WO2022175973A1 - An injectable composition for long term delivery of nalbuphine or nalbuphine ester prodrug or its salts and use thereof - Google Patents

An injectable composition for long term delivery of nalbuphine or nalbuphine ester prodrug or its salts and use thereof Download PDF

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WO2022175973A1
WO2022175973A1 PCT/IN2022/050131 IN2022050131W WO2022175973A1 WO 2022175973 A1 WO2022175973 A1 WO 2022175973A1 IN 2022050131 W IN2022050131 W IN 2022050131W WO 2022175973 A1 WO2022175973 A1 WO 2022175973A1
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nalbuphine
pain
ester
pyrrolidone
composition
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PCT/IN2022/050131
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French (fr)
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Kunal Saxena
Aakarsh SAXENA
Navin Saxena
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Navin Saxena Research And Technology Private Limited
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Publication of WO2022175973A1 publication Critical patent/WO2022175973A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • the present invention relates to sustained release injectable pharmaceutical composition of nalbuphine or a nalbuphine ester prodrug or the pharmaceutically acceptable salts of nalbuphine for the treatment of moderate to severe pain, post operative pain, pain in terminal cancer.
  • the formulation is non-oily, non-viscous, ensuring content uniformity and injectability.
  • Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain can significantly influence an individual's health status and can have serious negative consequences, including morbidity and mortality. Chronic and high-intensity persistent pain can lead to poor nutrition, decreased appetite, abnormal sleep patterns, fatigue, and impairment of daily living activities. Pain can cause psychological impairment and decrease healing and recovery from injuries and illness. Pain is one of the most common symptoms associated with cancer. The treatment of certain types of cancer pain, including neuropathic pain and cancer-induced bone pain might be a major challenge in cancer infected patients.
  • Morphine is a widely known compound, administered for various purposes, including analgesia. Morphine, in fact, is the compound most often used to treat moderate to severe pain. However, it has known limitations. With time, patients can develop tolerance to Morphine and/or become dependent on it or addicted to it. In addition, morphine can cause severe constipation. With larger amounts of the narcotic analgesic, e.g. morphine, in an amount of 0.5 to 1.0 mg/dose to prolong the effect, as described in the literature published by Baxter, A. D. et al (Can. J. Anesth. Vol 36, 503, 1989), fatal respiratory depression is likely to occur.
  • Nalbuphine is a synthetic opioid agonist-antagonist analgesic for parenteral use, related chemically to the opioid oxymorphone, and to the opioid antagonist naloxone. Nalbuphine simultaneously exhibits a dual action of agonism and antagonism towards opioids-receptors (Schmidt, W. F. et al., Drug Alcohol Depend., Vol. 14, page 339 (1985)). Receptor studies show that nalbuphine binds to mu, kappa, and delta receptors, but not to sigma receptors. Nalbuphine is primarily a kappa agonist/ mu antagonist analgesic.
  • nalbuphine Actions of nalbuphine at the kappa-receptors produce alterations in the perception of pain as well as the emotional response to pain, possibly by altering the release of neurotransmitters from afferent nerves sensitive to painful stimuli.
  • nalbuphine protects against the hemodynamic responses to stress produced by surgery.
  • nalbuphine paradoxically produces opiate withdrawal if administered to opiate-dependent patients, which is a function of antagonism at the mu-receptor. Stimulation at mu-receptor produces respiratory depression.
  • nalbuphine causes less respiratory depression than morphine or related agents.
  • Nalbuphine has been found to be effective in controlling of severe and deep pain caused by cardiac, pulmonary, abdominal, osteopathia, and obstetrical surgery, severe bum injury and the terminal stages of cancer via various administration routes, such as intramuscular, intravenous, intrathecal (Schmidt, W. K. et al., 1985).
  • the only drawback in the case of nalbuphine is the short duration of action.
  • Wang, J. J. et al. Mo. Tsui. Hsueh. Tsa. Chi., Vol 23, 3, 1985
  • the effect of nalbuphine can only be sustained for 3-5 hours after intravenous administration and 6-8 hours by intrathecal injection.
  • Nalbuphine is used as a supplement to surgical anesthesia, an adjunct to preoperative and postoperative analgesia, and obstetrical analgesia during labour and delivery.
  • the USFDA has approved medical use of nalbuphine in 1979.
  • any improvement in extending the duration of action of nalbuphine would be a great breakthrough in medicine and at the same time would provide a more economical therapeutic system.
  • the prodrug approach is widely used to increase the duration of action of the drugs that are rapidly eliminated.
  • nalbuphine ester prodrugs which are nalbuphine monoester and nalbuphine polyester.
  • nalbuphine monoester include, but are not limited to, nalbuphine propionate, Nalbuphine pivalate, Nalbuphine enanthate, nalbuphine decanoate, Nalbuphine behenate, Nalbuphine erucicate, nalbuphinearachidate, and nalbuphine benzoate.
  • nalbuphine polyester examples include, but are not limited to, adipoyldinalbuphine ester, sebacoyldinalbuphine ester(SDE) or dinalbuphinesebacoyl ester (DNS), 1,3-cyclohexane diaciddinalbuphine ester, docosanodicdinalbuphine ester, 3,3-dimethylglutaric diaciddinalbuphine ester, trinalbuphinetrimesoyl ester, 1,3, 5 -cyclohexane triacidtrinalbuphine ester, pyromellitoyltetranalbuphine ester.
  • DPS dinalbuphinesebacoyl ester
  • Sebacoyldinalbuphine ester also known as dinalbuphinesebacoyl ester (DNS) or dinalbuphinesebacate
  • SDE sebacoyldinalbuphine ester
  • DAS dinalbuphinesebacoyl ester
  • An advantage of the prodrugs of nalbuphine, particularly dinalbuphinesebacoyl ester (DNS), is the controlled release of nalbuphine in the body after a subcutaneous or intramuscular injection, which leads to its long-term efficacy with a single dose of and, thereby enhancing the duration of action after a single dose administration.
  • the dinalbuphinesebacoyl ester molecule includes two nalbuphine molecules esterified through a sebacic acid linker. Ester linkages of prodrugs tend to be hydrolyzed efficiently because of the wide availability of endogenous esterases, allowing for continuous release of active drug.
  • Naldebain ® (150 mg Nalbuphine sebacate, 75 mg/ml, 2 ml/vial), a single intramuscular administration of a long-acting prodrug of nalbuphine, i.e. dinalbuphinesebacatein oily solution, developed by Lumosa Therapeutics as the world's first extended-release analgesic injection of Nalbuphine sebacate for the relief of moderate/severe post-operative pain for 6 days without the side effects associated with opioids.
  • Naldebain ® was approved by the Taiwan Food and Drug Administration (TFDA) in March 2017.Naldebain Extended Release Injection contains 75 mg/ml of dinalbuphinesebacate along with benzyl benzoate and sesame oil.
  • US 6225321 discloses a composition of nalbuphine polyester derivative which includes sebacoyldinalbuphine ester wherein the composition contains a vehicle as oil as a carrier wherein the oil carrier in the composition in the form of peanut oil, soybean oil and sesame oil in the form of solution or suspension wherein the composition is used for the treatment of acute pain, chronic pain.
  • a single dose of the formulation could give an analgesic effect maintained for 4 to 5 days when the inj ection volume is 7.15 ml, however, 5 ml was reported for adults as the maximum volume for a single intramuscular injection.
