WO2022123607A1 - Pharmaceutical formulations of esketamine - Google Patents
Pharmaceutical formulations of esketamine Download PDFInfo
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- WO2022123607A1 WO2022123607A1 PCT/IN2021/051161 IN2021051161W WO2022123607A1 WO 2022123607 A1 WO2022123607 A1 WO 2022123607A1 IN 2021051161 W IN2021051161 W IN 2021051161W WO 2022123607 A1 WO2022123607 A1 WO 2022123607A1
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- WIPO (PCT)
- Prior art keywords
- esketamine
- nasal spray
- pharmaceutical composition
- unit
- dose
- Prior art date
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- YQEZLKZALYSWHR-ZDUSSCGKSA-N (S)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(NC)CCCCC1=O YQEZLKZALYSWHR-ZDUSSCGKSA-N 0.000 title claims abstract description 171
- 229960000450 esketamine Drugs 0.000 title claims abstract description 99
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 50
- 239000007922 nasal spray Substances 0.000 claims abstract description 99
- 229940097496 nasal spray Drugs 0.000 claims abstract description 97
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 3
- 229960003299 ketamine Drugs 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000007921 spray Substances 0.000 claims description 15
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000006172 buffering agent Substances 0.000 claims description 3
- 239000002738 chelating agent Substances 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000001430 anti-depressive effect Effects 0.000 description 13
- 208000024714 major depressive disease Diseases 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 9
- 229960004184 ketamine hydrochloride Drugs 0.000 description 9
- 239000000935 antidepressant agent Substances 0.000 description 8
- 230000006698 induction Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 229940005513 antidepressants Drugs 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
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- 230000001965 increasing effect Effects 0.000 description 4
- 210000002442 prefrontal cortex Anatomy 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 3
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960002303 citric acid monohydrate Drugs 0.000 description 3
- 230000002197 limbic effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000002739 subcortical effect Effects 0.000 description 3
- 241000282412 Homo Species 0.000 description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 2
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- 239000005557 antagonist Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
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- 210000002850 nasal mucosa Anatomy 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 2
- YQEZLKZALYSWHR-CYBMUJFWSA-N (R)-(+)-ketamine Chemical compound C=1C=CC=C(Cl)C=1[C@]1(NC)CCCCC1=O YQEZLKZALYSWHR-CYBMUJFWSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
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- 206010011971 Decreased interest Diseases 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 206010065604 Suicidal behaviour Diseases 0.000 description 1
- 206010042458 Suicidal ideation Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008503 anti depressant like effect Effects 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
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- 239000000969 carrier Substances 0.000 description 1
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- 238000010494 dissociation reaction Methods 0.000 description 1
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- 230000036963 noncompetitive effect Effects 0.000 description 1
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Classifications
-
- 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
- A61K9/0043—Nose
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- the present invention is directed to a pharmaceutical formulation of esketamine for nasal administration.
- the present invention further relates to pharmaceutical formulations of esketamine delivered through unit-dose nasal spray devices.
- the invention also relates to a process for the preparation of such a composition and to a method of treatment of a subject in need thereof.
- Major depressive disorder is a clinical condition characterized by a patient experiencing at least five of the nine symptoms given, for more than two weeks: depressed mood, poor sleep, loss of interest in day-to-day activities or hobbies an individual used to enjoy, feelings of guilt or worthlessness, reduced energy or chronic fatigue, poor attentiveness, lack of appetite or five percent change in weight (gain or loss), physical and/or psychomotor anxiety/retardation, and recurrent suicidal thoughts.
- the existing standard of maintenance for depression is mainly pharmacologic therapies that can modify neurological function of monoaminergic receptors within the central nervous system (CNS). These include serotonin selective reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and antipsychotics.
- SSRIs serotonin selective reuptake inhibitors
- SNRIs serotoninnorepinephrine reuptake inhibitors
- TCAs tricyclic antidepressants
- antipsychotics Treatment-resistant depression (TRD) is defined as MDD that does not adequately respond to treatment after proper courses of time with at least two anti-depressants.
- TRD Treatment-resistant depression
- SSRIs and other first-line pharmaceutical treatments take days or weeks to show clinical improvement for depression and produce an adequate response in less than two-thirds of patients.
- N-methyl-D-aspartate (NMD A) receptor antagonist is categorized as an N-methyl-D-aspartate (NMD A) receptor antagonist.
- NMD A N-methyl-D-aspartate receptor antagonist
- Esketamine (S- ketamine) is a nonselective, non-competitive antagonist of the N-methyl-D- aspartate (NMDA) receptor, which is claimed to be responsible for its analgesic-anaesthetic effects and/or antidepressant effect.
- NMDA N-methyl-D- aspartate
- the affinity for the NMDA receptor is approximately 3- to 4-fold greater for esketamine than for arketamine (R-ketamine, the R-enantiomer of ketamine) and might be associated with fewer side-effects. Esketamine is therefore considered to be a more potent and safer antidepressant.
