FIELD OF THE INVENTION

The present invention relates to an intravenous infusion dosage form for morphine and process for its preparation. BACKGROUND OF THE INVENTION

Preparation of a ready-to-infuse intravenous dosage form of morphine that can withstand the harsh conditions of autoclaving is problematic due to instability of morphine in aqueous solution under such conditions and upon storage. Xuan et al (International Journal of Pharmaceutical Compounding, Jan/Feb 2006: 10; 1; pp-69-73), has reported autoclaved intravenous solution of 1 mg/mL morphine sulfate in polypropylene infusion bags, for use in patient-controlled analgesia pumps for postoperative pain management. As per the description of Xuan et al, the autoclaved infusion bag were not covered with any secondary packaging during storage. The solution was reported to have no loss of morphine and impurity contents were low during its shelf life. However,when the present inventors reproduced the disclosure as per Xuan et al, it was observed that there was an unacceptable, high level of pseudomorphine impurity immediately upon autoclaving and its level was more than 0.2 % by weight of morphine, which is beyond acceptable levels. The total impurities levels were also very high.

The present inventors initially attempted to overcome the problem of instability of morphine aqueous solution due to autoclaving. One successful attempt was to provide an autoclavable intravenous infusion dosage form of morphine by placing the primary infusion container filled with aqueous solution inside a secondary packaging container and controlling the oxygen in the space between the two containers by filling an inert gas and/or placing an oxygen scavenger in the space, during autoclaving. A US patent application 15/694,243 was filed claiming this technique. However, a disadvantage of the method is that it is required that the aqueous solution in each container of the infusion dosage form be visually inspected after autoclaving. To enable visual inspection of the contents of the primary container it is necessary to remove the primary container from the secondary container. Further after visual inspection it is necessary to again place the primary container in a secondary container and restore the inert atmosphere in the space between the two containers. These requirements make the prior art process cumbersome, complex and costly. OBJECTS OF THE INVENTION

It is an object of the present invention to manufacture a stable, autoclavable, ready-to-infuse, intravenous infusion dosage form of morphine by a simple process. Particularly it is an object of the invention to allow for autoclaving of the first container without the need to surround the first container with a secondary packaging and without the need to place an oxygen scavenger or fill an inert gas in the space between the first container and the secondary packaging.

It is also an object of the present invention to prepare an intravenous infusion dosage form of morphine that is autoclavable (i.e. which can withstand the harsh conditions of autoclaving), and that maintains prolonged stability at room temperature. This is because terminal sterilization by autoclaving provides highest assurance of sterility for parenteral dosage form.

It is another object of the present invention to provide an intravenous infusion dosage form with a large volume of an aqueous solution of morphine that uses a minimum amount of excipients. It is an object of the present invention to avoid the use of antioxidants, complexing agents like cyclodextrins, chelating agents and amino acids in the large volume parenteral solution of morphine.

It is another object of the present invention to provide a stable intravenous infusion dosage form of morphine wherein degradation of morphine to pseudomorphine impurity is controlled, such that content of pseudomorphine remains within a limit of not more than 0.2 % by weight of morphine through-out the shelf life. Pseudomorphine is an undesirable oxidative degradation product of morphine having lower efficacy compared to morphine. Nadine et. al. (Biochem Pharmacol 2011, 81, 1248-54), studied the efficacy and potency of morphine and its nine major metabolites including pseudomorphine and categorized these metabolites under strong or weak agonists of the opioid receptor ligands. Nadine reported that pseudomorphine is a weak metabolite of morphine that exhibit lower efficacy at a similar concentration as morphine. Nadine reported that while morphine and its strong metabolites like morphine - 6-glucuronide, normorphine etc. exhibited efficacies in the nanomolar range, the weak metabolites like pseudomorphine show efficacy only in high micromolar range. It is therefore an objective of the present invention to prevent degradation of morphine to pseudomorphine such that the content of pseudomorphine in the intravenous infusion dosage form remains within a limit of not more than 0.2 % by weight of morphine.

The present invention meets the aforesaid objectives. Prior to the present invention, inventors had faced a problem in that infusion flexible plastic containers not free of a polyamide when employed for intravenous infusion dosage form for morphine were subjected to autoclaving for terminal sterilization, particles of unknown nature were found to be generated. The chemical nature of these particles was investigated by separating the particles from the aqueous solution that were generated during autoclaving. The filtered particles were then subjected to structural characterization techniques such as Raman spectroscopy and Mass Spectroscopy (LC-MS/MS). It was found that these particles were of polyamide-11 cyclic dimer and/or polyamide-11 cyclic trimer (hereinafter referred to as "polyamide particles"). It is believed that these particles may have been originated from one of the layers of the plastic container made up of polyamide. Without wishing to be bound by any theory, the inventors believed that upon autoclaving, the polyamide-11 cyclic dimer and/or polyamide-11 cyclic trimer may have migrated from the polyamide layer into the aqueous solution of morphine. Such polyamide particles may have toxicological and/or regulatory implications and are hazardous to health.

The present invention solved this problem. The present invention provides an intravenous infusion dosage form of morphine in a multilayered flexible plastic container that can be directly administered to the patients intravenously, and which allows autoclaving of the first container without the need to surround the first container with a secondary packaging. While attempting to arrive at such intravenous infusion dosage form of morphine in a multilayered flexible plastic container the present inventors discovered that the multilayer flexible plastic container needed to be necessarily free of a polyamide and the multilayered infusion container needed to have an oxygen scavenger layer sandwiched between the layers. However, this oxygen scavenger layer is not placed in direct contact with the aqueous solution of morphine. That is, the oxygen scavenger layer is always placed in middle layers away from the innermost layer. The present inventors further discovered that multilayered flexible plastic infusion containers that have an oxygen scavenger sandwiched between polymeric layers and wherein the container is free of polyamide 11, when filled with aqueous solution of morphine, could withstand autoclaving without any chemical or physical instability resulting from the autoclaving at 121 °C for 15 minutes. There is negligible chemical degradation of morphine and the known and unknown impurities are controlled. Further, there is no formation of particles of polyamide 11 cyclic dimer and/or polyamide 11 cyclic trimer upon autoclaving. Other particles if any remain within acceptable limits, not only immediately upon autoclaving but also on long term storage. No secondary packaging is required before the step of autoclaving and therefore visual inspection could be directly done on the first container and then the inspected containers could be packed into secondary packaging.

The present inventors further discovered that when packing the first containers of the present invention into secondary packaging it is not required to fill the space between the infusion container and secondary packaging with an inert gas. The intravenous infusion dosage form is advantageous in that when subjected to storage stability testing, the total impurities of morphine remain within a limit of not more than 1.0 % by weight of morphine and pseudo morphine impurity remain within a limit of not more than 0.2 % by weight of morphine. SUMMARY OF THE INVENTION

The present invention provides an intravenous infusion dosage form comprising: an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml and present in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container has an oxygen scavenger layer sandwiched between an outermost and an innermost layer of the container, the container being free of a polyamide and wherein the multilayered flexible plastic infusion container filled with the aqueous solution of morphine is autoclavable.

The present invention may be summarized as follows: i) . An intravenous infusion dosage form comprising: an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml and present in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container has an oxygen scavenger layer sandwiched between an outermost and an innermost layer of the container, the container being free of a polyamide and wherein the multilayered flexible plastic infusion container filled with the aqueous solution of morphine is autoclavable. ii) . An intravenous infusion dosage form comprising: an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml and present in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container has an oxygen scavenger layer sandwiched between an outermost and an innermost layer of the container, the container being free of a polyamide and wherein the multilayered flexible plastic infusion container filled with the aqueous solution of morphine is autoclavable, wherein the oxygen scavenger layer of the intravenous infusion dosage form is made up of a polymer selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer. iii) An intravenous infusion dosage form comprising: an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.5 mg/ml to 1.5 mg/ml and present in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container has an oxygen scavenger layer sandwiched between an outermost and an innermost layer of the container, the container being free of a polyamide wherein the oxygen scavenger layer is made up of a polymer selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene - vinyl acetate copolymer and wherein the outermost layer of the intravenous infusion dosage form is made up of a polymer selected from a group consisting of polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate and polyethylene naphthalate and/or wherein the innermost layer of the intravenous infusion dosage form is in direct contact with the aqueous solution of morphine and is made up of a polymer selected from a group consisting of polyethylene and cycloolefin and wherein the multilayered flexible plastic infusion container filled with the aqueous solution of morphine is autoclavable.

