WO2019171162A1

WO2019171162A1 - Parenteral acetaminophen for intravenous administration fortified with amino acids and vitamin for counteracting acetaminophen induced hepatotoxicity and nephrotoxicity

Info

Publication number: WO2019171162A1
Application number: PCT/IB2018/054905
Authority: WO
Inventors: Kalak Abdul HAFEEZ
Original assignee: Hafeez Kalak Abdul
Priority date: 2018-03-06
Filing date: 2018-07-02
Publication date: 2019-09-12

Abstract

Intravenous formulations of acetaminophen in admixture with beneficial agents are described which, when administered to a human patient, provides desired analgesic and/or antipyretic effect while preventing or reducing side effects or toxicity associated with acetaminophen administration. The beneficial agents utilized herein include at least one vitamin and at least one amino acid.

Description

PARENTERAL ACETAMINOPHEN FOR INTRAVENOUS ADMINISTRATION FORTIFIED WITH AMINO ACIDS AND VITAMIN FOR COUNTERACTING ACETAMINOPHEN INDUCED HEPATOTOXICITY AND NEPHROTOXICITY

FIELD OF THE INVENTION

[0001] The present disclosure relates to technical field of pharmaceutical formulation. In particular, the present disclosure relates to injectable composition of acetaminophen for intravenous administration, and to methods of preventing or reducing side effects or toxicity associated with acetaminophen administration.

BACKGROUND OF THE INVENTION

[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0003] Acetaminophen, also known as paracetamol or N-acetyl-p-aminophenol, is one of the most widely used pharmaceutical analgesic and antipyretic agents in the world. Acetaminophen, a non-steroidal analgesic and antipyretic drug, is used for the treatment of a variety of arthritic and rheumatic conditions with musculoskeletal pain and in other painful disorders such as headache, dysmenorrhea, myalgia, and neuralgia. It is also indicated in conditions accompanied by generalized discomfort or fever, such as common cold and viral infections. It is contained in over 100 products and is commonly found in the U.S. and other parts of world as immediate release tablets and as extended-release preparations. Various formulations such as children's chewable, suspension and elixir formulations that contain acetaminophen are prevalent.

[0004] Acetaminophen continues to be the most commonly encountered substance in toxic ingestions. In many cases, acetaminophen overdoses are unintentional and are undiagnosed until after substantial damage has already occurred. Acetaminophen is considered to be safe at the therapeutic levels. However, repeated administration of acceptable size doses of acetaminophen can produce toxicity symptoms. An overdose of Acetaminophen in human is fairly common, being yearly in USA the leading cause for calls to Poison Control Centres and accounting for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths. Acetaminophen overdose is often associated with acute liver failure and renal damage in humans. [0005] As reported by Donovan (1999) Academic Emergency Med. 6: 1079-1082, even in the simple case of a single acute ingestion of Acetaminophen, patients with no discernible risk factors for liver injury and low blood levels of Acetaminophen, still develop toxicity and even die. So, there is a need for beneficial agents to reduce toxicity for formulations comprising small doses of Acetaminophen.

[0006] Intravenous (IV) acetaminophen is indicated for the short-term treatment of moderate and severe pain following surgery and for the treatment of fever. Gastrointestinal tract (GIT) motility is decreased in the immediate post-operative period and it is the period when the patient needs immediate pain relief. As oral formulation cannot be given during this time period, IV acetaminophen offers the advantage of providing rapid analgesia and reduced opioid requirement. In short, IV acetaminophen offers immediate and short term treatment of pain and fever. However, when administering acetaminophen through IV route, one must be cautious in patients under 50 kilogram of weight. The introduction of IV acetaminophen in the field of critical care medicine has broaden the utilization of acetaminophen especially in patients who are unable to take oral medication due to impaired GIT motility contraindication to nasogastric tube use, or who require faster onset of pain or fever reduction. However, acetaminophen use may be a risk factor for the development of asthma, rhinoconjunctivitis and eczema in adolescent children.

