New formulations containing ketamine

Abstract

The present invention discloses oral abuse-resistant (tamper-resistant) dosage forms containing ketamine. Each dosage form is provided for oral use with a measured dose of ketamine. These dosage forms are easier to track and trace and include abuse-deterrent / tamper-resistant technology. In addition to being abuse-deterrent, the dosage forms exhibit immediate or rapid release of API (ketamine and / or its pharmaceutically acceptable salts, enantiomers, derivatives, or metabolites). [Selected Figure] Figure 1

Description

[Technical field]

[0001] The present disclosure provides novel formulations comprising ketamine. In particular, the present disclosure relates to abuse-resistant formulations comprising ketamine hydrochloride. The formulations may be for oral use in the treatment, prevention, management and / or control of a variety of clinical indications, including pain, mental / mental health / mood disorders, and suicidal thoughts and behaviors. [Background technology]

[0002] Ketamine is on the World Health Organization's list of essential medicines for human health. It is best known medically as an anesthetic for human and animal health and is "approved" or "licensed" by regulatory agencies for this purpose. It is also used worldwide for pain relief, but is not licensed for this use. Despite being discovered in the 1960s, ketamine's full potential to treat a variety of human diseases and disorders has only recently been realized. Awareness of ketamine's usefulness for certain patients is limited to a few experts in the field, leaving many patients in great pain, unable to work, or unable to fully participate in life and society. The one approved form is an injectable form, which means costly hospitalization or facilities and inconvenience to the patient. There is an unmet medical and commercial need for oral ketamine delivery. Currently, ketamine is approved and classified as an injectable anesthetic, a nasal spray, and is administered intramuscularly (IM) or intravenously (IV). There are two approved forms for medical use in humans: racemic (R,S)-ketamine hydrochloride and S-ketamine hydrochloride. Ketamine is used "off-label" in injectable form to treat a variety of pain conditions, mood disorders, psychiatric and mental health issues, and suicidal thoughts and behaviors. Ketamine is not approved for any of these conditions. In the United States in particular, the number of "ketamine-treatment-centres" has increased dramatically due to the many studies and patient experiences with the IV formulation. Many treatment centers use racemic ketamine hydrochloride.

[0003] Orally administered ketamine may have benefits for patients. However, it is not yet clear whether ketamine administered in this way has proven commercially effective in any of the above clinical areas. In the absence of a commercially available oral dosage form, nearly all clinical studies have been conducted academically using the commercially available IV dosage form. Ketamine is absorbed by intravenous, intramuscular, oral, and topical routes due to its water and lipid solubility. When administered orally, ketamine undergoes first-pass metabolism and is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes (by N-demethylation) to norketamine and finally to dehydronorketamine. The intermediate metabolism in the biotransformation of norketamine to dehydronorketamine is the hydroxylation of norketamine to hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, are the most common metabolites detected in urine. As the major metabolite of ketamine, norketamine is one-third to one-fifth the potency of the anesthetic agent, and plasma concentrations of this metabolite are three times higher than ketamine after oral administration. Bioavailability via the oral route reaches 17-20%; bioavailability via other routes is 93% intramuscularly, 8-50% intranasally, 30% sublingually, and 30% rectally. Peak plasma concentrations are reached within 1 minute intravenously, 5-15 minutes intramuscularly, and 30 minutes orally. The duration of action of ketamine in the clinical setting ranges from 30 minutes to 2 hours intramuscularly and 4-6 hours orally.

[0004] S-ketamine is known to be more potent than the racemic mixture in humans and to exhibit many psychoactive side effects. Some data from small animals are available for R-ketamine, but it is unclear whether it is effective in humans and has fewer side effects. Many studies suggest that S or esketamine have more medically useful pharmacological actions than R-ketamine or racemic ketamine. However, in mice, the rapid antidepressant effect of R or arketamine was found to be greater and longer lasting than esketamine. Thus, as an antidepressant, the opposite has been stated ("R-ketamine appears to be a potent and safe antidepressant compared to S-ketamine"; it has also been stated that "R-ketamine is a long-lasting antidepressant compared to lapastinel"). Ketamine metabolites appear to be important. When ingested orally, ketamine reaches the stomach and is then first-pass metabolized and converted to norketamine, largely. Norketamine is hypothesized to provide analgesia and have similar clinical benefits to ketamine with reduced side effects. At this time, it is unclear whether norketamine is an effective clinical treatment. Other metabolites, particularly those derived from R-ketamine, namely 6-hydroxynorketamine or R-hydroxynorketamine (HNK), are hypothesized to be important, and specifically (2S,6S;2R,6R)-HNK is responsible for ketamine's antidepressant-like effects in mice. Specifically, administration of (2R,6R)-HNK exhibited ketamine-type antidepressant-like effects, and prevention of metabolic conversion of ketamine to HNK blocked the antidepressant-like effects of the parent compound, but there is currently no evidence to support the benefits of (2R,6R)-HNK in humans.