  • lt employed a method which adds Nalbuphine polyester derivative to injectable oil vehicle, or to phosphate buffer, with the addition of common excipients to form a controlled release dosage form.
  • the injectable oil vehicles were selected from sesame oil, ethylester of peanut oil, or soybean oil. However, large-volume injections (3 ml or greater) are rarely administered clinically, and may cause serious injection site irritation.
  • Another patent US10183018 filed by Lumosa Therapeutics discloses an injectable composition of sebacoyldinalbuphine ester (SDE) which includes sesame oil and benzyl benzoate with a weight ratio of about 1.12:1, wherein the formulation is prepared by dissolving sebacoyldinalbuphine ester in benzyl benzoate and further mixing with sesame oil to form a solution in which the formulation contains sebacoyldinalbuphinein an amount of about 75 mg/ml, wherein the formulation is administered by intramuscular or subcutaneous injection and which is used for the treatment of post-surgical pain.
  • the formulation has the duration of action of less than about 6 days and/or the release period of the pharmaceutical formulation is less than about 14 days from dosing.
  • the pharmaceutically acceptable oil used in the composition is a vegetable oil, wherein the vegetable oil consisting of sesame oil, cottonseed oil, castor oil or a mixture thereof.
  • the oil-miscible solvent used in the composition consisting of benzyl benzoate, benzyl alcohol, or a mixture thereof.
  • this formulation is an oily injection and hence like any other oily injection, is painful upon injection of 2ml therapeutic dose.
  • Another patent EP2910242 B filed by Chang Chenchung discloses an injectable composition of dinalbuphinesebacoylester (DNS) injection which comprises a biodegradable PLGA polymer whereinthe dosage of the injectable composition of sebacoyldinalbuphine ester (DNS) is reduced by administering a controlled release composition of nalbuphine in the form of tablets, capsules, soft capsules, granules, suspensions, microspheres, oral implants, implantable injections, emulsion injections and intramuscular injections, whereinthe biodegradable PLGA polymer includes a PLA or a PGA polymer or a combination of PLA and PGA copolymer in the ratio of 1 :2 with a molecular weight in the range of 5000 Da -2000 Da.
  • DPS dinalbuphinesebacoylester
  • Another patentEP0615756 B discloses an injectable composition of nalbuphine decanoatewherein the composition contains a diluent or carrier in the form of anoil is selected from the group consisting of sesame oil, soybean oil or ethyl ester peanut oil which forms an oily solution or an oily suspension wherein the composition is administered through the intramuscular route. Therefore there remains a need for developing a sustained release drug composition which comprises a nalbuphineor a nalbuphine ester prodrug or its pharmaceutically acceptable salts thereof, for better patient compliance which is affordable, safe and also easy to administer and mitigating the pain at the site of injection.
  • the objective of the present invention is to provide a sustained release injectable composition of Nalbuphine or its pharmaceutically acceptable salts thereof or a nalbuphine ester prodrug, preferably the nalbuphine ester prodrug is sebacanoyldinalbuphine ester (SDE) which is injected into the body and which causes less pain on injection.
  • SDE sebacanoyldinalbuphine ester
  • the present invention provides a liquid injectable pharmaceutical composition which comprises nalbuphine or its pharmaceutically acceptable salts thereof or a prodrug of nalbuphine present in the concentration of 0.5 to 50.0% w/w, and biocompatible non-aqueous solvent(s)in an amount of 10.0% to 90.0% w/w, wherein the composition releases nalbuphine in an extended or sustained manner.
  • the prodrug of Nalbuphine is selected from a Nalbuphine monoester or a Nalbuphine polyester, preferably a Nalbuphine polyester, wherein the Nalbuphine polyester is sebacoyldinalbuphine ester.
  • the liquid injectable pharmaceutical composition comprises a biocompatible water soluble non-aqueous solvent which is selected from the group consisting of N-methyl-2-pyrrolidone, benzyl benzoate, polyethylene glycol, propylene glycol, dimethyl suphoxide, 2-pyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, benzyl alcohol and the like.
  • the biocompatible water soluble non- aqueous solvent is N-methyl-2-pyrrolidone and/or benzyl benzoate or a combination thereof.
  • the ratio of N-methyl-2-pyrrolidone and benzyl benzoate is 0.1: 1 to 1:0.1, preferably the ratio of N-methyl-2-pyrrolidone and benzyl benzoate is 0.5:1 to 1:0.5.
  • the liquid injectable pharmaceutical composition of the present invention comprises sebacoyldinalbuphine ester present in an amount of about 0.5% to 50.0% w/w; biocompatible non-aqueous solvent(s) selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof present in an amount of about 10.0% to 90.0% w/w.
  • the invention provides a process for preparation of liquid injectable pharmaceutical composition which process comprises dissolving sebacoyldinalbuphine ester present in biocompatible non-aqueous solvent(s) to obtain homogeneous liquid injectable composition, which causes less pain when injected into the body.
  • the pharmaceutically acceptable water soluble non- aqueous solvent is used preferably N-methyl-2-pyrrolidone and benzyl benzoate which are used as a strong solubilizing agent in the composition.
  • N-methyl-2-pyrrolidone and benzyl benzoate includes ease of availability, biocompatibility and cheaper price makes the liquid injectable pharmaceutical composition of the present composition affordable, biocompatible, low viscous and can be administered using a fine needle and also the composition is manufactured without the need of any special manufacturing equipment or control. This ensures robust, easy and reproducible method for the preparation of the present formulation.
  • the present invention provides a sustained release liquid injectable pharmaceutically acceptable composition which comprises: a.
  • Sebacoyldinalbuphine ester present in the concentration of about 5.0% to 50.0% w/w of the total composition; b. biocompatible non-aqueous solvent(s) present in the concentration of about 10.0% to 90.0% w/w of the total composition and c. stabilizer (s) present in the concentration of about 0.01% to 10.0% w/w of the total composition.
  • a stabilizer in the liquid injectable pharmaceutical composition is selected from the group consisting of butylatedhydroxytoluene, butylatedhydroxyanisole, tocopherol, ascorbic acid, sodium bisulfite, sodium metabisulfite and the like, preferably the stabilizer is butylatedhydroxytoluene.
  • the liquid injectable pharmaceutical composition of the present invention comprises sebacoyldinalbuphine ester present in an amount of about 0.5% to 50.0% w/w; biocompatible non-aqueous solvent(s) selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof present in an amount of about 10.0% to 90.0% w/w; and butylatedhydroxytoluene present in an amount of 0.01% to 10.0% w/w.
  • the invention provides a process for preparation of liquid injectable pharmaceutical composition, which comprises dissolving 0.5 to 50.0% w/w of sebacoyldinalbuphineester, in a biocompatible solvent(s) selected from N- methyl-2-pyrrolidone, benzyl benzoate or a combination thereof in an amount of 10.0% to 90.0% w/w and optionally 0.01% to 10% butylated hydroxyl toluene as a stabilizer to form a homogeneous liquid injectable composition, which causes less pain when injected into the body.
  • a biocompatible solvent(s) selected from N- methyl-2-pyrrolidone, benzyl benzoate or a combination thereof in an amount of 10.0% to 90.0% w/w and optionally 0.01% to 10% butylated hydroxyl toluene as a stabilizer
  • the invention provides a method for treating pain which method comprises administering therapeutically effective amount of the sustained release injectable composition provided according to the present invention with the duration of action of about 7 to 15 days with the release of the composition for about 15 days after administering an effective amount of the liquid injectable pharmaceutical composition of nalbuphine or a nalbuphine ester prodrug or its pharmaceutically acceptable salts thereof.
