WO2021198995A1

WO2021198995A1 - Stable aqueous parenteral solutions of desglymidodrine

Info

Publication number: WO2021198995A1
Application number: PCT/IB2021/052765
Authority: WO
Inventors: Kannan Essakimuthu MUTHAIYYAN; Jay Shantilal Kothari; Ravindra Mittal; Priteshkumar Chandrakant MISTRY; Gaurav Navinbhai Mistry; Sachin Gahoi; Anuj Kumar SAINI
Original assignee: Cadila Healthcare Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2020-04-02
Filing date: 2021-04-02
Publication date: 2021-10-07
Anticipated expiration: 2022-10-02

Abstract

The present invention relates to stable aqueous parenteral solutions comprising desglymidodrine and one or more pharmaceutically acceptable excipients comprising one or more pH adjusting agents, wherein pH of the solution is from about 4 to about 8 and the invention also relates to processes for preparing such aqueous parenteral solutions for treating hepatorenal syndrome comprising administering such aqueous parenteral solutions through a parenteral route.

Description

STABLE AQUEOUS PARENTERAL SOLUTIONS OF DESGLYMIDODRINE

Field of the invention

The present invention relates to stable aqueous parenteral solutions comprising desglymidodrine and one or more pharmaceutically acceptable excipients. It also relates to processes for preparing such aqueous parenteral solutions. It also relates to a method of treating hepatorenal syndrome comprising administering such aqueous parenteral solutions through a parenteral route, viz., intravenous route, subcutaneous route, or intramuscular route.

Background of the invention

Desglymidodrine is an active metabolite of midodrine. ProAmatine^® (midodrine hydrochloride tablets) is an approved drug product of Upsher Smith Labs in the United States and is approved as 5 mg tablets for oral administration. ProAmatine^® is indicated for the treatment of symptomatic orthostatic hypotension (OH).

U.S. Publication No. 2002/0147232 discloses pharmaceutical compositions comprising desglymidodrine. It discloses that the pharmaceutical composition may be presented in a suitable dosage form for oral, buccal, sublingual, parenteral, nasal, topical, vaginal, rectal or ocular administration. It also discloses a method for treating mammals (e.g. humans) suffering from septic shock with a sufficient amount of desglymidodrine.

U.S. Publication No. 2018/0228745 discloses a substance selected from midodrine, a pharmaceutical salt, a prodrug and an active metabolite thereof, for use in the treatment of obstructive cardiopathy.

U.S. Patent No. 7,070,803 discloses a controlled release pharmaceutical composition for oral use containing midodrine and/or its active metabolite, desglymidodrine. It also discloses a method for treating orthostatic hypotension and/or urinary incontinence.

International Publication No. (PCT) WO2019/126770 discloses a pharmaceutical composition comprising an active agent, e.g., midodrine, a pharmaceutically acceptable salt of midodrine, desglymidodrine, a pharmaceutically acceptable salt of desglymidodrine, or any combination thereof. It also discloses a method of treating or reducing the incidence of orthostatic hypotension using disclosed pharmaceutical compositions. Hepatorenal syndrome (HRS) is a type of progressive kidney failure that occurs in individuals with severe liver damage, most often caused by cirrhosis, and leads to increased amount of toxins in the body. HRS is classified into two types, Type 1 and Type 2. Type 1 HRS is associated with rapid kidney failure and an overproduction of creatinine. Type 2 HRS is associated with more gradual kidney damage.

Several researchers have attempted to evaluate safety and/or efficacy of various drugs and therapeutic approaches in order to find treatment options for hepatorenal syndrome.

Angelo et al. (Annals of Hepatology; Vol. 18, 2019; 287-290) discloses the role of vasoconstrictors in the management of hepatorenal syndrome (HRS). It discloses usage of terlipressin and noradrenaline for the treatment of HRS.

Alessandria et al. (Digestive and Liver Disease; Vol. 41, 2009; 298-302) discloses that midodrine does not seem to be effective in preventing type 2 HRS recurrence after terlipressin withdrawal.