- Ketamine can be administered in intravenous (IV), intranasal (IN), and oral forms, among others
- IV ketamine has demonstrated rapid antidepressant effects, its disadvantages has led to the investigation of intranasal or oral dosage forms of ketamine treatment.
- Intranasal administration of ketamine has been shown to be safe, effective, and equally potent as IV ketamine.
- U.S Patent 8785500 relates to a method of treating depression, comprising intranasally administering ketamine at a dosage sufficient to alleviate symptoms of said depression in patient who has not responded to at least two adequate antidepressant treatments.
- US Patent Application 20200253894 relates to a method for treating of extreme Major Depressive Disorder (MDD) which comprises intranasally administering to the patient an effective amount of ketamine and, further administering a second composition containing a conventional pharmaceutical antidepressant agent.
- MDD extreme Major Depressive Disorder
- US Patent Application 20200246279 relates to a method of treating depression in a suicidal human patient, comprising: intranasal administering of ketamine in an induction dosage to the patient in an amount in the range of from about 56 mg to about 84 mg in an induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase,
- US Patent Application 20190117591 relates to a pharmaceutical composition comprising (i) S-ketamine hydrochloride and water; wherein the S-ketamine is present in a concentration range of eq. 125 mg/mL to eq. 250 mg/mL, based on the total volume of the pharmaceutical composition.
- US Patent Application 20160338977 relates to a method of treating depression, said method comprising: (a) administering an effective amount of esketarnine at a given frequency and during an induction phase of defined duration; and (b) administering an effective amount of esketarnine to said patient less frequently during a subsequent maintenance phase of defined duration, wherein the pharmaceutical composition is customized tor intranasal administration to humans.
- SPRAVATO® is indicated, in conjunction with an oral antidepressant, for the treatment of Treatment-Resistant Depression (TRD) in adults and depressive symptoms in adults with Major Depressive Disorder (MDD) with acute suicidal ideation or behaviour.
- TRD Treatment-Resistant Depression
- MDD Major Depressive Disorder
- SPRAVATO® is in the form of a ‘spray’ administered intra-nasally (intended for nasal administration).
- Each nasal spray device of SPRAVATO® delivers two sprays containing a total of 28 mg of esketamine (supplied as 32.3 mg of esketamine hydrochloride).
- esketamine hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device.
- Each device delivers two sprays (one spray for each nostril) with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5.
- Each spray delivers 14 mg/0. 1ml of esketamine.
- SPRAVATO® is available in two presentations:
- Dose Kit Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose)
- Dose Kit Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose)
- Patient thus needs to use two devices for 56 mg and three devices for 84 mg with 5-minute rest between the use of each device.
- the dispensed volume per actuation is set between 50 and 140 pl, and an administered volume of 100 pl per nostril is optimum in adults. Higher volumes of administration are prone to drip out immediately and there are chances of drug loss through anterior leakage, resulting inadequate absorption. The anticipated dose therefore should fit into a volume of roughly 100-200 pl when both nostrils are sprayed. In conclusion for nasal administration of the drug, higher amount of the drug should be loaded or delivered in minimal dosing volume of 100 pl to avoid drug loss.
- the present invention addresses these shortcomings and provides intranasal pharmaceutical formulations of esketamine that are delivered through unit-dose nasal spray devices.
- the present invention provides for esketamine formulation that has higher amount of esketamine in minimal dosing volume and requires reduced consecutive administration of nasal sprays than otherwise required with the product available in the market to deliver the same amount of drag.
- the present invention is directed to a pharmaceutical composition of esketamine free base or pharmaceutically acceptable salts thereof for nasal administration.
- the present invention relates to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration range from about 250 mg/ml to 400 mg/ml, based on the total volume of the pharmaceutical composition.
- the present invention is directed to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration of more than 250 mg/ml based on the total volume of the pharmaceutical composition.
- the present invention is further directed to esketamine formulation delivered through a unitdose nasal spray.
- the present invention relates to a pharmaceutical composition of esketamine which is delivered through a single nasal spray.
- the present invention is directed to a pharmaceutical composition delivered as a ‘single nasal spray of 0.1 mT.
- the present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0.1 ml” wherein the single nasal spray of 0. 1 ml is intended to deliver about 28 mg of esketamine free base.
- the present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0. 1 ml” wherein the single nasal spray of 0.
- 1 ml is intended to deliver about 14 mg of esketamine free base.
- the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 14 mg of esketamine free base.
- the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 28 mg of esketamine base.
- the present invention further relates to a kit for delivery of esketamine comprising more than one unit-dose nasal spray devices.
- the present invention relates to a kit for delivery of esketamine comprising two unit-dose nasal spray devices wherein each unit-dose nasal spray device delivers a single nasal spray of about 28 mg of esketamine free base.
- the present invention relates to a kit for delivery of esketamine comprising four unit-dose nasal spray devices wherein two unit-dose nasal spray devices deliver about 28 mg of esketamine free base each and the other two unit-dose nasal spray devices deliver about 14 mg of esketamine free base each.
- the present invention also provides a kit comprising more than one single spray devices to be used in consecutive manner. The present invention provides methods and compositions for the treatment of depression.
