Compositions of ready to use oxytocin formulations and methods of preparation in a device

Abstract

The present invention relates to the compositions of ready to use oxytocin formulations and methods of preparation in a device. The device is a container comprising single or two chambers. In a two-chambered container each chamber comprises component A comprising oxytocin and Component B comprising one or more pharmaceutically acceptable excipient and / or diluent(s).

Description

[0001] COMPOSITIONS OF READY TO USE OXYTOCIN FORMULATIONS AND METHODS OF PREPARATION IN A DEVICE

[0002] Field of Invention:

[0003] The invention relates to a drug-device combination comprising oxytocin ready to use formulation in a single chamber or multi-chambered container.

[0004] Background of Invention:

[0005] Oxytocin is a nonapeptidic hormone that is released from the posterior lobe of the pituitary gland of the hypothalamus. It consists of a six-amino acid ring with a tail of three amino acids as shown below:

[0006]

[0007] Synthetic oxytocin which is used as medicine is indicated for (1) induction of labour; (2) stimulation or reinforcement of labour, as in selected cases of uterine inertia; (3) as adjunctive therapy in the management of incomplete or inevitable abortion. It is also indicated to produce uterine contractions during the third stage of labour and to control postpartum bleeding or haemorrhage.

[0008] Products of oxytocin present in the market today as solution in single-dose and multi-dose vials that comprises 10 US pharmacopoeia (USP) units per mL of oxytocin. Clinically these products are administered to the patient by intravenous infusion after dilution to 500 mL or 1000 mL. To prepare composition for infusion, the solution in the vial is diluted to the required volume aseptically using appropriate diluent and rotated or stirred thoroughly to ensure uniform mixing. The diluted composition of oxytocin is stable at room temperature (20°C to 25°C) for 24 hrs and at refrigerated temperature (2°C to 8°C) for 7 days.

[0009] Since the diluted formulation has limited shelf life, it is necessary for the hospital staff or pharmacy to dilute the composition in the vial with suitable diluentwhenever required. Such ad hoc dilutions are prone to contamination due to human errors or surrounding environment as the dilution may be carried out under unhygienic conditions or there might be spillage during mixing. Such loss of product is an extra cost burden on the patient. Therefore, there is a need for development of oxytocin product that has no possibility of contaminations or human errors and that would save an extra burden of cost that patient may have to incur. The already diluted formulations of oxytocin are one of the solutions.

[0010] There is an immediate need to resolve the issues faced by patients due to products that are present in the market today.

[0011] Object of Invention:

[0012] The object of invention is to develop a product comprising oxytocin formulation which is easy to handle and transport, stable at room temperature and can be easily made available to the patient in the diluted form without the process of conventional reconstitution and mixing. The product is cost effective, efficient and economical for the patients.

[0013] Summary of Invention:

[0014] According to an aspect, the present invention provides a pharmaceutical product comprising two-chambered container, wherein at least one chamber comprises oxytocin or pharmaceutically acceptable salt thereof.

[0015] According to another aspect, the present invention provides a pharmaceutical product comprising component A and component B, wherein the components A and B are independently present in different chambers of a two-chambered container, and wherein component A comprises oxytocin and component B comprises pharmaceutically acceptable excipients and / or diluent(s).

[0016] According to another aspect, the present invention provides use of pharmaceutical product comprising component A and component B, wherein the components Aand B are independently present in different chambers of a two-chambered container, and wherein component A comprises oxytocin and component B comprises pharmaceutically acceptable excipients and / or diluent(s).

[0017] According to yet another aspect, the present invention provides a method of treating a subject suffering from a condition treatable using oxytocin composition, wherein method comprises administering to the subject oxytocin composition prepared by combining component A comprising oxytocin and component B comprising pharmaceutically acceptable excipients and / or diluent(s), wherein components A and B are independently present in different chambers of a twochambered container.

[0018] According to yet another aspect, the present invention provides a method of administration of a formulation comprising oxytocin, wherein the formulation comprises component A and component B, wherein component A comprises oxytocin or pharmaceutically acceptable salt thereof; and component B comprises one or more pharmaceutically acceptable excipient and / or diluent(s), wherein components A and B are independently packed in each chamber of twochambered container, and wherein the method comprises breaking of the seal between the two chambers and mixing components of A and B.

[0019] According to an aspect, the present invention provides a process to prepare a pharmaceutical product comprising two-chambered container, wherein at least one chamber comprises oxytocin or pharmaceutically acceptable salt thereof.

[0020] According to an aspect, the present invention relates to a ready to use pharmaceutical product comprising oxytocin composition.

[0021] According to an aspect, the present invention relates to a stable, ready to use, pharmaceutical product comprising oxytocin composition.Brief Description of Drawings:

[0022] Fig. 1 illustrates a dual chamber bag.