The present invention further provides a process of preparing the intravenous infusion dosage form of morphine or its pharmaceutically acceptable salt.

DESCRIPTION OF THE FIGURES

FIGURE 1 provides the Raman spectrum of reference substance of polyamide-11 cyclic monomer.

FIGURE 2 provides the Raman spectrum of reference substance of polyamide-11 cyclic dimer.

FIGURE 3 provides the Raman spectrum of particles which were formed after autoclaving of the intravenous infusion dosage form of the aqueous solution, prepared as per Comparative Example II. Comparative Example II uses multilayered flexible plastic infusion containers having no oxygen scavenger layer and the outer layer is made up of polyamide 11.

FIGURE 4A provides the HPLC-MS chromatogram obtained when a solvent extract of polyamide 11 resin sample of Sigma Aldrich containing a mixture of polyamide-11 cyclic monomer, polyamide-11 cyclic dimer and polyamide-11 cyclic trimer was injected. Three peaks were observed at retention time of 1.600, 2.019 and 2.438 minute.

FIGURE 4B provides the mass spectrum of the peak having a retention time of 2.438 minute (See Figure 4A). Its mass ion was 550.6 which corresponds to polyamide-11 cyclic trimer.

FIGURE 4C provides the mass spectrum of the peak having a retention time of 2.019 minute (See Figure 4A). Its mass ion was found to be 367.2 which corresponds to polyamide-11 cyclic dimer.

FIGURE 4D provides the mass spectrum of the peak having a retention time of 1.600 minute (Figure 4A). Its mass ion was found to be 184.6 which corresponds to polyamide-11 cyclic monomer. FIGURE 5A provides the HPLC-MS chromatogram obtained for the sub-visible particles as per Comparative Example III. Two peaks were observed at retention times of 2.474 and 2.019 minutes.

FIGURE 5B provides the mass spectrum of the peak at retention time of 2.438 minutes (See Figure 5A). Its mass ion was 550.7 which corresponds to polyamide-11 cyclic trimer. FIGURE 5C provides the mass spectrum of the peak at retention time of 2.019 minutes (See Figure 5 A). Its mass ion was 367.2 which corresponds to polyamide-11 cyclic dimer.

DETAILED DESCRIPTION OF THE INVENTION

The term 'autoclavable' as used herein means that the multilayered flexible plastic infusion containers according to the present invention can withstand autoclaving without affecting the chemical and physical stability of aqueous solution of morphine.

By the term chemical stability, it is meant that the levels of pseudomorphine impurity is not more than 0.2 % by weight of morphine and the level of total impurities is not more than 1.0 % by weight of morphine when the autoclaved intravenous infusion dosage form according to the present invention is stored at room temperature for at least one year. By the term 'physical stability', it is meant that the aqueous solution of morphine contained in the intravenous infusion dosage form according to the present invention when autoclaved and stored at room temperature for at least one year, the aqueous solution is found to be free of particles of polyamide-11 cyclic monomer and/or polyamide-11 cyclic dimer and/or polyamide-11 cyclic trimer. Other particles, if present, are found to be within the limits of particulate matter count specified for parenteral products by regulatory agencies, such as United States Pharmacopoeia Convention, Revision Bulletin 2011. United States Pharmacopoeia Convention specifies the limit of particulate matter count based on the volume of preparation in the container. For a container of nominal volume of 100 ml or less, the count of particles having size >10 μπι should be not more than 6000 counts per container during the shelf life of the product and the count of particles having size > 25 μπι should be not more than 600 counts per container during the shelf life of the product. Also, for a container of nominal volume of more than 100 ml, the count of particles having size >10 μπι should be not more than 25 particles per millilitre of the solution during the shelf life of the product and the count of particles having size >25 μπα should be not more than 3 particles per millilitre of the container during the shelf life of the product. The count of particulate matter can be determined by techniques known in the art, such as microscopic particulate count or light obstruction particulate count. The term 'ready-to-infuse' intravenously is a ready to administer intravenous dosage form. This means there is no step of reconstitution, dilution, transfer, sterilization or compounding of the medicament and the medicament can be directly infused into venous circulation from the dosage form. The existing products which are either freeze dried dosage forms require reconstitution or those that are in the form of pre-concentrates require dilution and are ready to dilute but not ready-to-infuse. Also, the ready-to-infuse dosage form is different from the dosage form suitable for bolus injection such as that available under the brand name of Duramorph ^® or Infumorph ^® in which the aqueous solution is filled into small volume of 10 ml containers such as ampoule or dosette and it requires transfer of many such ampoules into an infusion container so as to deliver a higher dose. In contrast, the ready-to-infuse intravenous dosage form of present invention includes the aqueous solution that can be directly administered via intravenous route of administration, using conventional techniques of intravenously delivering under the gravitational force and does not require any complicated assembly such as pump, micro-pump systems or auto-injector. Further, the dosage form is said to be ready-to-infuse dosage form as it is a terminally sterilized i.e. autoclaved dosage form and is ready to be infused in that there are no chances of contamination or adulteration or exposure to non sterile environment. The dosage form is sterile and is safe to be directly infused intravenously without any risk. The terminally sterilized ready-to-infuse intravenous dosage form is intact and its sterility is maintained at all time, storage and during intravenous administration since there is no manipulation carried out to the dosage form before administration.

The intravenous infusion dosage form of the present invention is storage stable and remains stable over prolonged period of at least 1 year for example upto 1 year, more preferably up to 2 years meaning thereby that the total impurities of morphine remain not more than 1.0 % by weight of morphine. Upon storage of the intravenous dosage form of the present invention for six months at accelerated storage condition of 40°C/25% relative humidity, and for twelve months at room temperature (25°C/40% relative humidity), the content of known pseudomorphine impurity and other known impurities like Normorphine, Morphine - N-Oxide, pseudomorphine, 10-alpha hydroxyl morphine, morphinone, oripavine, apomorphine and codeine sulphate remains not more than 0.2 % by weight of morphine; the content of total impurities remains not more than 1.0 % by weight of morphine and the content of highest unknown impurity remains not more than 0.1 % by weight of morphine.

By the term 'free of a polyamide' as used herein means that the container does not include polyamide material in any of its layers (which is also generally referred to as Nylon).

The term Oxygen scavenger' as used herein means any material that possesses oxygen absorbing or oxygen scavenging property. The term 'large volume' as used herein means that the volume of the aqueous solution in the containers is in the range of 50 ml to 1000 ml, such as for example 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 ml.

The term 'multilayered flexible plastic infusion container' means a container having multiple layers of flexible films that are adhered, molded or sealed together by any means and have at least one layer made up of a plastic or polymeric material. The term multilayered means three or more layers.

The term 'infusion container' means a container from which a large volume of the aqueous solution is directly infused intravenously to the patient without further dilution.

The term 'innermost layer' refers to the layer of multilayered flexible plastic infusion container which is in contact with the filled aqueous solution.

The term 'total impurities' as used herein refers to summation of all known and unknown impurities of morphine or its pharmaceutically acceptable salt present in the intravenous infusion dosage form of the present invention, either initially or upon storage during the shelf life. The total impurities are expressed as % by weight i.e. % of the labelled morphine content of the intravenous infusion dosage form of the present invention.