- the present invention is directed to a pharmaceutical composition of esketamine for nasal administration.
- the present invention relates to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration range of about 250 mg/ml to 400 mg/ml, based on the total volume of the pharmaceutical composition.
- the present invention is directed to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration of more than 250 mg/ml based on the total volume of the pharmaceutical composition.
- composition as used herein relates to any pharmaceutical preparation or formulation that is tailored for being administered to a human being or animal.
- the composition contains one or more physiologically acceptable carriers and/or excipients.
- esketamine is employed in the composition of the present invention in the form of its pharmaceutically acceptable salt.
- esketamine employed in the preparation of the compositions of the present invention is esketamine hydrochloride.
- the present invention is further directed to esketamine formulation delivered through a unitdose nasal spray.
- the present invention relates to a pharmaceutical composition of esketamine which is delivered through a single nasal spray.
- the present invention is directed to a pharmaceutical composition delivered as a ‘single nasal spray of 0.1 mT.
- the present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0.1 ml” wherein the single nasal spray of 0. 1 ml is intended to deliver about 28 mg of esketamine free base.
- the present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0. 1 ml” wherein the single nasal spray of 0.
- 1 ml is intended to deliver about 14 mg of esketamine free base.
- the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 14 mg of esketamine free base.
- the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 28 mg of esketamine base.
- Tire present invention further provides an aqueous composition of esketamine hydrochloride which can be administered to the nasal mucosa.
- the esketamine nasal formulations of the present invention further comprises at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier.
- the pharmaceutically acceptable excipients such as, but not limited to, buffering agents, antioxidants, pH adjusting agents, chelating agents and the like may be included in the pharmaceutical compositions of the present invention.
- Suitable buffering agent that may be employed includes citric acid, citric acid monohydrate and the like.
- Suitable pH modifier that may be employed includes, but is not limited to, sodium hydroxide and the like.
- Suitable chelating agent that may be employed includes, but is not limited to, disodium edetate and the like.
- the compositions of the present invention further comprise at least one pharmaceutically acceptable carrier.
- the pharmaceutically acceptable earner for the pharmaceutical compositions of the present invention comprises water.
- the pharmaceutically acceptable carrier is substantially entirely water.
- the composition is substantially free of any organic earner, such as an organic solvent.
- the composi tion of the present invention is a solution.
- compositions of the present invention have a pH in the range of 3 to 6. In another embodiment, the compositions of the present invention have a pH in the range of 4 to 5.
- the composition of the present invention is in the form of a nasal spray.
- the present invention further provides a nasal spray device comprising (i) a housing containing the pharmaceutical composition of esketamine and (li) means enabling the application of the composition from within the housing to the nasal mucosa.
- the housing containing the pharmaceutical formulation is, but not limited to, a vial and the like.
- the filled and stoppered vial is assembled into a manually actuated nasal spray device comprising the vial holder and the actuator.
- each nasal spray device upon manual actuation delivers a single spray.
- each nasal spray device delivers a single spray of esketamine formulation. In yet another embodiment, each nasal spray device delivers a single spray equivalent to about 5 mg to about 50 mg of esketamine base. In another embodiment, each nasal spray device delivers a single spray equivalent to about 28 mg of esketamine base. In a further embodiment, each nasal spray device delivers a single spray equivalent to about 14 nig of esketamine base.
- each nasal spray device is for use per nostril. In another embodiment, the nasal spray device must be discarded after each use. In one embodiment, each nasal spray device is packaged in a blister pack. In a still another embodiment of the present invention, the nasal spray device does not require priming.
- the aqueous esketamine formulations of the present invention can be prepared by mixing S-ketamine hydrochloride and disodium edetate in water and then adding sodium hydroxide to adjust the pH.
- the formulations of the present invention are prepared aspectically.
- the present invention is directed to a pharmaceutical composition of S-ketamine hydrochloride which comprise higher concentrations of S-ketamine so that desired dose of the S-ketamine can be administered intranasally with minimal dosing volume.
- the present invention further relates to a kit for delivery of esketamine comprising more than one unit-dose nasal spray devices.
- the present invention relates to a kit for delivery of esketamine comprising two unit-dose nasal spray devices wherein each unit-dose nasal spray device delivers a single nasal spray of 28 mg of esketamine free base.
- the present invention relates to a kit for delivery of esketamine comprising four unit-dose nasal spray devices wherein two unit-dose nasal spray devices deliver 28 mg of esketamine free base each and the other two unit-dose nasal spray devices deliver 14 mg of esketamine free base each.
- the present invention also provides a kit comprising more than one single spray devices to be used in consecutive manner.
- the present invention is further directed to methods for the treatment of depression, such as, but not limited to, resistant depression or treatment refractory depression, comprising administering to a subject in need thereof, therapeutically effective amount of esketamine composition of the present invention by nasal route.
- depression such as, but not limited to, resistant depression or treatment refractory depression
- the present invention further relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device after a 5-minute rest between the use of each device.
- Tire present invention also relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device.
- the present invention relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in one nostril followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril after a 5-minute rest between the use of each device.
