Patent Publication Number: US-2022226423-A1

Title: Stable pharmaceutical composition of vasopressin

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application is a Continuation of application Ser. No. 16/981,892, filed Sep. 17, 2020, which is U.S. national stage application under 35 U.S.C. § 371 of PCT Application No. PCT/IB2019/052117, filed Mar. 15, 2019, which claims priority to Indian Patent Application No. 201811010144, filed Mar. 20, 2018, the entireties of which are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to a stable pharmaceutical composition comprising vasopressin or pharmaceutically acceptable salts thereof. 
     BACKGROUND OF THE INVENTION 
     Vasopressin is a polypeptide hormone. Vasopressin contains nine amino acids, with a disulfide bridge between cysteine residues. Chemically vasopressin is cyclo(1-6)-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-L-arginyl-L-glycinamide. 
     Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock (e.g. postcardiotomy or sepsis) who remain hypotensive despite fluids and catecholamines. It is available under the trade name of Vasostrict® Solution; Intravenous (IV) for Infusion with pH of 3.8 and supplied as 20 units/ml and 200 units/10 ml. 
     U.S. Pat. No. 9,375,478 and its family discloses a pharmaceutical composition comprising vasopressin and a buffer having acidic pH. It also discloses that greatest level of stability of vasopressin formulation was observed at pH 3.5. However, the formulation claimed in U.S. &#39;478 patent is having pH of 3.8. 
     US Pub. No. 2017/0354708 A1 discloses pharmaceutical composition comprising vasopressin, or a pharmaceutically-acceptable salt thereof; and a polymeric pharmaceutically-acceptable excipient. It also discloses that vasopressin assay in the vasopressin formulations with citrate buffer is lower than in the vasopressin formulations with acetate buffer. It also discloses that vasopressin formulations are stable at pH values in the range of 3.5 to 4.5. The results of the experiments suggested that the stability of a vasopressin formulation was highest between pH 3.6 and pH 3.8. 
     U.S. Pat. No. 9,744,239 discloses a method of increasing blood pressure with a unit dosage form of vasopressin, wherein the unit dosage form is diluted in 0.9% saline or 5% dextrose in water to provide a concentration from about 0.1 units/mL to about 1 unit/mL of vasopressin and administering the diluted unit dosage form to the human by intravenous administration. 
     US Pub. No. 2018/0015168 A1 discloses therapeutic formulation comprising a protein active ingredient and a stabilizing excipient such as polypropylene glycol homopolymer. 
     U.S. Pat. No. 6,949,509 discloses stable composition of vasopressin free of preservatives wherein the composition has a pH between 3.5 and 6. 
     U.S. Pat. No. 5,482,931 discloses aqueous composition for administration of small and medium-size peptides comprising buffer, a quaternary amine preservative or disinfectant and an osmotic pressure-controlling agent. It also discloses pH of the composition between about 4 and 6. 
     US Pub. No. 2011/0237508 discloses formulation comprising vasopressin or an analogue thereof, a buffer and at least one non-toxic source of divalent metal ions in a concentration of at least 2 mM. It further discloses that such formulation is having a pH between 3 and 6, preferably between 3 and 5, more preferably between 3.8 and 4.8. 
     Aqueous formulations of therapeutic peptides are susceptible to degradation through a number of different mechanisms and as a result of several types of stress conditions like freeze/thaw cycles, agitation, long term storage, pumping, filtration, or unrefrigerated storage. 
     Peptides can undergo deamidation during which an amide group is removed from an amino acid, and can be associated with protein degradation, apoptosis, and other regulatory functions within the cell. The susceptibility to deamidation can depend on primary sequence of the protein, three-dimensional structure of the protein, and solution properties including, for example, pH, temperature, ionic strength, and buffer ions. Deamidation can be catalyzed by acidic conditions. 
     In view of the above, it is therefore desirable to provide a stable pharmaceutical composition of therapeutic peptides to make the therapeutic peptides more resistant to demidation and the stress conditions encountered during their distribution and storage. Applicant has developed a composition of vasopressin which is having pH less than or equal to 3.6 and is still stable with total impurities less than 5% upon storage at 2 to 8° C. 
     SUMMARY OF THE INVENTION 
     The present invention relates to a stable aqueous composition for administration of small and medium-size peptides, particularly vasopressin, which can maintain stability during its storage. 
     According to one aspect, the present invention provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 
     According to one embodiment, the pharmaceutical composition is in the form of aqueous solution or a lyophilized powder, which can be diluted or reconstituted just prior to use. 
     According to another embodiment, the pharmaceutical composition is in the form of ready to use composition. 
     According to another embodiment, the present invention provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising buffering agents, tonicity agents, pH adjusting agents, preservatives, vehicles, bulking agents and lyoprotectants and/or combinations thereof. 
     According to another embodiment, the present invention provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition has pH in the range of 2.4 to 3.6, preferably in the range of 2.8 to 3.2. 
     According to another embodiment, the present invention provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition has less than 5% total impurities upon storage at 2 to 8° C. According to another embodiment, the present invention provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients which is useful for increasing blood pressure in adults with vasodilatory shock. 
    