  • the pain may be moderate to severe pain, preferably, the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, visceral pain, idiopathic pain, post-operative pain and pain in terminal cancer.
  • the liquid injectable pharmaceutical composition is administered by subcutaneous injection or intramuscular injection.
  • Figure 1 In vitro drug release profile for dinalbuphinesebacate composition and percentage of nalbuphine released in aqueous solution wherein the composition of dinalbuphinesebacate is prepared in non-aqueous solvent, N-methyl-2-pyrrolidone as explained in example 1.
  • Figure 2 pharmacokinetic parameters of nalbuphine obtained after intramuscular injection of different dinalbuphinesebacate long acting preparation of example 1(NSRT variant 1) and 3 (NSRT variant 2) compared to marketed formulation Naldebain ER injection at 50 mg/kg dose in the blood plasma of rats.
  • Figure 1 shows the in vitro drug release profile for dinalbuphinesebacate composition and percentage of nalbuphine released in aqueous solution wherein the composition of dinalbuphinesebacate is prepared in non-aqueous solvent, N- methyl-2-pyrrolidone as explained in example 1.
  • N- methyl-2-pyrrolidone as explained in example 1.
  • approximately 2.5% of nalbuphine was released into the aqueous solution from the composition of dinalbuphinesebacate in 10 days.
  • Figure 2 shows the pharmacokinetic parameters of nalbuphine obtained after intramuscular injection of different dinalbuphinesebacate long acting preparation of example 1(NSRT variant 1) and 3 (NSRT variant 2) compared to marketed formulation Naldebain ER injection at 50 mg/kg dose in the blood plasma of rats. It is apparent from the figure 2 that drug release occurred in a sustained manner.
  • Figure 2 shows that both the formulations resulted into near zero order release of nalbuphine after intramuscular injection.
  • the concentration of nalbuphine during the burst release phase is well below the maximum safe concentration (MSC) of nalbuphine achieved at the single intravenous dose of nalbuphine injection provided according to the examples 1 and 3.
  • the formulation of example 3 resulted into more controlled release when compared to marketed formulation Naldebain ER injection.
  • the term "pharmaceutically acceptable salt” used herein refers to an addition of a salt with an inorganic acid or an organic acid.
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid.
  • the organic acid includes phosphoric acid, acetic acid, oxalic acid, citric acid, sebacic acid, malic acid, tartaric acid, maleic acidand fumaric acid.
  • prodrug refers to a derivative of a pharmaceutically active agent, wherein said derivative, when administered to a warm blooded animal, such as a human, is converted into the pharmaceutically active agent. The conversion of the derivative may occur through chemical, enzymatic or other reactions. The cleavage of prodrug according to the present invention may also contribute to sustained release of active ingredient.
  • nalbuphine ester prodrug used herein refers to a nalbuphine monoester or a nalbuphinepolyester.
  • the nalbuphine polyester used in the present invention is preferably a nalbuphine polyester, preferably a sebacoyldinalbuphine ester.
  • terapéuticaally effective amount refers to an amount of drug or agent that is sufficient to elicit desired therapeutic or prophylactic response.
  • liquid injectable pharmaceutical composition has its ordinary meaning as understood by those skilled in the art and thus refers to a pharmaceutical composition of a drug or drugs which is administrable through injection to a human.
  • sustained release has its ordinary meaning as understood by those skilled in the art and thus refers to the controlled release of a drug from a pharmaceutical composition over an extended period of time.
  • the present invention provides a sustained release liquid injectable composition of Nalbuphine or its pharmaceutically acceptable salts thereof or a nalbuphine ester prodrug in which the liquid injectable composition comprises one or more biocompatible non-aqueous solvent(s)and optionally one or more stabilizer(s), wherein the injection is administered subcutaneously or intramuscularly.
  • the active ingredient in the sustained release liquid injectable pharmaceutical composition of the present invention includes Nalbuphine or its pharmaceutically acceptable salts thereof or a nalbuphine ester prodrug thereof, wherein the nalbuphine ester prodrug comprises a nalbuphine monoester or a nalbuphine polyester wherein the nalbuphine polyester used in the present invention is preferably sebacoyldinalbuphine ester.
  • the present invention provides a liquid injectable pharmaceutical composition which comprises a) sebacoyldinalbuphine ester in an amount of 5% to 50.0% w/w; and b) biocompatible non-aqueous solvent(s) in an amount of 10.0% to 90.0% w/w.
  • the biocompatible non-aqueous solvent is selected from group consisting of N- methyl-2-pyrrolidone, benzyl benzoate, dimethyl suphoxide, 2-pyrrolidone, N, N- dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, propylene glycol, benzyl alcohol, which is used individually or a mixture thereof.
  • the biocompatible non-aqueous solvents are selected from N-methyl-2-pyrrolidone, benzyl benzoate, or a combination thereof.
  • the liquid injectable composition according to the present invention preferably contains biocompatible pharmaceutically acceptable non-aqueous solvent(s), viz., N-methyl-2-pyrrolidone and/or benzyl benzoate which are used as a solubilizing agent which solubilizes the drug in the composition.
  • biocompatible pharmaceutically acceptable non-aqueous solvent(s) viz., N-methyl-2-pyrrolidone and/or benzyl benzoate which are used as a solubilizing agent which solubilizes the drug in the composition.
  • N-methyl-2-pyrrolidone is also called by several other names, such as l-methyl-2-pyrrolidinone,l-methyl-5- pyrrolidinone, 1 -methylazacyclopentan-2-one, 1 -methylpyrrolidinone, 1 -methyl pyrrolidone and methyl-pyrrolidone.
  • the liquid injectable pharmaceutical composition of the present invention comprises about 5% to 50.0% w/w of sebacoyldinalbuphine ester; about 10.0% to 90.0% w/w of biocompatible solvent(s) selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof.
  • the liquid injectable pharmaceutical composition of the present invention comprises about 5% to 50.0% w/w of sebacoyldinalbuphine ester; about 10.0% to 90.0% w/w of biocompatible solvent(s) and about 0.01% to 10.0% w/w of a stabilizer.
  • the stabilizer which is selected from the group consisting of butylated hydroxyl toluene, butylated hydroxyl anisole, tocopherol, ascorbic acid, sodium bisulfite, sodium metabisulfite and the like.
  • the stabilizer is butylated hydroxyl toluene.
  • the liquid injectable pharmaceutical composition of the present invention comprises about 5% to 50.0% w/w of sebacoyldinalbuphine ester; about 10.0% to 90.0% w/w of biocompatible solvent(s) selected from N-methyl-2- pyrrolidone, benzyl benzoate or a combination thereof and about 0.01% to 10.0% w/w of butylatedhydroxytoluene.
  • Sebacoyldinalbuphine ester also called dinalbuphinesebacate (DNS)
  • DAS dinalbuphinesebacate
  • An advantage of prodrugs, particularly SDE, is their long-term efficacy and sustained release, enhancing the effective time followed by a single dose.
  • the SDE molecule includes two nalbuphine molecules esterified through a sebacic acid linker. Ester linkages of prodrugs tend to be hydrolyzed efficiently because of the wide availability of endogenous esterases, allowing for continuous release of active drug.
  • the liquid injectable pharmaceutical composition of nalbuphine prodrug is in the form of a solution or suspension, wherein the composition is filled into an ampoule, vial or prefilled syringe.