- the present invention also relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in one nostril followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril.
- the present invention further relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device, followed by subsequent administration of third and fourth doses of esketamine hydrochloride equivalent to 14 mg of esketamine free base through separate unit dose nasal spray devices with a 5-minute rest between the use of each device.
- the present invention also relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by subsequent administration of third and fourth doses of esketamine hydrochloride equivalent to 14 mg of esketamine free base through separate unit dose nasal spray devices.
- the present invention relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in one nostril followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril, followed by administration of third dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the first nostril, followed by subsequent administration of fourth dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the other nostril, with each of the administrations being made after a 5-minute rest between the use of each device.
- the present invention relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray de vice in one nostril followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril, followed by administration of third dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the first nostril, followed by subsequent administration of fourth dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the other nostril, with each of the administrations being made after a 5-minute rest between the use of each device.
- the unit dose nasal spray devices of the present invention deliver either about 28 mg or about 14 mg of esketamine free base and to prevent loss of medication, in one embodiment the devices are not required to be primmed.
- the present invention is further directed to a method of treatment of depression (preferably, treatment resistant depression), comprising administering to the patient in need thereof an esketamine formulation of the present invention intranasally using unit dose nasal spray devices.
- depression preferably, treatment resistant depression
- the present invention relates to a method of treatment of depression (preferably, treatment resistant depression), comprising: administering to the patient in need thereof an esketamine formulation of the present invention intranasally with the treatment comprising (i) an induction dosing phase; wherein the induction phase comprises a treatment period of for 4 weeks wherein esketamine is administered in the range of from about 56 mg to about 84 mg; and wherein the esketamine is administered at a dosing frequency of once to twice per week);and (b) a maintenance phase; wherein the maintenance phase comprises a treatment period of at least 6 weeks wherein the esketamine is administered at a dosage in an amount in the range of from about 56 mg to about 84 mg; -wherein the esketamine is administered at a dosing frequency in the range of once per week to once every two weeks; and wherein the maintenance phase preferably continues until further treatment is not required.
- an induction dosing phase comprising (i) an induction dosing phase; wherein the
- Citric acid monohydrate USP and Disodium edetate NF were solubilised under stirring in Water for Injection.
- the volume was made up with Water for Injection. •
- the nasal spray solution is filled into vials and delivered through a unit dose nasal spray device.
- Citric acid monohydrate USP and Disodium edetate NF were solubilised under stirring in Water for Injection.
- the nasal spray solution is filled into vials and delivered through a unit dose nasal spray device.
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Abstract
The present invention is directed to a pharmaceutical formulation of esketamine for nasal administration. The present invention further relates to pharmaceutical formulations of esketamine delivered through unit-dose nasal spray devices. The invention also relates to a process for the preparation of such a composition and to a method of treatment of a subject in need thereof.
Description
PHARMACEUTICAL FORMULATIONS OF ESKETAMINE
FIELD OF THE INVENTION
The present invention is directed to a pharmaceutical formulation of esketamine for nasal administration. The present invention further relates to pharmaceutical formulations of esketamine delivered through unit-dose nasal spray devices. The invention also relates to a process for the preparation of such a composition and to a method of treatment of a subject in need thereof.
BACKGROUND OF THE INVENTION
Over 350 million people worldwide suffer from depression. Major depressive disorder (MDD) is a clinical condition characterized by a patient experiencing at least five of the nine symptoms given, for more than two weeks: depressed mood, poor sleep, loss of interest in day-to-day activities or hobbies an individual used to enjoy, feelings of guilt or worthlessness, reduced energy or chronic fatigue, poor attentiveness, lack of appetite or five percent change in weight (gain or loss), physical and/or psychomotor anxiety/retardation, and recurrent suicidal thoughts.
The existing standard of maintenance for depression is mainly pharmacologic therapies that can modify neurological function of monoaminergic receptors within the central nervous system (CNS). These include serotonin selective reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and antipsychotics. Treatment-resistant depression (TRD) is defined as MDD that does not adequately respond to treatment after proper courses of time with at least two anti-depressants. Regrettably, SSRIs and other first-line pharmaceutical treatments take days or weeks to show clinical improvement for depression and produce an adequate response in less than two-thirds of patients.
Research into novel treatments for TRD emerged with one new therapy i.e. esketamine that has been tested to attempt and achieve better results for patients who have not had success with more traditional pharmacotherapies.
The discovery of S-ketamine or esketamine for its antidepressant effects is amongst the most important findings and the same in fact began with the discovery of ketamine and subsequently
the identification of the anti-depressant properties thereof. (R,S)-ketamine was not developed as an antidepressant. It took a long and captivating journey for clinicians and researchers to determine its rapid-acting antidepressant effects. In 1965, (R,S)-ketamine was established to be an effective analgesic and anaesthetic. Ketamine was later approved in 1970 for anaesthetic use by the US Food Drug Administration (FDA). The discovery of (R, S)-ketamine's antidepressant effects in humans began in the 1970s. In 1975, (R, S)-ketamine was reported to show antidepressant-like effects in animal models. As part of times gone by, it is worth noticing that (R,S)-ketamine was shown to be an NMDAR antagonist in 1983.. Several randomized single- and double-blind placebo- or drug-controlled studies have replicated the antidepressant effects of (R,S) -ketamine in both major depressive disorder and bipolar disorder, even after a single intravenous dose of 0.5 mg/kg.