[0007] Intravenous (IV) Acetaminophen is an excellent post-operative analgesic and antipyretic in children. It is believed that acetaminophen works by inhibiting cyclooxygenase- 2 (COX-2) enzymes. Studies bring to light that therapeutic doses of IV acetaminophen are effective and tolerable in children with least chances of hepatotoxicity. However, overdose toxicity has been reported in children and drug induced hypotension in febrile critically ill patients. Therapeutic doses according to body weight of neonates and children can be administered in hospital settings. Special education of health care staff regarding precise dose and solution is necessary to assess the role of IV acetaminophen preparation in pediatric practice.

[0008] Acetaminophen is packed under different trade names by various companies, causing unexpected overdosing in patients and parents who are not educated well about the product and package information. Moreover, most of the over-the-counter preparations given for common cold and pain generally comprise acetaminophen, which is listed among a series of generic drug names that are difficult for patients and parents to read. Therefore, patients often do not know how much acetaminophen that they have received. The antipyretic value of acetaminophen clearly has been demonstrated and hence acetaminophen is widely used in hospitals for this purpose. However, acetaminophen may not be the antipyretic agent of choice under circumstances where renal or hepatic function is in danger of being compromised. Children are especially vulnerable to accidental exposure due to their smaller size, the presence of acetaminophen in multiple over-the-counter remedies, and a reluctance to administer aspirin and other NSAIDs to children for fever due to the risk of Reye's Syndrome and renal tubular injury.

[0009] Excess acetaminophen is metabolized in the liver via the mixed function oxidase P450 system to a toxic, N-acetyl-p-benzoquinone-Imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPQI formation or reduced glutathione stores, NAPQI is free to bind to vital proteins and the lipid bilayer of hepatocytes. This results in hepatocellular death and subsequent centrilobular liver necrosis. Immuno- histochemical studies have suggested that NAPQI-protein adducts appear even at sub- hepatotoxic acetaminophen doses and before depletion of total hepatic glutathione which may be related to rare cases of hypersensitivity. In addition, decreased intracellular cysteine/glutathione can contribute to cell death via mechanisms that do not involve NAPQI.

[00010] The direct cost of acetaminophen overdose has been estimated to be $87 million annually. Effective protocols have been developed and tested to stratify risk and treat patients who present soon after a single large dose of acetaminophen. However, many patients present after a delay long enough to metabolize all the acetaminophen, after two or more ingestions over several hours, or after several days of excessive self-medication. Under these circumstances it is difficult for the clinician to estimate the risk of adverse outcome before hepatic or renal injury occurs. However, early treatment of acetaminophen over-dosage is considered to be crucial, and vigorous supportive therapy is essential when intoxication is severe.

[00011] Consequently, there remains a recognized need for improved injectable formulations of acetaminophen that provide desired therapeutic effect while preventing or reducing side effects or toxicity associated with acetaminophen administration.

[00012] The present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

[00013] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[00014] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability.

OBJECTS OF THE INVENTION

[00015] It is an object of the present disclosure to provide an intravenous composition of acetaminophen that can reduce or prevent side effects or toxicity arising from the use of acetaminophen.

[00016] It is another object of the present disclosure to provide an intravenous composition of acetaminophen that can prevent or reduce liver damage and hepatotoxicity associated with acetaminophen administration.

[00017] It is another object of the present disclosure to provide an intravenous composition of acetaminophen that can prevent or reduce renal damage and nephrotoxicity associated with acetaminophen administration.

[00018] It is yet another object of the present disclosure to provide a method for preventing or reducing acetaminophen-induced side effects or toxicity arising from the use of acetaminophen in a patient in need of acetaminophen therapy.

SUMMARY

[00019] According to one aspect of the present disclosure there is provided an acetaminophen-containing injectable composition for intravenous administration, comprising a therapeutically effective amount of acetaminophen in admixture with beneficial agents which are effective in preventing and/or reducing the incidence of side effects or toxicity associated with acetaminophen therapy. According to embodiments of the present disclosure, beneficial agents that can be used in combination with acetaminophen can include a vitamin and an amino acid.