Angeli et al. (Hepatology; Vol. 29, No. 6, 1999; 1690-1697) discloses a therapeutic approach involving prolonged administration of oral midodrine and octreotide combined with plasma volume expansion (by means of albumin) which may provide a therapeutic perspective in the treatment of type 1 HRS and further investigations are required to confirm the effectiveness and safety of this therapeutic approach.

Ali et al. (Clinical Drug Investigation; Vol. 36, No. 2, 2016; 147-55) discloses that midodrine is an a-agonist prodrug used for the management of hypotension and can also be used for hepatorenal syndrome and cirrhotic patients with tense ascites.

Although some medications have shown promise for the treatment of hepatorenal syndrome but currently there are not many options available. Due to the availability of limited treatment options, there remains a significant need for the efficacious treatment of hepatorenal syndrome. Accordingly, the present invention provides a stable solution of desglymidodrine, suitable for administration through parenteral route which may provide a treatment option for the treatment of hepatorenal syndrome. Summary of the invention

In one general aspect, the present invention provides a stable aqueous parenteral solution comprising desglymidodrine and one or more pharmaceutically acceptable excipients.

In another general aspect, the present invention provides a stable aqueous parenteral solution comprising levodesglymidodrine and one or more pharmaceutically acceptable excipients.

In one general aspect, the present invention provides a stable aqueous parenteral solution comprising desglymidodrine and one or more pharmaceutically acceptable excipients, wherein concentration of desglymidodrine in the solution is from about 0.1 mg/mL to about 50 mg/mL.

In another general aspect, the present invention provides a stable aqueous parenteral solution comprising levodesglymidodrine and one or more pharmaceutically acceptable excipients, wherein concentration of levodesglymidodrine in the solution is from about 0.05 mg/mL to about 25 mg/mL.

Embodiments of the aqueous parenteral solution may include one or more of the following features. For example, the pharmaceutically acceptable excipient may include one or more stabilizers, chelating agents, preservatives, antioxidants, pH adjusting agents, buffering agents and isotonicity adjusting agents.

In one general aspect, the present invention provides a process for preparing a stable aqueous parenteral solution comprising desglymidodrine and one or more pharmaceutically acceptable excipients, wherein concentration of desglymidodrine in the solution is from about 0.1 mg/mL to about 50 mg/mL.

In another general aspect, the present invention provides a process for preparing a stable aqueous parenteral solution comprising levodesglymidodrine and one or more pharmaceutically acceptable excipients, wherein concentration of levodesglymidodrine in the solution is from about 0.05 mg/mL to about 25 mg/mL. The stable aqueous parenteral solution comprising desglymidodrine or levodesglymidodrine in a therapeutically effective dose may be contained in a pre-filled syringe (PFS), an auto injector, or both.

Accordingly, in one aspect, the present invention provides a pre-filled syringe (PFS), wherein the PFS contains desglymidodrine or levodesglymidodrine aqueous parenteral solution in a therapeutically effective dose.

In another general aspect, the present invention provides an auto-injector which contains a PFS (a PFS assembled/placed in an auto-injector), wherein the PFS contains desglymidodrine or levodesglymidodrine aqueous parenteral solution in a therapeutically effective dose.

In another general aspect, the present invention provides a kit comprising an auto-injector and a PFS, wherein the PFS contains desglymidodrine or levodesglymidodrine aqueous parenteral solution in a therapeutically effective dose.

In one general aspect, the present invention provides a method of treating hepatorenal syndrome (HRS) comprising administering parenteral solution comprising a therapeutically effective amount of levodesglymidodrine to a patient in need thereof.

In one general aspect, the present invention provides a method of treating hepatorenal syndrome (HRS) in a subject in need thereof, comprising administering to the subject parenteral solution comprising a therapeutically effective amount of levodesglymidodrine, through intravenous injection, to a patient in need thereof, with minimal or no pain at the site of injection.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

Detailed description of the invention

The inventors of the invention have developed an aqueous parenteral solution of desglymidodrine having sufficient stability required for a pharmaceutically acceptable parenteral solution. The inventors of the invention have also found that when such a stable parenteral solution of desglymidodrine is administered through parenteral route to a patient in need thereof in a therapeutically effective amount, it may provide a method for treating hepatorenal syndrome (HRS).

