WO2019150381A1

WO2019150381A1 - A stable pharmaceutical composition and process for production of isoproterenol hydrochloride injection

Info

Publication number: WO2019150381A1
Application number: PCT/IN2018/000028
Authority: WO
Inventors: Mahendra R. Joshi; Kamalanathan S; Ravindhar Reddy MANDAPATI; Trinath Kumar IMMANNI; Ananya De BHOWMICK
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-02-01
Filing date: 2018-05-14
Publication date: 2019-08-08
Anticipated expiration: 2020-08-01

Abstract

In one aspect, the invention relates to a stable liquid formulation for parenteral composition comprising a therapeutically effective amount of Isoproterenol 1n an aqueous solution having controlled oxygen level in the head space of a container and in bulk solution.

Description

A stable pharmaceutical composition and process for production of Isoproterenol Hydrochloride Injection

FIELD OF THE INVENTION

The present invention refers to stable pharmaceutical compositions of Isoproterenol Hydrochloride for pharmaceutical use and to a method of preparation.

BACKGROUND OF THE INVENTION

It is common knowledge that some active ingredients are having stability problems in solution. Some of these problems are due to the fact that the active ingredients easily oxidize, by reacting either with atmospheric oxygen or with dissolved oxygen in the aqueous solution, with consequent production of non-desirable degradation products.

Isoproterenol Hydrochloride is 3,4-Dihydroxy-a-[(isopropylamino)methyl] benzyl alcohol hydrochloride, a synthetic sympathomimetic amine that is structurally related to epinephrine but acts almost exclusively on beta receptors. Isoproterenol hydrochloride is a racemic compound. Isoproterenol Hydrochloride Injection 0.2 mg/mL administered by intravenous infusion or bolus intravenous injection use in the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alphaadrenergic receptors. Intravenous infusion of Isoproterenol in man lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds. Innovator product is available in the brand name of ISUPREL^™ (Isoproterenol Hydrochloride) sterile Injection, USP in US market.

The sterile solution is nonpyrogenic and can be administered by the intravenous, intramuscular, subcutaneous, or intracardiac routes. ISUPREL^™ is supplied in 1 mL & 5ml ampoule 0.02% sterile, non-pyrogenic aqueous solution. Catecholamines such as Isoproterenol and epinephrine are highly subject to degradative oxidation in solutions. During Drug product development stage, it is observed that, Isoproterenol HC injection in aqueous solutions is highly unstable when packed without control on dissolved oxygen and head space oxygen in glass vials and ampoules. Due to the fact that lsoproterenol in aqueous medium is unstable in the presence of oxygen and/or light, it is difficult to obtain a pharmaceutical ready-to-use solution for intravenous perfusion.

Various attempts were undertaken to develop a stable Isoproterenol solutions. One of the attempt was by Nayak et al., (1986) investigated the effect of various additives on the stability of Isoproterenol Hydrochloride solutions (Nayak et al., Drug Development and Industrial Pharmacy, Volume 12, 1986, Pages 589-601). They_, found that Ascorbic acid and sodium bisulfite appear to be the most efficient antioxidants in the system. Further they concluded the effectiveness of Sequestering agents such as EDTA and citric acid in reducing degradation rate of Isoproterenol. They observed that the reaction appears to be an oxidation of the catechol ring system of Isoproterenol similar to that observed with epinephrine.

Smith et al (1984) investigated the effects of ascorbic acid and disodium edetate on the stability of isoprenaline hydrochloride injection (Smith et al., J ClinHosp Pharm. 1984 Sep; 9(3):209- 15). Experimentation results further concluded that Disodium edetate (0.01%), either alone or in combination with ascorbic acid (0.1%) was an effective stabilizer for isoprenaline injection B.P., but adjustment to pH 2.8 was necessary. The bubbling of nitrogen through the solution in the ampoule before sealing did not prevent degradation in unprotected solutions. Solutions sterilized by filtration or by autoclaving for 30 min at 1 16 degrees C were stable for at least 1 year at 5 degrees C or 25 degrees C.

US patent 3039928 also address the problem of stability of Isoproteronol and solutions by adding ascorbic acid effectively prevents breakdown and deterioration of isoproteronol in aqueous compositions. The inherent properties of ascorbic acid are unique because many other antioxidants fail to display the beneficial properties of stabilizing Isoproteronol. Among other antioxidants which have been found undesirable are butylatedhydroxy anisole, propyl gal late nor-dihydroguaretic acid sodium metabisulfite, ethyl hydrocatfeate, di-tertbutyl-paracresol and others.

