Patent Application
20230190639
Vasopressin is a polypeptide hormone that causes contraction of vascular and other smooth muscles. The vasoconstrictive effects of vasopressin are mediated by vascular Vl receptors. Vasopressin is indicated to increase blood pressure in adults with vasodilatory shock, who remain hypotensive despite fluids and catecholamines. The chemical name of vasopressin is Cyclo (1-6) L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide.
Vasopressin has been marketed as a therapeutic agent since 1938. Intravenous vasopressin Injection was marketed and sold as an unapproved drug in the United States.
Vasopressin Injection is available under the name Vasostrict® in U.S. It is a sterile, aqueous solution of synthetic arginine vasopressin for intravenous administration. 1 mL solution contains vasopressin 20 units/mL, water for Injection and sodium acetate buffer adjusted to a pH of 3.8. 10 mL solution contains vasopressin 20 units/mL, chlorobutanol 0.5%, water for Injection, and sodium acetate buffer adjusted to a pH of 3.8.
Synthetic vasopressins and derivatives have been disclosed in the following U.S. Pat. No.: 3,371,080 Boissonnas et al., U.S. Pat. No.3,415,805 Siedel et al., U.S. Pat. No.3,418,307 Boissonnas et al., U.S. Pat. No.3,454,549 Boissonnas et al. U.S. Pat. No.3,497,491 Zaoral et al., U.S. Pat. No.4,148,787 Mulder et al.
U.S. Pat. No.5,482,931 to Harris et al., discloses aqueous composition consisting essentially of oxytocin, vasopressin, or its analogues and derivatives; a buffering agent; a quaternary amine preservative or disinfectant and an osmotic pressure-controlling agent.
U.S Pat application 2011/237508 to Jean-Pierre et al., discloses an aqueous formulation comprising of oxytocin, 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, having a pH between 3 and 6. The publication specifies that stability can be achieved in buffered solutions only in the presence of divalent metal ions in a concentration of at least 2 mM.
U.S Pat Nos. 9,375,478; 9,687,526; 9,744,209; 9,750,785; 9,744,239 to Matthew et al., disclose pharmaceutical compositions of vasopressin. U.S. Pat. No. 9,375,478 claims unit dosage form consisting of vasopressin, acetate buffer and water, wherein the unit dosage form has a pH of 3.8. U.S. Pat. No. 9,744,239 claims a pharmaceutical composition for intravenous administration consisting of vasopressin, optionally chlorobutanol; acetic acid, acetate, or a combination thereof; wherein the unit dosage form has a pH of 3.5 to 4.1.
All the patents assigned to Matthew et al., disclose the use of acetate buffer. During the patent prosecution, the applicants explained that greatest stability of vasopressin formulations was observed in formulations with acetate buffer with a pH of 3.8.
The inventors of the present invention developed a formulation using alternate stabilizers. These formulations are free of acetate buffer and do not contain divalent metal ions used for stabilizing the formulations of the conventional art.
An aspect relates to stable parenteral formulations of vasopressin comprising one or more stabilizers, wherein the formulation is free of acetate buffer.
Another aspect of embodiments of the invention relates to stable parenteral formulations of vasopressin comprising one or more stabilizers, solvents and other pharmaceutically acceptable excipients, wherein the formulation is free of acetate buffer.
Yet another aspect of embodiments of the invention relates to stable parenteral formulations of vasopressin comprising of stabilizers and other pharmaceutically acceptable excipients, wherein the stabilizer comprises (i) one or more buffers and (ii) optionally one or more excipients selected from amino acids and chelating agents.
Yet another aspect of embodiments of the invention relates to ready to use formulations of vasopressin comprising vasopressin in a concentration range of 0.01 units/ml to 2.5 units/ml.
Yet another aspect of embodiments of the invention relates to ready to dilute formulations of vasopressin comprising vasopressin in a concentration range of 2.5units/ml to 100 units/ml.
In the context of embodiments of the invention “vasopressin” refers to pharmaceutically acceptable salts, solvates, hydrates, acids, anhydrous and free base forms thereof, vasopressin.
The term “about” is meant to encompass a range of ±0.5 from the specified value or range.
The term “stable” means the formulations which remain stable, during the entire shelf-life of the composition. The formulation shows an assay of 90 to 110 percent of the original assay value when stored under specified controlled conditions.
The term “stabilizer” refers to an agent which helps in making the formulation stable.
The term “chelating agent” means a compound which helps in improving the stability of the formulation and minimizes the degradation of vasopressin in the formulation.
The term “buffer” means a compound or mixture of compounds that by their presence in the solution resist changes in the pH upon the addition of small quantities of acid or base.
The term “parenteral formulation” encompasses sterile liquid formulations of vasopressin intended for parenteral administration.
Peptides are inherently unstable substances and need to have specific excipients for imparting stability to the formulation. Stabilizers play an important role in maintaining the stability of peptides, particularly those in solution form. The conventional art disclosures describe using acetate buffer or divalent metal ions for stabilizing vasopressin formulations. The pH disclosed in the conventional art in various formulations ranges from about 2.5-4.5. Inventors of the present invention carried out experiments to develop a stable formulation using alternate stabilizers without the use of acetate buffer or divalent metal ions.
One embodiment of the invention comprises parenteral formulations of vasopressin comprising vasopressin, stabilizers and one or more solvents, wherein the formulation is free of acetate buffer.