  • the liquid injectable pharmaceutical composition shows sustained drug release of nalbuphine ester prodrug or its salts thereof when injected in aqueous media as it forms depot at the site of injection, which gradually releases the drug due to diffusion followed by conversion of nalbuphine ester prodrug to the active, nalbuphine, at the site of action of the drug in the body.
  • a 20% solution of sebacoyldinalbuphine ester was prepared in N-methyl-2- pyrrolidone as the biocompatible non-aqueous solvent.
  • the solution was filtered using polytetrafluoroethylene (PTFE) syringe filter.
  • PTFE polytetrafluoroethylene
  • a 20% solution of sebacoyldinalbuphine was prepared in N-Methyl-2-pyrrolidone as the biocompatible non-aqueous solvent which contains 0.02% to 0.5% butylated hydroxy toluene (BHT) as the stabilizer.
  • BHT butylated hydroxy toluene
  • the solution was filtered using polytetrafluoroethylene (PTFE) syringe filter.
  • PTFE polytetrafluoroethylene
  • a sustained release liquid injectable pharmaceutically acceptable composition which comprises 200 mg/mL sebacoyldinalbuphine ester, 0.3 mg/ml butylated hydroxytoluene in quantity sufficient N-methyl-2- pyrrolidone, filled in vials, to deliver a dose of 150 mg sebacoyldinalbuphine ester in 0.75 ml.
  • Sebacoyldinalbuphine ester drug solution in solvent mixture Solution of sebacoyldinalbuphine ester was prepared in mixture of N-methyl-2- pyrrolidone (NMP)and Benzyl benzoate as the biocompatible non-aqueous solvent. Briefly, 6.4g sebacoyldinalbuphine ester was dissolved in 16 mL NMP. The solution volume was made upto 40 mL using Benzyl benzoate. The solution was filtered using polytetrafluoroethylene (PTFE) syringe filter.
  • PTFE polytetrafluoroethylene
  • a sustained release liquid injectable pharmaceutically acceptable composition which comprises 160 mg/mL sebacoyldinalbuphine ester, 0.3 mg/ml butylated hydroxytoluene, 0.4 ml N-methyl-2-pyrrolidone and benzyl benzoate in a quantity sufficient to make up the volume upto 1ml, filled in vials, to deliver a dose of 150 mg sebacoyldinalbuphine ester in 0.94 ml.
  • Blood samples were withdrawn from the rats of all the three groups at time intervals of 1 hour, 4hour, 8hour, 24hour (lday), 48hour (2days), 72hour(3days), 120hour(5days), 144 hour(6days), 168hour(7days), 240hour(10days) and 360hour(15days), after drug administration.
  • NSRT variant 2, example 3
  • NSRT shows the plasma concentration of nalbuphine to above 10 ng/ml for a period of 7 to 15 days, which is similar to the plasma concentration of Naldebain extended release injection.
  • the formulation of example 3 resulted into more controlled release when compared to marketed formulation Naldebain ER injection.
  • Example 5
  • Sebacoyldinalbuphine ester rapidly metabolizes to nalbuphine under the physiological condition in blood plasma, wherein the mechanism involves the conversion of sebacoyldinalbuphine ester into nalbuphine and further slow absorption of nalbuphine under the physiological condition, wherein no other metabolite and apparently no other unexpected compounds were formed both in vitro and in vivo , wherein the administration of sebacoyldinalbuphine ester into the subject is considered as safe, efficacious and have better controlled release over the marketed composition of Naldebain extended release injection.

Abstract

The present invention provides a long term, liquid injectable pharmaceutically acceptable composition for sustained release of nalbuphine or a nalbuphine ester prodrug, or the pharmaceutically acceptable salts of nalbuphine, comprising one or more biocompatible non-aqueous solvents with one or more stabilizers, wherein the injection is administered subcutaneously or intramuscularly. The invention also provides method for treating pain with the duration of action of the injectable pharmaceutical composition of about 7 days to 15 days and/or the release period of the pharmaceutical formulation is about 15 days from dosing in patients by administering an effective amount of the liquid injectable pharmaceutical composition of nalbuphine or a nalbuphine ester prodrug, or the pharmaceutically acceptable salts of nalbuphine. The pain may be moderate to severe, acute pain, chronic pain, nociceptive pain, neuropathic pain, visceral pain, idiopathic pain, post-operative pain and pain in terminal cancer.

Description

“AN INJECTABLE COMPOSITION FOR LONG TERM DELIVERY OF NALBUPHINE OR NALBUPHINE ESTER PRODRUG OR ITS SALTS
AND USE THEREOF”
Field of the invention:
The present invention relates to sustained release injectable pharmaceutical composition of nalbuphine or a nalbuphine ester prodrug or the pharmaceutically acceptable salts of nalbuphine for the treatment of moderate to severe pain, post operative pain, pain in terminal cancer. The formulation is non-oily, non-viscous, ensuring content uniformity and injectability.
Background of the invention:
The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain can significantly influence an individual's health status and can have serious negative consequences, including morbidity and mortality. Chronic and high-intensity persistent pain can lead to poor nutrition, decreased appetite, abnormal sleep patterns, fatigue, and impairment of daily living activities. Pain can cause psychological impairment and decrease healing and recovery from injuries and illness. Pain is one of the most common symptoms associated with cancer. The treatment of certain types of cancer pain, including neuropathic pain and cancer-induced bone pain might be a major challenge in cancer infected patients.
Morphine is a widely known compound, administered for various purposes, including analgesia. Morphine, in fact, is the compound most often used to treat moderate to severe pain. However, it has known limitations. With time, patients can develop tolerance to Morphine and/or become dependent on it or addicted to it. In addition, morphine can cause severe constipation. With larger amounts of the narcotic analgesic, e.g. morphine, in an amount of 0.5 to 1.0 mg/dose to prolong the effect, as described in the literature published by Baxter, A. D. et al (Can. J. Anesth. Vol 36, 503, 1989), fatal respiratory depression is likely to occur.
Nalbuphine is a synthetic opioid agonist-antagonist analgesic for parenteral use, related chemically to the opioid oxymorphone, and to the opioid antagonist naloxone. Nalbuphine simultaneously exhibits a dual action of agonism and antagonism towards opioids-receptors (Schmidt, W. F. et al., Drug Alcohol Depend., Vol. 14, page 339 (1985)). Receptor studies show that nalbuphine binds to mu, kappa, and delta receptors, but not to sigma receptors. Nalbuphine is primarily a kappa agonist/ mu antagonist analgesic.
Actions of nalbuphine at the kappa-receptors produce alterations in the perception of pain as well as the emotional response to pain, possibly by altering the release of neurotransmitters from afferent nerves sensitive to painful stimuli. As an adjunct to anesthesia, nalbuphine protects against the hemodynamic responses to stress produced by surgery. Additionally, nalbuphine paradoxically produces opiate withdrawal if administered to opiate-dependent patients, which is a function of antagonism at the mu-receptor. Stimulation at mu-receptor produces respiratory depression. However, nalbuphine causes less respiratory depression than morphine or related agents.