    
     DESCRIPTION OF THE INVENTION 
     The present invention relates to a stable aqueous composition for administration of small and medium-size peptides, particularly vasopressin, which can maintain stability during its storage. 
     Applicant has developed a stable pharmaceutical composition of vasopressin which can encounter stress conditions like freeze/thaw cycles, agitation, long term storage, pumping, filtration, or unrefrigerated storage. Applicant has developed a stable composition of vasopressin having lower pH compared to prior art compositions having higher pH range. 
     While working on the present invention inventors have developed a stable pharmaceutical composition of vasopressin with glycine buffer. The formulation showed maximum stability in the pH range of 2.4 to 3.6. 
     The pharmaceutical composition as per the present invention comprises vasopressin or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the pharmaceutical composition comprises from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or pharmaceutically acceptable salts thereof. 
     The pharmaceutical composition is suitable for parenteral administration to a patient. The pharmaceutical compositions can be in a form suitable for parenteral injection such as a sterile suspension, solution, or emulsion in oily or aqueous vehicles. 
     The pharmaceutical composition as per the present invention may be filled into single dose vial or multi dose vial. The pharmaceutical composition is free from preservatives when filled into a multi-dose vial/container. 
     The pharmaceutical composition as per the present invention comprises therapeutically effective amount of vasopressin or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising buffering agents, tonicity agents, pH adjusting agents, preservatives, vehicles, bulking agents and lyoprotectants and/or combinations thereof. 
     Suitable buffering agent may include one or more of buffers such as, for example, citrate, phosphate, tris HCl, acetic acid, sodium acetate, amino acids such as glycine, aspartate/aspartic acid, histidine, cysteine, tyrosine, phenylalanine, proline, arginine, threonine, serine, valine, isoleucine, lysine and glutamine. More preferably, the present invention comprises glycine as a buffer in a concentration of between 0.006 mM to 0.16 mM. 
     In an embodiment of the present invention, there is provided a pharmaceutical composition comprising vasopressin or a pharmaceutically-acceptable salt thereof and a buffer having acidic pH. 
     In another embodiment of the present invention, there is provided a pharmaceutical composition comprising vasopressin or a pharmaceutically-acceptable salt thereof, wherein the pharmaceutical composition is free of acetate buffer. 
     In another embodiment of the present invention, the composition of the present invention has a pH in the range of 2.4 to 3.6. Preferably, the composition has a pH in the range of 2.8 to 3.2. 
     In another embodiment of the present invention, the composition of the present invention has glycine as a buffering agent and has a pH in the range of 2.8 to 3.2. 
     In another embodiment of the present invention, the composition of the present invention has sodium acetate as a buffering agent. 
     In another embodiment of the present invention, the composition of the present invention has aspartic acid as a buffering agent. 
     In another embodiment, the suitable pH adjusting agent include hydrochloric acid, sodium hydroxide, and succinic acid. 
     In another embodiment, suitable vehicles are selected from the group comprising water for injection, ethanol, glycerin, propylene glycol, corn oil, peanut oil, and cotton seed oil. 
     In another embodiment, suitable tonicity agents include dextrose, glycerol, sodium chloride, potassium chloride, glycerine, and mannitol. 
     In another embodiment, suitable preservative is selected from benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, and thiomersal. 
     In another embodiment, suitable lyoprotectants include sucrose, trehalose, mannitol, glycine, lysine and dextran. 
     In another embodiment, suitable bulking agents include sucrose, lactose, trehalose, mannitol, sorbitol, glucose, PVP, and hydroxyethyl starch. 
     In a preferred embodiment of the present invention, the pharmaceutical composition comprises of about 0.01 mg/mL to about 0.07 mg/mL of vasopressin, about 0.01 mg/ml to about 20 mg/ml of glycine buffer, water for injection and the said composition is adjusted with 0.1 N HCl or sodium hydroxide to pH of about 2.8 to 3.2. 
     In one another embodiment, the present invention provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically-acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of ready to use composition. 
     In one another embodiment, the present invention provides a pharmaceutical composition comprising vasopressin or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipients, wherein the pharmaceutical composition is in the form of aqueous solution or a lyophilized powder, which can be diluted or reconstituted just prior to use. 
     In one another embodiment, the present invention further provides a stable pharmaceutical composition comprising vasopressin or a pharmaceutically-acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition has total impurities less than 10% upon storage at 2 to 8° C., preferably less than 5%. 
     The pharmaceutical compositions as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam), preferably by filtration. The container in which composition is filled can be sterilized using gamma irradiation or ethylene oxide or pre-acetic acid or any other conventional method of sterilization. 
     The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don&#39;t limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. 
     Example 1 
       
