Stable aqueous composition of calcium gluconate

Abstract

The present invention provides a stable aqueous composition for parenteral use comprising calcium gluconate and calcium saccharate. The composition provides a stable, terminally sterilized composition that is suitable for immediate use.

Description

[0001] STABLE AQUEOUS COMPOSITION OF CALCIUM GLUCONATE

[0002] FIELD OF THE INVENTION

[0003] The present invention provides a stable aqueous composition for parenteral use comprising calcium gluconate and calcium saccharate. The composition provides a stable, terminally sterilized composition that is suitable for immediate use.

[0004] BACKGROUND OF THE INVENTION

[0005] Calcium gluconate, or Calcium D-gluconate, is a form of calcium approved for use in pediatric and adult patients for the treatment of acute symptomatic hypocalcemia. The product has been available on the market in the form of a preconcentrate for dilution, as well as a ready-to-use solution. Typically, the calcium gluconate solution is administered to the patient intravenously (bolus or continuous infusion) via a secure intravenous line, using a solution of strength 20mg / ml. The ready-to-use solution is available in the strength of 20mg / ml, while the preconcentrate needs to be manually diluted to 20mg / ml with physiological saline or dextrose before administration to the patient. Manual dilution involves withdrawal of the required quantity of preconcentrate of calcium gluconate from the vial, followed by dilution with a suitable quantity of an appropriate dilution. As can be envisaged, such a process has scope for manual error, which can lead to incorrect dosing due to under or over-dosing, resulting from mistakes in calculation and / or error in withdrawal of the right quantity of the calcium gluconate preconcentrate, or diluent or both.

[0006] The commercially available preconcentrate of calcium gluconate (Fresenius NDA #208418) as well as the ready-to-use solution (HQ Specialty NDA #210906, Fresenius sNDA #208418) are terminally sterilized, and contain calcium saccharate as a stabilizer. Aseptically manufactured solutions of calcium gluconate in sodium chloride have also been available as ready-to-use solutions. These commercially available products are being incorporated herein by reference.

[0007] CN203852649 discloses bags containing Ig / lOml of calcium gluconate solution in a container that is connected by a connecting tube to a container containing 500ml of physiological saline. The connecting tube is easily breakable and upon breaking, causes a mixing of the calcium gluconate solution with the saline, thereby providing a calcium gluconate solution of strength 1.96mg / ml. This product has been disclosed to be used for administration to blood donor, so as to ensure that their blood calcium levels are maintained. However, it does not disclose the contents of the calcium gluconate solution, and certainly does not disclose the use of calcium saccharate with calcium gluconate. Further, it does not provide any details on stability of the solution, and has no teachings or suggestions on preparing stable calcium gluconate solutions of strength 20mg / ml.

[0008] CN114533759 discloses a sodium potassium magnesium calcium glucose injection. The summary of the invention states - “The injection contains sodium chloride, potassium chloride, calcium gluconate, magnesium chloride, sodium acetate, sodium citrate and glucose. The injection is prepared by terminal sterilization, and the obtained sodium potassium magnesium calcium glucose injection has a high sterility guarantee level. At the same time, the molar concentration, osmotic pressure, and pH value of various ions contained in the injection are close to the composition of human plasma electrolytes, which can be used for Extracellular fluid supplementation when circulating blood volume and interstitial fluid decrease, correction of metabolic acidosis.” While the disclosure discusses the stability of the glucose component of the injection, there is no discussion about the stability of the calcium gluconate contained therein. Also, there is no disclosure or teaching on using dual -chambered plastic containers that can provide a ready-to-administer solution of calcium gluconate and calcium saccharate.

[0009] CN112426359 discloses a double chambered bag with dextrose solution in one chamber and a mixture of sodium chloride, potassium chloride, magnesium chloride, calcium gluconate, sodium acetate, sodium citrate and pH-adjusting amount of sodium hydroxide. The bag is terminally sterilised at 121°C for 12 minutes. The publication states that the purpose of the invention is to provide a double -chambered bag containing Ringer's solution with dextrose, which can not only separate glucose from inorganic salts, but also keep glucose in a more suitable acid-base environment, with less impurities. It does not provide any details on stability of the calcium gluconate solution, and has no teachings or suggestions on preparing stable calcium gluconate solutions of strength 20mg / ml.