The term “desglymidodrine”, as used herein, means, (R)-(-)-enantiomer of desglymidodrine, (S)-(+)-enantiomer of desglymidodrine, or a mixture thereof. In one embodiment, the stable aqueous parenteral solution of the present invention contains (R)-(-)-enantiomer of desglymidodrine (levodesglymidodrine).

In one embodiment, the present invention provides a stable aqueous parenteral solution comprising desglymidodrine, wherein concentration of desglymidodrine in the solution is from about 0.1 mg/mL to about 50 mg/mL. The concentration of desglymidodrine in the solution may be, for example, 0.5 mg/mL, 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, or 45 mg/mL.

In another embodiment, the present invention provides a stable aqueous parenteral solution comprising levodesglymidodrine, wherein concentration of levodesglymidodrine in the solution is from about 0.05 mg/mL to about 25 mg/mL. The concentration of desglymidodrine in the solution may be, for example, about 0.10 mg/mL, about 0.50 mg/mL, about 1 mg/mL, about 2.5 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, or about 20 mg/mL.

The term “about”, as used herein, means in reasonable vicinity of the stated numerical value, for example, plus or minus 10% or 5%.

In another embodiment, the present invention provides a stable aqueous parenteral solution comprising desglymidodrine or levodesglymidodrine and water. The stable aqueous parenteral solution of the present invention may further comprise one or more pharmaceutically acceptable stabilizers, chelating agents, antioxidants, preservatives, pH adjusting agents, buffering agents, and isotonicity adjusting agents.

Examples of suitable stabilizers may include, but not limited to, ascorbic acid, disodium edetate, aminoethyl sulfonic acid, L-arginine, butylhydroxyanisol, polyvinylpyrrolidone, L- cysteine, cysteine hydrochloride, diethanolamine, diethylene triaminepentaacetic acid, ferric chloride, inositol, D,L-methionine, or any combination thereof. The stable aqueous parenteral solution of the present invention may comprise ascorbic acid in a concentration from about 0.05% w/v to about 0.5% w/v, for example, about 0.1% w/v, about 0.2% w/v, about 0.3% w/v, or about 0.4% w/v.

Examples of suitable chelating agents may include, but not limited to, ethylene diamine tetraacetic acid (EDTA), triethanolamine, 8-hydroxyquinoline, citric acid, tartaric acid, phosphoric acid, gluconic acid, saccharic acid, thiodipropionic acid, acetonic dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerin, sorbitol, diethylene triaminepentaacetic acid (DTPA), ethylene glycol-bis(3-aminoethyl ether) tetraacetic acid (EGTA), N (hydroxy ethyl) ethylene diaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), and pharmaceutically acceptable salts thereof. These chelating agents may be used alone or in combination thereof. The stable aqueous parenteral solution of the present invention may comprise disodium EDTA in a concentration from about 0.01% w/v to about 0.5% w/v, for example, about 0.05% w/v, about 0.1% w/v, about 0.2% w/v, about 0.3% w/v, or about 0.4% w/v.

Examples of suitable antioxidants may include, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, monothioglycerol, ascorbic acid, sodium ascorbate, erythorbic acid, propionic acid, sodium formaldehyde sulphoxylate, reduced glutathione, thiourea, cysteine, n-acetylcysteine, methionine, alkyl gallate, including propyl gallate, vitamin E, or other tocopherol analogs, including tocopherol acetate or TPGS, or any combination thereof.

Examples of suitable preservatives may include, but not limited to, benzyl alcohol, chlorobutanol, benzalkonium chloride, methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, thiomersal, merthiolate, chlorhexidine, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, or any combination thereof. The stable aqueous parenteral solution of the present invention may comprise benzyl alcohol in a concentration from about 0.10% v/v to about 3% v/v, for example, about 0.50% v/v, about 1% v/v, about 1.5% v/v, about 2% v/v, or about 2.5% v/v.

The stable aqueous parenteral solution of the present invention may comprise benzyl alcohol in a concentration from about 1 mg/mL to about 30 mg/mL, for example, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, or about 25 mg/mL.