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Quantity 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 mg/mL 
                 % w/v 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Vasopressin 
                 20 IU equivalent to 0.045 
                 0.0045 
               
               
                 Glycine 
                 0.45 
                 0.045 
               
               
                 Hydrochloric Acid/ 
                 q.s. to pH range 
                 q.s. to pH range 
               
               
                 Sodium hydroxide 
                 2.4 to 3.6 
                 2.4 to 3.6 
               
               
                 Water for Injection 
                 q.s. 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Process: 
     
         
         
           
             1. Collecting 80% of water for injection and cooling it to room temperature (20-25° C.). 
             2. Adding glycine in above collected water, and keep stirring till clear solution is formed. 
             3. Adjusting the pH with hydrochloric acid or sodium hydroxide in the range of 2.4 to 3.6. 
             4. Adding Vasopressin in step 3 solution and keep stirring till clear solution is formed. 
             5. Making up the volume to 100% batch size. 
             6. Filtering the solution and then filling in a glass vial. 
             7. Storing the solution at 2-8° C. 
           
         
       
    
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Quantity 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 mg/mL 
                 % w/v 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Vasopressin 
                 20 IU equivalent to 0.045 
                 0.0045 
               
               
                 Glycine 
                 0.90 
                 0.090 
               
               
                 Hydrochloric Acid/ 
                 q.s. to pH range 
                 q.s. to pH range 
               
               
                 Sodium hydroxide 
                 2.8 to 3.2 
                 2.8 to 3.2 
               
               
                 Water for Injection 
                 q.s. 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Example 2 
     Process: 
     
         
         
           
             1. Collecting 80% of water for injection and cooling it to room temperature (20-25° C.). 
             2. Adding glycine in above collected water, and keep stirring till clear solution is formed. 
             3. Adjusting the pH with hydrochloric acid or sodium hydroxide in the range of 2.8 to 3.2. 
             4. Adding Vasopressin in step 3 solution and keep stirring till clear solution is formed. 
             5. Making up the volume to 100% batch size. 
             6. Filtering the solution and then filling in a glass vial. 
             7. Storing the solution at 2-8° C. 
           