[0010] Similar other prior art references that disclose calcium gluconate containing solutions include CN 104224829 and CN101167740, none of which provide any details on stability of the solution, and none of them have any teachings or suggestions on preparing stable solutions containing calcium gluconate and calcium saccharate. US8404274 discloses dual-chambered bags wherein one chamber has a solution of calcium gluconate with several other electrolytes, and the other chamber has a solution containing other actives and / or electrolytes. The two solutions are prepared and fdled aseptically into the dualchambered bags, followed by terminal heat sterilization of the bags. The components are separated into two chambers to be able to provide a stable solution, i.e. to overcome the instability arising out of their mixture and long term storage . However, nothing therein provides any teachings or suggestions on preparing stable solutions containing calcium gluconate, with calcium saccharate as a stabilizer, wherein the strength of the calcium gluconate solution is 20mg / ml.

[0011] US 10130646 and US 10342813 disclose terminally sterilized aqueous calcium gluconate solution comprising 1 to 15 wt % calcium gluconate and from 1 to 19 weight parts calcium saccharate per 100 wt parts of calcium gluconate packaged in a flexible plastic container with the remainder water. It also discloses solutions that may contain sodium chloride as isotonicity agent. However, the patent publications do not disclose a composition wherein a preconcentrate of calcium gluconate of strength lOOmg / ml is packaged with a suitable diluent composition in a double -chambered plastic container, and wherein the strength of the final composition upon mixture with the diluent composition is 20mg / ml of calcium gluconate.

[0012] In light of the above, there is a need for ready-to-dilute compositions containing calcium gluconate, that would avoid manual dilution. This would avoid manual handling of the calcium gluconate solution, and would also avoid any errors that may occur at the point of administration. In order to make such compositions, a suitable solvent system / diluent is essential, along with a packaging system that is robust and maintains the quality and purity of the product over a long period of time. The solution also would need to be sterile for use as a parenteral, and would need to be so preserved until it is administered to the patient. Further, the active ingredients must not degrade in the solution and must remain stable throughout its shelf life.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention relates to a stable ready-to-dilute aqueous composition containing calcium gluconate that is sterile, aqueous and that does not require manual reconstitution. The calcium gluconate composition of the present invention is useful as a form of calcium for use in pediatric and adult patients for the treatment of acute symptomatic hypocalcemia. The present disclosure provides the following -

[0015] (1) A terminally sterilised aqueous preparation to be mixed at the time of use, wherein calcium gluconate (drug composition) and 0.675% sodium chloride solution (diluent composition) are divided and accommodated in two chambers of a plastic container, such as a bag, separated by a partition wall.

[0016] (2) The sterile preparation according to the above (1), wherein the two chambers are arranged in one container, either side by side on a horizontal axis, or one below the other on a vertical axis.

[0017] (3) The sterile preparation according to (1) or (2) above, wherein the solution contains 94mg / ml of calcium gluconate, or 98mg / ml of calcium gluconate monohydrate, and 4.5mg / ml of calcium saccharate prior to mixing of the constituents of the two chambers.

[0018] (4) The sterile preparation according to (1) or (2) above, wherein the solution contains 18.8mg / ml of calcium gluconate and 0.9mg / ml of calcium saccharate subsequent to mixing of the constituents of the two chambers.

[0019] (5) The sterile preparation according to any one of the above (1) to (4) above, wherein the container is a plastic container in which the partition wall between the chambers can be peeled off or broken at the time of use, to provide a calcium gluconate solution of strength 20mg / ml.