[0023] Fig. 2 illustrates an infusion bag.

[0024] Description of Drawings:

[0025] The given drawing is for representation and clarity purpose only and it does not restrict the scope of the invention in any manner.

[0026] Figure 1 shows a representative diagram of dual chamber bag. In the figure, chambers (1) and (2) are divided by a peelable seal (A). The tube attached to an intravenous canula (B) and a secondary port tube (C) . The given drawing is for representation and clarity purpose only and it does not restrict the scope of the invention in any manner.

[0027] Figure 2 shows a representative drawing of an infusion bag. The figure, consist of bag or a pouch (1) which contains drug product, a nozzle (2) of the bag and a port (3) to connect with the IV set up. The given figure is representative only and does not restrict the invention in any manner.

[0028] Description of Invention

[0029] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. As used herein, the following terms and phrases shall have the meaning set forth below.

[0030] Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

[0031] Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

[0032] For the purpose of this specification, the term “Component A” comprises active compound, and “Component B” comprises pharmaceutically acceptable excipients.

[0033] Described herein is the oxytocin injection that is intended for intravenous infusion.

[0034] According to an embodiment, the injections of the present invention are prepared by mixing the components of two chambers by breaking or removing the seal between the two chambers, wherein the two chambers are part of a single container.

[0035] According to another embodiment, the present invention is a ready to use injection. As understood by the skilled person the term ‘ready to use’ mean a formulation that is readily available for administration to the subject. Such formulations do not require further processing such as transferring contents from one container to the other or reconstituting or thawing before administration.According to an embodiment, the container of the present invention is a bag, bottle or a pouch or any other such container for medical use analogous to the infusion bag. The container is equally or unequally divided into two chambers, wherein one chamber is separated from the other using a seal that can be broken or removed externally. According to another embodiment the container has single chamber and is not divided into more than 1 chambers.

[0036] According to above embodiment the container is sterile, pharmaceutical grade and effective for medical use. It may be prepared by polymeric materials such as polyolefin polymers, polyethylene, polypropylene; cyclo olefin polymers, cyclo olefin copolymers, polypropylene based polyolefin polymers; polycarbonates; modified polyolefin-polyethylene polymers or styrene-polyolefin based polymers or block co-polymers thereof. The container may be prepared with multilayer polymers or single layer polymers. In an embodiment, the container is multilayered polymeric bag or pouch. Each layer of such polymeric bag may be prepared by same polymeric material or different materials.

[0037] The seal of the container may be a peel seal or any other such seal.

[0038] According to an embodiment, the oxytocin injection of the present invention is prepared by mixing the components of the two chambers of the two-chambered container, wherein the components of two chambers are component A and component B. According to an embodiment, component A comprises oxytocin or pharmaceutically acceptable salt thereof.

[0039] According to preferred embodiment component A comprises oxytocin or pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt of oxytocin may be an acid salt such as acetic acid salt or trifluoroacetic acid salt. According to another embodiment, the component A may optionally comprise a preservative. A preservative may be selected from chlorobutanol, m-cresol, phenol, benzyl alcohol and such others known to the person skilled in the art.According to one preferred embodiment the preservative is chlorobutanol. According to another preferred embodiment the preservative is benzyl alcohol. According to yet another preferred embodiment the preservative is phenol.

[0040] Component A may further comprise pharmaceutically acceptable excipients including but not limited to tonicity agent, buffer, pH adjusting agent, solvent or co-solvent.

[0041] According to an embodiment, Component A optionally comprises tonicity agent selected from the group of Sodium chloride (NaCl), Dextrose, Mannitol, Glycerol, Potassium chloride (KC1) and Sugars.

[0042] According to another embodiment, Component A optionally comprises buffers such as sodium acetate, Tris, citrate, Succinate, Lactate or tartrate.

[0043] According to yet another embodiment, Component A optionally comprises pH adjusting agent selected from the group of sodium hydroxide, hydrochloric acid, acetic acid and citric acid. The person skilled in the art will appreciate that the pH adjusting agent in combination with listed buffer may also act as a buffer or a buffer in combination with pH adjusting agent may act as pH adjusting agent. Therefore buffer and pH adjusting agent may be used in combination to act as both.

[0044] According to yet another embodiment, Component A optionally comprises solvent and / or co-solvents selected from the group of water for injection, ethanol, glycerol, polyethylene glycol and mixture thereof.

[0045] Component B comprises one or more pharmaceutically acceptable excipient and / or diluent. According to an embodiment, the excipient may be a pH adjuster or water for injection or combination thereof. According to another embodiment, component B may further comprise a diluent. The diluent may be a tonicity agentor water for injection or mixture thereof. The non-limiting examples of dilutes are dextrose, lactated ringers, sodium chloride or mixture thereof. The tonicity agent may be diluted using water for injection.