The present inventors have carried out various researches in order to develop a Isoproterenol pharmaceutical formulation in the form of a solution for injection, having an improved stability. The present inventors surprisingly found that, when headspace oxygen in the vials & ampoules filled with solution for injection was substantially removed (i.e.. approximately less than 2%) by e.g.. bubbling of nitrogen gas into the solution & purging nitrogen gas over head space of vials/ ampoules after solution filling, a stable liquid formulation containing isoproterenol or its salt is obtained.

Therefore, the present invention provides a method for preparing a pharmaceutical formulation in the form of a stable solution for injection containing Isoproterenol or its salt as an active ingredient.

The present invention overcomes the limitations of lsoproterenol solutions by stabilizing solutions of Isoproterenol by controlling the level of dissolved oxygen content and head space oxygen in the container.

BRIEF SUMMARY OF THE INVENTION

Two factors affecting the stability of pharmaceutical composition of Isoproterenol solution such as exposure to oxygen in the unfilled area of a container carrying the drug solution (headspace) as well as the absorption of gaseous oxygen (dissolved oxygen) into the drug solution. Methods for controlling the oxygen content of the headspace are insufficient for reliably controlling the levels of oxygen necessary to obtain a stable liquid formulation of lsoproterenol having desirable potency and stability over the shelf li fe of the composition.

Stringent control of the oxygen levels in the headspace and the dissolved oxygen that is absorbed into the drug solution provide beneficial effects for decreasing the total impurities of the drug product. Purging a sufficient amount of nitrogen over headspace of the composite solution affords an overall more stable formulation of lsoproterenol.

We have determined that to provide a stable composition of lsoproterenol formulation, the composition should have less than or equal to 5-Oppin oxygen in bulk solution, and less than or equal to 2% head space oxygen content in the unit dose container.

Therefore one object of the present invention relates to providing a composition of lsoproterenol having low oxygen levels of less than or equal to 5.0 ppm oxygen in bulk solution.

Another object of the invention relates to preparing a unit dose system in a sealed vessel comprising an aqueous solution of a therapeutic amount of Isoproterenol having oxygen levels less than or equal to 2.0% in the headspace.

In one aspect, the invention relates to a composition comprising a therapeutically effective amount of lsoproterenol in an aqueous solution having less than or equal to 2.0% oxygen in the headspace of a container when determined immediately after container sealing, said solution consisting essentially of a complexing agent and buffers. The compositions provide a stable low oxygen formulation having less than or equal to 5 ppm of oxygen.

Yet another aspect of the invention relates to a process for preparing a low oxygen composition of aqueous lsoproterenol, comprising the steps of: Step-l : Add and dissolve batch quantity of complexing agent in 80% of water for injection at 60- 65°C.

Step-2: To the step-l solution add buffers and stabilizing agents at room temperature.

Step-3: Nitrogen purge the bulk solution continuously to get dissolved oxygen below 5ppm. Step-4: Add and dissolve drug substance to step-3 solution and adjust the pH of bulk solution to 3.5 - 4.5 either by use of hydrochloric acid or sodium hydroxide.

Step-5: Make up the volume to 100% V/V with use of water for injection.

Step-6: Continuously nitrogen purge the bulk solutions to maintain dissolved oxygen below 5ppm.

Step-7: Filter the bulk solution using 0.2 micron PVDF sterile filter membrane.

Step-8: Fill the filtered solution in to 5 mL clear glass vial (USP type I glass) stoppered with coated rubber stopper and flip off seal. And ensure that the head space was blanketed with nitrogen gas.

The composition can be prepared in a vial according to steps (1 ) through (8) as described above. Appropriate means of closure was placed into the opening of the filled container in a manner which does not allow the exchange of gas from an interior side of the container to an exterior side of the container. The container headspace was treated with vacuum and purging the container headspace with an inert gas (nitrogen); and repeating the vacuum treating and purging step to control oxygen content in the container headspace before suitably sealing the container.

DETAILED DESCRIPTION OF THE INVENTION

Drug stability means the ability of the pharmaceutical dosage form to maintain the physical, chemical, therapeutic and microbial properties during the time of storage and usage by the patient. It is measured by the rate of changes that take place in the pharmaceutical dosage forms. Stability is defined by the criteria set by ICH Q1 A for injections.

The invention relates to the use of a stable Pharmaceutical composition of Isoproterenol.