[0020] (6) The sterile preparation according to any one of the above (1) to (5) above, wherein the components of the two chambers are mixed easily, aseptically and accurately to provide a calcium gluconate solution of strength 20mg / ml, just before administration to the patient.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention provides a sterile aqueous composition of calcium gluconate that is stable, and which provides the advantages of reduced dosing errors and ease of administration. The present invention particularly provides a terminally sterilised aqueous preparation comprising (a) calcium gluconate as a drug product composition and (b) 0.675% sodium chloride solution as a diluent composition, accommodated in two chambers of a plastic container separated by a partition wall, wherein the drug composition and diluent composition are mixed at the time of use, and wherein upon storage of the preparation at 25°C, 45% relative humidity for 6 months, or at 40°C, 25% relative humidity for 6 months, the assay for calcium gluconate is more than 99%, the aluminum content in the preparation is below 25mcg / L, and the pH is in the range of about 6 to about 7.5.

[0023] The sterile stable aqueous composition of the present invention contains a drug product composition containing calcium gluconate and a diluent composition, each packaged in a separate chamber of a dual chambered plastic container, wherein the two chambers are connected through a seal or lid or wall that can be easily broken to facilitate mixing of the contents of the two chambers at the time of administration to the patient.

[0024] Additives or excipients are generally employed in parenteral compositions to enhance the chemical and physical stability, i.e, shelflife and aesthetic appearance of the compositions. To provide efficacious and safe parenteral dosage forms, the added excipients must frequently be incorporated into the composition to maintain pharmaceutical stability, control product attributes, ensure sterility and aid in parenteral administration.

[0025] The present invention provides a sterile aqueous composition comprising (1) a drug product composition consisting of therapeutically effective amount of calcium gluconate, calcium saccharate as a stabilizer and a pH modifying agent, and (2) a diluent composition containing 0.675% saline, wherein the drug product composition and the diluent composition are packaged in two separate chambers of a dual-chambered plastic container, and wherein the composition is stable over its shelf-life.

[0026] The drug product composition contains calcium gluconate or its pharmaceutically acceptable solvate, such as monohydrate, in an amount of 94mg / ml (if calcium gluconate monohydrate is present the amount is 98mg / ml). The drug product composition further contains calcium saccharate, or its pharmaceutically acceptable solvate such as tetrahydrate, as a stabilizer, and sodium hydroxide or hydrochloric acid as pH adjusting agent to adjust pH to about 6.0 to about 8.2. Typically, the drug product composition is filled in one chamber of the dual -chambered container in an amount of 10ml, 50ml or 100ml.

[0027] The calcium saccharate used in the composition of the present disclosure functions as a stabilizer, and also acts as a source of calcium, along with calcium gluconate. The calcium saccharate is typically used in the form of calcium saccharate tetrahydrate.

[0028] The diluent composition contains sodium chloride in water for injection in an amount of 0.675% by weight of the diluent composition. Typically, the diluent composition is fdled in the second chamber of the dual -chambered container in an amount of 40ml, 200ml or 400ml.

[0029] Typically, the stable aqueous ready-to-use composition of the present invention contains 20mg / ml of calcium gluconate, upon mixture of the drug product composition with the diluent composition. In preferred embodiments of the present invention, 10ml of the drug product composition is packaged with 40ml of the diluent composition. In other preferred embodiments of the present invention, 50ml of the drug product composition is packaged with 200ml of the diluent composition. In still other preferred embodiments of the present invention, 100ml of the drug product composition is packaged with 400ml of the diluent composition.

[0030] In an embodiment, the terminally sterilised preparation contains a drug product composition having 94mg / ml of calcium gluconate and 4.5mg / ml of calcium saccharate. In one embodiment, the terminally sterilised preparation contains a drug product composition having 98mg / ml of calcium gluconate monohydrate and 4.5mg / ml of calcium saccharate. In a second embodiment, the terminally sterilised preparation contains 20mg / ml of calcium gluconate subsequent to mixing of the drug composition and the diluent composition.

[0031] In another embodiment, the terminally sterilised preparation contains 18.8mg / ml of calcium gluconate and 0.9mg / ml of calcium saccharate subsequent to mixing of the drug composition and the diluent composition.