Vasopressin formulations prepared according to embodiments of the invention were found to be stable over a wide range of pH.
Stabilizers play a significant role in maintaining the stability of vasopressin in liquid formulations. According to embodiments of the present invention, stabilizers include one or more excipients selected from buffers, amino acids and chelating agents. Amino acids are selected from, but not limited to arginine, glycine, alanine, proline, methionine, lysine, leucine, cysteine and isoleucine. Suitable buffers include, but are not limited to Tris, phosphate buffer, citrate buffer, sodium carbonate, sodium bicarbonate, tartarate, benzoate, aspartic acid, ascorbic acid, succinic acid, lactic acid, glutaric acid, malic acid, boric acid, orthophosphoric acid and carbonic acid, alkali or alkaline earth salt of one of these acids. Suitable chelating agents can be selected from, but not limited to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylene triamine-N,N,N′,N″,N″-pentaacetate)/pentetic acid, EDTA (Ethylenediamine tetraacetic acid), calcium disodium edetate or their salts. Further other excipients can be selected from lactose, L-aspartic acid, sodium chloride, chlorobutanol.
Suitable solvents include ethanol, glycerine, propylene glycol, polyethylene glycol, water and the like. Water is used as the most common solvent.
The pharmaceutical compositions of embodiments of the present invention may also contain other pharmaceutically acceptable excipients selected from anti-oxidants, preservatives, tonicity modifiers and pH adjusting excipients.
The compositions of embodiments of the present invention can be made as “ready to use” compositions, i.e they can be used without dilution. The concentration of vasopressin in the ready to use formulations ranges from 0.01 units/ml to 2.5 units/ml (i.e 0.00002 mg/ml to 0.0047 mg/ml); additionally in the range of 0.1 units/ml to 1 unit/ml (i.e 0.00019 mg/ml to 0.0019 mg/ml). The compositions of embodiments of the present invention can also be prepared in a “ready to dilute form”, where they need to be diluted with appropriate physiological solutions before administration. The concentration of vasopressin in these formulations ranges from 2.5units/ml to 100 units/ml (i.e 0.0047 mg/ml to 0.18 mg/ml); additionally in the concentration ranges from 5units/ml to 20 units/ml (i.e 0.0094 mg/ml to 0.038 mg/ml); and also in the concentration is in the range of 20 units/ml (0.038 mg/ml).
Inventors carried out experiments to test the stability of vasopressin formulations comprising stabilizers selected from amino acids, buffers and chelating agents. Formulations prepared were tested for stability by subjecting to stress study, at 60° C. for 12 hours.
Formulations prepared using one or more amino acids as stabilizers were tested for stability and the results are given below in table 1.
The inventors also carried out trials using buffers. Product made with acetate buffer is used as a reference product.
Data from tables 1 and 2 shows that (i) amino acids alone will not help in achieving a stable formulation of vasopressin and (ii) buffers help in achieving better impurity profile. Subsequent trials were carried out using a combination of amino acids and buffers and the data is tabulated in table 3.
The level of impurities was considerably higher, for the reference product, made using acetate buffer, when stored at same conditions as embodiments of the invention formulation.
Subsequent trials were carried out to check the stabilizing effect of chelating agents on vasopressin formulation. Various trials were designed, and the samples were stored at an accelerated temperature of 60° C. for 12 hours. The addition of chelating agent was found to further enhance the stability of vasopressin formulations.
One embodiment of the invention provides parenteral formulations of vasopressin comprising 0
a) vasopressin
Another embodiment of the invention provides parenteral formulations of vasopressin comprising
An embodiment of the invention comprises
wherein the formulation is free of acetate buffer
The following examples are intended to illustrate embodiments of the invention in more detail and are not to be considered as limiting the scope of embodiments of the invention.
Formulations prepared according to example 1 were subjected to stability study for a period of 2 months at 25° C./60% RH. Formulation prepared with sodium acetate buffer was taken as reference product. Comparative stability is summarized in table 5.
Concentration: 1 unit/mL (E.Q. to 0.0019 mg/mL)
Concentration: 0.1 unit/mL (E.Q. to 0.00019 mg/mL)
Concentration: 0.2 unit/mL (E.Q. to 0.00038 mg/mL)
Q.S: Quantity sufficient;
*Compensated with Assay, Acetic Acid Content and Water Content
Brief Manufacturing Procedure:
The stability was carried out in glass vials and COP vials. The stability data was found to be satisfactory. These unexpected results show that the product can be packaged in COP vials with acceptable stability. This is particularly surprising because there is no product of vasopressin that is packed in COP vials.
Although the invention has been illustrated and described in greater detail with reference to the preferred exemplary embodiments, the invention is not limited to the examples disclosed, and further variations can be inferred by a person skilled in the art, without departing from the scope of protection of the invention.
For the sake of clarity, it is to be understood that the use of “a” or “an” throughout this application does not exclude a plurality, and “comprising” does not exclude other steps or elements.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201741046283 | Dec 2017 | IN | national |
This application is a continuation of U.S. application Ser. No. 16/956,631, having a filing date of Jun. 22, 2020, which claims priority to PCT Application No. PCT/IB2018/060498, having a filing date of Dec. 21, 2018, based on IN 201741046283, having a filing date of Dec. 22, 2017, the entire contents all of which are hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16956631 | Jun 2020 | US |
| Child | 18110202 | US |