Nalbuphine has been found to be effective in controlling of severe and deep pain caused by cardiac, pulmonary, abdominal, osteopathia, and obstetrical surgery, severe bum injury and the terminal stages of cancer via various administration routes, such as intramuscular, intravenous, intrathecal (Schmidt, W. K. et al., 1985). The only drawback in the case of nalbuphine is the short duration of action. Wang, J. J. et al. (Ma. Tsui. Hsueh. Tsa. Chi., Vol 23, 3, 1985) have reported that the effect of nalbuphine can only be sustained for 3-5 hours after intravenous administration and 6-8 hours by intrathecal injection. Nalbuphine is used as a supplement to surgical anesthesia, an adjunct to preoperative and postoperative analgesia, and obstetrical analgesia during labour and delivery. The USFDA has approved medical use of nalbuphine in 1979.
However, severe pain usually cannot be relieved in such short periods of time. The plasma half-life of nalbuphine is 5 hours and in clinical studies the duration of analgesic activity has been reported to range from 3 to 6 hours at the lowest dose that provides adequate pain relief. This needs the administration of frequent injections of nalbuphine and causes discomfort to the patient.
Therefore, any improvement in extending the duration of action of nalbuphine would be a great breakthrough in medicine and at the same time would provide a more economical therapeutic system. The prodrug approach is widely used to increase the duration of action of the drugs that are rapidly eliminated.
There are two kinds of nalbuphine ester prodrugs, which are nalbuphine monoester and nalbuphine polyester. Examples of nalbuphine monoester include, but are not limited to, nalbuphine propionate, Nalbuphine pivalate, Nalbuphine enanthate, nalbuphine decanoate, Nalbuphine behenate, Nalbuphine erucicate, nalbuphinearachidate, and nalbuphine benzoate. Examples of nalbuphine polyester include, but are not limited to, adipoyldinalbuphine ester, sebacoyldinalbuphine ester(SDE) or dinalbuphinesebacoyl ester (DNS), 1,3-cyclohexane diaciddinalbuphine ester, docosanodicdinalbuphine ester, 3,3-dimethylglutaric diaciddinalbuphine ester, trinalbuphinetrimesoyl ester, 1,3, 5 -cyclohexane triacidtrinalbuphine ester, pyromellitoyltetranalbuphine ester. Among the nalbuphine ester prodrugs, dinalbuphinesebacoyl ester (DNS) is the most preferred one which is used in the injectable composition.
Sebacoyldinalbuphine ester (SDE), also known as dinalbuphinesebacoyl ester (DNS) or dinalbuphinesebacate, is a prodrug of nalbuphine with a molecular weight of 881 Da. An advantage of the prodrugs of nalbuphine, particularly dinalbuphinesebacoyl ester (DNS), is the controlled release of nalbuphine in the body after a subcutaneous or intramuscular injection, which leads to its long-term efficacy with a single dose of and, thereby enhancing the duration of action after a single dose administration. The dinalbuphinesebacoyl ester molecule includes two nalbuphine molecules esterified through a sebacic acid linker. Ester linkages of prodrugs tend to be hydrolyzed efficiently because of the wide availability of endogenous esterases, allowing for continuous release of active drug.
Naldebain®, (150 mg Nalbuphine sebacate, 75 mg/ml, 2 ml/vial), a single intramuscular administration of a long-acting prodrug of nalbuphine, i.e. dinalbuphinesebacatein oily solution, developed by Lumosa Therapeutics as the world's first extended-release analgesic injection of Nalbuphine sebacate for the relief of moderate/severe post-operative pain for 6 days without the side effects associated with opioids. Naldebain® was approved by the Taiwan Food and Drug Administration (TFDA) in March 2017.Naldebain Extended Release Injection contains 75 mg/ml of dinalbuphinesebacate along with benzyl benzoate and sesame oil.
The patent, US 6225321 discloses a composition of nalbuphine polyester derivative which includes sebacoyldinalbuphine ester wherein the composition contains a vehicle as oil as a carrier wherein the oil carrier in the composition in the form of peanut oil, soybean oil and sesame oil in the form of solution or suspension wherein the composition is used for the treatment of acute pain, chronic pain.
It is stated that a single dose of the formulation could give an analgesic effect maintained for 4 to 5 days when the inj ection volume is 7.15 ml, however, 5 ml was reported for adults as the maximum volume for a single intramuscular injection.lt employed a method which adds Nalbuphine polyester derivative to injectable oil vehicle, or to phosphate buffer, with the addition of common excipients to form a controlled release dosage form. The injectable oil vehicles were selected from sesame oil, ethylester of peanut oil, or soybean oil. However, large-volume injections (3 ml or greater) are rarely administered clinically, and may cause serious injection site irritation. Another patent US10183018 filed by Lumosa Therapeutics discloses an injectable composition of sebacoyldinalbuphine ester (SDE) which includes sesame oil and benzyl benzoate with a weight ratio of about 1.12:1, wherein the formulation is prepared by dissolving sebacoyldinalbuphine ester in benzyl benzoate and further mixing with sesame oil to form a solution in which the formulation contains sebacoyldinalbuphinein an amount of about 75 mg/ml, wherein the formulation is administered by intramuscular or subcutaneous injection and which is used for the treatment of post-surgical pain. The formulation has the duration of action of less than about 6 days and/or the release period of the pharmaceutical formulation is less than about 14 days from dosing. The pharmaceutically acceptable oil used in the compositionis a vegetable oil, wherein the vegetable oil consisting of sesame oil, cottonseed oil, castor oil or a mixture thereof. The oil-miscible solvent used in the compositionconsisting of benzyl benzoate, benzyl alcohol, or a mixture thereof. However, this formulation is an oily injection and hence like any other oily injection, is painful upon injection of 2ml therapeutic dose.
Another patent EP2910242 B filed by Chang Chenchung discloses an injectable composition of dinalbuphinesebacoylester (DNS) injection which comprises a biodegradable PLGA polymer whereinthe dosage of the injectable composition of sebacoyldinalbuphine ester (DNS) is reduced by administering a controlled release composition of nalbuphine in the form of tablets, capsules, soft capsules, granules, suspensions, microspheres, oral implants, implantable injections, emulsion injections and intramuscular injections, whereinthe biodegradable PLGA polymer includes a PLA or a PGA polymer or a combination of PLA and PGA copolymer in the ratio of 1 :2 with a molecular weight in the range of 5000 Da -2000 Da. Another patentEP0615756 B discloses an injectable composition of nalbuphine decanoatewherein the composition contains a diluent or carrier in the form of anoil is selected from the group consisting of sesame oil, soybean oil or ethyl ester peanut oil which forms an oily solution or an oily suspension wherein the composition is administered through the intramuscular route. Therefore there remains a need for developing a sustained release drug composition which comprises a nalbuphineor a nalbuphine ester prodrug or its pharmaceutically acceptable salts thereof, for better patient compliance which is affordable, safe and also easy to administer and mitigating the pain at the site of injection.
Thus, the objective of the present invention is to provide a sustained release injectable composition of Nalbuphine or its pharmaceutically acceptable salts thereof or a nalbuphine ester prodrug, preferably the nalbuphine ester prodrug is sebacanoyldinalbuphine ester (SDE) which is injected into the body and which causes less pain on injection.
Summary of the invention:
In line with the above objective, the present invention provides a liquid injectable pharmaceutical composition which comprises nalbuphine or its pharmaceutically acceptable salts thereof or a prodrug of nalbuphine present in the concentration of 0.5 to 50.0% w/w, and biocompatible non-aqueous solvent(s)in an amount of 10.0% to 90.0% w/w, wherein the composition releases nalbuphine in an extended or sustained manner.