[00020] In various embodiments, the acetaminophen-containing injectable composition can be presented as a liquid formulation for intravenous administration by dissolving or dispersing acetaminophen and beneficial agents of this disclosure, namely vitamin and amino acid, in an aqueous vehicle. [00021] In certain preferred embodiments, the vitamin used in the acetaminophen- containing injectable composition of the present disclosure can be a vitamin B₆ compound. Preferred vitamin B₆ compound can include pyridoxine, esters of pyridoxine, amines of pyridoxine, salts of pyridoxine and a mixture thereof.

[00022] In an embodiment, the amino acid used in the acetaminophen-containing injectable composition of the present disclosure can include both essential and non-essential amino acids.

[00023] In one embodiment, the amino acid includes at least one essential amino acid.

[00024] In one embodiment, the amino acid includes at least one non-essential amino acid.

[00025] In an embodiment, the aqueous vehicle used in the acetaminophen-containing injectable composition of the present disclosure can be selected from the group consisting of water, saline and aqueous dextrose solution.

[00026] In various embodiments, the acetaminophen-containing injectable composition disclosed herein can further include at least one pharmaceutically acceptable excipient.

[00027] In various embodiments, the acetaminophen-containing injectable composition disclosed herein is suitable for intravenous injection or infusion.

[00028] Another aspect of the present disclosure is directed to a method of preventing and/or reducing acetaminophen-induced side effects or toxicity arising from the use of acetaminophen in a patient in need of acetaminophen therapy, the method comprising administering to the patient an injectable composition comprising a therapeutically effective amount of acetaminophen, a toxicity-reducing amount of a vitamin, a toxicity-reducing amount of an amino acid and an aqueous vehicle.

[00029] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION

[00030] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims. [00031] Unless the context requires otherwise, throughout the specification which follow, the word“comprise” and variations thereof, such as,“comprises” and“comprising” are to be construed in an open, inclusive sense that is as“including, but not limited to.”

[00032] Reference throughout this specification to“one embodiment” or“an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases“in one embodiment” or“in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[00033] As used in the description herein and throughout the claims that follow, the meaning of“a,”“an,” and“the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of“in” includes“in” and “on” unless the context clearly dictates otherwise.

[00034] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, process conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term“about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

[00035] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[00036] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[00037] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

[00038] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

[00039] Aspects of the present disclosure provide an acetaminophen-containing injectable composition for intravenous administration, comprising a therapeutically effective amount of acetaminophen in admixture with beneficial agents. The beneficial agents of the present disclosure, which when administered in conjunction with acetaminophen, prevent and/or reduce the side effects or toxicity of acetaminophen in human patients. According to embodiments of the present disclosure, beneficial agents that can be used in combination with acetaminophen can include at least one vitamin and at least one amino acid.

[00040] In a particular embodiment, the acetaminophen-containing injectable composition includes an aqueous vehicle having dissolved or dispersed therein a therapeutically effective amount of acetaminophen, a toxicity-reducing amount of a vitamin and a toxicity-reducing amount of an amino acid.

[00041] In certain preferred embodiments, the vitamin used in the acetaminophen- containing injectable composition of the present disclosure can be a vitamin B₆ compound. Preferred vitamin B₆ compound can include pyridoxine, esters of pyridoxine, amines of pyridoxine, salts of pyridoxine and a mixture thereof.

[00042] In an embodiment, the amino acid used in the acetaminophen-containing injectable composition of the present disclosure can include both essential and non-essential amino acids.

[00043] In one embodiment, the amino acid includes at least one essential amino acid. Preferred essential amino acid can be selected from the group consisting of arginine, isolucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, and mixtures thereof.

[00044] In one embodiment, the amino acid includes at least one non-essential amino acid. Preferred non-essential amino acid can be selected from the group consisting of glutamic acid, cysteine, aspartic acid, ornithine, glutathione, taurine, alanine, asparagine, glutamine, glycine, proline, serine, tyrosine, and mixtures thereof. [00045] In various embodiments, the aqueous vehicle used in the acetaminophen- containing injectable composition of the present disclosure can be a sterile aqueous vehicle that is normally used as liquid vehicle for injection. Exemplary aqueous vehicle includes, but not limited to, water, saline and aqueous dextrose solution. Preferably, sterile water used for injections can be used as aqueous vehicle in the present disclosure.