(R,S)-ketamine is categorized as an N-methyl-D-aspartate (NMD A) receptor antagonist. Proof from numerous studies implicates alteration in the functions of the prefrontal, subcortical, and limbic brain systems in MDD. These regions of the brain are accountable for regulating administrative functions like decision-making, emotional-processing, and social behaviour. Patients suffering from MDD have been shown to have increased sensitivity to negative stimuli, such as pain and suffering, which directly relates to increased activity in the limbic and subcortical regions. By contrast, patients in remission from MDD commonly show increased activity in the pre-frontal cortex (PFC), which directly relates to the upregulation of glutamate activity in the PFC. (R,S)-Ketamine was considered to be an alternative treatment for TRD due to its ability to simultaneously reduce neural activity in the limbic and subcortical regions while increasing activity in the PFC.
However, adverse events such as transient blood pressure increase, sedation, dissociation, cognitive impairment and driving performance associated with the use of (R,S)-ketamine limited its use as an anti-depressant.
Esketamine (S- ketamine) is a nonselective, non-competitive antagonist of the N-methyl-D- aspartate (NMDA) receptor, which is claimed to be responsible for its analgesic-anaesthetic effects and/or antidepressant effect. The affinity for the NMDA receptor is approximately 3- to 4-fold greater for esketamine than for arketamine (R-ketamine, the R-enantiomer of ketamine) and might be associated with fewer side-effects. Esketamine is therefore considered to be a more potent and safer antidepressant.
Ketamine can be administered in intravenous (IV), intranasal (IN), and oral forms, among others Although IV ketamine has demonstrated rapid antidepressant effects, its disadvantages has led to the investigation of intranasal or oral dosage forms of ketamine treatment. Intranasal administration of ketamine has been shown to be safe, effective, and equally potent as IV ketamine.
U.S Patent 8785500 relates to a method of treating depression, comprising intranasally administering ketamine at a dosage sufficient to alleviate symptoms of said depression in patient who has not responded to at least two adequate antidepressant treatments. US Patent Application 20200253894 relates to a method for treating of extreme Major Depressive Disorder (MDD) which comprises intranasally administering to the patient an effective amount of ketamine and, further administering a second composition containing a conventional pharmaceutical antidepressant agent. US Patent Application 20200246279 relates to a method of treating depression in a suicidal human patient, comprising: intranasal administering of ketamine in an induction dosage to the patient in an amount in the range of from about 56 mg to about 84 mg in an induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase, US Patent Application 20190117591 relates to a pharmaceutical composition comprising (i) S-ketamine hydrochloride and water; wherein the S-ketamine is present in a concentration range of eq. 125 mg/mL to eq. 250 mg/mL, based on the total volume of the pharmaceutical composition. US Patent Application 20160338977 relates to a method of treating depression, said method comprising: (a) administering an effective amount of esketarnine at a given frequency and during an induction phase of defined duration; and (b) administering an effective amount of esketarnine to said patient less frequently during a subsequent maintenance phase of defined duration, wherein the pharmaceutical composition is customized tor intranasal administration to humans.
Esketarnine (Spravato). the S-enantiomer of racemic ketamine, was approved on 5 th March, 2019. SPRAVATO® is indicated, in conjunction with an oral antidepressant, for the treatment of Treatment-Resistant Depression (TRD) in adults and depressive symptoms in adults with Major Depressive Disorder (MDD) with acute suicidal ideation or behaviour. SPRAVATO® is in the form of a ‘spray’ administered intra-nasally (intended for nasal administration). Each
nasal spray device of SPRAVATO® delivers two sprays containing a total of 28 mg of esketamine (supplied as 32.3 mg of esketamine hydrochloride).
Further, in SPRAVATO® esketamine hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each device delivers two sprays (one spray for each nostril) with a total of 32.3 mg of esketamine hydrochloride (equivalent to 28 mg of esketamine) in 0.2 mL of a clear, colorless aqueous solution with a pH of 4.5. Each spray delivers 14 mg/0. 1ml of esketamine.
SPRAVATO® is available in two presentations:
56 mg Dose Kit: Unit-dose carton containing two 28 mg nasal spray devices (56 mg total dose) 84 mg Dose Kit: Unit-dose carton containing three 28 mg nasal spray devices (84 mg total dose)
Patient thus needs to use two devices for 56 mg and three devices for 84 mg with 5-minute rest between the use of each device.
With SPRAVATO®, however there is a possibility of inaccuracy in dosing between the two doses or two sprays of a bi-dose nasal spray device. There also exists a likelihood of potential oversight by the end user in administering the second dose. Additionally, ambiguity in dose delivery due to malfunctioning of the dose counter/ dose indicator is also likely.