In another aspect, the prodrug of Nalbuphine is selected from a Nalbuphine monoester or a Nalbuphine polyester, preferably a Nalbuphine polyester, wherein the Nalbuphine polyester is sebacoyldinalbuphine ester.
In another aspect, the liquid injectable pharmaceutical composition comprises a biocompatible water soluble non-aqueous solvent which is selected from the group consisting of N-methyl-2-pyrrolidone, benzyl benzoate, polyethylene glycol, propylene glycol, dimethyl suphoxide, 2-pyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, benzyl alcohol and the like. According to one of the preferred aspects, the biocompatible water soluble non- aqueous solvent is N-methyl-2-pyrrolidone and/or benzyl benzoate or a combination thereof.
The ratio of N-methyl-2-pyrrolidone and benzyl benzoate is 0.1: 1 to 1:0.1, preferably the ratio of N-methyl-2-pyrrolidone and benzyl benzoate is 0.5:1 to 1:0.5.
According to a preferred aspect, the liquid injectable pharmaceutical composition of the present invention comprises sebacoyldinalbuphine ester present in an amount of about 0.5% to 50.0% w/w; biocompatible non-aqueous solvent(s) selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof present in an amount of about 10.0% to 90.0% w/w.
According to another aspect, the invention provides a process for preparation of liquid injectable pharmaceutical composition which process comprises dissolving sebacoyldinalbuphine ester present in biocompatible non-aqueous solvent(s) to obtain homogeneous liquid injectable composition, which causes less pain when injected into the body.
In another embodiment, the pharmaceutically acceptable water soluble non- aqueous solvent is used preferably N-methyl-2-pyrrolidone and benzyl benzoate which are used as a strong solubilizing agent in the composition. The advantage of N-methyl-2-pyrrolidone and benzyl benzoate includes ease of availability, biocompatibility and cheaper price makes the liquid injectable pharmaceutical composition of the present composition affordable, biocompatible, low viscous and can be administered using a fine needle and also the composition is manufactured without the need of any special manufacturing equipment or control. This ensures robust, easy and reproducible method for the preparation of the present formulation. In another aspect, the present invention provides a sustained release liquid injectable pharmaceutically acceptable composition which comprises: a. Sebacoyldinalbuphine ester present in the concentration of about 5.0% to 50.0% w/w of the total composition; b. biocompatible non-aqueous solvent(s) present in the concentration of about 10.0% to 90.0% w/w of the total composition and c. stabilizer (s) present in the concentration of about 0.01% to 10.0% w/w of the total composition.
In another aspect, a stabilizer in the liquid injectable pharmaceutical composition is selected from the group consisting of butylatedhydroxytoluene, butylatedhydroxyanisole, tocopherol, ascorbic acid, sodium bisulfite, sodium metabisulfite and the like, preferably the stabilizer is butylatedhydroxytoluene.
According to another aspect, the liquid injectable pharmaceutical composition of the present invention comprises sebacoyldinalbuphine ester present in an amount of about 0.5% to 50.0% w/w; biocompatible non-aqueous solvent(s) selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof present in an amount of about 10.0% to 90.0% w/w; and butylatedhydroxytoluene present in an amount of 0.01% to 10.0% w/w.
In yet another aspect, the invention provides a process for preparation of liquid injectable pharmaceutical composition, which comprises dissolving 0.5 to 50.0% w/w of sebacoyldinalbuphineester, in a biocompatible solvent(s) selected from N- methyl-2-pyrrolidone, benzyl benzoate or a combination thereof in an amount of 10.0% to 90.0% w/w and optionally 0.01% to 10% butylated hydroxyl toluene as a stabilizer to form a homogeneous liquid injectable composition, which causes less pain when injected into the body.
According to another aspect, the invention provides a method for treating pain which method comprises administering therapeutically effective amount of the sustained release injectable composition provided according to the present invention with the duration of action of about 7 to 15 days with the release of the composition for about 15 days after administering an effective amount of the liquid injectable pharmaceutical composition of nalbuphine or a nalbuphine ester prodrug or its pharmaceutically acceptable salts thereof.
In another preferred aspect, the pain may be moderate to severe pain, preferably, the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, visceral pain, idiopathic pain, post-operative pain and pain in terminal cancer.
According to another aspect, the liquid injectable pharmaceutical composition is administered by subcutaneous injection or intramuscular injection.
Brief description of drawings:
Figure 1 : In vitro drug release profile for dinalbuphinesebacate composition and percentage of nalbuphine released in aqueous solution wherein the composition of dinalbuphinesebacate is prepared in non-aqueous solvent, N-methyl-2-pyrrolidone as explained in example 1.
Figure 2: pharmacokinetic parameters of nalbuphine obtained after intramuscular injection of different dinalbuphinesebacate long acting preparation of example 1(NSRT variant 1) and 3 (NSRT variant 2) compared to marketed formulation Naldebain ER injection at 50 mg/kg dose in the blood plasma of rats.
Detailed description of drawings:
Figure 1 shows the in vitro drug release profile for dinalbuphinesebacate composition and percentage of nalbuphine released in aqueous solution wherein the composition of dinalbuphinesebacate is prepared in non-aqueous solvent, N- methyl-2-pyrrolidone as explained in example 1. In in vitro study using example 1, approximately 2.5% of nalbuphine was released into the aqueous solution from the composition of dinalbuphinesebacate in 10 days. Figure 2 shows the pharmacokinetic parameters of nalbuphine obtained after intramuscular injection of different dinalbuphinesebacate long acting preparation of example 1(NSRT variant 1) and 3 (NSRT variant 2) compared to marketed formulation Naldebain ER injection at 50 mg/kg dose in the blood plasma of rats. It is apparent from the figure 2 that drug release occurred in a sustained manner. Figure 2 shows that both the formulations resulted into near zero order release of nalbuphine after intramuscular injection. The concentration of nalbuphine during the burst release phase is well below the maximum safe concentration (MSC) of nalbuphine achieved at the single intravenous dose of nalbuphine injection provided according to the examples 1 and 3. The formulation of example 3 resulted into more controlled release when compared to marketed formulation Naldebain ER injection.
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The term "pharmaceutically acceptable salt" used herein refers to an addition of a salt with an inorganic acid or an organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid. The organic acid includes phosphoric acid, acetic acid, oxalic acid, citric acid, sebacic acid, malic acid, tartaric acid, maleic acidand fumaric acid.
The term "prodrug", used herein refers to a derivative of a pharmaceutically active agent, wherein said derivative, when administered to a warm blooded animal, such as a human, is converted into the pharmaceutically active agent. The conversion of the derivative may occur through chemical, enzymatic or other reactions. The cleavage of prodrug according to the present invention may also contribute to sustained release of active ingredient. The term "nalbuphine ester prodrug”, used herein refers to a nalbuphine monoester or a nalbuphinepolyester. The nalbuphine polyester used in the present invention is preferably a nalbuphine polyester, preferably a sebacoyldinalbuphine ester.
The term "therapeutically effective amount" refers to an amount of drug or agent that is sufficient to elicit desired therapeutic or prophylactic response.
The term "liquid injectable pharmaceutical composition", as used herein, has its ordinary meaning as understood by those skilled in the art and thus refers to a pharmaceutical composition of a drug or drugs which is administrable through injection to a human.
The term "sustained release", as used herein, has its ordinary meaning as understood by those skilled in the art and thus refers to the controlled release of a drug from a pharmaceutical composition over an extended period of time.