The known impurities of morphine include pseudomorphine, 10-alpha hydroxyl morphine, morphinone, oripavine, apomorphine, bimorphine and codeine sulphate. The level of known, unknown and total impurities of drug may be analysed by any suitable means. Preferably, it may be analysed by high performance liquid chromatography method. Any other suitable chromatographic technique may however be used.

The term "sterile" as used in the context of the invention, means that the aqueous solution has been brought to a state of sterility and the solution complies with the sterility requirements of the standard Pharmacopoeias like United States Pharmacopoeias (USP) until the shelf life.

The term polyamide 11 polymer as used herein refers to a polymer formed by polymerization of 11- aminoundecanoic acid, an amino acid having 11 carbon atoms.

The 11 -aminoundecanoic acid and Polyamide 11 polymer are represented by Formula I and II respectively.

Formula I Formula II

The polyamide 11 cyclic dimer and polyamide 11 cyclic trimers, as used herein in the specification are cyclic dimer and cyclic trimer of 11-aminoundecanoic acid, represented by Formula III and IV below respectively. Further structural details of the polyamide 11 cyclic dimer and polyamide 11 cyclic trimers are respectively described in journal references (1) Biopolymers, 2000 Oct 15; 54(5): 365-73 and (2) Macromolecules, 2001, 34: 837-843.

Formula III

Formula IV

In specific embodiments, the intravenous infusion dosage form of the present invention comprises an aqueous solution of morphine or its pharmaceutically acceptable salt filled in a multi-layered flexible plastic infusion container having more than two layers such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 layers or more, wherein at least one layer of oxygen scavenger is sandwiched between the layers.

In preferred embodiments, the multilayered flexible plastic infusion container is made up of at least three layers comprising an oxygen scavenger layer which is sandwiched between an outermost and an innermost layer of the multi-layered flexible plastic container wherein the container is free of a polyamide and wherein the container filled with the aqueous solution of morphine is autoclavable. In some embodiments, the multilayer flexible plastic infusion container may have other intermediate layers present in between the outermost and oxygen scavenger layer and and in between the oxygen scavenger layer and innermost layer. In some embodiments, multi-layered flexible plastic infusion container have tie layer/s which sandwiches the layer having oxygen scavenger on both sides and helps the oxygen scavenger layer to bond with the other polymeric layers on either side.

The oxygen scavenger layer comprises one or more oxygen scavenger material which has oxygen absorbing or scavenging property. In one or more embodiments, the oxygen scavenger layer is made up of material selected from, but not limited to, ethylene vinyl alcohol copolymer, ethylene-vinyl acetate copolymer, metallocene polyethylenes, polymethylpentene; ethylene/vinyl aralkyl copolymer; atactic-1,2- polybutadiene, polyoctenamer, 1 ,4-polybutadiene; ethylene/vinyl cyclohexene copolymer; ethylene/methyl acrylate/ cyclohexenyl methyl acrylate terpolymer; homopolymer or a copolymer of cyclohexenylmethyl acrylate; ethylene/methyl acrylate/ cyclohexenylmethyl acrylate terpolymer, ethylene/ vinyl cyclohexene copolymer, ethylene/cyclohexenylmethyl acrylate copolymer and mixtures thereof. In some embodiments, the oxygen scavenger layer may have oxygen absorbing agents or catalysts as a part of the layer, for example transition metal salt of iron, nickel, copper, manganese, cobalt, rhodium, titanium, chromium, vanadium, ruthenium, and the like such as stearic acid cobalt, a neodecanoic acid cobalt; zeolites, silica based oxygen absorbers, iron based scavengers, charcoal etc. In preferred embodiments, the oxygen scavenger layer is made up of polymer selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer. In one embodiment, the oxygen scavenger layer is made up of ethylene vinyl alcohol copolymer. In a specific embodiment, the oxygen scavenging layer has a thickness in the range of about 1 micron to about 80 micron, preferably about 5 micron to 20 micron, such as for example 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 micron. In one preferred embodiment, the oxygen scavenging layer has a thickness of 10 micron.

In one or more embodiments, the outermost layer of the multilayered flexible plastic infusion container according to the intravenous dosage form of the present invention is made up of a polymer selected from but not limited to homopolymer or copolymer of polyalkylene terephthalates like polyethylene terephthylate (PET), polypropylene terephthalate, polybutylene terephthalate; polyalkylene naphthylates like polyethylene naphthalate, polypropylene naphthylate and the like. The outermost layer acts as a protective barrier layer. In preferred embodiments, the outermost layer of the flexible plastic infusion container is made up of a polymer selected from a group consisting of polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate and polyethylene naphthalate. In one preferred embodiment, the outermost layer is made up of polyethylene terephthalate (PET). The outermost layer is also free of polyamide. In preferred embodiments, the outermost layer has a thickness in the range of about 5 microns to about 50 microns, preferably 5 to 20 microns such as for example 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 microns. In one preferred embodiment, the outermost layer has a thickness of 12 microns.

In one or more embodiments, the innermost layer of the multilayered flexible plastic infusion container which is in direct contact with the aqueous solution of morphine is made up of polymeric materials selected from but not limited to polyalkylene polymers or copolymers like polyethylene polymer or copolymer; cycloolefin homopolymers or co-polymers like cycloolefin polymer; ethylene propylene block copolymer; ethylene/alpha-olefin copolymer; oxygen permeating polyolefins and the like. The innermost layer is free of polyamide. Preferably, the innermost layer is selected from the group consisting of polyethylene layer and cycloolefin layer. In one preferred embodiment, the innermost layer is composed of polyethylene based polymer. Example of polyethylene polymers that are preferably used include, low density polyethylene polymer, linear low density polyethylene polymer, straight-chain low- density poly ethylenes, super low density polyethylene, high density polyethylene polymer or a mixed composition thereof. In one preferred embodiment, the inner layer is composed of a low density polyethylene polymer which is linear or non-linear. In another preferred embodiment, the inner layer is composed of a high density polyethylene polymer. In one embodiment, a mixture of a linear low-density polyethylene and a high-density polyethylene is preferably used, in that the mixture has a property that supplements each other.

In an alternate embodiment, the innermost layer is composed of cyclo-olefin polymer or copolymer. The cyclic olefin polymer may be a cyclooolefin homopolymer (COP) or a cycloolefin copolymer (COC) or a mixture thereof. Cycloolefin homopolymers (cycloolefin polymers, or COP) are homopolymers comprising single type of cycloolefin monomers. Cycloolefins (cyclic olefins) are mono or polyunsaturated, mono or polycyclic ring systems such as cycloalkenes (like cyclopropene, cyclopentene, cyclobutene, cyclohexene), bicycloalkenes (like norbornene, dicyclopentadiene), tricycloalkenes, tetracycloalkenes (tetracyclododecene) and the like. The ring system can be monosubstituted or polysubstituted. Cycloolefin copolymers (COC) comprise cycloolefins and co-monomers, wherein cycloolefins are copolymerized with one or more comonomers. Suitable co-monomers are unsubstituted or substituted olefins, of 2 to 20 carbon atoms, preferably 2 to 6 carbon atoms, such as ethylene, butylene, etc. Any of these olefins may be used individually, or two or more types of olefins may be used in combination. In preferred embodiments, the innermost layer is made up of a polymer selected from ultra- low density polyethylene, low density polyethylene, linear low density polyethylene, medium density polyethylene, high density polyethylene or cycloolefin polymer and is free of a polyamide. In one preferred embodiment, the innermost layer of the flexible plastic infusion container that in direct contact with the aqueous solution is made up of a polymer selected from a group consisting of polyethylene and cycloolefin. The innermost layer has a thickness in the range of about 10 microns to about 220 microns, preferably 10 microns to about 50 microns, more preferably 15 to 30 microns such as for example 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 micron. In one specific embodiment, the outermost layer has a thickness of 20 microns.