It also relates to said composition characterized in that it is as a liquid stable Isoproterenol formulation.

Preferably the solution is an aqueous solution. The formulations as developed by the Inventors of the present Application are suitable for parenteral administration. Such stable liquid formulation of Isoproterenol can be developed with the use of tonicity agent, chelating agents and buffers and by controlling the oxygen content of drug solution and vial/ampoule headspace with the use of an inert gas viz nitrogen. These formulations are presented as a single unit dose (vial/ ampoule) presentation having Isoproterenol concentrations 0.2 mg/ml. These pharmaceutical compositions are then administered usually via intravenous infusion or bolus intravenous injection. In dire emergencies, the drug may be administered by intracardiac injection. If time is not of the utmost importance, initial therapy by intramuscular or subcutaneous injection is preferred.

The stable ready-to-use pharmaceutical composition of Isoproterenol is usually solvated in an aqueous solvent comprising water for injection. In one embodiment of the present invention, the ready-to-use pharmaceutical composition of Isoproterenol has a pH between about 2.5 and about 4.5, preferably between about 3.5 and about 4.5 and more preferably in the range of about 3.5 and about 4.0.

The pl-l of such ready-to-use pharmaceutical compositions of Isoproterenol may be achieved by use of suitable buffers and adjusted with a pharmacologically acceptable pH adjusting agent such as an acid& base. In an embodiment of the present invention, the pH adjusting agents are citrate buffers, acid and bases or their combination thereof. The hydrochloric acid or sodium hydroxide may be in any suitable form, such as a 0.01N to 1N solution. In addition, the composition can contain one or more chelating agents whose presence will further improve the stability of the Isoproterenol present therein. Chelating agents which may be mentioned in particular are ethy!enediamine tetraacetic acid, diethy!enetriaminepentaacetic acid, 1 ,4,7, 10-tetraazacyclododecane-N,N',N",N^M,-tetraacetic acid, trans- 1 ,2-cycIohexylenediamine- N,N,N',N'-tetraacetic acid, N⁶ -carboxymethyl-N³,N⁹ - 2,3-dihydroxy-N- methylpropylcarbamoylmethyI-3,6,9-triazaundecanedioic acid, N⁶ -carboxymethyl-N³,N⁹ -bis (methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid, N³,N⁶ -bis (carboxymethyl) -N⁹ -3- oxapentamethyIene-carbamoy!methyl-3,6,9-triazaundecanedioic acid or N³,N⁶ -bis (carboxymethyl)-N⁹ - 3,3-bis (dihydroxyphosphoryI)-3-hydroxypropyl-carbamoylmethyl!-3,6,9- triazaundecanedioic acid. The chelating agents can be present in a quantity 0.02% by weight, relative to the total weight of the composition.

According to the invention .the compositions are obtained by a deoxygenation process and inerting. Deoxygenation and inerting is carried out by use of inert gas and preferably dense as nitrogen is circulated and / or sparging facilities and other tubing and solutions in order to eliminate most of any trace of oxygen and residual volumes in solution.

According to the invention the pharmaceutical composition is characterized by its oxygen content which is less than 5ppm in bulk solution and less than 5% in head space. In other embodiments and depending on the intended stability times, the oxygen content may be less than 5ppm in bulk solution and less than 2% in head space.

The gas used for purging the sealable container may be any appropriate inert gas known to those in the art, the most commonly used gases being argon, helium or nitrogen, or mixtures thereof. However the most preferred inert gas is nitrogen. In another embodiment of the present invention, so as to minimize oxidation of the sensitive material it is also desirable to remove headspace oxygen from the sealable vessel as quickly as possible. This may be aided by, for example, purging the sealable container with a gas which is substantially oxygen-free, or substantially oxygen and moisture free before, during or after step, or any combination thereof. Purging can be expected to reduce the oxygen level in the sealable container to a level of from about 0%to about 5% typically about 2%or lower, depending on the efficiency of flushing and how quickly the container is sealed after flushing.

The invention is further illustrated by way of the following example, which in no way should be construed as limiting the scope of the invention. The following examples further illustrates the invention and is not to be construed as limiting of the specification and claims in any way. Below are the experiment details performed to demonstrate the product instability when packed without head space nitrogen purging in 5mL glass vials.