[0032] Parenteral drug products must be sterile so as to ensure patient safety. The term “sterile” refers to the pharmaceutical composition which is free from contamination caused by harmful bacteria, viruses, or other microorganisms wherein the pharmaceutical composition is surgically sterile or sterilized. Typically, a sterile ready-to-dilute composition of the present invention can be obtained by (1) terminally sterilizing the composition in its final container, i.e., the dual-chambered plastic container, using moist heat sterilization, dry heat sterilization or radiation sterilization, or (2) by manufacturing and filling the ready-to-dilute composition in an aseptic manner, ensuring that the infrastructure used and the processes employed do not contribute to introduction of microbial contamination at any time. A person of skill in the art is aware of these methods and how these are to be carried out.

[0033] As disclosed herein, the drug product composition is a preconcentrate comprising calcium gluconate and calcium saccharate, and is a solution that is ready-to-dilute. Upon mixture of the drug product composition, i.e., the preconcentrate, with the diluent composition, upon breaking of the seal or lid between the two chambers of the dual-chambered plastic container, the solution of calcium gluconate obtained is a ready-to-dilute composition.

[0034] In preferred embodiments, the aqueous ready-to-dilute composition (or preconcentrate) of the present invention is manufactured using aseptic processing and sterile filtration, followed by terminal sterilization of the dual-chambered plastic container, along with the diluent composition being present in the second chamber. The terminal sterilization of pharmaceutical composition is preferably performed with saturated steam / super-heated water / counter pressure at about 121 °C in an autoclave for at least about 15 minutes.

[0035] Aluminium contamination of parenteral nutrition solutions has been documented for 3 decades. It can result in elevated blood, bone, and whole body aluminium levels associated with neurotoxicity, reduced bone mass and mineral content, and perhaps hepatotoxicity. The primary aluminium source among parenteral nutrition components is glass-packaged calcium gluconate, in which aluminium concentration in the past 3 decades has averaged approximately 4000 pg / L, compared with <200 pg / L in plastic container packaged calcium gluconate. A concern about plastic packaging is leaching of plasticizers, including phthalates, which have the potential to cause endocrine (male reproductive system) disruption and neurotoxicity (See Yokel RA et al, “Aluminum and Phthalates in Calcium Gluconate: Contribution from Glass and Plastic Packaging” ; J Pediair Gastroenterol Nutr. 2017 Jan;64(l): 109-114). Therefore, there is a need to reduce, control and monitor the level of aluminium in parenteral dosage forms of calcium gluconate that are prescribed for acute conditions to infants and children, as well as patients with serious disease conditions. The use of a dual chambered bag of the present invention solves this problem. Typically, the calcium gluconate preparation of the present invention contains not more than lOOpg / L of aluminium. In preferred embodiments, the aluminium content on the calcium gluconate preparations of the present invention, i.e. those obtained upon mixing the drug product composition and the diluent composition, is less than 25pg / L. In highly preferred embodiments, the aluminium content is less than 12.5pg / L.

[0036] The term “shelflife” refers to the amount of time the ready-to-dilute composition of the present invention may be stored without loss of potency and / or performance profile. In some embodiments of the present invention, shelf life refers to the amount of time the ready-to-use composition may be stored without loss of not more than about 6%, preferably not more than about 4%, preferably not more than about 3%, preferably not more than about 2% or still preferably not more than about 1% of the potency and / or performance, when stored at room temperature of 25°C and 40% relative humidity. As described and exemplified herein, potency and / or performance is measured as the assay of calcium gluconate in the drug product composition. The stable drug product composition provided herein is designed to have shelf life of at least about 12 months, preferably about 15 months, more preferably about 18 months, even more preferably about 24 months, i.e. the assay of the drug product composition of the present invention is not less than 95%, preferably not less than 98%, and in highly preferred embodiments, not less than 99%, when measured after storing the drug product composition after storing it at 25°C and 40% relative humidity for 6 months. In other words, the drug product composition of the present invention has an assay of calcium gluconate of not less than 95% at the end of storage at 25°C and 40% relative humidity for 6 months, indicating a shelf life of the drug composition product of at least about 24 months. In simpler terms, assay quantifies how much of calcium gluconate is present in the drug product composition over a period of storage at the aforementioned storage conditions.