The present invention provides a sustained release liquid injectable composition of Nalbuphine or its pharmaceutically acceptable salts thereof or a nalbuphine ester prodrug in which the liquid injectable composition comprises one or more biocompatible non-aqueous solvent(s)and optionally one or more stabilizer(s), wherein the injection is administered subcutaneously or intramuscularly.
The active ingredient in the sustained release liquid injectable pharmaceutical composition of the present invention includes Nalbuphine or its pharmaceutically acceptable salts thereof or a nalbuphine ester prodrug thereof, wherein the nalbuphine ester prodrug comprises a nalbuphine monoester or a nalbuphine polyester wherein the nalbuphine polyester used in the present invention is preferably sebacoyldinalbuphine ester.
Accordingly, in an embodiment, the present invention provides a liquid injectable pharmaceutical composition which comprises a) sebacoyldinalbuphine ester in an amount of 5% to 50.0% w/w; and b) biocompatible non-aqueous solvent(s) in an amount of 10.0% to 90.0% w/w.
The biocompatible non-aqueous solvent is selected from group consisting of N- methyl-2-pyrrolidone, benzyl benzoate, dimethyl suphoxide, 2-pyrrolidone, N, N- dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, propylene glycol, benzyl alcohol, which is used individually or a mixture thereof.
In one of the preferred embodiments, the biocompatible non-aqueous solvents are selected from N-methyl-2-pyrrolidone, benzyl benzoate, or a combination thereof.
The liquid injectable composition according to the present invention preferably contains biocompatible pharmaceutically acceptable non-aqueous solvent(s), viz., N-methyl-2-pyrrolidone and/or benzyl benzoate which are used as a solubilizing agent which solubilizes the drug in the composition. N-methyl-2-pyrrolidone is also called by several other names, such as l-methyl-2-pyrrolidinone,l-methyl-5- pyrrolidinone, 1 -methylazacyclopentan-2-one, 1 -methylpyrrolidinone, 1 -methyl pyrrolidone and methyl-pyrrolidone.
Accordingly, in a preferred embodiment, the liquid injectable pharmaceutical composition of the present invention comprises about 5% to 50.0% w/w of sebacoyldinalbuphine ester; about 10.0% to 90.0% w/w of biocompatible solvent(s) selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof. In another preferred embodiment, the liquid injectable pharmaceutical composition of the present invention comprises about 5% to 50.0% w/w of sebacoyldinalbuphine ester; about 10.0% to 90.0% w/w of biocompatible solvent(s) and about 0.01% to 10.0% w/w of a stabilizer.
The stabilizer which is selected from the group consisting of butylated hydroxyl toluene, butylated hydroxyl anisole, tocopherol, ascorbic acid, sodium bisulfite, sodium metabisulfite and the like. In one of the preferred embodiments, the stabilizer is butylated hydroxyl toluene.
Accordingly, the liquid injectable pharmaceutical composition of the present invention comprises about 5% to 50.0% w/w of sebacoyldinalbuphine ester; about 10.0% to 90.0% w/w of biocompatible solvent(s) selected from N-methyl-2- pyrrolidone, benzyl benzoate or a combination thereof and about 0.01% to 10.0% w/w of butylatedhydroxytoluene.
Sebacoyldinalbuphine ester (SDE), also called dinalbuphinesebacate (DNS), is a prodrug of nalbuphine with a molecular weight of 881 Da. An advantage of prodrugs, particularly SDE, is their long-term efficacy and sustained release, enhancing the effective time followed by a single dose. The SDE molecule includes two nalbuphine molecules esterified through a sebacic acid linker. Ester linkages of prodrugs tend to be hydrolyzed efficiently because of the wide availability of endogenous esterases, allowing for continuous release of active drug.
The liquid injectable pharmaceutical composition of nalbuphine prodrug is in the form of a solution or suspension, wherein the composition is filled into an ampoule, vial or prefilled syringe.
The liquid injectable pharmaceutical composition shows sustained drug release of nalbuphine ester prodrug or its salts thereof when injected in aqueous media as it forms depot at the site of injection, which gradually releases the drug due to diffusion followed by conversion of nalbuphine ester prodrug to the active, nalbuphine, at the site of action of the drug in the body.
The invention will now be illustrated with help of examples. The aforementioned embodiments and below mentioned examples are for illustrative purpose and are not meant to limit the scope of the invention. Various modifications of aforementioned embodiments and below mentioned examples are readily apparent to a person skilled in the art.
Examples Example 1:
Sebacoyldinalbuphine ester drug solution in N-methyl-2-pyrrolidone
A 20% solution of sebacoyldinalbuphine ester was prepared in N-methyl-2- pyrrolidone as the biocompatible non-aqueous solvent. The solution was filtered using polytetrafluoroethylene (PTFE) syringe filter. In vitro release of this solution was studied using dialysis method with the help of an incubator shaker at 37±0.5°C at 50 RPM. Approximately -2.5% nalbuphine was released in 10 days.
Example 2:
Sebacoyldinalbuphine ester solution with a biocompatible non-aqueous solvent and a stabilizer
A 20% solution of sebacoyldinalbuphine was prepared in N-Methyl-2-pyrrolidone as the biocompatible non-aqueous solvent which contains 0.02% to 0.5% butylated hydroxy toluene (BHT) as the stabilizer. The solution was filtered using polytetrafluoroethylene (PTFE) syringe filter. The resulting composition has high solubility to be used for an injection and has an excellent stability.
Accordingly, a sustained release liquid injectable pharmaceutically acceptable composition was prepared which comprises 200 mg/mL sebacoyldinalbuphine ester, 0.3 mg/ml butylated hydroxytoluene in quantity sufficient N-methyl-2- pyrrolidone, filled in vials, to deliver a dose of 150 mg sebacoyldinalbuphine ester in 0.75 ml.
Example 3:
Sebacoyldinalbuphine ester drug solution in solvent mixture Solution of sebacoyldinalbuphine ester was prepared in mixture of N-methyl-2- pyrrolidone (NMP)and Benzyl benzoate as the biocompatible non-aqueous solvent. Briefly, 6.4g sebacoyldinalbuphine ester was dissolved in 16 mL NMP. The solution volume was made upto 40 mL using Benzyl benzoate. The solution was filtered using polytetrafluoroethylene (PTFE) syringe filter.
Accordingly, a sustained release liquid injectable pharmaceutically acceptable composition was prepared which comprises 160 mg/mL sebacoyldinalbuphine ester, 0.3 mg/ml butylated hydroxytoluene, 0.4 ml N-methyl-2-pyrrolidone and benzyl benzoate in a quantity sufficient to make up the volume upto 1ml, filled in vials, to deliver a dose of 150 mg sebacoyldinalbuphine ester in 0.94 ml.