In one or more embodiments, the multilayered flexible plastic infusion container is free of polypropylene polymer.

In one or more embodiments, the multilayered flexible plastic infusion container according to the present invention has a total thickness in the range of 50 microns to 500 microns; preferably in the range of 100 micron to 450 microns, more preferably in the range of 200 to 350 microns such as for example 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345 or 350 microns. In one or more embodiments, the multilayered flexible plastic infusion container according to the present invention has an oxygen transmission rate of less than 100 cc/ (m ^{2 -} day aim), preferably less than 50 cc/ (m ^{2 -} day ^• aim), more preferably less than 20 cc/ (m ^{2 -} day aim), more preferably less than 10 cc/ (m ^{2 -} day* aim) and most preferably less than 1 cc/ (m ^{2 -} day aim). The multi-layered flexible plastic containers available in the art that do not have any oxygen scavenger layer have an oxygen transmission rate ranging from 400 to 1500 cc/ (m ² · day · atm).

In a preferred embodiment, the multilayered flexible plastic infusion container comprises at least three layers including an outermost layer of a polymer selected from polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate or polyethylene naphthalate, a middle layer comprising an oxygen scavenger and an innermost layer selected from a polyethylene layer or a cycloolefin layer. In a yet preferred embodiment, the multilayered flexible plastic infusion container is made up of at least three layers comprising an outermost layer of a polymer selected from a group consisting of polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate and polyethylene naphthalate, a middle oxygen scavenger layer comprising an oxygen scavenger selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer and an innermost layer made up of a polymer selected from a group consisting of polyethylene and cycloolefin. In a preferred embodiment, the multilayered flexible plastic infusion container is made up of at least ten layers including an outermost layer of a polymer selected from a group consisting of polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate and polyethylene naphthalate, a middle oxygen scavenger layer comprising an oxygen scavenger selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer and an innermost layer made up of a polymer selected from a group consisting of polyethylene and cycloolefin, wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable.

In a preferred embodiment, the multilayered flexible plastic infusion container is made up of thirteen layers including an outermost layer of polyethylene terephthalate, an oxygen scavenger layer made up of ethylene vinyl alcohol copolymer, adhesive tie layers on either side of oxygen scavenger layer, an innermost layer made up of high density polyethylene polymer and other inner layers present in between the outermost and oxygen scavenger layer and in between the oxygen scavenger and innermost layer. These inner layers are made up of linear low density polyethylene, high density polyethylene, cycloolefin and adhesive polymer. The multilayered flexible plastic infusion container is free of a polyamide. In another embodiment, the multilayered flexible plastic infusion container comprises at least three layers including an outermost layer made up of polyethylene terephthalate, a middle layer made up of ethylene vinyl alcohol copolymer and an innermost layer made up of polyethylene polymer, wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable.

In a further preferred embodiment, the multilayered flexible plastic infusion container consists of thirteen layers including an outermost layer made up of polyethylene terephthalate, a middle layer made up of ethylene vinyl alcohol copolymer and an innermost layer made up of polyethylene polymer, and other inner layers present in between the outermost and oxygen scavenger layer and in between the oxygen scavenger and innermost layer, wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable. In a further preferred embodiment, the multilayered flexible plastic infusion container comprises at least three layers including an outermost layer made up of polyethylene terephthalate, a middle layer made up of ethylene vinyl alcohol copolymer and an innermost layer made up of cycloolefin polymer, wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable.

In one or more embodiments, the multilayered flexible plastic infusion container according to the present invention may further comprise additional layers present in between the outermost layer and middle oxygen scavenger layer and/or in between the middle oxygen scavenger layer and innermost layer. The one or more layers that may be present include layers made up of a material selected from a group consisting of polyethylene polymers and cyclo-olefin polymers as described above, such as for example high density polyethylene, low density polyethylene, linear low density polyethylene, cycloolefin polymer and cycloolefin copolymers. In one or more embodiments, the multi-layered flexible plastic infusion container according to the present invention may further comprise adhesive layer/s, also referred to as lamination layer/s or tie layer/s. These adhesive layers may be present to affect proper binding of outer, intermediate and inner layers with each other. In one embodiment, the outermost layer is bound to an inner/middle layer comprising of oxygen scavenger by a dry lamination. In another embodiment, the outermost layer is adhered with an inner/middle layer comprising of oxygen scavenger by an adhesive resin layer. In one preferred embodiment, a tie layer is present on both sides of the oxygen scavenger layer, or in between the outermost layer and middle layers and/or middle layers and innermost layer. The adhesive layer may be made up of adhesive material selected from ethylene (meth) acrylic acid ester or copolymer, a modified EVA, epoxy resin composition, polyethylene-based resin adhesive which is selected from, but not limited to, linear low density polyethylene adhesive resin, high density polyethylene adhesive resin, straight chain low-density polyethylene adhesive resins. In another embodiment, the adhesive layer comprises a copolymer of a-olefin and a monomer of an unsaturated carboxylic acid or an anhydride of an unsaturated dicarboxylic acid. In one embodiment, the adhesive layer has a damp-proofing property. In another embodiment, the adhesive layer preferably contains a thermoplastic resin having adhesive properties. In one specific embodiment the tie layer sandwiches the layer comprising of oxygen scavenger. The tie layers may be made up of modified polyolefins blended with unmodified polyolefins or other suitable polymers. The modified polyolefins are typically polyethylene polymers or polyethylene copolymers. The modified poly ethylenes can be ultra-low density polyethylene (ULDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE), medium density polyethylene (MDPE), and high density polyethylenes (HDPE).

In one preferred embodiment, the present invention provides an intravenous infusion dosage form comprising an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml, preferably 0.5 to 1.5 mg/ml, filled in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable, wherein the multilayered flexible plastic infusion container has an oxygen scavenger layer sandwiched between the multiple layers and wherein the outermost layer of the multilayered flexible plastic infusion container is made up of a polymer selected from a group consisting of homopolymer or copolymer of polyalkylene terephthalates and polyalkylene naphthylates like polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate, polyethylene naphthalate or polypropylene naphthylate and the innermost layer is made up of a polymer selected from a group consisting of polyethylene and cycloolefin polymer.

In another embodiment, the present invention provides an intravenous infusion dosage form comprising an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml, preferably 0.5 to 1.5 mg/ml, filled in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container have an oxygen scavenger layer sandwiched between the multiple layers and wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable, wherein the multi-layered film of the multilayered flexible plastic infusion container has an oxygen transmission rate of less than 100 cc/ (m ² · day · atm), preferably less than 50 cc/ (m ^{2 -} day atm), more preferably less than 1 cc/ (m ^{2 -} day atm). The multi-layered film has a total thickness in the range of 50 μπα to 500 μπι; preferably in the range of 100 μπι to 450 μπι, more preferably in the range of 200 to 350 μπι. The outermost layer of the multilayered flexible plastic infusion container is made up of polyethylene terephthalate (PET) polymer and the innermost layer is made up of a polymer selected from a group consisting of polyethylene and cycloolefin polymer.