[0046] According to an embodiment, the oxytocin injection of the present invention is in a single chamber container, wherein the injection comprises pre-mixed component A and component B in the container.

[0047] According to an embodiment, the total volume of component B is not more than 1000 mL. Further, the total volume of component B is not more than 500 mL., The total volume of component B is between about 500 mL and about 50 mL. Further, the total volume of component B is 500 mL.

[0048] According to an embodiment, the total volume of the container in case of single chamber container is not more than 1000 mL. According to preferred embodiment, the total volume of the container in case of single chamber container is not more than 500 mL. According to more preferred embodiment, the total volume of the container in case of single chamber container is between about 500 mL and about 50 mL.

[0049] It will be appreciated by the skilled person that the amount of diluent is such that the osmolality of the component B when mixed with component A results in about 250 to about 400 milliosmoles per kilogram.

[0050] According to an embodiment, the amount of oxytocin in component A ranges from about 10 United States Pharmacopoeia (USP) units to about 60 USP units. According to preferred embodiment, the amount of oxytocin in component A is about 30 USP units.The container of the present invention may be further covered or overwrapped by aluminium layer with or without oxygen scavengers for the purpose of protection of light or oxygen or both.

[0051] According to one of the embodiments, the present invention provides a pharmaceutical product dispensed in a two-chambered container, wherein at least one chamber comprises oxytocin or pharmaceutically acceptable salt thereof.

[0052] According to another embodiment, the present invention provides a pharmaceutical product comprising component A and component B, wherein the components A and B are independently present in different chambers of a twochambered container, and wherein component A comprises oxytocin and component B comprises pharmaceutically acceptable excipients and / or diluent(s).

[0053] According to yet another embodiment, the present invention provides a pharmaceutical product comprising component A and component B, wherein the components A and B are pre-mixed in a container such as bag or a pouch, and wherein component A comprises oxytocin and component B comprises pharmaceutically acceptable excipients and / or diluent(s).

[0054] According to an embodiment, the present invention relates to a ready to use pharmaceutical product comprising oxytocin composition.

[0055] According to another embodiment, the present invention relates to a stable, ready to use, pharmaceutical product comprising oxytocin composition.

[0056] According to an embodiment, the present invention provides a process to prepare the pharmaceutical product of present invention. According to an embodiment the process comprises filling of component A in chamber 1 and component B in chamber 2, sterilizing the components before filling them in the container and optionally overwrapping the container.In an embodiment, the component A may be prepared by mixing oxytocin or its salt with at least one pharmaceutically acceptable excipient. In another embodiment, the component A may be prepared by just adding oxytocin or its salt to chamber 1. In one embodiment, component B may be prepared by purging inert gas through required amount of water for injection and mixing the excipients and / or diluent(s) to dissolve followed by adjusting the pH using pH adjuster. It would be understood by the person skilled in the art that the process is carried under sterile conditions. Also, the skilled person would understand the known variations to the process. All such variations are part of this invention.

[0057] According to another embodiment, the product of the present invention may be prepared by purging inert gas through required amount of water for injection and mixing the excipients and / or diluent(s) to dissolve followed by adjusting the pH using pH adjuster. Optionally adding preservative, buffer, stabilizer, solvent or cosolvent and mixing the solution to dissolve. Finally, adding oxytocin or its salt, dissolving and filling it in a container under sterile conditions. The composition is optionally sterilized and / or filtered by known methods before it is filled in the container and optionally overwrapping the container.

[0058] The pharmaceutical product of the present invention is stable at room temperature (from about 20°C to about 25°C) for about 6 months to about 24 months. Stability of the product includes the stability of the components present in the composition. As understood by the skilled person the stability of the composition mean the composition is physically and chemically in the same condition at the beginning and end of the stability period. The methods of determination of physical and chemical conditions of the composition are as known in the prior art.

[0059] According to an embodiment the composition present in the two-chambered bag is stable at least for 9 months at room temperature.According to another embodiment the composition present in a single chamber container is stable at least for 6 months at room temperature.

[0060] According to another embodiment the composition present in a single chamber container is stable at least for 6 months when stored refrigerated at 2°C to 8°C. According to another embodiment the composition present in a single chamber container is stable at least for 9 months when stored refrigerated at 2°C to 8°C.

[0061] According to another embodiment the composition present in a single chamber container is stable for not less than 12 months when stored refrigerated at 2°C to 8°C.

[0062] According to another embodiment the composition present in a single chamber container is stable for not less than 24 months when stored refrigerated at 2°C to 8°C.

[0063] According to an embodiment, the compositions of the present invention exhibit less than 15% total impurities when stored for not less than 6 months at room temperature.