Further, for most nasal spray devices the dispensed volume per actuation is set between 50 and 140 pl, and an administered volume of 100 pl per nostril is optimum in adults. Higher volumes of administration are prone to drip out immediately and there are chances of drug loss through anterior leakage, resulting inadequate absorption. The anticipated dose therefore should fit into a volume of roughly 100-200 pl when both nostrils are sprayed. In conclusion for nasal administration of the drug, higher amount of the drug should be loaded or delivered in minimal dosing volume of 100 pl to avoid drug loss.
With the bi-dose nasal spray device of SPRAVATO® as mentioned hereinabove, for the administration of maximum amount of 84 mg of esketamine, 6 nasal sprays (3 in each nostril) are required with “resting period” in between. Further lesser drug loading makes the existing ‘bi-dose’ nasal spray system require repeated administration to deliver necessary amount of the
drug which may result into reduced patient compliance and loss of drug due to a probable anterior leakage and thereby an inadequate intranasal drug absorption,
The present invention addresses these shortcomings and provides intranasal pharmaceutical formulations of esketamine that are delivered through unit-dose nasal spray devices. The present invention provides for esketamine formulation that has higher amount of esketamine in minimal dosing volume and requires reduced consecutive administration of nasal sprays than otherwise required with the product available in the market to deliver the same amount of drag.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition of esketamine free base or pharmaceutically acceptable salts thereof for nasal administration. In an embodiment the present invention relates to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration range from about 250 mg/ml to 400 mg/ml, based on the total volume of the pharmaceutical composition. In another embodiment, the present invention is directed to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration of more than 250 mg/ml based on the total volume of the pharmaceutical composition.
The present invention is further directed to esketamine formulation delivered through a unitdose nasal spray. In another embodiment, the present invention relates to a pharmaceutical composition of esketamine which is delivered through a single nasal spray. In a further embodiment, the present invention is directed to a pharmaceutical composition delivered as a ‘single nasal spray of 0.1 mT. The present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0.1 ml” wherein the single nasal spray of 0. 1 ml is intended to deliver about 28 mg of esketamine free base. In a further embodiment, the present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0. 1 ml” wherein the single nasal spray of 0. 1 ml is intended to deliver about 14 mg of esketamine free base. In another embodiment, the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 14 mg of esketamine free base. In one embodiment, the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 28 mg of esketamine base.
The present invention further relates to a kit for delivery of esketamine comprising more than one unit-dose nasal spray devices. In one embodiment, the present invention relates to a kit for delivery of esketamine comprising two unit-dose nasal spray devices wherein each unit-dose nasal spray device delivers a single nasal spray of about 28 mg of esketamine free base. In a further embodiment, the present invention relates to a kit for delivery of esketamine comprising four unit-dose nasal spray devices wherein two unit-dose nasal spray devices deliver about 28 mg of esketamine free base each and the other two unit-dose nasal spray devices deliver about 14 mg of esketamine free base each. In an embodiment, the present invention also provides a kit comprising more than one single spray devices to be used in consecutive manner. The present invention provides methods and compositions for the treatment of depression.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a pharmaceutical composition of esketamine for nasal administration. In an embodiment, the present invention relates to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration range of about 250 mg/ml to 400 mg/ml, based on the total volume of the pharmaceutical composition. In another embodiment, the present invention is directed to a pharmaceutical composition of esketamine wherein esketamine free base is present in a concentration of more than 250 mg/ml based on the total volume of the pharmaceutical composition.
The term “pharmaceutical composition” as used herein relates to any pharmaceutical preparation or formulation that is tailored for being administered to a human being or animal. Preferably, the composition contains one or more physiologically acceptable carriers and/or excipients.
In one embodiment, esketamine is employed in the composition of the present invention in the form of its pharmaceutically acceptable salt. In another embodiment, esketamine employed in the preparation of the compositions of the present invention is esketamine hydrochloride.
The present invention is further directed to esketamine formulation delivered through a unitdose nasal spray. In another embodiment, the present invention relates to a pharmaceutical composition of esketamine which is delivered through a single nasal spray. In a further embodiment, the present invention is directed to a pharmaceutical composition delivered as a ‘single nasal spray of 0.1 mT. The present invention relates to a pharmaceutical composition
delivered as a “single nasal spray of 0.1 ml” wherein the single nasal spray of 0. 1 ml is intended to deliver about 28 mg of esketamine free base. In a further embodiment, the present invention relates to a pharmaceutical composition delivered as a “single nasal spray of 0. 1 ml” wherein the single nasal spray of 0. 1 ml is intended to deliver about 14 mg of esketamine free base. In another embodiment, the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 14 mg of esketamine free base. In one embodiment, the present invention relates to a unit-dose nasal spray device for delivery of unit dose of S-ketamine hydrochloride equivalent to about 28 mg of esketamine base.
Tire present invention further provides an aqueous composition of esketamine hydrochloride which can be administered to the nasal mucosa.