Examples of suitable pharmaceutically acceptable pH adjusting agents may include, but not limited to, sodium hydroxide, hydrochloric acid, boric acid, citric acid, phosphoric acid, succinic acid, acetic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof.

The stable aqueous parenteral solution of the present invention may comprise pH adjusting agents in an amount sufficient to provide pH of the solution from about 4 to about 8, for example, from about 5 to about 7, or about 6.

Examples of suitable pharmaceutically acceptable buffering agents may include, but not limited to, acetate (e.g. sodium acetate etc.), citrate (e.g. citric acid/sodium citrate etc.), phosphate (e.g. monobasic sodium phosphate, dibasic sodium phosphate etc.), carbonate, or any combination thereof.

Examples of suitable isotonicity adjusting agents may include, but not limited to, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glucose, sucrose, dextrose, mannitol, glycerol, or any combination thereof.

The stable aqueous parenteral solution of the present invention may comprise sodium chloride in a concentration of from about 2 mg/mL to about 9 mg/mL, for example, from about 4 mg/mL to about 7 mg/mL, about 5 mg/mL, or about 6.

In another embodiment, the stable desglymidodrine aqueous parenteral solution may comprise about 0.25% w/v desglymidodrine, about 1% v/v benzyl alcohol, 0.1% w/v ascorbic acid, 0.05% w/v disodium EDTA, one or more pH adjusting agents in an amount sufficient to provide pH of the solution from about 4 to about 8 and water.

In another embodiment, the stable desglymidodrine aqueous parenteral solution may comprise about 1.50% w/v desglymidodrine, about 1% v/v benzyl alcohol, 0.1% w/v ascorbic acid, 0.05% w/v disodium EDTA, one or more pH adjusting agents in an amount sufficient to provide pH of the solution from about 4 to about 8 and water.

In another embodiment, the stable aqueous parenteral solution comprises about 2.5 mg/mL levodesglymidodrine, about 10.4 mg/mL benzyl alcohol, 5.6 mg/mL sodium chloride, one or more pH adjusting agents in an amount sufficient to provide pH of the solution from about 6 to about 8, and water. The solution may remain physico-chemically stable after storage for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months, at 2-8°C or at room temperature (25°C). The physico-chemical stability includes certain parameters, for example, solution remains clear (free of any crystals / precipitation) and/or solution does not contain total impurities, as determined by HPLC, more than 0.5%, for example, does not contain total impurities more than 0.4%, 0.3%, 0.2% or 0.1%.

In one embodiment, the stable aqueous parenteral solution of the present invention, after intravenous administration, may provide minimal or no pain at the site of injection.

In another embodiment of the invention, there is provided a parenteral solution comprising desglymidodrine or levodesglymidodrine, wherein the solution does not contain any single unknown impurity more than 0.2%, as determined by HPLC, for example, does not contain any single unknown impurity more than 0.1% or 0.05%, and/or does not contain total impurities more than 0.5%, as determined by HPLC, for example, does not contain total impurities more than 0.4%, 0.3%, 0.2%, or 0.1%, after storage for more than 3 months, for example, 6 months, 12 months, 18 months, or 24 months, when stored at (i) 2°C - 8°C temperature, or at (ii) 25±2 °C temperature and 60±5 % RH.

In one embodiment, the present invention provides a storage stable aqueous parenteral solution comprising desglymidodrine, wherein the solution retains at least 95% of the desglymidodrine (% assay), as determined by HPLC, after storage for more than 3 months, for example, 6 months, 12 months, 18 months, or 24 months, when stored at (i) 2°C - 8°C temperature, or at (ii) 25±2 °C temperature and 60±5 % RH.

In one embodiment, the present invention provides a storage stable aqueous parenteral solution comprising levodesglymidodrine, wherein the solution retains at least 95% of the levodesglymidodrine (% assay), as determined by HPLC, after storage for more than 3 months, for example, 6 months, 12 months, 18 months, or 24 months, when stored at (i) 2°C - 8°C temperature, or at (ii) 25±2 °C temperature and 60±5 % RH.