[00046] As used herein, the term“therapeutically effective amount of acetaminophen” refers to an amount of acetaminophen sufficient to achieve an analgesic or antipyretic effect. Preferably, acetaminophen is present in the injectable composition of the present disclosure in an amount ranging from 1 mg to 500 mg per ml of total volume of the injectable composition, and is more preferably present in an amount of 1 mg/ml to 50 mg/ml.

[00047] In various embodiments, the acetaminophen-containing injectable composition can be presented as a liquid formulation for intravenous administration by dissolving or dispersing acetaminophen and beneficial agents of this disclosure in an aqueous vehicle. In some embodiments, such a liquid formulation comprises acetaminophen in a concentration of 10 mg/ml, presented in 50 ml and 100 ml glass vials providing 500 mg and 1000 mg of acetaminophen per vial respectively.

[00048] As used herein, the term“toxicity-reducing amount of a vitamin” refers to an amount of vitamin that prevents or reduces liver damage, renal damage, hepatotoxicity and/or nephrotoxicity associated with the administration of acetaminophen. In various embodiments, the vitamin is present in the injectable composition of the present disclosure at a concentration in the range of from 0.1 mg to 20 mg per ml of the injectable composition.

[00049] As used herein, the term“toxicity-reducing amount of an amino acid” refers to an amount of amino acid that prevents or reduces liver damage, renal damage, hepatotoxicity and/or nephrotoxicity associated with the administration of acetaminophen. In various embodiments, the amino acid is present in the injectable composition of the present disclosure at a concentration in the range of from 0.1 mg to 50 mg per ml of the injectable composition.

[00050] In various embodiments, the disclosed acetaminophen-containing injectable composition can further include at least one pharmaceutically acceptable excipient. Exemplary pharmaceutically acceptable excipient includes, but not limited to, antioxidant, buffering agent, pH adjusting agent, diluent, non-aqueous vehicle, viscosity enhancing agent, stabilizing agent, lubricant, preservative, chelating agent, surfactant, tonicity adjusting agent, and mixtures thereof. [00051] In certain preferred embodiments, the pharmaceutically acceptable excipient includes one or more of antioxidant, diluent, buffering agent and pH adjusting agent. Preferred diluent includes saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, lactose, dextrose, sucrose, fructose, maltose, mannitol, erythritol, sorbitol, xylitol, lactitol, and other diluents, such as powdered cellulose, microcrystalline cellulose, starch, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide, purified sugar and derivatives thereof. More preferably, the diluent is manniol. If diluent is used, it may be present in an amount ranging from 1 mg to 50 mg per ml of total volume of the injectable composition.

[00052] Preferred antioxidant includes ascorbic acid, sodium metabi sulfite, sodium sulfite, sodium formaldehyde sulfoxylate, propyl gallate and monothioglycerol. In a particularly preferred embodiment, the antioxidant is ascorbic acid. If antioxidant is used, it may be present in an amount ranging from 1 mg to 50 mg per ml of total volume of the injectable composition.

[00053] Preferred buffering agent includes phosphate buffering agents such as, monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and combinations thereof. In a particularly preferred embodiment, the buffering agent is dibasic sodium phosphate. If buffering agent is used, it may be present in an amount ranging from 0.05 mg to 2 mg per ml of total volume of the injectable composition.

[00054] In one embodiment, the pH adjusting agent is selected from the group consisting of sodium hydroxide, hydrochloric acid and a combination thereof. The pH adjusting agent can be used in an amount sufficient to maintain the injectable composition at a pH between 5 and 8.

[00055] In an exemplary embodiment, each 1 ml of the injectable composition of the present disclosure comprises:

[00056] Another aspect of the present disclosure is directed to a method of preventing and/or reducing acetaminophen-induced side effects or toxicity arising from the use of acetaminophen in a patient in need of acetaminophen therapy, the method comprising administering to the patient an injectable composition comprising a therapeutically effective amount of acetaminophen, a toxicity-reducing amount of a vitamin, a toxicity-reducing amount of an amino acid and an aqueous vehicle.