[0037] The stable sterile aqueous ready-to-dilute composition of the present invention is packaged in a dual-chambered container that is made up of any flexible plastic material, such as but not limited to, PVC or polypropylene / Polyolefin which is non-PVC and DEHP free, with a peelable aluminium foil / break seal in between the chambers allowing the dilution of calcium gluconate injection, 100 mg / mL with 0.675 % sodium chloride injection, USP just before the administration to the patient. The two chambers may be arranged in one container, either side by side on a horizontal axis, or one below the other on a vertical axis. The product may be packaged in a primary packaging that may be a flexible container, followed by packing it in the secondary packaging or pouch which is oxygen impermeable, in the presence of vacuum, or an oxygen absorber which removes any oxygen that may be present. In one embodiment, the primary packaging may be flushed with nitrogen, followed by packing in the secondary packaging without oxygen absorber. In yet another embodiment, the primary packaging may be flushed with nitrogen, followed by packing in the secondary packaging with an oxygen absorber.

[0038] The calcium gluconate solution that is finally available for administration to the patient, subsequent to dilution with the diluent composition, complies with the requirements laid down in the United States Pharmacopoeia (USP29-NF24) for calcium gluconate injection. The monograph is incorporated herein by reference.

[0039] The present invention provides the following embodiments:

[0040] Embodiment 1 : A stable aqueous composition for parenteral use comprising 50 m IV bag consisting of two chambers. One chamber consists of 10 m of calcium gluconate Injection, USP 100 mg / mb. Other chamber consists of 40 mb of 0.675 % sodium chloride injection, USP. Upon peeling off of the aluminium foil or breaking of the seal, the contents of 0.675% sodium chloride injection, USP mix with calcium gluconate Injection, 100 mg / mb to provide 50 mb of ready-to-administer calcium gluconate Injection, 20 mg / mb.

[0041] Embodiment 2 : A stable aqueous composition for parenteral use comprising 250 mb IV bag consisting of two chambers. One chamber consists of 50 mb of calcium gluconate Injection, USP 100 mg / mb. Other chamber consists of 200 mb of 0.675 % sodium chloride injection, USP. Upon peeling off of the aluminium foil or breaking of the seal, the contents of 0.675% sodium chloride injection, USP mix with calcium gluconate Injection, 100 mg / mb to provide 250 mb of ready-to-administer calcium gluconate Injection, 20 mg / mb.

[0042] Embodiment 3 : A stable aqueous composition for parenteral use comprising 500 mb IV bag consisting of two chambers. One chamber consists of 100 mb of calcium gluconate Injection, 100 mg / mb. Other chamber consists of 400 mb of 0.675 % sodium chloride injection, USP. Upon peeling off of the aluminium foil or breaking of the seal, the contents of 0.675 % sodium chloride injection, USP mix with calcium gluconate Injection, 100 mg / mL to provide 500 mL of ready-to-administer calcium gluconate Injection, 20 mg / mL.

[0043] All publications, patent applications, patents, and other references mentioned are incorporated by reference herein in their entirety for all purposes.

[0044] As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” solvent can mean a single solvent or a multiplicity of solvents.

[0045] Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0046] The terms “preparation”, “composition”, “formulation”, “solution” have been used interchangeably herein.

[0047] The term “manually diluted” as used herein, means a process in which a healthcare professional withdraws the required amount of calcium gluconate preconcentrate from a vial and dilutes it with a suitable diluent.

[0048] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound, related compound, impurity or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10% of the specified amount.

[0049] The present invention is further illustrated by reference to the following examples which are for illustrative purpose only and do not limit the scope of the invention in any manner.

[0050] EXAMPLES

[0051] Example 1

[0052] The calcium gluconate solution (drug product composition) was prepared using the ingredients mentioned below in Table 1, and the diluent composition was also prepared by using the ingredients detailed below in Table 2.