In another embodiment, the stable aqueous desglymidodrine or levodesglymidodrine parenteral solution of the present invention is a clear solution (free of any crystals / precipitation) by visual inspection. The solution may provide the value of absorbance not more than 1 AU, for example, not more than 0.8, 0.6, 0.4, 0.2, or 0.1 AU. The solution may provide the value of % transmittance not less than 90%, for example, not less than 95%, 96%, 97%, 98%, or 99%.

In another embodiment, the aqueous stable desglymidodrine parenteral solution of the present invention may have osmolality value of between about 280 mOsm/kg and about 320 mOsm/kg, for example, 290 mOsm/kg, 300 mOsm/kg, or 310 mOsm/kg.

In another embodiment, the aqueous stable levodesglymidodrine parenteral solution of the present invention may have osmolality value of between about 280 mOsm/kg and about 320 mOsm/kg, for example, 290 mOsm/kg, 300 mOsm/kg, or 310 mOsm/kg.

In one embodiment, the stable aqueous parenteral solution of the present invention is supplied as a ready to administer solution. It does not require further dilution before administration.

In another embodiment, the stable aqueous parenteral solution of the present invention is supplied as a solution ready for dilution and it requires further dilution before administration. The diluted solution is for administration as intravenous infusion.

In another embodiment, the present invention provides a stable aqueous parenteral solution comprising desglymidodrine, wherein desglymidodrine is the sole active ingredient present in the solution. In another embodiment, the present invention provides a stable aqueous parenteral solution comprising levodesglymidodrine, wherein levodesglymidodrine is the sole active ingredient present in the solution.

In another embodiment, the stable aqueous parenteral solution of the present invention does not contain any local anesthetic, for example, lidocaine, prilocaine, tetracaine, bupivacaine, mepivacaine and/or xylocaine. The stable aqueous parenteral solution of the present invention when administered may have minimal or no pain at the site of injection.

In one embodiment, the present invention provides a process for preparing a stable desglymidodrine aqueous parenteral solution of the present invention. The process may include steps of:

(a) adding desglymidodrine, ascorbic acid and benzyl alcohol in a required quantity of water under continuous stirring to form a clear solution,

(b) adding disodium EDTA into the solution obtained at step (a) and under continuous stirring to form a clear solution,

(c) checking pH of the solution obtained at step (b) and adding one or more pH adjusting agents in an amount sufficient to provide pH of the solution from about 4 to about 8, if required,

(d) making up the final volume of the solution by adding remaining quantity of water into the solution prepared in step (c),

(e) filtering the solution obtained in the step (d) using 0.2 m filter,

(f) filling the solution obtained in the step (e) into a suitable packaging material, and

(g) sealing the packaging material to yield the finished product. The stable aqueous parenteral solution of the present invention may be suitable to undergo a sterilization process to provide a sterile desglymidodrine aqueous parenteral solution.

In one embodiment, the stable aqueous parenteral solution of the present invention may be supplied in a suitable packaging material, for example, in a glass vial, in a glass ampoule, in a glass bottle, in a plastic bottle, in a PFS, in an auto-injector which contains a PFS or in a kit comprising a PFS and an auto-injector. In one embodiment, the present invention provides a PFS containing a stable aqueous parenteral solution of the present invention, wherein the PFS may contain various constituent parts, for example, a sterile clear glass syringe barrel, a hypodermic needle fitted with rigid needle shield and a laminated bromobutyl plunger stopper.

In one embodiment, the present invention provides a pre-filled syringe (PFS) containing a stable desglymidodrine aqueous parenteral solution of the present invention, wherein the stable desglymidodrine aqueous parenteral solution may comprise, between about 0.1 mg and 50 mg desglymidodrine, about 0.01 mL benzyl alcohol, aboutl mg ascorbic acid, about 0.50 mg disodium EDTA, one or more pH adjusting agents in an amount sufficient to provide pH of the solution from 4 to 8 and water.

In another embodiment, the present invention provides an auto-injector which contains a PFS (a PFS assembled/placed in the auto-injector), wherein the PFS contains a stable desglymidodrine aqueous parenteral solution of the present invention. The auto-injector may provide convenience to the patient for self-admini strati on.