[0064] According to another embodiment, the compositions of the present invention exhibit less than 10% total impurities when stored for not less than 6 months at room temperature.

[0065] According to yet another embodiment, the compositions of the present invention exhibit less than 10% total impurities when stored for at least 12 months at room temperature.

[0066] According to an embodiment, the compositions of the present invention contain not less than 85% oxytocin after storage for at least about 3 months at room temperature. According to another embodiment, the compositions of the presentinvention contain not less than 85% oxytocin after storage for at least about 6 months at room temperature.

[0067] According to yet another embodiment, the compositions of the present invention contain not less than 90% oxytocin after storage for at least about 6 months at room temperature.

[0068] According to yet another embodiment, the compositions of the present invention contain not less than 90% oxytocin after storage for at least about 12 months at room temperature.

[0069] According to an embodiment, the present invention provides use of the pharmaceutical product of the present invention. In an embodiment the pharmaceutical product comprises component A and component B, wherein the components A and B are independently present in different chambers of a twochambered container, and wherein component A comprises oxytocin and optionally a pharmaceutically acceptable excipients and component B comprises pharmaceutically acceptable excipients and / or diluent(s). In another embodiment, the pharmaceutical product comprises a pre-mixed composition of component A and component B in a single chamber, ready to use container.

[0070] According to an embodiment, the pharmaceutical product of the present invention is used for intravenous infusion of oxytocin injection, wherein the components of the injection are present in different chambers of a two-chambered container and wherein the product is used by removing or breaking the seal separating the two chambers.

[0071] According to an embodiment, the ready to use pharmaceutical product of the present invention is used for intravenous (IV) infusion of oxytocin injection by directly attaching it to the IV set up.According to an embodiment, the pharmaceutical product of the present invention is used for the treatment of a subject suffering from a condition treatable using oxytocin composition. Such conditions include but not limited to induction of labour; stimulation or reinforcement of labour, management of incomplete or inevitable abortion, uterine contractions during the third stage of labour and to stop or control bleeding or haemorrhage following delivery.

[0072] According to yet another embodiment, the present invention provides a method of treatment of a subject suffering from a condition treatable using oxytocin composition, wherein method comprises administering to the subject oxytocin composition from the pharmaceutical product of the present invention.

[0073] In an embodiment the composition is prepared by combining component A comprising oxytocin and component B comprising pharmaceutically acceptable excipients and / or diluent(s), wherein components A and B are independently present in different chambers of a two-chambered container. The components of two chambers are combined by removing or breaking the seal between the two chambers. In another embodiment the composition is ready to administer composition.

[0074] According to yet another embodiment, the present invention provides a method of administration of a formulation comprising oxytocin, wherein the formulation comprises component A and component B, wherein component A comprises oxytocin or pharmaceutically acceptable salt thereof; and component B comprises one or more pharmaceutically acceptable excipient and / or diluent(s), wherein components A and B are independently packed in each chamber of twochambered container, and wherein the method comprises breaking the seal between the two chambers and mixing the components of A and B.According to yet another embodiment, the present invention provides a method of administration of a formulation comprising oxytocin, wherein the formulation is a ready to administer formulation present in a single chamber container.

[0075] According to an embodiment, the method of present invention comprises breaking or removal of the seal between the two chambers each comprising component A and component B and mixing the components thoroughly before administration or the method comprises direct administration of the ready to administer composition. It would be appreciated by the skilled person that the oxytocin injection thus prepared for administration does not involve opening or exposing content of any chamber to the outside environment or reconstituting it manually by the skilled hospital staff or personnel from pharmacy. It makes the process of preparation of injection very easy to handle, non-contaminable, non-risky and there is no possibility of loss of content of the injection, thus making it efficient and cost effective. The present invention thus addresses issues and problems with the existing technic effectively. The ultimate injection that is prepared by mixing component A and B is a formulation already tried and tested therefore the present invention provides a pharmaceutical product that has industrial usefulness and certainty of success.

[0076] The present invention is further clarified through following examples and the drawings provided, however the examples and drawings given below are for clarification and demonstration purpose only and they do not restrict the invention in any manner. The variations of the examples or drawings are well within the knowledge of the person skilled in the art and therefore such variations are included and are part of the scope of this invention.

[0077] Examples

[0078] Several examples are set forth below to further illustrate the nature of the invention and the manner of carrying it out. However, the invention should not be considered as being limited to the details thereof.Example 1:

[0079]

[0080] Manufacturing Process:

[0081] a) Dispensed batch quantity of chlorobutanol was added and dissoved into the manufacturing vessel containing water for Injection (WFI);

[0082] b) Dispensed batch quantity of oxytocin was added to the to the step a) under continuous stirring and continue the stirring still clear solution obtained; c) The clear solution in step b) was filtered using 0.2p filter;

[0083] d) The filtered solution of step c) was filled into the chamber- 1 of dual bag chamber;

[0084] e) 120% of batch size water for injection (WFI) was collected and cooled to 20°C -25 °C.