Table #1 : Formula composition for evaluation of product stability in glass vials

S. Batch No. IDRSFDO 10-FD/042-015

No. lngredients Mg/mL

1. Isoproterenol 0.20

Hydrochloride, USP

2. Edetate Disodium 0.20

3. Sodium chloride USP 7.00

4. Trisodium citrate, Dihydrate 2.07

5. Citric acid anhydrous 2.50

6. Hydrochloric acid/NaOH pH adjusted to 3.5 to 4.5

7. Water for injection Q.S. tol .O mL

Process variables

j Bulk solution Nitrogen Yes (Dissolved oxygen <5ppm)

purging

2. Head space N₂ purging Yes

3. Filtration (with N₂ gas) Yes

5 ml clear glass (USP type 1 ) vial stoppered with

4. Packing material

coated rubber stopper Manufacturing Procedure:

Step- 1 : Add and dissolve batch quantity of edetate disodium in 80% of water for injection at 60- 65 C.

Step-2: To the step- l solution add sodium chloride, trisodium citrate and citric acid at room temperature.

Step-3: Nitrogen purge the bulk solution continuously to get dissolved oxygen below 5ppm. Step-4: Add and dissolve drug substance to step-3 solution and adjust the pH of bulk solution to 3.5 - 4.5 either by useof dilute Hydrochloric acid or sodium hydroxide solution.

Step-5: Make up the volume to 100% V/V with use of water for injection.

Step-7:Fiiter the bulk solution using 0.2 micron PVDF sterile filter membrane.

Table#2: Results of with and without head space nitrogen blanketing samples-015 vial batch

Batch no.: IDRFD010-FD/042-015

Parameter _ Batch with <5 ppm DO Level packed in 5 ml vial

S. Condition RT 60°C 60°C

No. Stage Initial 2 week 2 week

Head space

With Nitrogen Without Nitrogen With Nitrogen

N2 purging

7. Related substances % w/w @RRT

0.81 ND 0.22 ND

0.93 0.03 0.95 0. 10

1 .07 ND 1 . 16 ND

1.18 ND 0.23 0.03

1MP-AJ .21 0.01 0.01 0.01

2.08 ND 0.22 ND

2.95 ND 0.44 ND

3.06 ND 0.55 ND

3.12 ND 0.37 ND

3.31 ND 0.30 ND

3.35 ND 0.56 ND

3.36 ND 0.42 ND

3.45 ND 0.65 ND

3.51 ND 0.25 ND

3.70 ND 0.71 ND

4.05 _ ND _ 0.68 ND

Total Imps_ 0.09 10.49 0.24

Remarks: <0.2% impurities are not reported in table as the no. of impurities are more, but included in total impurity. ND-Not detected. NP-Not performed

Inference: From the above study (with and without head space nitrogen purging) without nitrogen head space samples packed in 5mL vials has 10.49% total impurities, indicating that head space oxygen & nitrogen plays major role in product stability, thus complete head space blanketing with nitrogen gas should be done to avoid degradation and to maintain product stability throughout shelf life. Below are the experiment details performed to demonstrate the product stability when packed with purging head space nitrogen at different times i.e without nitrogen purging, 2sec, 4 sec & 6 sec (pre and post purging time) nitrogen purging on head space for 5mL ampoules.

Table #3: Formula composition and parameters for different head space nitrogen purging trials

S. Fill volume 5.3 ml ( 1 mg/5 ml)

No. Ingredients Mg/mL

1 . lsoproterenol Hydrochloride, 0.20

USP

2. Edetate Disodium 0.20

3. Sodium chloride USP 7.00

4. Trisodium citrate, Dihydrate 2.07

5. Citric acid anhydrous 2.50

6. Hydrochloric acid/NaOH pH adjusted to 3.5 to 4.5

7. Water for injection Q.S. to l .O mL

Process variables

Batch No: 1DRFD010- FD/042-026 FD/042-027 FD/042-028 FD/042-029

Head space (pre and post Without head

8. . „ , . . _x. _n 2 sec 4sec 6 sec

N₂ Hushing ) purging time space N₂ Purge

9. Filtration (N₂ gas)

10. Packing material 5 ml fiolax clear scoring ampoule with blue band

Note: Dissolved oxygen level less than 2 ppm and head space of ampoules were purged with nitrogen gas (preandpost N₂ purging) as per the respective plan.