In another embodiment, the present invention provides a kit comprising (a) a PFS containing a stable desglymidodrine aqueous parenteral solution of the present invention and (b) an auto injector.

In another embodiment, the present invention provides a single-dose PFS containing a stable desglymidodrine aqueous parenteral solution of the present invention with an auto-injector, wherein the PFS with an auto-injector is suitable to administer the therapeutically effective dose of desglymidodrine through subcutaneous route. The single dose PFS may comprise the dose of desglymidodrine from about 0.1 mg to about 50 mg, for example, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 45 mg.

In another embodiment, the present invention provides a single-dose PFS containing a stable levodesglymidodrine aqueous parenteral solution with an auto-injector, wherein the PFS with an auto-injector is suitable to administer the therapeutically effective dose of levodesglymidodrine through subcutaneous route. The single dose PFS may comprise the dose of levodesglymidodrine from about 0.05 mg to about 25 mg. In another embodiment, the present invention provides a single-dose vial or ampoule containing a stable desglymidodrine aqueous parenteral solution of the present invention, wherein the content of vial or ampoule is suitable to administer the therapeutically effective dose of desglymidodrine through intravenous route, as a bolus injection or as an infusion. The single dose vial or ampoule may comprise the dose of desglymidodrine from about 0.1 mg to about 40 mg, for example, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 35 mg. The intravenous administration through infusion includes dilution of the desglymidodrine aqueous parenteral solution of the present invention with suitable vehicles, viz., 0.9% NaCl (Saline solution) or 5% Dextrose solution, before administration as intravenous infusion.

In another embodiment, the present invention provides a single-dose vial or ampoule containing a stable levodesglymidodrine aqueous parenteral solution, wherein the content of vial or ampoule is suitable to administer the therapeutically effective dose of levodesglymidodrine through intravenous route, as a bolus injection or as an infusion. The single dose vial or ampoule may comprise the dose of levodesglymidodrine from about 0.05 mg to about 20 mg, for example, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, or about 15 mg. The intravenous administration through infusion includes dilution of the levodesglymidodrine aqueous parenteral solution of the present invention with suitable vehicles, viz., 0.9% NaCl (Saline solution) or 5% Dextrose solution, before administration as intravenous infusion.

In yet another embodiment, the present invention provides a method of treating hepatorenal syndrome in a subject in need thereof, comprising administering to the subject an aqueous solution comprising a therapeutically effective amount of desglymidodrine or levodesglymidodrine as disclosed herein, to the individual in need thereof.

The present invention is illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. Examples Example 1 and 2:

Table 1:

Process:

All the ingredients were used in quantity mentioned in Table 1, to prepare a stable desglymidodrine aqueous parenteral solution. Batch size: lOOOmL. a) Desglymidodrine, ascorbic acid and benzyl alcohol were added in a required quantity of water under continuous stirring and stirred till complete dissolution, b) Disodium EDTA was added to the solution obtained into step (a) under continuous stirring and stirred till complete dissolution, c) pH was checked for the solution obtained into step (b) and was found 8.0 for example 1 and 10.5 for example 2, d) Hydrochloric acid was added into the solution obtained into step (b) in an amount sufficient to arrive at pH of the solution from about 3 to about 8, e) Final volume of the solution was made by adding remaining quantity of water into the solution prepared in step (d), f) The solution obtained in the above step (e) was filtered with 0.2 m filter, g) The solution obtained in the step (f) was filled into a glass vial, and h) The glass vial obtained in the step (g) was sealed to yield the finished product.

Example 3:

Table 2:

Process:

All the ingredients were used in quantity mentioned in Table 2, to prepare a stable levodesglymidodrine parenteral solution. Batch size: 500 mL. a) levodesglymidodrine, benzyl alcohol and sodium chloride were added in a required quantity of water under continuous stirring and stirred till complete dissolution, b) pH was checked for the solution obtained into step (a) and was found 10.37, c) Hydrochloric acid was added into the solution obtained into step (a) in an amount sufficient to arrive at pH about 5.97, d) Final volume of the solution was made by adding remaining quantity of water into the solution prepared in step (c), e) The solution obtained in the above step (d) was filtered with 0.2 m filter, f) The solution obtained in the step (e) was filled into a glass vial, and g) The glass vial obtained in the step (f) was sealed to yield the finished product.