[0085] f) To the 90% of WFI of step e) at 20°C -25 °C in manufacturing vessel, dispensed quantity of sodium chloride was added while continuous stirring till clear solution was obtained;

[0086] g) Dispensed quantity of dextrose was added to the sodium chloride solution of step f) while continuous stirring till clear solution was obtained;

[0087] h) Volume of the solution of step g) was made up to 100% by using remaining WFI from step e) and continued stirring for 30 minutes to get uniform solution;

[0088] i) Filtered solution of step h) using 0.2p filter;j) Filtered solution of step i) was filled into the chamber-2 of dual chamber bag; and

[0089] k) The filled dual chamber bag of step j) was further packed in aluminium pouch containing oxygen adsorbers.

[0090] Example 2:

[0091]

[0092] Manufacturing process:

[0093] a) Dispensed batch quantity of oxytocin was filled into the chamber-1 of dual bag chamber;

[0094] b) 120% of batch size water for injection (WFI) was collected and cooled to 20°C -25 °C.

[0095] c) To the 90% to the batch size WFI of step b) at 20°C -25 °C in manufacturing vessel, dispensed quantity of sodium chloride was added while continuous stirring till clear solution was obtained;

[0096] d) Dispensed quantity of dextrose was added to the sodium chloride solution of step c) while continuous stirring till clear solution was obtained;

[0097] e) Volume of the batch was made up to 100% by using remaining WFI from step d) and continued stirring for 30 minutes to get uniform solution; f) Filtered solution of step e) using 0.2p filter;

[0098] g) Filtered solution of step f) was filled into the chamber-2 of dual chamber bag; andh) The filled dual chamber bag of step g) was further packed in aluminium pouch containing oxygen adsorbers.

[0099] Example 3:

[0100]

[0101] Manufacturing Process:

[0102] The composition of Example 3 was prepared using similar process as that in Example 1.

[0103] Example 4:

[0104]

[0105] Manufacturing Process:

[0106] The composition of Example 4 was prepared using similar process as that in Example 2.Example 5:

[0107]

[0108] Manufacturing Process:

[0109] a) Dispensed batch quantity of chlorobutanol was added and dissolved into the manufacturing vessel containing WFI;

[0110] b) Dispensed batch quantity of oxytocin was added to the to the step a) under continuous stirring and continue the stirring still clear solution obtained; c) The clear solution in step b) was filtered using 0.2p filter;

[0111] d) The filtered solution of step c) was filled into the chamber- 1 of dual bag chamber;

[0112] e) 120% of batch size water for injection (WFI) was collected and cooled to 20°C -25 °C.

[0113] f) To the 90% of the WFI of step e) at 20°C -25 °C in manufacturing vessel, dispensed quantity of sodium chloride was added while continuous stirring till clear solution was obtained;

[0114] g) Dispensed quantity of Sodium Lactate was added to the sodium chloride solution of step f) while continuous stirring till clear solution was obtained;

[0115] h) Dispensed quantity of Potassium Chloride was added to the solution of step g) while continuous stirring till clear solution was obtained;

[0116] i) Dispensed quantity of calcium chloride was added to the solution of step h) while continuous stirring till clear solution was obtained;

[0117] j) pH of the clear solution of step i) was adjusted to 6.0-7.5 by usinghydrochloric acid or sodium hydroxide solution;

[0118] k) Volume of the solution of step j) was made up to 100% by using remaining WFI from step e) and continued stirring for 30 minutes to get uniform solution;

[0119] l) Filtered solution of step k) using 0.2p filter;

[0120] m) Filtered solution of step 1) was filled into the chamber-2 of dual chamber bag; and

[0121] n) The filled dual chamber bag of step m) was further packed in aluminium pouch containing oxygen adsorbers.

[0122] Example 6:

[0123]

[0124] Manufacturing Process:

[0125] a) Dispensed batch quantity of oxytocin was filled into the chamber-1 of dual bag chamber;

[0126] b) 120% of batch size water for injection (WFI) was collected and cooled to 20°C -25 °C.