         
       
    
     Example 3 
       
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Quantity 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 mg/mL 
                 % w/v 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Vasopressin 
                 20 IU equivalent to 0.045 
                 0.0045 
               
               
                 Glycine 
                 12.0 
                 1.20 
               
               
                 Hydrochloric Acid/ 
                 q.s. to pH range 
                 q.s. to pH range 
               
               
                 Sodium hydroxide 
                 2.8 to 3.2 
                 2.8 to 3.2 
               
               
                 Water for Injection 
                 q.s. 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Process: 
     
         
         
           
             1. Take approx 80% of batch size quantity of Water for injection. 
             2. Add Glycine in it and stir for 20 minutes till clear solution formed. Check the pH of bulk solution. 
             3. Adjust the pH of solution with 0.1N hydrochloric acid or sodium hydroxide to 2.8 to 3.2. 
             4. Add the required quantity of vasopressin API in step 3 solution and continue stirring for 15 min or till clear solution formed. 
             5. Volume make up to 100% of batch size with remaining quantity of water for injection. 
             6. Check the final pH of bulk solution. 
             7. Filter the solution through 0.22p sterilizing grade filter. 
             8. Fill the solution in USP-Type-I clear glass vial and seal with 13 mm rubber stopper. 
           
         
       
    
     Example 4 
       
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Quantity 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 mg/mL 
                 % w/v 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Vasopressin 
                 20 IU equivalent to 0.045 
                 0.0045 
               
               
                 Sodium acetate trihydrate 
                 1.36 
                 0.136 
               
               
                 Hydrochloric Acid/ 
                 q.s. to pH range 
                 q.s. to pH range 
               
               
                 Sodium hydroxide 
                 2.8 to 3.2 
                 2.8 to 3.2 
               
               
                 Water for Injection 
                 q.s. 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Process: 
     
         
         
           
             1. Take approx 80% of batch size quantity of Water for injection. 
             2. Add sodium acetate in it and stir for 20 minutes till clear solution formed. Check the pH of bulk solution. 
             3. Adjust the pH of solution with 0.1N hydrochloric acid or sodium hydroxide to 2.8 to 3.2. 
             4. Add the required quantity of vasopressin API in step 3 solution and continue stirring for 15 min or till clear solution formed. Check the pH of solution. 
             5. Volume make up to 100% of batch size with remaining quantity of water for injection. 
             6. Check the final pH of bulk solution and maintain the final pH in the range of 2.8 to 3.2. 
             7. Filter the solution through 0.22p sterilizing grade filter. 
             8. Fill the solution in USP-Type-I clear glass vial and seal with 13 mm rubber stopper. 
           
         
       
    
     Example 5 
       
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Quantity 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 mg/mL 
                 % w/v 
               
               
                   
               
               
                 Vasopressin 
                 20 IU equivalent to 0.045 
                 0.0045 
               
               
                 Acetic acid 
                 q.s. 
                 q.s. 
               
               
                 Sodium hydroxide 
                 q.s. to pH range 
                 q.s. to pH range 
               
               
                   
                 2.8 to 3.2 
                 2.8 to 3.2 
               
               
                 Water for Injection 
                 q.s. 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Process: 
     
         
         
           
             1. Take approx 80% of batch size quantity of Water for injection. 
             2. Add acetic acid in it and stir for 20 minutes till clear solution formed. Check the pH of bulk solution. 
             3. Adjust the pH of solution with sodium hydroxide in the range of 2.8 to 3.2. 
             4. Add the required quantity of vasopressin API in step 3 solution and continue stirring for 15 min or till clear solution formed. Check the pH of solution. 
             5. Volume make up to 100% of batch size with remaining quantity of water for injection. 
             6. Check the final pH of bulk solution and maintain the final pH in the range of 2.8 to 3.2. 
             7. Filter the solution and filled into glass vial. 
           
         
       
    
     Example 6 
       
     
       
         
           
               
               
            
               
                   
                   
               
               
                   
                 Quantity 
               
            
           
           
               
               
               
            
               
                 Ingredient 
                 mg/mL 
                 % w/v 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Vasopressin 
                 20 IU equivalent to 0.045 
                 0.0045 
               
               
                 Aspartic acid 
                 0.30 
                 0.03 
               
               
                 Sodium hydroxide 
                 q.s. to pH range 
                 q.s. to pH range 
               
               
                   
                 2.8 to 3.2 
                 2.8 to 3.2 
               
               
                 Water for Injection 
                 q.s. 
                 q.s. 
               