Stability data for Example 3

The levodesglymidodrine containing solution obtained at Example 3 was tested for its physical and chemical stability, at initial time point as well as after one-month and two months stability testing time points, and results are reported in the Table 3 below.

Table 3:

ND: Not Detected Example 4:

Preclinical studies will be performed to demonstrate the efficacy of levodesglymidodrine administered through intravenous route in the treatment of Hepatorenal syndrome (HRS). The reported efficacy models for HRS, such as carbon tetrachloride (CCU) induced, bile duct ligation and other available models will be explored. In the bile duct ligation experiment, the bile duct ligation will be kept up to approximately 4-6 weeks, thereafter levodesglymidodrine will be administered about 1-2 weeks through intravenous route and change in liver function, kidney function parameters and mean arterial blood pressure will be evaluated to demonstrate the efficacy of levodesglymidodrine in HRS. While the present invention has been described in terms of its specific embodiments, 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.

Claims

Claims:

1. An aqueous parenteral solution comprising desglymidodrine and one or more pH adjusting agents, wherein pH of the solution is from about 4 to about 8.

2. The aqueous parenteral solution according to claim 1, wherein the desglymidodrine is in the form of levodesglymidodrine.

3. The aqueous parenteral solution according to claim 1, wherein the pH adjusting agent is hydrochloric acid and/or sodium hydroxide.

4. The aqueous parenteral solution according to claim 1 further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of stabilizers, chelating agents, preservatives, antioxidants, buffering agents and isotonicity adjusting agents.

5. The aqueous parenteral solution according to claim 4, wherein the excipient is isotonicity adjusting agent.

6. The aqueous parenteral solution according to claim 5, wherein the isotonicity adjusting agent is sodium chloride.

7. The aqueous parenteral solution according to claim 6, wherein the sodium chloride is present in a concentration of from about 4 mg/mL to about 7 mg/mL.

8. The aqueous parenteral solution according to claim 1, wherein the solution has an osmolality value of between about 280 mOsm/kg and about 320 mOsm/kg.

9. The aqueous parenteral solution according to claim 1, wherein the solution does not contain total impurities, as determined by HPLC, more than 0.5% after storage for 3 months at 25±2 °C temperature and 60±5 % RH.

10. The aqueous parenteral solution according to claim 1, wherein the solution does not contain any single unknown impurity, as determined by HPLC, more than 0.2% after storage for 3 months at 25±2 °C temperature and 60±5 % RH.

11. The aqueous parenteral solution according to claim 1, wherein the solution remains clear after storage for 3 months at 25±2 °C temperature and 60±5 % RH.

12. The aqueous parenteral solution according to claim 1, wherein the solution retains at least 95% of the desglymidodrine (% assay), as determined by HPLC, after storage for 3 months at 25±2 °C temperature and 60±5 % RH.

13. The aqueous parenteral solution according to claim 2, wherein the solution retains at least 95% of the levodesglymidodrine (% assay), as determined by HPLC, after storage for 3 months at 25±2 °C temperature and 60±5 % RH.

14. A method of treating hepatorenal syndrome in a subject in need thereof, comprising administering to the subject an aqueous solution comprising a therapeutically effective amount of desglymidodrine through intravenous injection.

15. The method of treating hepatorenal syndrome according to claim 14, wherein the intravenous injection is in the form of an infusion.

16. The method of treating hepatorenal syndrome according to claim 14, wherein the intravenous injection is in the form of a bolus injection.

17. The method of treating hepatorenal syndrome according to claim 14, wherein the method comprising administering desglymidodrine at a dose of from about 0.1 mg to about 40 mg.

18. The method of treating hepatorenal syndrome according to claim 14, wherein the desglymidodrine is in the form of levodesglymidodrine.

19. The method of treating hepatorenal syndrome according to claim 18, wherein the method comprising administering levodesglymidodrine at a dose of from about 0.05 mg to about 20 mg.