formulation in two packaging system i.e., (Example 1) and (Example 2), impurity Profile at long term storage condition were analysed. Result of said analysis are summarized in below Table 3.

[0167] Table 3: Impurity Profile at Long Term Storage Condition (5 ± 3°C):

[0168] As can be seen from Table 3, Cysteamine dihydrochloride impurity in case of Example 2 (packaging system of present invention) is significantly lower than Cystadrops and Example 1 (packaging system of prior art) even after storage of 3 months. Similarly, total impurities are also very much low for inventive packaging system of Example 2 of the present invention as compared to other packaging system of the prior arts. Thus, the packaging system of the present invention provides better long-term storage stability for cysteamine formulation as compared to other packaging systems of the prior arts. Further, impurity Profile of ophthalmic formulation in packaging system of Example 1 and Example 2 during In-use Storage were analysed. Result of said analysis are summarized in below Table 4.

[0169] Table 4: Impurity Profile at 25 ± 2°C / 60 ± 5% RH / Room Temperature (In-use Storage): As can be seen from Table 4, Cysteamine dihydrochloride impurity in case of packaging system of Example 2 (of present invention) is significantly lower than packaging system of Example 1 (of prior art) even after in use storage of 2 weeks. Similarly, total impurities are also very much low for packaging system of Example 2 as compared to packaging system of Example 1. Thus, packaging system of the present invention provides better in use stability for the cysteamine formulation as compared to other packaging system.

Claims

WE CLAIM1. A packaging system for packaging and delivering cysteamine formulation comprising: a primary container; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the primary container; one or more layers selected from metallic layer, plastic barrier layer, and sealing layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulationWherein,The primary container has no or minimal head space reducing the availability of free oxygen;The container is made up of a material that is compatible and does not interact with the cysteamine or a pharmaceutically acceptable salt thereof during storage;One or more layers do not allow oxygen transmission.

2. The packaging system as claimed in claim 1 , wherein the primary container is made up of oxygen-impermeable material.

3. The packaging system as claimed in claim 2, wherein the oxygen-impermeable material is selected from metals such as Aluminium, tin, lead, and steal, preferably Aluminium.

4. The packaging system as claimed in claim 1 , wherein the metallic barrier layer is made up of one or more metals such as aluminium, tin, lead, and steel.

5. The packaging system as claimed in claim 1, wherein the metallic barrier layer further comprises a protective or non-reactive lacquer contacting the cysteamine formulation.

6. The packaging system as claimed in claim 5, wherein the protective or non-reactive lacquer is made up of material selected from Resins, Epoxy Phenolic Lacquers, Epoxy-Polyester Lacquers, Phenolic Lacquers, Acrylic Lacquers, Polyamide Lacquers, Vinyl-based Lacquers, BPA-free Lacquers, Polyester Lacquers, Polyurethane Lacquers, and a combination thereof.

7. The packaging system as claimed in claim 1, further comprises a secondary container to enclose the primary container.

8. The packaging system as claimed in claim 7, wherein the secondary container comprises an oxygen scavenger selected from Activated carbon, Sodium sulfite, Silica gel, Iron powder, Ascorbic acid, Citric acid, Zinc powder, zinc oxide, Glucose oxidase and Catalase.

9. The packaging system as claimed in claim 1, further comprises a nozzle configured to control dispensing the formulation.

10. The packaging system as claimed in claim 1, further comprises a shoulder and a neck for precise dispensing of the formulation.

11. The packaging system as claimed in claim 1 , optionally comprises a sealed laminated pouch to keep the packaging system.

12. The packaging system as claimed in claim 11, wherein the sealed laminated pouch further comprises an oxygen scavenger.

13. The packaging system as claimed in claim 1, wherein the resealable closure system is selected from a lid, a twist-off cap, and a screw cap.

14. The packaging system as claimed in claim 1, wherein the packaging system is in the form of a multilayered bottle, or a tube selected from an Aluminium tube or laminated tube.

15. The packaging system as claimed in claim 14, wherein the tube is Aluminium tube.

16. The packaging system as claimed in claim 2, wherein the oxygen-impermeable material of primary containers is a poly foil laminate.

17. The packaging system as claimed in claim 16, wherein the metallic layer is sandwiched between plastic barrier layers in poly foil laminate.

18. The packaging system as claimed in claim 1 or 17, wherein the plastic barrier layer is made up of material selected from Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE), Polypropylene (PP), Ethylene Vinyl Acetate (EVA), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof.

19. The packaging system as claimed in claim 14, wherein the laminated tube is selected from Polyethylene (PE) laminated tube, Polyethylene terephthalate (PET) laminated tube, Polypropylene (PP) laminated tube, Ethylene vinyl alcohol (EVOH) laminated tube, Nylon laminated tube.

20. The packaging system as claimed in claim 1, optionally comprises a special lining of sealing layer that prevents the metal from reacting with the formulation inside.

21. The packaging system as claimed in claim 20, wherein the sealing layer is made of a polymer material that is compatible with the formulation.

22. The packaging system as claimed in claim 21, wherein the polymer material is selected from Polyethylene (PE), High-density polyethylene (HDPE), Low density polyethylene (LDPE) Polypropylene (PP), Ethylene Vinyl Acetate (EVA), Ethylene Vinyl Alcohol (EVOH), Polyamide (PA), Polyvinyl Chloride (PVC), Polyethylene terephthalate (PET, or PET-P), Biaxially oriented PET (BOPET) and a combination thereof23. The packaging system as claimed in claim 1, wherein the packaging system provides better product stability, convenience, superior protection against microbial contamination,superior protection against light and oxygen degradation, extended product shelf life and enhanced user experience.

24. The packaging system as claimed in claims 1 to 23, for use in ophthalmic disease therapy in an individual.

25. A packaging system for packaging and delivering cysteamine formulation comprising: an Aluminium container having no or minimal head space reducing availability of free oxygen; the cysteamine or a pharmaceutically acceptable salt thereof packaged in the Aluminium container; aluminium metallic layer; a dispenser or an administration port to dispenses a precise amount of formulation reducing the risk of overuse; a resealable closure system to reseal the container after each dispensing of the formulation.

26. A method for delivering the cysteamine formulation, method comprising the following steps: removing the resealable closure mechanism; dispensing the desired amount of cysteamine formulation, and securely resealing the container after each use to prevent environmental oxygen exposure and maintain formulation stability.

27. The method as claimed in claim 26, for dispensing cysteamine formulation for use in ophthalmic disease therapy in an individual.

28. The method as claimed in claims 26 and 27, for dispensing the cysteamine ophthalmic formulation to improve convenience, provides ease of use, and protection against microbial contamination, protection against light and oxygen to enhance the overall user experience and product stability, extended shelf life and in-use period.

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