The esketamine nasal formulations of the present invention further comprises at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable excipients such as, but not limited to, buffering agents, antioxidants, pH adjusting agents, chelating agents and the like may be included in the pharmaceutical compositions of the present invention. Suitable buffering agent that may be employed includes citric acid, citric acid monohydrate and the like. Suitable pH modifier that may be employed includes, but is not limited to, sodium hydroxide and the like. Suitable chelating agent that may be employed includes, but is not limited to, disodium edetate and the like. The compositions of the present invention further comprise at least one pharmaceutically acceptable carrier. In one embodiment the pharmaceutically acceptable earner for the pharmaceutical compositions of the present invention comprises water. In a further embodiment, the pharmaceutically acceptable carrier is substantially entirely water. In another embodiment, the composition is substantially free of any organic earner, such as an organic solvent. Tn yet another embodiment the composi tion of the present invention is a solution.
In a further embodiment, the compositions of the present invention have a pH in the range of 3 to 6. In another embodiment, the compositions of the present invention have a pH in the range of 4 to 5.
In one embodiment, the composition of the present invention is in the form of a nasal spray. For the purpose of nasal administration of the pharmaceutical composition of esketamine, the present invention further provides a nasal spray device comprising (i) a housing containing the
pharmaceutical composition of esketamine and (li) means enabling the application of the composition from within the housing to the nasal mucosa. In a further embodiment, the housing containing the pharmaceutical formulation is, but not limited to, a vial and the like. In another embodiment, the filled and stoppered vial is assembled into a manually actuated nasal spray device comprising the vial holder and the actuator. In one embodiment of the present invention, each nasal spray device upon manual actuation delivers a single spray. In another embodiment, each nasal spray device delivers a single spray of esketamine formulation. In yet another embodiment, each nasal spray device delivers a single spray equivalent to about 5 mg to about 50 mg of esketamine base. In another embodiment, each nasal spray device delivers a single spray equivalent to about 28 mg of esketamine base. In a further embodiment, each nasal spray device delivers a single spray equivalent to about 14 nig of esketamine base.
In a further embodiment of the present invention, each nasal spray device is for use per nostril. In another embodiment, the nasal spray device must be discarded after each use. In one embodiment, each nasal spray device is packaged in a blister pack. In a still another embodiment of the present invention, the nasal spray device does not require priming.
In one embodiment, the aqueous esketamine formulations of the present invention can be prepared by mixing S-ketamine hydrochloride and disodium edetate in water and then adding sodium hydroxide to adjust the pH. In a further embodiment the formulations of the present invention are prepared aspectically.
In another embodiment, the present invention is directed to a pharmaceutical composition of S-ketamine hydrochloride which comprise higher concentrations of S-ketamine so that desired dose of the S-ketamine can be administered intranasally with minimal dosing volume.
The present invention further relates to a kit for delivery of esketamine comprising more than one unit-dose nasal spray devices. In one embodiment, the present invention relates to a kit for delivery of esketamine comprising two unit-dose nasal spray devices wherein each unit-dose nasal spray device delivers a single nasal spray of 28 mg of esketamine free base. In a further embodiment, the present invention relates to a kit for delivery of esketamine comprising four unit-dose nasal spray devices wherein two unit-dose nasal spray devices deliver 28 mg of esketamine free base each and the other two unit-dose nasal spray devices deliver 14 mg of
esketamine free base each. In an embodiment, the present invention also provides a kit comprising more than one single spray devices to be used in consecutive manner.
The present invention is further directed to methods for the treatment of depression, such as, but not limited to, resistant depression or treatment refractory depression, comprising administering to a subject in need thereof, therapeutically effective amount of esketamine composition of the present invention by nasal route.
The present invention further relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device after a 5-minute rest between the use of each device.
Tire present invention also relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device.
In another embodiment, the present invention relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in one nostril followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril after a 5-minute rest between the use of each device.
The present invention also relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 56 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of
esketamine free base through a unit dose nasal spray device in one nostril followed by subsequent administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril.
The present invention further relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device, followed by subsequent administration of third and fourth doses of esketamine hydrochloride equivalent to 14 mg of esketamine free base through separate unit dose nasal spray devices with a 5-minute rest between the use of each device.
The present invention also relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device followed by subsequent administration of third and fourth doses of esketamine hydrochloride equivalent to 14 mg of esketamine free base through separate unit dose nasal spray devices.
Tn another embodiment, the present invention relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in one nostril followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril, followed by administration of third dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the first nostril, followed by subsequent administration of fourth dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the other nostril, with each of the administrations being made after a 5-minute rest between the use of each device.
In another embodiment, the present invention relates to a dosing regimen for nasal administration of esketamine hydrochloride equivalent to 84 mg of esketamine free base comprising administering to the patient in need thereof, first dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray de vice in one nostril followed by administration of second dose of esketamine hydrochloride equivalent to 28 mg of esketamine free base through a unit dose nasal spray device in the other nostril, followed by administration of third dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the first nostril, followed by subsequent administration of fourth dose of esketamine hydrochloride equivalent to 14 mg of esketamine free base through a unit dose nasal spray device in the other nostril, with each of the administrations being made after a 5-minute rest between the use of each device.