Table#4: Head space oxygen content measured by FMS- Oxygen Head space analyzer from Lighthouse

Batch No. Batch Details Head space oxygen content (%)

1DRFD010-FD/042-026 Without head space 20.042

1DRFD010-FD/042-027 2 sec head space 0.957

IDRFD010-FD/042-028 4 sec head space 0.335

1DRFD010-FD/042-029 6 sec head space 0.655

Inference: From above stress condition (60°C) stability results, without head space nitrogen purged batch (head space oxygen content (20.042%) has more impurity formation compared to all other batches, Head space oxygen content is significantly affecting product stability. Hence final drug product should have low head space oxygen content (<2%) to maintain drug product stability throughout shelf life

Experiments performed to demonstrate the product instability when packed without head space nitrogen purging in 5mL glass vials. Experiments showed that without nitrogen head space samples packed in 5mL vials had higher total impurities, indicating that head space oxygen plays major role in product stability, thus complete head space blanketing with nitrogen gas should be done to avoid degradation and to maintain product stability throughout shelf life.

The foregoing specification, including the specific embodiments and example, is proposed to be illustrative of the present invention and is not to be taken as limiting. Numerous other variations and modi ications can be effected without departing from the true spirit and scope of the present invention.

Claims

I/WE claim

1. A stable Pharmaceutical composition of Isoproterenol having head space oxygen content less than or equal to 5.0% and dissolved oxygen in solution is less than or equal to 5ppm.

2. A stable Pharmaceutical composition of Isoproterenol according to Claim I having head space oxygen content less than or equal to 2.0% and dissolved oxygen in solution is less than or equal to 5ppm.

3. A stable Pharmaceutical composition of Isoproterenol according to Claim 1 is liquid composition.

4. A stable Pharmaceutical composition of Isoproterenol according to Claim 1 wherein liquid composition is in an aqueous solvent.

5. A stable Pharmaceutical composition of Isoproterenol according to Claim 1 wherein the Isoproterenol formulation in said solvent is deoxygenated by flushing an inert gas into the bulk solution during manufacturing and purging inert gas into the headspace of the final container.

6. A stable Isoproterenol aqueous formulation comprising excipients selected from stabilizer, complexing agent, buffering agent, tonicity agent, a base and an acid.

7. A stable Isoproterenol aqueous formulation according to claim 6 wherein the stabilizer is chelating agent and antioxidant.

8. A stable Isoproterenol aqueous formulation according to claim 6 wherein the chetalting agent is selected from the group consisting of ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, 1 ,4,7, 10-tetraazacyclododecane-N,N’,N",N"’-tetraacetic acid, trans- 1 ,2-cyclohexylenediamine-N,N,N',N'-tetraacetic acid, N6 -carboxymethy!-N3,N9 - 2,3- dihydi_Oxy-N-methylpropylcarbamoylmethyl!-3,6,9-triazaundecanedioic acid, N6 carboxymethyl-N3.N9 -bis (methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid, N3,N6 -bis (carboxymethyl) - 9 -3-oxapentamethylene-carbamoylmethyl-3,6_s9-triazaundecanedioic acid or N3.N6 -bis (carboxymethyl)-N9 - 3,3-bis (dihydroxyphosphoryl)-3-hydroxypropyl- carbamoylmethyl!-3,6,9-triazai)ndecanedioic acid.

9. A liquid stable Isoproterenol aqueous formulation according to claim 7 wherein the chelating agent is ethylenediamine tetraacetic acid (disodium edetate)

10. A liquid stable Isoproterenol aqueous formulation according to any one of the claims 1 to 9 wherein the buffering agent is selected from the group consisting of phosphates and/or citrates.

1 1. A liquid stable Isoproterenol aqueous formulation according to claim 10 wherein the buffering agent is citrate buffer, i.e. Trisodium citrate Dihydrate, Citric acid anhydrous.

12. A liquid stable Isoproterenol aqueous formulation according to any one of the claims 1 to 12 wherein the concentration of Isoproterenol is 15 mg/ml.

13. A liquid stable Isoproterenol aqueous formulation according to any one of the claims I to 1 1 wherein the concentration of Isoproterenol is 0.2mg/ml.

14. A process for producing a liquid stable Isoproterenol aqueous formulation wherein the formulation in said solvent is deoxygenated by flushing an inert gas into the headspace of a tank and into the headspace of the final container and wherein said formulation comprises at least one of the following excipients: Edetate Disodium, Sodium chloride USP, Trisodium citrate, Dihydrate. Citric acid anhydrous, Hydrochloric acid/NaOH.

15. A process for producing a liquid stable Isoproterenol aqueous formulation according to claim 14 wherein the inert gas is argon, nitrogen, helium or neon.

16. A process for producing a liquid stable Isoproterenol aqueous formulation according to claims 14 wherein the inert gas is nitrogen.