In a preferred embodiment, the present invention provides an intravenous infusion dosage form comprising an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml, such as for example 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 mg/ml filled in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container comprises at least three layers including an outermost layer of a polymer selected from a group consisting of polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate and polyethylene naphthalate, a middle layer made up of an oxygen scavenger selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer, adhesive tie layers on either side of oxygen scavenger layer, an innermost layer made up of a polyethylene polymer or cycloolefin polymer, and optionally other inner layer present in between the outermost and oxygen scavenger layer and in between the oxygen scavenger and innermost layer. The inner layer/s can be made up of linear low density polyethylene, high density polyethylene, cycloolefin and adhesive polymer. The multilayered flexible plastic infusion container has oxygen transmission rate of less than 100 cc/ (m ^{2 -} day atm) and thickness of 50 μπι to 500 μπι, preferably 10 to 300 μπι; further wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable. In a preferred embodiment, the present invention provides an intravenous infusion dosage form comprising an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, the aqueous solution consisting essentially of morphine or its pharmaceutically acceptable salt at a concentration ranging from 0.2 mg/ml to 2.0 mg/ml, such as for example 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 mg/ml, an osmotic agent, a pH adjusting agent and water for injection, wherein the aqueous solution has a pH in the range of about 4.0 to 7.5 and is filled in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container comprises at least three layers including an outermost layer of a polymer selected from a group consisting of polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate and polyethylene naphthalate, a middle layer made up of an oxygen scavenger selected from a group consisting of ethylene vinyl alcohol copolymer and ethylene-vinyl acetate copolymer, adhesive tie layers on either side of oxygen scavenger layer, an innermost layer made up of a polyethylene polymer or cycloolefin polymer, and optionally other inner layer present in between the outermost and oxygen scavenger layer and in between the oxygen scavenger and innermost layer. The inner layer can be made up of linear low density polyethylene, high density polyethylene, cycloolefin and adhesive polymer; wherein multilayered flexible plastic infusion container has oxygen transmission rate of less than 100 cc/ (m ^{2 -} day aim) and thickness of 50 to 500 μπι; further wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable.

In yet another preferred embodiment, the present invention provides an intravenous infusion dosage form comprising an aqueous solution of morphine or a pharmaceutically acceptable salt thereof, the aqueous solution consisting essentially of morphine or its pharmaceutically acceptable salt at a concentration ranging from 0.5 mg/ml to 1.5 mg/ml, such as for example 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5 mg/ml, an osmotic agent, a pH adjusting agent and water for injection, wherein the aqueous solution is free of added stabilizers such as antioxidants, amino acids, amines, complexing agents, cyclodextrins, chelating agents, co-solvents, alcohols, glycerine and propylene glycol; wherein the aqueous solution has a pH in the range of 4.0 to 5.0 and is filled in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container is made up of thirteen layers including an outermost layer of polyethylene terephthalate, a middle oxygen scavenger layer made up of ethylene vinyl alcohol copolymer, adhesive tie layers on either side of oxygen scavenger layer, an innermost layer made up of a polyethylene polymer and other inner layer/s present in between the outermost and oxygen scavenger layer and in between the oxygen scavenger and innermost layer, wherein the inner layer are made up of linear low density polyethylene, high density polyethylene, cycloolefin and adhesive polymer; wherein the multilayered flexible plastic infusion container has oxygen transmission rate of less than 100 cc/ (m ^{2 -} day atm) and thickness of 30 to 300 μπι; further wherein the multilayered flexible plastic infusion container is free of a polyamide and is autoclavable.

According to the present invention, the multilayered flexible plastic infusion container filled with the aqueous solution of morphine, after autoclaving can be packaged in a secondary packaging having simple configuration during long term storage without any sophisticated or complicated configuration. Due to the unique configuration of the multilayered flexible plastic infusion container which oxygen scavenger layer sandwiched between the innermost and outmost layers, it allows use of a secondary packaging having simple configuration that does not have any special feature such as an oxygen scavenging or absorbing layer. That is, such secondary packaging can be a simple pouch or carton that does not have any sophisticated features such as oxygen barrier or scavenger. This offers lower cost as the secondary packaging does not contain any additives that can otherwise increase the cost. The secondary packaging may be in the form of an overwrap pouch or a bag or a film or a carton or other suitable package. The secondary packaging can be made up of an aluminum material such as for example aluminum pouch or film. According to the present invention there is no requirement to place a sachet of oxygen scavenger in the space between the multilayered flexible plastic infusion container and the secondary overwrap pouch.

The amount or concentration of morphine or a pharmaceutically acceptable salt thereof referred to in the present disclosure is expressed as amounts equivalent to morphine free acid form. The pharmaceutically acceptable salt of morphine according to the present invention includes, but is not limited to, sulphate, hydrochloride, tartrate, hydrobromide, citrate, methobromide, lactate, bitartrate, hydroiodide, tannate, phosphate, ascorbate, acetate. The term morphine includes its free base form, salts, hydrates, polymorphs, solvates, isomers, tautomers, racemate etc. The present invention includes morphine or its salt as the sole active ingredient. Although any suitable pharmaceutically acceptable salt of morphine may be used, preferably, the pharmaceutically acceptable salt of morphine is morphine sulphate. In one embodiment, morphine or its pharmaceutically acceptable salt is morphine sulphate pentahydrate. Morphine or its pharmaceutically acceptable salt may be present in the aqueous solution used in the intravenous dosage form according to the present invention at a concentration ranging from about 0.2 mg/ml to about 2.0 mg/ml, such as for example 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 mg/ml, preferably in an amount ranging from about 0.5 mg/ml to about 1.5 mg/ml.

The volume of the aqueous solution in each of the multilayered plastic infusion container is a large volume, meaning thereby that the volume ranges from about 50 to 1000 ml, preferably 50 ml to 500 ml, more preferably 50 ml to 250 ml such as for example 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 ml. It is possible that the volume may range from 250 ml to 500 ml. According to one preferred embodiment, the volume of aqueous solution filled in the container is 100 ml. According to another preferred embodiment, the volume of aqueous solution filled in the container is 200 ml. According to another preferred embodiment, the volume of aqueous solution filled in the container is 250 ml. In one or more embodiments, the flexible plastic infusion container of the intravenous infusion dosage form contains 50 mg, lOOmg, 150 mg, 200 mg, 250 mg or 500 mg of morphine in the form of its pharmaceutically acceptable salt.

In one or more embodiments, the dissolved oxygen content in the aqueous solution of the intravenous infusion dosage form of the present invention is 2.0 parts per million (ppm) or less i.e. 0 to 2.0 parts per million, preferably 0 to 1.0 ppm, more preferably 0 to 0.5 ppm, such as for example 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23,0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48 or 0.49 ppm. To achieve and maintain dissolved oxygen content in the range of 0 to 2 ppm, the aqueous solution is purged with an inert gas like nitrogen or argon. The dissolved oxygen content in the solution contained in the container may be determined by using dissolved oxygen meters such as marketed under the brand name Seven GO™, Seven Duo Go Pro™ (registered trademark -METTLER TOLEDO), or by using other methods known in the art such as Winkler-Azide titration method, method using diaphragm electrode (instrumental analysis) etc.

The aqueous solution of the present invention can comprise parenterally acceptable excipients such as, but not limited to, osmotic agents or tonicity adjusting agents, pH adjusting agents or buffers. In one embodiment, an osmotic agent is used to adjust the tonicity of the solution and make the solution iso- osmolar to the parenteral/plasma fluids. The osmotic agent that may be used is selected from, but is not limited to sodium chloride, potassium chloride, mannitol, sorbitol, dextrose, glucose, sucrose and the like or mixtures thereof.

The aqueous solution of morphine according to the present invention has a pH in the range of 2.5 to 7.5, preferably in the range of 4.0 to 7.5, more preferably in the range of 4.0 to 5.0 such as for example 4.05, 4.10, 4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70, 4.75, 4.80, 4.85, 4.90, 4.95 or 5.0 or intermediate ranges thereof. The pH of the solution may be adjusted in the desired range by use of a pH adjusting agent and if needed a buffer may be used to maintain the pH in the said range. The pH adjusting and/or buffering agent that may be used include, but are not limited to hydrochloric acid, sulfuric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium acetate, sodium tartrate and the like and mixtures thereof. In one preferred embodiment, the pH adjusting agent is sodium hydroxide and sulphuric acid or hydrochloric acid. The buffers or buffering agents that may be used to adjust and maintain the pH may be selected from a non-limiting group of pharmaceutically acceptable buffer systems such as citrate buffer, tartrate buffer, phosphate buffer, acetate buffer, lactate buffer, glycine buffer and the like or mixtures thereof. In one embodiment, the pH may be auto-adjusted in the desired range by the ingredients present in the solution of the present invention. The headspace of the infusion container, i.e. the space above the solution in the container, if present, may be replaced by an inert gas, by flushing the inert gas in the head space. Preferably, the head space in the container is less than 5% by volume.