In a further embodiment of the present invention, the unit dose nasal spray devices of the present invention deliver either about 28 mg or about 14 mg of esketamine free base and to prevent loss of medication, in one embodiment the devices are not required to be primmed.
The present invention is further directed to a method of treatment of depression (preferably, treatment resistant depression), comprising administering to the patient in need thereof an esketamine formulation of the present invention intranasally using unit dose nasal spray devices.
In another embodiment, the present invention relates to a method of treatment of depression (preferably, treatment resistant depression), comprising: administering to the patient in need thereof an esketamine formulation of the present invention intranasally with the treatment comprising (i) an induction dosing phase; wherein the induction phase comprises a treatment period of for 4 weeks wherein esketamine is administered in the range of from about 56 mg to about 84 mg; and wherein the esketamine is administered at a dosing frequency of once to twice per week);and (b) a maintenance phase; wherein the maintenance phase comprises a treatment period of at least 6 weeks wherein the esketamine is administered at a dosage in an amount in the range of from about 56 mg to about 84 mg; -wherein the esketamine is administered at a dosing frequency in the range of once per week to once every two weeks; and wherein the maintenance phase preferably continues until further treatment is not required.
While the invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all embodiments falling within the scope thereof. Details of the present invention, including its objects and advantages, are provided in the non-limiting exemplary illustrations below.
EXAMPLE 1
Nasal Spray Composition of S-ketamine hydrochloride equivalent to 280 mg base per ml
Procedure:
• Weighed quantity of Citric acid monohydrate USP and Disodium edetate NF were solubilised under stirring in Water for Injection.
• Calculated and weighed quantity Esketamine hydrochloride, USP was added to the above solution and solubilised under stirring of 150 RPM for the period of 15 minutes
• The above solution pH was adjusted to 4.5 using 1 N NaOH solution.
• The volume was made up with Water for Injection.
• The nasal spray solution is filled into vials and delivered through a unit dose nasal spray device.
EXAMPLE 2
Nasal Spray Composition of S-ketamine hydrochloride equivalent to 140 mg base per ml
Procedure:
• Weighed quantity of Citric acid monohydrate USP and Disodium edetate NF were solubilised under stirring in Water for Injection.
• Calculated and weighed quantity Esketamine hydrochloride, USP was added to the above solution and solubilised under stirring of 150 RPM for the period of 15 minutes
• The above solution pH was adjusted to 4.5 using 1 N NaOH solution.
• The volume was made up with Water for Injection.
• The nasal spray solution is filled into vials and delivered through a unit dose nasal spray device.
Claims
1. A pharmaceutical composition for intranasal administration comprising ketamine or its pharmaceutically acceptable salts, esters, solvates, polymorphs and enantiomers; wherein the ketamine is present in a concentration of above 250 mg/mL based on the total volume of the pharmaceutical composition.
2. The pharmaceutical composition according to claim 1, wherein the composition further comprises at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable excipient comprises buffering agents, antioxidants, pH adjusting agents, or chelating agents.
4. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable carrier is water.
5. The pharmaceutical composition according to claim 1, wherein the composition has a pH in the range from about 3 to about 6.
6. The pharmaceutical composition according to claim 1, wherein the composition comprises esketamine hydrochloride.
7. The pharmaceutical composition according to claim 6, wherein the composition comprises esketamine hydrochloride as esketamine base in a concentration of about 28 mg/0.1 ml.
8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is delivered as unit-dose nasal spray.
9. A kit for intranasal delivery of esketamine comprising more than one unit-dose nasal spray devices.
10. The kit according to claim 9, wherein the kit comprises two unit-dose nasal spray devices, each device delivering a single nasal spray of about 28 mg of esketamine free base.
11. The kit according to claim 9, wherein the kit comprises four unit-dose nasal spray devices, wherein two unit-dose nasal spray devices deliver about 28 mg of esketamine free base each and the other two unit-dose nasal spray devices deliver 14 mg of esketamine free base each.
12. A unit-dose nasal spray device comprising esketamine hydrochloride in a concentration of above about 250 mg/mL based on the total volume of the pharmaceutical composition.
13. A unit-dose nasal spray device comprising esketamine base in a concentration of about 28 mg/ 0. ImL.
14. A unit-dose nasal spray device comprising esketamine base in a concentration of about 14 mg/ 0. ImL.
15. A pharmaceutical composition comprising esketamine base in a concentration of about 14 mg/ O. lmL wherein the composition is delivered through a unit-dose nasal spray device as a single spray.
16. A pharmaceutical composition comprising esketamine base in a concentration of about 28 mg/ O. lmL wherein the composition is delivered through a unit-dose nasal spray device as a single spray.
17. A process for manufacturing the pharmaceutical composition of claim 1, comprising mixing esketamine hydrochloride and disodium edetate in water and then adding sodium hydroxide to adjust the pH under aspectic conditions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| WO2020240279A1 (en) * | 2019-05-31 | 2020-12-03 | Lionheart Pharmaceuticals Aps | Intranasal administration of ketamine to cluster headache patients |
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