[0053] Table 1 : Drug Product Composition

[0054] Table 2 : Diluent Composition

[0055] The compositions were prepared by the process detailed in flow charts provided in Figures 1- 3. Figure 1 provides the process for preparing the diluent composition. Figure 2 provides the process for preparing the drug product composition. Figure 3 provides process for filling the drug product composition and diluent composition in the dual chamber bags, followed by sterilization of the filled bags. The composition of Example 1 was prepared, filled and stored by the same process. Figure 4 provides a clear view of the design of the dual chamber bag for calcium gluconate solution which is described in the embodiment.

[0056] The compositions were prepared in different strengths and with different fills, as described in

[0057] Table 3 below -

[0058] Table 3

[0059] Example 2

[0060] The compositions of Example 1 were subjected to stability testing. The results of the same are included below - Table 4

[0061] Clear colorless solution; M: Month; CCS: Clear Colorless Solution; NA : Not analyzed; NMT: Not More Than; NLT: Not Less Than; LOQ: Limit of Quantification; BQL: Below Quantification Limit (25mcg / L); BDL: Below detection Limit (12.5 mcg / L); RH : Relative humidity

[0062] Table 5

[0063] Clear colorless solution; M: Month; CCS: Clear Colorless Solution; NA : Not analyzed; NMT: Not More Than; NLT: Not Less Than; LOQ: Limit of Quantification; BQL: Below Quantification Limit (25mcg / L); BDL: Below detection Limit (12.5 mcg / L); RH : Relative humidity Table 6

[0064] Clear colorless solution; M: Month; CCS: Clear Colorless Solution; NA : Not analyzed; NMT: Not More Than; NLT: Not Less Than; LOQ: Limit of Quantification; BQL: Below Quantification Limit (25mcg / L); BDL: Below detection Limit (12.5 mcg / L); RH : Relative humidity

[0065] Table 7

[0066] Clear colorless solution; M: Month; CCS: Clear Colorless Solution; NA : Not analyzed; NMT: Not More Than; NLT: Not Less Than; LOQ: Limit of Quantification; BQL: Below Quantification Limit (25mcg / L); BDL: Below detection Limit (12.5 mcg / L); RH : Relative humidity.

Claims

WE CLAIM:

1. A terminally sterilised aqueous preparation comprising (a) calcium gluconate as a drug product composition and (b) 0.675% sodium chloride solution as a diluent composition, accommodated in two chambers of a plastic container separated by a partition wall, wherein the drug composition and diluent composition are mixed at the time of use, and wherein upon storage of the preparation at 25°C, 40% relative humidity for 6 months, or at 40°C, 25% relative humidity for 6 months, the assay for calcium gluconate is more than 99%, the aluminum content in the preparation is below 25pg / L, and the pH is in the range of about 6 to about 7.5.

2. The terminally sterilised aqueous preparation as claimed in claim 1, wherein the two chambers are arranged in one container, either side by side on a horizontal axis, or one below the other on a vertical axis.

3. The terminally sterilised aqueous preparation as claimed in claim 1, wherein the drug product composition contains 94mg / ml of calcium gluconate and 4.5mg / ml of calcium saccharate.

4. The terminally sterilised aqueous preparation as claimed in claim 1, wherein the drug product composition contains 98mg / ml of calcium gluconate monohydrate and 4.5mg / ml of calcium saccharate.

5. The terminally sterilised aqueous preparation as claimed in claim 1, wherein the preparation contains 20mg / ml of calcium gluconate.

6. The terminally sterilised aqueous preparation as claimed in claim 5, wherein the preparation contains 18.8mg / ml of calcium gluconate and 0.9mg / ml of calcium saccharate subsequent to mixing of the drug composition and the diluent composition.

7. The terminally sterilised aqueous preparation as claimed in claim 1, wherein the container is a plastic container in which the partition wall between the chambers can be peeled off or broken at the time of use.

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