Example 4:
In vivo pharmacokinetic study in rats
Wistar male rats weighing approximately 400 g, were administered by intramuscular injection using the drug composition prepared in example l(n=6) & example 3(n=3), at a dose of 50mg/kg. One group of rats (n=6) were injected with marketed formulation Naldebain ER injection at 50mg/kg. Blood samples were withdrawn from the rats of all the three groups at time intervals of 1 hour, 4hour, 8hour, 24hour (lday), 48hour (2days), 72hour(3days), 120hour(5days), 144 hour(6days), 168hour(7days), 240hour(10days) and 360hour(15days), after drug administration. The blood plasma samples of the rats from all the three groups were immediately separated from red blood cells by centrifugation and the concentration of nalbuphine in blood plasma was analysed by using LC-MS method. The formulations NSRT (variant 2, example 3) shows the plasma concentration of nalbuphine to above 10 ng/ml for a period of 7 to 15 days, which is similar to the plasma concentration of Naldebain extended release injection. Moreover, the formulation of example 3 resulted into more controlled release when compared to marketed formulation Naldebain ER injection. Example 5:
Results of the studies of sebacoyldinalbuphine ester composition
The in vitro metabolic study of sebacoyldinalbuphine ester in aqueous solution and in vivo study in male rats after intramuscular injection of sebacoyldinalbuphine ester solution demonstrated that the designed nalbuphine prodrug composition fulfilled the efficacy of sustained drug release by maintaining the required plasma concentration of nalbuphine for a period of 7 to 15 days. Sebacoyldinalbuphine ester rapidly metabolizes to nalbuphine under the physiological condition in blood plasma, wherein the mechanism involves the conversion of sebacoyldinalbuphine ester into nalbuphine and further slow absorption of nalbuphine under the physiological condition, wherein no other metabolite and apparently no other unexpected compounds were formed both in vitro and in vivo , wherein the administration of sebacoyldinalbuphine ester into the subject is considered as safe, efficacious and have better controlled release over the marketed composition of Naldebain extended release injection.

Claims

We claim:
1. A sustained release liquid injectable pharmaceutically acceptable composition comprises: a. a nalbuphine ester prodrug or its derivative present in the concentration of 0.5 to 50.0% w/w. b. biocompatible non-aqueous solvent(s) in an amount of 10.0% to 90.0% w/w.
2. The sustained release liquid injectable pharmaceutically acceptable composition as claimed in claim 1, wherein nalbuphine ester prodrug is selected from a nalbuphine monoester or a nalbuphine polyester, preferably a nalbuphine polyester, preferably a sebacoyldinalbuphine ester.
3. The sustained release liquid injectable pharmaceutically acceptable composition as claimed in claim 1, wherein the biocompatible non-aqueous solvent is selected from the group consisting of N-methyl-2-pyrrolidone, benzyl benzoate, dimethyl suphoxide, 2-pyrrolidone, N, N- dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, propylene glycol and benzyl alcohol, or a mixture thereof.
4. The biocompatible non-aqueous solvent as claimed in claim 1, wherein the non-aqueous solvent isN-methyl-2-pyrrolidone.
5. The biocompatible non-aqueous solvent as claimed in claim 1, wherein the biocompatible non-aqueous solvent is benzyl benzoate.
6. The biocompatible non-aqueous solvent as claimed in claim 1, wherein the biocompatible non-aqueous solvent is a mixture of N-methyl-2-pyrrolidone and benzyl benzoate.
7. The biocompatible non-aqueous solvent mixture as claimed in claims 3 and 5, wherein the ratio of N-methyl-2-pyrrolidone and benzyl benzoate is 0.1 : 1 to 1:0.1, preferably the ratio of N-methyl-2-pyrrolidone and benzyl benzoate is 0.5:1 to 1:0.5.
8. A sustained release liquid injectable pharmaceutically acceptable composition comprises: a. sebacoyldinalbuphine ester present in the concentration of about 5.0% to 50.0% w/w of the total composition; b. biocompatible non-aqueous solvent(s) present in the concentration of about 10.0% to 90.0% w/w of the total composition and c. stabilizer (s) present in the concentration of about 0.01% to 10.0% w/w of the total composition.
9. The sustained release liquid injectable pharmaceutically acceptable composition as claimed in claim 8, wherein the biocompatible non-aqueous solvent is selected from the group consisting of N-methyl-2-pyrrolidone, benzyl benzoate, dimethyl suphoxide, 2-pyrrolidone, N, N- dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, propylene glycol and benzyl alcohol, or a mixture thereof.
10. The sustained release liquid injectable pharmaceutically acceptable composition as claimed in claim 8, wherein the biocompatible non-aqueous solvent is selected from N-methyl-2-pyrrolidone, benzyl benzoate or a combination thereof.
11. The sustained release liquid injectable pharmaceutically acceptable composition as claimed in claim 8, wherein the stabilizer is selected from the group consisting of butylatedhydroxytoluene, butylatedhydroxyanisole, tocopherol, tocopherol derivatives, ascorbic acid, ascorbic acid derivatives, sodium bisulfite, sodium metabi sulfite or a mixture thereof, preferably the stabilizer is butylatedhydroxytoluene.
12. The sustained release liquid injectable pharmaceutically acceptable composition as claimed claim 8, comprises 200 mg/mL sebacoyldinalbuphine ester, 0.3 mg/ml butylated hydroxytoluene in sufficient quantity of N-methyl-2-pyrrolidone, filled in vials, deliver a dose of 150 mg sebacoyldinalbuphine ester in 0.75 ml.
13. The sustained release liquid injectable pharmaceutically acceptable composition as claimed in claim 8 comprises 160 mg/mL sebacoyldinalbuphine ester, 0.3 mg/ml butylated hydroxytoluene, 0.4 ml N-methyl-2-pyrrolidone and benzyl benzoate in sufficient quantity to make the volume upto 1ml, filled in vials, to deliver a dose of 150 mg sebacoyldinalbuphine ester in 0.94 ml.
14. A method of treating pain which comprises administering an amount of the sustained release injectable composition as claimed in claim 1 or 8, wherein the treatment period by administering the single dose of the injectable pharmaceutical composition in humans are about 7 days to 15 days.
15. The method of treating pain comprising administering an amount of the sustained release injectable composition as claimed in claim 14, wherein the pain is acute pain, chronic pain, nociceptive pain, neuropathic pain, visceral pain, idiopathic pain, post-operative pain and pain in terminal cancer.
16. The method of treating pain comprising administering an effective amount of the pharmaceutical composition as claimed in claim 1 or claim 8 wherein the pharmaceutical composition is administered by subcutaneous injection or intramuscular injection.
PCT/IN2022/050131 2021-02-18 2022-02-15 An injectable composition for long term delivery of nalbuphine or nalbuphine ester prodrug or its salts and use thereof WO2022175973A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140112957A1 (en) * 2012-10-19 2014-04-24 Oliver Yao-Pu Hu Analegisic (Sebacoyl dinalbuphine ester) PLGA controlled release formulation form
US20190160053A1 (en) * 2015-05-28 2019-05-30 Lumosa Therapeutics Co., Ltd. Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester
US20190298702A1 (en) * 2018-03-29 2019-10-03 Lumosa Therapeutics Co., Ltd. Compositions and methods for treating pruritus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140112957A1 (en) * 2012-10-19 2014-04-24 Oliver Yao-Pu Hu Analegisic (Sebacoyl dinalbuphine ester) PLGA controlled release formulation form
US20190160053A1 (en) * 2015-05-28 2019-05-30 Lumosa Therapeutics Co., Ltd. Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester
US20190298702A1 (en) * 2018-03-29 2019-10-03 Lumosa Therapeutics Co., Ltd. Compositions and methods for treating pruritus

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHRISTIAN I. N ET AL.: "Clinically established biodegradable long acting injectables: An industry perspectiv e", ADVANCED DRUG DELIVERY REVIEWS, vol. 167, 2020, pages 19 - 46, XP086399228, ISSN: 0169-409X, DOI: 10.1016/j.addr. 2020.11.00 8 *

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