               
                   
               
            
           
         
       
     
     Process: 
     
         
         
           
             1. Take approx 80% of batch size quantity of Water for injection. 
             2. Add aspartic acid in it and stir for 20 minutes till clear solution formed. 
             3. Adjust the pH of solution with sodium hydroxide in the range of 2.8 to 3.2. 
             4. Add the required quantity of vasopressin API in step 3 solution and continue stirring for 15 min or till clear solution formed. 
             5. Volume make up to 100% of batch size with remaining quantity of water for injection. 
             6. Check the final pH of bulk solution and maintain the final pH in the range of 2.8 to 3.2. 
             7. Filter the solution and filled into glass vial. 
           
         
       
    
     Stability Studies: 
     The pharmaceutical compositions of the present invention as prepared according to examples 3 and 4 were tested for stability for 3 months at 2 to 8° C. The results of the same are provided in table 1 below. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 1 
               
             
            
               
                   
                   
               
               
                   
                 Vasotrict ® 
                   
               
            
           
           
               
               
               
               
            
               
                   
                 End of 
                 Example 3 
                 Example 4 
               
               
                   
                 Shelf 
                 2-8° C. 
                 2-8° C. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Test Parameters 
                 Specification 
                 Initial 
                 life 
                 Initial 
                 3 M 
                 Initial 
                 3 M 
               
               
                   
               
               
                 Assay 
                  90% to 110% 
                 103.5   
                 103.1   
                 102.4   
                 99.10  
                 102.70  
                 99.01  
               
               
                 pH 
                 2.5 to 4.5 
                 3.90 
                 Not 
                 2.80 
                 2.90 
                 2.80 
                 2.90 
               
               
                   
                   
                   
                 done 
               
               
                 Des Pro 
                 NMT 1.0% 
                 ND 
                 ND 
                 0.15 
                 0.09 
                 0.14 
                 0.10 
               
               
                 Vasopressin 
               
               
                 8 Orn 
                 NMT 1.0% 
                 0.09 
                 0.37 
                 0.42 
                 0.24 
                 0.33 
                 0.31 
               
               
                 Vasopressin 
               
               
                 Endo gln 
                 NMT 1.0% 
                 0.29 
                 0.22 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 Vasopressin 
               
               
                 Vasopressin BIS- 
                 NMT 1.0% 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 SH 
               
               
                 Vasopressin Acid 
                 NMT 1.0% 
                 0.30 
                 0.36 
                 0.06 
                 0.28 
                 0.08 
                 0.35 
               
               
                 5-Asp 
                 NMT 1.0% 
                 0.08 
                 0.08 
                 ND 
                 0.1  
                 ND 
                 0.07 
               
               
                 Vasopressin 
               
               
                 4-Glu 
                 NMT 1.0% 
                 0.22 
                 0.37 
                 0.12 
                 0.37 
                 0.27 
                 0.43 
               
               
                 Vasopressin 
               
               
                 Vasopressin 
                 NMT 1.0% 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 Parallel Dimer 
               
               
                 Vasopressin 
                 NMT 1.0% 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                  0.004 
               
               
                 Antiparallel 
               
               
                 Dimer 
               
               
                 N-Acetyl 
                 NMT 1.0% 
                 0.21 
                 0.21 
                 0.08 
                 0.08 
                 0.07 
                 0.07 
               
               
                 Vasopressin 
                   
                   
               
               
                 Total Impurities 
                 NMT 10% 
                 1.36 
                 1.74 
                 1.09 
                 1.53 
                 1.45 
                 1.96 
               
               
                   
               
            
           
         
       
     
     Results: 
     The vasopressin content was measured to be in range of 99.1 to 99.0 for compositions of example 3 and 4 respectively, which is in acceptable limits range (Limit 90.0-110.0%). Total impurities were measured to be 1.53% and 1.96% for compositions of examples 3 and 4 respectively which are also within the acceptable limit of NMT 10%. 
     Hence, it is concluded from the above stability data that the compositions prepared as per the present invention have an unexpected enhanced stability.