The aqueous solution according to the present invention is free of antioxidants, complexing agents like cyclodextrins, chelating agents, and amino acids. It is important to note that although the aqueous solution of morphine of the present invention is free of added stabilizers such as antioxidants, amino acids, amines, complexing agents such as cyclodextrins or co-solvents such as glycerine, propylene glycol, the dosage form is robust and chemically stable, even though subjected to autoclaving. It is physically and chemically stable and is also directly administrable in that the sterility is intact.

The aqueous solution of morphine according to the present invention consists essentially of morphine or its pharmaceutically acceptable salt, an osmotic agent, a pH adjusting agent and an aqueous vehicle like water for injection, wherein the aqueous solution has a pH in the range of 2.5 to 7.5. By the term "consisting essentially of as used herein, it means that the aqueous solution of morphine or its pharmaceutically acceptable salt according to the intravenous infusion dosage form of the present invention is free of added stabilizers such as antioxidants, amino acids, amines, complexing agents such as cyclodextrins, chelating agents or co-solvents such as alcohols, glycols, glycerine, propylene glycol and the like.

Morphine is the preferred strong opioid analgesic for pain relief particularly in cancer patients. The dose is titrated up to achieve adequate relief of pain. There is no upper limit. Dose requirements may vary 1000-fold, but few patients need daily doses above 200-300 mg. Accordingly, there is also provided a method of relieving pain in cancer patients, or as an anesthetic and pain reliever during surgery like open heart surgery or as preanesthetic medication, by intravenously administering aqueous solution filled in a single multilayered plastic infusion container of the intravenous infusion dosage form, in volume in the range of 50 ml to 500 ml comprising morphine in the form of its pharmaceutically acceptable salt in amount in the range of 50 mg to 500 mg when the concentration is 1 mg/ml, wherein the ready-to-infuse intravenous dosage form is autoclaved. It may be important to note that intravenous administration of morphine for pain relief is necessary in patients with poor peripheral circulation. In one aspect, the intravenous infusion dosage form of morphine according to the present invention may be used for any one of the following indications:

1) for the management of pain severe enough to require use of an opioid analgesic by intravenous administration, and for which alternative treatments are not expected to be adequate

2) for the management of pain not responsive to nonnarcotic analgesics

3) for the relief of moderate to severe pain

4) for the relief of severe and very severe pain as an analgesic

5) for relief of dyspnoea of left ventricular failure and pulmonary oedema

6) for pre-operative use as preanesthetic medication

7) for the symptomatic relief of severe and intractable pains of various categories in terminal cancer patients

8) for open heart surgery

9) for management of severe chronic pain associated with terminal cancer

10) for pre-operative use for relief of pain

The dosage of morphine administered through the intravenous infusion dosage form of the present invention may be based on the severity of the pain and the response and opiate tolerance of the patient.

In one embodiment, morphine is administered to the patients through the intravenous infusion dosage form of the present invention at a rate of infusion of more than 0.5 mg/hour and the rate can be modulated for each patient individually, taking into consideration patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, morphine tolerance and misuse.

In one embodiment, morphine is administered to patients above 12 years of age through the intravenous infusion dosage form of the present invention via continuous intravenous infusion at a starting doses of 1- 2 mg per hour, wherein daily doses does not usually exceed 100 mg per day, however, in cancer patients chronic administration of higher doses up to 4 g per day may be administered.

Particularly, in one specific embodiment, the present invention provides a method of relieving pain in cancer patients by intravenously administering an aqueous solution of morphine or its pharmaceutically acceptable salt filled in a multilayered flexible plastic infusion container in volume in the range from 50 ml to 500 ml and comprising morphine in an amount ranging from 50 mg to 500 mg at concentration of 1 mg/ml to the patient, wherein the multilayered flexible plastic infusion container filled with the aqueous solution has an oxygen scavenger layer sandwiched between an outermost and an innermost layer of the container, the container is free of a polyamide and is autoclavable.

According to the present invention, the intravenous infusion dosage form of morphine when subjected to autoclaving , the increase in the levels of total impurities in the aqueous solution upon autoclaving is not more than 0.1 % by weight of morphine; the increase in the levels of pseudomorphine impurity in the aqueous solution upon autoclaving is not more than 0.1 % by weight of morphine and the solution does not show presence of polyamide-11 cyclic dimer and/or polyamide-11 cyclic trimer upon autoclaving.

According to the present invention, when the intravenous infusion dosage form of morphine is subjected to autoclaving, not more than 0.2 % by weight of pseudomorphine is present in the aqueous solution and the solution is free of particles of polyamide 11-cyclic dimer or polyamide 11-cyclic trimer, immediately upon autoclaving.

The intravenous infusion dosage form of morphine according to the present invention is stable when stored at room temperature i.e. at 25°C/40%RH for at least one year or when stored at accelerated stability condition of 40°C/25% relative humidity for 6 months. The aqueous solution in the intravenous infusion dosage form remains chemically and physically stable upon autoclaving and upon storage during the shelf life period of at least 1 year for example upto 1 year, more preferably upto 2 years. The total impurities of morphine remain not more than 1.0 % by weight of morphine and the content of pseudomorphine remain not more than 0.2 % by weight of morphine upon autoclaving and upon storage for at least 1 year. The content of known pseudomorphine impurity and other known impurities like Normorphine, Morphine-N-Oxide, pseudomorphine, 10-alpha hydroxyl morphine, morphinone, oripavine, apomorphine and codeine sulphate remains not more than 0.2 % by weight of morphine; the content of total impurities remains not more than 1.0 % by weight of morphine and the content of highest unknown impurity remains not more than 0.1 % by weight of morphine, when the intravenous dosage form of the present invention is stored for six months at accelerated storage condition of 40°C/25% relative humidity and/or for twelve months at room temperature (25°C/40% relative humidity). The six month accelerated storage stability data at 40°C/25% relative humidity corresponds to about two years storage stability at room temperature. The aqueous solution of the ready-to-infuse intravenous infusion dosage form remains free of polyamide- 11 -cyclic dimer or polyamide- 11 -cyclic trimer upon autoclaving and upon storage at room temperature for the shelf life of at least 1 year and is therefore safe for intravenous adminisrtation to human patients. Other particles, if present, remains within the limits of particulate matter count specified for parenteral products by United States Pharmacopoeia Convention, Revision Bulletin 2011. The present invention further provides a process of preparing the intravenous infusion dosage form of morphine, the process comprising steps of:

a) filling an aqueous solution comprising morphine or a pharmaceutically acceptable salt thereof, at a concentration of 0.2 to 2.0 mg/ml in a multilayered flexible plastic infusion container, wherein the multilayered flexible plastic infusion container has an oxygen scavenger layer sandwiched between the outermost and innermost layers of the container and the container is free of a polyamide, and

b) autoclaving the filled container of step (a) whereby upon autoclaving the aqueous solution of morphine has total impurities not more than 1.0 % by weight of morphine and is free of polyamide 11-cyclic dimer or polyamide 11-cyclic trimer.