[00057] In one embodiment of this aspect, the injectable composition can be administered by intravenous injection or intravenous infusion to a patient in need of acetaminophen therapy.

[00058] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.

EXAMPLES

[00059] The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention. [00060] Acetaminophen-containing injectable composition for intravenous infusion, in accordance with embodiments of the present disclosure, was prepared at 1000 ml scale using the ingredients and quantities thereof listed in the below table.

Preparation Process:

i. 700 mL (70%) of sterile water was taken in a sterilized vessel, and it was stirred at room temperature under nitrogen purging until dissolved oxygen level of sterile water was not more than 5 ppm.

ii. Mannitol was added to the nitrogen-purged sterile water and stirred until a clear solution was obtained.

iii. Dibasic sodium phosphate was added to the above solution and stirred until a clear solution was obtained.

iv. Ascorbic acid was added to the above solution and stirred until a clear solution was obtained.

v. L-Glutamic acid was added to the above solution and stirred until a clear solution was obtained.

vi. L-cysteine was added to the above solution and stirred until a clear solution was obtained. vii. Pyridoxine was added to the above solution and stirred until a clear solution was obtained.

viii. Taurine was added to the above solution and stirred until a clear solution was obtained.

ix. Glutathione was added to the above solution and stirred until a clear solution was obtained.

x. L-Arginine was added to the above solution and stirred until a clear solution was obtained.

xi. L-omithine was added to the above solution and stirred until a clear solution was obtained.

xii. L-aspartic acid was added to the above solution and stirred until a clear solution was obtained.

xiii. Acetaminophen was added to the above solution and stirred until a clear solution was obtained.

xiv. pH of the above solution was adjusted to 5.5 with 1N NaOH and 1N HC1.

xv. After pH adjustment, the above solution was made up to 1000 mL with sterile water. The resultant solution was stirred at room temperature for 15 minutes to obtain a final solution.

xvi. The above final solution was filtered through a 0.22 Micron Filter, and the filtrate was filled into glass vials.

Claims

I Claim:

1. An injectable composition comprising, a therapeutically effective amount of acetaminophen, a toxicity-reducing amount of a vitamin, a toxicity-reducing amount of an amino acid and an aqueous vehicle.

2. The injectable composition as claimed in claim 1, wherein the vitamin comprises vitamin B₆ compound.

3. The injectable composition as claimed in claim 2, wherein the vitamin B₆ compound is selected from the group consisting of pyridoxine, esters of pyridoxine, amines of pyridoxine, salts of pyridoxine and a mixture thereof.

4. The injectable composition as claimed in claim 1, wherein the amino acid comprises at least one essential amino acid.

5. The injectable composition as claimed in claim 1, wherein the amino acid comprises at least one non-essential amino acid.

6. The injectable composition as claimed in claim 5, wherein the at least one non-essential amino acid is selected from the group consisting of glutamic acid, cysteine, aspartic acid, ornithine, glutathione, taurine, alanine, asparagine, glutamine, glycine, proline, serine, tyrosine, and mixtures thereof.

7. The injectable composition as claimed in claim 4, wherein the at least one essential amino acid is selected from the group consisting of arginine, isolucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, and mixtures thereof.

8. The injectable composition as claimed in claim 1, wherein the aqueous vehicle is selected from the group consisting of water, saline and aqueous dextrose solution.

9. The injectable composition as claimed in claim 1 further comprises at least one pharmaceutically acceptable excipient.

10. The injectable composition as claimed in claim 9, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of antioxidant, buffering agent, pH adjusting agent, diluent, non-aqueous vehicle, viscosity enhancing agent, stabilizing agent, lubricant, preservative, chelating agent, surfactant, tonicity adjusting agent, and mixtures thereof.

11. A method of preventing or reducing acetaminophen-induced side effects or toxicity in a patient in need of acetaminophen therapy, the method comprising administering to the patient an injectable composition comprising a therapeutically effective amount of acetaminophen, a toxicity-reducing amount of a vitamin, a toxicity-reducing amount of an amino acid and an aqueous vehicle.