[0127] c) To the 90% of the WFI of step b) at 20°C -25 °C in manufacturing vessel, dispensed quantity of sodium chloride was added while continuous stirring till clear solution was obtained;

[0128] d) Dispensed quantity of Sodium Lactate was added to the sodium chloride solution of step c) while continuous stirring till clear solution was obtained;

[0129] e) Dispensed quantity of Potassium Chloride was added to the solution of step d) while continuous stirring till clear solution was obtained;

[0130] f) Dispensed quantity of Calcium Chloride was added to the solution of step e) while continuous stirring till clear solution was obtained;g) pH of the clear solution of step f) was adjusted to 6.0-7.5 by using hydrochloric acid or sodium hydroxide solution;

[0131] h) Volume of the solution of step g) was made up to 100% by using remaining WFI from step b) and continued stirring for 30 minutes to get uniform solution;

[0132] i) Filtered solution of step h) using 0.2p filter;

[0133] j) Filtered solution of step i) was filled into the chamber-2 of dual chamber bag; and

[0134] k) The filled dual chamber bag of step j) was further packed in aluminium pouch containing oxygen adsorbers.

[0135] Example 7:

[0136]

[0137] Manufacturing Process:

[0138] The composition of Example 7 was prepared using similar process as that in Example 1.

[0139] Example 8:

[0140]

[0141] Manufacturing Process:

[0142] The composition of Example 8 was prepared using similar process as that in Example 2.

[0143] Example 9:

[0144]

[0145] Manufacturing Process:

[0146] a) 120% of batch size water for injection (WFI) was collected, cooled to 20°C -25 °C, and purged with nitrogen to get dissolve oxygen not more than 1 ppm;

[0147] b) To the 90% of the WFI of step a) at 20°C -25 °C in manufacturing vessel, dispensed quantity of Chlorobutanol was added while continuous stirring till clear solution was obtained;

[0148] c) Dispensed quantity of Sodium chloride was added to the solution of step b) while continuous stirring till clear solution was obtained;

[0149] d) Dispensed quantity of dextrose was added to the solution of step c) while continuous stirring till clear solution was obtained;

[0150] e) Dispensed quantity of oxytocin was added to the solution of step d) while continuous stirring till clear solution was obtained;

[0151] f) Volume of the solution of step e) was made up to 100% by using remaining WFI from step a) and continued stirring for 30 minutes to get uniform solution;g) Filtered solution of step f) using 0.2p filter;

[0152] h) Filtered solution of step g) was filled into the IV bag;

[0153] i) The filled bag of step h) was further packed in aluminium pouch containing oxygen adsorbers.

[0154] Example 10:

[0155]

[0156] Manufacturing Process:

[0157] a) 120% of batch size water for injection (WFI) was collected, cooled to 20°C -25 °C, and purged with nitrogen to get dissolve oxygen not more than 1 ppm;

[0158] b) To the 90% of the WFI of step a) at 20°C -25 °C in manufacturing vessel, dispensed quantity of Sodium chloride was added while continuous stirring till clear solution was obtained;

[0159] c) Dispensed quantity of dextrose was added to the solution of step b) while continuous stirring till clear solution was obtained;

[0160] d) Dispensed quantity of oxytocin was added to the solution of step c) while continuous stirring till clear solution was obtained;

[0161] e) Volume of the solution of step d) was made up to 100% by using remaining WFI from step a) and continued stirring for 30 minutes to get uniform solution;

[0162] f) Filtered solution of step e) using 0.2p filter;

[0163] g) Filtered solution of step f) was filled into the IV bag;

[0164] h) The filled bag of step g) was further packed in aluminium pouch containing oxygen adsorbers.Example 11:

[0165]

[0166] Manufacturing Process:

[0167] The composition of Example 11 was prepared using similar process as that in Example 9.

[0168] Example 12:

[0169]

[0170] Manufacturing Process:

[0171] The composition of Example 12 was prepared using similar process as that in Example 10.

[0172] Example 13:

[0173]

[0174] Manufacturing Process:

[0175] a) 120% of batch size water for injection (WFI) was collected, cooled to 20°C -25 °C, and Nitrogen was purged to get dissolved oxygen of not more than 1 ppm;

[0176] b) To the 90% of the WFI of step a) at 20°C -25 °C in manufacturing vessel, dispensed quantity of sodium chloride was added while continuous stirring till clear solution was obtained;

[0177] c) Dispensed quantity of Sodium Lactate was added to the sodium chloride solution of step b) while continuous stirring till clear solution was obtained;

[0178] d) Dispensed quantity of Potassium Chloride was added to the solution of step c) while continuous stirring till clear solution was obtained;

[0179] e) Dispensed quantity of Calcium Chloride, dihydrate was added to the solution of step d) while continuous stirring till clear solution was obtained;

[0180] f) pH of the clear solution of step e) was adjusted to 6.0-7.5 by using hydrochloric acid or sodium hydroxide solution;

[0181] g) Volume of the solution of step f) was made up to 100% by using remaining WFI from step a) and continued stirring for 30 minutes to get uniform lactate ringer solution;

[0182] h) 90% of the batch size of Lactate ringer solution of step g) was collected into a suitable manufacturing vessel and purged with nitrogen to get dissolve oxygen content not more than 1 ppm;

[0183] i) Dispensed quantity of Chlorobutanol was added to the solution of step h) while continuous stirring till clear solution was obtained;

[0184] j) Dispensed quantity of Oxytocin was added to the solution of step i) while continuous stirring till clear solution was obtained;

[0185] k) Volume of the solution of step j) was made up to 100% by using remaining lactate ringer solution from step g) and continued stirring for 30 minutes to get uniform solution;

[0186] l) Filtered solution of step k) using 0.2p filter;m) Filtered solution of step 1) was filled into the IV bag; and

[0187] n) The filled bag of step m) was further packed in aluminium pouch containing oxygen adsorbers.