The present invention in one preferred embodiment provides a process of preparing a stable intravenous infusion dosage form of morphine, the process comprising steps of:

a) filling an aqueous solution comprising morphine or a pharmaceutically acceptable salt thereof, at a concentration of 0.2 to 2.0 mg/ml in a multilayered flexible plastic infusion container, the multilayers comprising at least three layers, an outermost layer, an oxygen scavenger layer and an innermost layer, wherein the multilayered flexible plastic infusion container is free of a polyamide,

b) autoclaving the filled container of step (a) at a temperature in the range of 110°C to 125°C for a period of time in the range of 5 minutes to 60 minutes and at a sterilization pressure in the range of about 2.0 to 4.0 bar G,

wherein the container is not packed or overwrapped by a secondary packaging during autoclaving, and

c) packing the autoclaved multilayered flexible plastic infusion container in a secondary packaging.

The autoclaving is preferably carried out at 121°C for 15 minutes.

In one specific embodiment, the present invention provides a process of preparing a stable intravenous infusion dosage form of morphine, the process comprising the steps of:

a) preparing an aqueous solution consisting essentially of morphine or a pharmaceutically acceptable salt thereof, at a concentration of 0.2 to 2.0 mg/ml, an osmotic agent and pH adjusting agent, whereby the aqueous solution is free of preservatives and/or antioxidants, b) purging the solution with nitrogen,

c) filling the aqueous solution of (b) in a multilayered flexible plastic infusion container in volume in the range from about 50 ml to 500 ml, the multilayers comprising at least three layers, an outermost layer, a middle oxygen scavenger layer and an innermost layer wherein the multilayered flexible plastic infusion container is free of a polyamide d) filling the head-space with inert gas and sealing the container;

e) autoclaving the filled container of step (d) by subjecting it to steam sterilization at temperature in the range of 120°C to 125°C for a period of time in the range of about 10 minutes to 25 minutes and at a sterilization pressure of about 2.5 to 3.5 bar G, wherein the container is not packed or overwrapped by a secondary packaging during autoclaving and whereby upon autoclaving the aqueous solution has pseudomorphine impurity not more than 0.1 % by weight of morphine and is free of polyamide 11-cyclic dimer or polyamide 11 -cyclic trimer, and

f) packing the inspected multilayered flexible plastic infusion container in a secondary container;

In one aspect, the present invention provides an intravenous infusion dosage form of morphine prepared by a process comprising the steps of :- a) filling an aqueous solution comprising morphine or a pharmaceutically acceptable salt thereof, at a concentration of 0.2 to 2.0 mg/ml in a multilayered flexible plastic infusion container, the multilayers comprising at least three layers, an outermost layer, an oxygen scavenger layer and an innermost layer wherein the multilayered flexible plastic infusion container is free of a polyamide,

b) autoclaving the filled container of step (a) at a temperature in the range of 110°C to 125°C for a period of time in the range of 5 minutes to 60 minutes and sterilization pressure in the range of about 2.0 to 3.5 bar G, wherein the container is not packed or overwrapped by a secondary packaging during autoclaving, and

c) packing the autoclaved multilayered flexible plastic infusion container in a secondary packaging.

Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.

Hereinafter, the invention is more specifically described by way of examples. The examples are not intended to limit the scope of the invention and are merely used as illustrations. COMPARATIVE EXAMPLE I

This comparative example demonstrates the problem associated with ready-to-infuse dosage form of morphine, in that even if the solution is purged with nitrogen and headspace filled with nitrogen, the pseudomorphine impurity and total impurities increase significantly upon autoclaving.

Table 1 : Details of aqueous solution of Morphine

Sodium chloride was dissolved in water for injection. Nitrogen gas was purged into it to obtain dissolved oxygen level of less than 1 ppm. Morphine sulphate pentahydrate was then added to sodium chloride solution and solution was stirred till it gets dissolved. The pH of solution was adjusted with 1% sulfuric acid/hydrochloric acid to a pH of 4.0 to 5.0. The volume was made up with water for injection. The Nitrogen gas purging was carried out continuously to maintain dissolved oxygen level of less than 1 ppm. The aqueous solution was then filtered through membrane filter of pore size 0.2 micron. 100 ml of the filtered aqueous solution was filled into each of the following multilayered flexible plastic infusion containers:

(i) Multilayered flexible plastic container made up of multilayer polyolefin film having layers from outside to inside made up of - poly cyclohexanedimethyl cyclohexanedicarboxylate elastomer; functionalized ethylene alpha-olefin copolymer; ethylene alpha-olefin copolymer; styrene-ethylene- butylene-styrene block copolymer; and ethylene propylene copolymer, (referred as CPET-Tie-PE- Tie-EPC).

(ii) Multilayered flexible plastic container made up of an outer layer of polypropylene polymer with styrene-ethylene-butylene (SEB) block copolymer, middle and inner layer both made up of polypropylene based polyolefin polymer with styrene-ethylene butylene block copolymer.

The solution of morphine in this container/bag represents the intravenous solution of morphine in polypropylene bags according to the prior art reference Xuan et al.

(iii) Multilayered flexible plastic container made up of an inner layer of a cycloolefin polymer, a middle layer of linear low density polyethylene polymer and an outer layer of low density polyethylene polymer. These infusion containers are free of oxygen scavenger in any of its layer.

The filled multi-layered plastic infusion containers (i), (ii), (iii) were sealed after replacing the headspace with nitrogen. The containers were not covered or wrapped and were as such subjected to autoclaving at 121 °C for 15 minutes. The chemical stability was determined before and after autoclaving by measuring the content of known impurities like pseudomorphine and total impurity by high performance liquid chromatography method, results whereof are presented below in Table 2:

Table 2: Results of chemical analysis

It was observed that in each of these containers, upon autoclaving, the level of % pesudomorphine increased substantially from initial, whereby the content of pesudomorphine increased to more than 0.2 % by weight upon autoclaving . Also, the level of % total impurity increased by more than 3.0 fold with a substaintial increase of more than 0.25 % from initial, upon autoclaving.

COMPARATIVE EXAMPLE II

This comparative example demonstrated the discovery of the problem associated with the use of multilayered flexible plastic infusion container containing polyamide layer and not having an oxygen scavenger layer.

The aqueous solution of morphine was prepared as per comparative Example I and was filled into multilayered flexible plastic infusion container having the outermost layer made up of polyamide 11 polymer, middle layer made up of modified polyolefin polymer and the innermost layer made up of polyethylene polymer without having oxygen scavenger in any of its layer. The head space of the filled containers was replaced with nitrogen and then these containers were sealed. These sealed infusion containers were not covered or wrapped and were subjected as such to autoclaving at 121° C for 15 minutes. The chemical stability was determined by measuring the % pseudomorphine impurity and % total impurities before and after autoclaving by high performance liquid chromatography method. The results of chemical analysis are presented below in Table 3.

Table 3 : Results of chemical analysis

It was observed that upon autoclaving the level of % pesudomorphine increased by about 4 fold with an increase of 0.159 % from initial, whereby the content of pesudomorphine increased to more than 0.2 % by weight upon autoclaving. Also, the content of % total impurity increased by more than 3 fold with an increase of 0.312 % from initial, upon autoclaving.

COMPARATIVE EXAMPLE III

The physical observation of the aqueous solution of comparative Example II indicated presence of rod shaped sub-visible particles. These sub-visible particles were separated from the solution by filtration using 0.2 μπα Polyethersulfone filter and were subjected to characterization by Raman spectroscopy.

The Raman spectrum of these particles was recorded by placing these filtered particles on Quartz plate of Raman G3 ID. The spectrum is provided in Figure 3. The Raman spectrum of reference substances of polyamide 11 cyclic monomer and polyamide 11 cyclic dimer were recorded and are provided in Figure 1 and Figure 2, respectively. The prominent peaks observed at 700-1260 cm ^"1 (functional group: C-C), 1410-1460 cm ^"1 (Functional group: CH ₃ & CH ₂ deformations), and 1620-1690 cm ^"1 (functional group: >C=0 mixed with NH deformations) positions in Raman spectra of particles shown in Figure 3 matched to the peaks observed in same positions in Raman spectrum of polyamide reference substance of polyamide 11 cyclic monomer and polyamide 11 cyclic dimer given in Figure 1 and Figure 2 respectively, indicating the presence of polyamide 11 cyclic monomer and polyamide 11 cyclic dimer in the particles. The rod shaped sub-visible particles separated from the solution upon filtration as in comparative example II were further characterized by mass spectroscopy using LC -MS/MS technique. A triple quadrupole mass spectrometer AB-Sciex API 3200 with atmospheric pressure chemical ionization (APCI) (with positive molecule ionization) was used for the analysis. Scanning was performed with a mass range m/z from 100 to 1350 Dalton.

Reference substance - Preparation of polyamide-11 cyclic monomer, polyamide-11 cyclic dimer and polyamide-11 cyclic trimer reference standard and their mass spectroscopy: Polyamide 11 resin was procured from Sigma Aldrich and was dissolved in a suitable solvent. The polyamide-11 cyclic monomer, polyamide-11 cyclic dimer and polyamide-11 cyclic trimer present in polyamide 11 resin were separated from polyamide resin using preparatory HPLC. The separated polyamide-11 cyclic monomer, polyamide- 11 cyclic dimer and polyamide-11 cyclic trimer were dissolved in methanol and mixed together to form a composite mixture. This methanolic solution containing composite mixture was injected into column of HPLC -Mass spectrometer and HPLC -MS chromatogram of mixture of polyamide-11 cyclic monomer, polyamide-11 cyclic dimer and polyamide-11 cyclic trimer was recorded. The HPLC -MS chromatogram showed a peak at retention time of 2.438 minutes, 2.019 minutes, and 1.600 minutes as shown in Figure 4A. The mass spectrum at retention time 2.438 minutes was of polyamide-11 cyclic trimer having a molecular ion mass of 550.6, as shown in figure 4B; the mass spectrum at retention time 2.019 minutes was of polyamide-11 cyclic dimer having a molecular ion mass of 367.2, as shown in Figure 4C; and the mass spectrum at retention time 1.600 minute was of polyamide-11 cyclic monomer having a molecular ion mass of 184.6, as shown in Figure 4D.

Mass spectroscopy of sub-visible particles - The rod shaped sub-visible particles of comparative Example II separated from the solution by filtration were dissolved in methanol and the methanolic solution was injected into column of HPLC-mass spectrometer and chromatogram was recorded. The HPLC-MS chromatogram in Figure 5A showed peaks at retention time 2.474 minutes and 2.019 minutes. The mass spectrum at retention time 2.474 minute showed a molecular ion mass of 550.7 correspoding to polyamide-11 cyclic trimer (see Figure 5B) and the mass spectrum at retention time 2.019 minutes showed a molecular ion mass of 367.2 correspoding to polyamide-11 cyclic dimer, as shown in Figure 5C.

The molecular ion mass (M+l) ⁺ observed for the sub-visible particles as well as for the reference substances is provided below in Table 4. Table 4: Molecular ion mass of sub-visible particles and molecular ion mass of solvent extract from Polyamide 11 resin sample procured from Sigma Aldrich

The results indicated that the observed molecular ion mass (M+l) ⁺ of 550.7 (M+l) ⁺ and 367.2 (M+l) ⁺ for the sub-visible particles matched with the molecular ion mass of polyamide- 11 cyclic dimer and polyamide- 11 cyclic trimer respectively, confirming that the particles were of polyamide- 11 cyclic dimer and polyamide- 11 cyclic trimer.

EXAMPLE I

Table 5: Composition of the aqueous solution filled in 100 ml volume per container

This example illustrates an infusion dosage form according to the present invention. The dosage form is prepared in multiple steps as follows: (a) Sodium chloride was dissolved in water for injection. Nitrogen gas was purged into it to obtain dissolved oxygen level of less than 1 ppm. Morphine sulphate pentahydrate was then added to sodium chloride solution and solution was stirred till it gets dissolved. The pH of solution was adjusted with 1% sulfuric acid/hydrochloric acid to a pH of 4.0 to 5.0. The volume was made up with water for injection. The Nitrogen gas purging was carried out continuously to maintain dissolved oxygen level of less than 1 ppm. The aqueous solution was then filtered through membrane filter of pore size 0.2 micron. 100 ml of the filtered aqueous solution was filled into flexible plastic infusion multilayered container comprising an outermost layer made up of polyethylene terephthalate, a middle oxygen scavenger layer (made up of ethylene vinyl alcohol copolymer) and an innermost layer made up of high density polyethylene polymer. The container was free of polyamide layer. The headspace of filled multilayered flexible plastic infusion container was filled with inert gas (Nitrogen) and then the container was sealed, (b) The filled containers were not covered or wrapped with a secondary packaging but were as such subjected to autoclaving at 121° C for 15 minutes in an autoclave.

The content of pseudomorphine impurity, highest unknown impurity and total impurities present in the aqueous solution was quantified before and after autoclaving by using high performance liquid chromatography method. The results of chemical analysis are presented below in Table 6.

Table 6: Results of chemical analysis

The results in Table 6 indicated that upon autoclaving, the % pseudomorphine impurity and the % total impurities were significantly lower compared to the corresponding levels observed in the other containers such as those described in comparative Examples I and II. The % pseudomorphine impurity in aqueous solution upon autoclaving was not more than 0.1 %. The impurities level does not increase substantially upon autoclaving. The increase in the % pseudomorphine impurity and % total impurities upon autoclaving, was not more than 0.1 % .The pseudomorphine impurity in example I showed a marginal increase of just 0.021 % upon autoclaving while in comparative Example I {containers (i), (ii) and (iii)} , the content of pseudomorphine impurity increased substantially with an increase of 0.191 %, 0.201 % and 0.161 % respectively. Also in case of comparative Example II, the content of pseudomorphine impurity increased substantially with an increase of 0.159 % upon autoclaving. Similarly, the total impurities in Example I showed a marginal increase of just 0.003 % upon autoclaving while in comparative Example I (containers (i), (ii) and (iii) and in comparative Example II, the % total impurities increased substantially with an increase of more than 0.25 % upon autoclaving. In working Example I according to the present invention, the increase in levels of other known impurities upon autoclaving was also marginal while in comparative examples the level of these impurities increased substantially.

This demonstrates the discovery of the inventors that if the first container has a middle oxygen scavenger layer it is not necessary to have the secondary packaging for the purpose of subjecting the infusion dosage form to autoclaving.

Step (c) The autoclaved containers obtained from step (b) were subjected to visual inspection. Step (d) The inspected containers were packed in an aluminium pouch.

The stability of the packaged containers were tested at two different storage conditions, i.e. at 25°C/40% relative humidity (room temperature) and at 40°C/25% relative humidity (accelerated storage condition). The results of the analysis of impurities are given in Table 7.

Table 7: Results of chemical analysis

RH- Relative Humidity

Upon storage for twelve months at room temperature (25°C/40% relative humidity) and upon storage for six months at accelerated storage condition of 40°C/25% relative humidity, the content of pseudomorphine was not more than 0.2 % by weight of morphine; the content of highest unknown impurity was not more than 0.1 % by weight of morphine and the content of total impurities was not more than 1.0 % by weight of morphine. The content of other known impurities were also found to be not more than 0.2 % by weight of morphine. It is understood from the above six month accelerated stability data that the intravenous infusion dosage form of the present invention would remain stable over long periods of at least 2 years when stored at room temperature.

Further, it was observed that no particle of the polyamide-11 cyclic monomer, polyamide-11 cyclic dimer and polyamide-11 cyclic trimer was found in the solution of morphine according to Example I, either upon autoclaving or upon storage.