[0188] Example 14:

[0189]

[0190] Manufacturing Process:

[0191] a) 120% of batch size water for injection (WFI) was collected, cooled to 20°C -25 °C, and Nitrogen was purged to get dissolved oxygen of not more than 1 ppm;

[0192] b) To the 90% of the WFI of step a) at 20°C -25 °C in manufacturing vessel, dispensed quantity of sodium chloride was added while continuous stirring till clear solution was obtained;

[0193] c) Dispensed quantity of Sodium Lactate was added to the sodium chloride solution of step b) while continuous stirring till clear solution was obtained;

[0194] d) Dispensed quantity of Potassium Chloride was added to the solution of step c) while continuous stirring till clear solution was obtained;

[0195] e) Dispensed quantity of Calcium Chloride, dihydrate was added to the solution of step d) while continuous stirring till clear solution was obtained;

[0196] f) pH of the clear solution of step e) was adjusted to 6.0-7.5 by using hydrochloric acid or sodium hydroxide solution;

[0197] g) Volume of the solution of step f) was made up to 100% by using remaining WFI from step a) and continued stirring for 30 minutes to get uniform lactate ringer solution;

[0198] h) 90% of the batch size of Lactate ringer solution of step g) was collectedinto a suitable manufacturing vessel and purged with nitrogen to get dissolve oxygen content not more than 1 ppm;

[0199] i) Dispensed quantity of Oxytocin was added to the solution of step h) while continuous stirring till clear solution was obtained;

[0200] j) Volume of the solution of step i) was made up to 100% by using remaining lactate ringer solution from step g) and continued stirring for 30 minutes to get uniform solution;

[0201] k) Filtered solution of step j) using 0.2p filter;

[0202] l) Filtered solution of step k) was filled into the IV bag; and

[0203] m) The filled bag of step 1) was further packed in aluminium pouch containing oxygen adsorbers.

[0204] Example 15:

[0205]

[0206] Manufacturing Process:

[0207] The composition of Example 15 was prepared using similar process as that in Example 9.

[0208] Example 16:

[0209]

[0210] Manufacturing Process:

[0211] The composition of Example 16 was prepared using similar process as that inExample 10.

[0212] Example 17:

[0213]

[0214] 5 Manufacturing Process:

[0215] The composition of Example 17 was prepared using similar process as that in Example 1.

[0216] Example 18:

[0217]

[0218] 0

[0219] Manufacturing Process:

[0220] The composition of Example 17 was prepared using similar process as that in Example 1.Example 19:

[0221]

[0222] Manufacturing Process:

[0223] The composition of Example 17 was prepared using similar process as that in Example 1.

[0224] Example 20:

[0225]

[0226] Manufacturing Process:

[0227] The composition of Example 20 was prepared using similar process as that in Example 5.Example 21:

[0228]

[0229] Manufacturing Process:

[0230] The composition of Example 20 was prepared using similar process as that in Example 5.

[0231] Example 22:

[0232]

[0233] Manufacturing Process:

[0234] The composition of Example 20 was prepared using similar process as that in Example 5.Example 23:

[0235]

[0236] Manufacturing Process:

[0237] The composition of Example 20 was prepared using similar process as that in Example 14.

[0238] Example 24:

[0239]

[0240] Manufacturing Process:

[0241] The composition of Example 20 was prepared using similar process as that in Example 14.

Claims

We Claim,1. A sterile drug-device combination product comprising a two-chambered container separated by a seal, wherein Component A in a first chamber comprises oxytocin or a pharmaceutically acceptable salt thereof, and Component B in a second chamber comprises one or more pharmaceutically acceptable excipients and / or diluent(s).

2. The sterile drug-device combination product as claimed in claim 1, wherein the seal is configured to be broken to mix Components A and B within the container to yield an oxytocin infusion composition ready for intravenous administration.

3. The sterile drug-device combination product as claimed in claim 1, wherein the container is a bag, bottle, or pouch for medical use analogous to an infusion bag.

4. The sterile drug-device combination product as claimed in claim 1, wherein component A further comprises excipients selected from the group of tonicity agent, buffer, pH adjusting agent, and solvent and / or co-solvent selected from water for injection (WFI), ethanol, glycerol, polyethylene glycol, or mixtures thereof.

5. The sterile drug-device combination product as claimed in claim 4, wherein the tonicity agent selected from the group of sodium chloride, dextrose, mannitol, glycerol, potassium chloride, sugars and mixture thereof.

6. The sterile drug-device combination product as claimed in claim 4, wherein the buffer selected from the group of sodium acetate, Tris, citrate, lactate, succinate, tartrate buffer and mixture thereof.

7. The sterile drug-device combination product as claimed in claim 4, wherein the pH adjusting agent selected from the group of sodium hydroxide, hydrochloric acid, acetic acid, citric acid, lactic acid, succinic acid and mixture thereof.

8. The sterile drug-device combination product as claimed in claim 4, wherein the solvent and co-solvent is selected from the group of water for injection (WFI), ethanol, glycerol, polyethylene glycol and mixtures thereof.

9. The sterile drug-device combination product as claimed in claim 1, wherein Component B comprises WFI and one or more diluents selected from sodium chloride solution, dextrose solution, lactated Ringer’s solution, or mixtures thereof.

10. The sterile drug-device combination product as claimed in claim 1, wherein the total volume of Component B is between about 50 mL and about 500 mL.

11. The sterile drug-device combination product as claimed in claim 1, wherein the amount of oxytocin in Component A is about 10 to about 60 USP units.

12. The sterile drug-device combination product as claimed in claim 1, wherein the drug in the product exhibits stability at room temperature for at least 6 months.

13. The sterile drug-device combination product as claimed in claim 12, wherein total impurities in the drug are less than 15% after at least 3 months of storage at room temperature.

14. The sterile drug-device combination product as claimed in claim 13, wherein total impurities in the drug are less than 10% after at least 6 months of storage at room temperature.

15. The sterile drug-device combination product as claimed in claim 13, wherein total impurities in the drug are less than 10% when stored at room temperature for about 9 months to about 12 months.

16. The sterile drug-device combination product as claimed in claim 1, wherein composition contains not less than 85% oxytocin when stored for at least 3 months at room temperature.

17. The sterile drug-device combination product as claimed in claim 16, wherein composition contains not less than 90% oxytocin when stored for at least 6 months at room temperature.

18. The sterile drug-device combination product as claimed in claim 17, wherein composition contains not less than 90% oxytocin when stored for at room temperature for about 9 months to about 12 months.

19. The sterile drug-device combination product as claimed in claim 4, optionally comprises chlorobutanol.

20. The sterile drug-device combination product as claimed in claim 1, wherein the device is of polymeric materials.

21. A sterile, ready-to-use pharmaceutical product comprising a single-chamber container pre-filled with an oxytocin infusion composition comprising oxytocin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and / or diluent(s), the container being adapted to directly attach to an intravenous setup.

22. The product as claimed in claim 21, wherein composition comprises WFI and a diluent selected from sodium chloride solution, dextrose solution, lactated Ringer’s solution, or mixtures thereof, with osmolality about 250- 400 mOsm / kg.

23. The product as claimed in claim 22, wherein composition optionally comprises a preservative selected from chlorobutanol, benzyl alcohol, or phenol.

24. The product as claimed in claim 21, wherein the composition exhibits stability at room temperature for at least 6 months, with total impurities below 15% and oxytocin assay of not less than 85%.

25. A process for manufacturing the product as claimed in claim 1, comprising:a. aseptically preparing Component A by dissolving oxytocin or a pharmaceutically acceptable salt in WFI, optionally with preservative, buffer, pH adjuster, tonicity agent, and / or solvent / co-solvent;b. aseptically preparing Component B by dissolving one or more excipient and / or diluent in WFI / cosolvent;c. aseptically filling Component A into chamber 1 and Component B into chamber 2 of a two-chamber container.

26. A process for manufacturing the product as claimed in claim 21, comprising:a. aseptically dissolving excipient or diluent in WFIb. optionally aseptically adding preservative and buffer, stabilizer, solvent, or co-solvent;c. adding oxytocin to step a or step b, aseptically;d. aseptically filling into a single chamber container.

27. A method of treating a human subject in need of oxytocin therapy, the method comprising breaking or removing the seal between Component A and Component B in the product of claim 1 to mix the components within the container, and intravenously administering the resulting oxytocin infusion composition to the said subject.

28. Oxytocin or a pharmaceutically acceptable salt thereof for use in a method of treatment of human subject in need of oxytocin therapy, wherein the oxytocin is provided as an infusion composition prepared in-container by mixing Components A and B of the product of claim 1 or as the ready-to-use composition of claim 21.

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