[0005] Ketamine enantiomers: Ketamine exists in different optical isomers and salt forms. Some of these forms and metabolites have been shown to have positive clinical benefits, with increased or decreased side effects. Many of the isomers, enantiomers and salt forms lack evidence of usefulness in humans, with the exception of the S-enantiomer and the racemic R,S hydrochloride salt, which are available as licensed injectable products. The optical rotation of a given enantiomer of ketamine can vary between its salt and free base forms. The free base form of (S) ketamine exhibits dextrorotatory power and is therefore classified as (S)(+) ketamine. However, its hydrochloride salt exhibits levorotatory power and is therefore classified as (S)(-) ketamine hydrochloride. The difference comes from the conformation of the cyclohexanone ring. In both the free base and the hydrochloride salt, the cyclohexanone ring adopts a chair conformation, but the orientation of the substituents varies. In the free base, the o-chlorophenyl group adopts an equatorial position and the methylamino group adopts an axial position. In the hydrochloride salt, the configuration is reversed, with the o-chlorophenyl group being axial and the methylamino group being equatorial. Not all salts of ketamine exhibit different optical rotations from the free base: (S)-ketamine (R,R)-tartrate is levorotatory like (S) ketamine.

[0006] Ketamine Mechanism: The complete mechanisms, pathways, and combination of pathway actions required for ketamine to be effective in different clinical areas are currently unknown. Ketamine is primarily known as an NMDA antagonist, and more recently as an AMPAR. However, ketamine also has effects at opioid, sigma, dopamine, serotonin, muscarinic, nicotinic, and estrogen receptors, inhibits cholinesterase, serotonin, norepinephrine, and dopamine reuptake inhibitors, PCP site 2 ligands, blocks sodium calcium channels, HCN1 cation channels, and inhibits nitric oxide synthase. With a few exceptions (including interactions with D2high receptors, nicotinic acetylcholine receptors (via metabolites), ERα, and HCN1 channels), these effects are much weaker than ketamine's antagonism of NMDA receptors, and it has been hypothesized that allosteric binding at other sites compensates for ketamine's activity at these sites. Ketamine metabolites, including dehydronorketamine, hydroxynorketamine, and norketamine, have been found to act as negative allosteric modulators of the α7 nicotinic acetylcholine receptor at subanesthetic and nanomolar potencies (e.g., IC50=55 nM for dehydronorketamine) in the KXa7R1 cell line (HEK293 cells transfected with the rat nicotinic acetylcholine receptor gene), whereas ketamine itself was inactive at the same concentrations (<1 μM). These findings suggest that metabolites can significantly contribute to ketamine pharmacodynamics by means other than NMDA receptor antagonism.

[0007] It is not yet entirely clear how ketamine produces its potent and rapid-onset antidepressant effects. In any case, it has been shown that acute blockade of NMDA receptors in the brain activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptors), which in turn modulate various downstream signaling pathways to affect neurotransmission in the limbic system, resulting in the antidepressant effects of NMDA receptor antagonists such as ketamine. Such downstream effects of AMPA receptor activation include upregulation of brain-derived neurotrophic factor (BDNF) and activation of its signaling receptor tropomyosin receptor kinase B (TrkB), activation of the mammalian target of rapamycin (mTOR) pathway, inactivation of glycogen synthase kinase 3 (GSK-3), and inhibition of phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase. In addition to blockade of NMDA receptors, an active metabolite of ketamine known as hydroxynorketamine may also or instead be involved in ketamine's rapid-onset antidepressant effects. Hydroxynorketamine does not interact significantly with NMDA receptors, but nevertheless indirectly activates AMPA receptors as well. Recent studies have demonstrated that acute inhibition or in a sense "resetting" of the lateral habenula, a part of the limbic brain called the "anti-reward system" (which projects to and inhibits the mesolimbic reward pathway and regulates other limbic regions), may be responsible for ketamine's antidepressant effects. Summary of the Invention

[0008] The present disclosure provides oral ketamine formulations that are encapsulated, exhibit high tamper / abuse resistance, exhibit acceptable (or suitable) dissolution profiles, and are stable during storage. Disclosed herein are oral abuse-resistant (tamper-proof) formulations containing ketamine. Each formulation is provided for oral use and has a measured dose of ketamine (aka "active pharmaceutical ingredient (API)"). These formulations are easier to track and trace and include abuse-resistant / tamper-proof technology. In addition to being abuse-resistant, the formulations exhibit suitable API release profiles. For example, the formulations can exhibit controlled and / or immediate or rapid release of the active ingredient (ketamine). The present disclosure provides novel formulations comprising ketamine and / or its pharma- ceutically acceptable salts, enantiomers, derivatives, or metabolites.

[0009] The disclosed formulations exhibit abuse deterrence, active ingredient (ketamine) stability and advantageous dissolution profiles. The disclosed formulations may be for oral administration. The disclosed formulation cannot be prepared into tablets. The disclosed formulations can be provided as a capsule. For example, the disclosed formulations can be encapsulated in a hard capsule. The disclosed formulations can be resistant to misuse and abuse. The disclosed compositions can exhibit a predetermined API release profile. For example, the formulations can exhibit controlled release characteristics. For example, the API can be released (from the formulations) slowly or immediately. It should be noted that throughout this specification, the term "comprising" is used to indicate that embodiments of the invention "comprise" prominent features, i.e. may include other features as well. However, in the context of the present invention, the term "comprising" may also encompass embodiments in which the invention "consists essentially of" or "consists of" the relevant features.

[0010] In a first aspect, the present disclosure provides novel formulations that may include ketamine. The disclosed formulations may include a ketamine suspension. Ketamine is a water-soluble phencyclidine derivative with an asymmetric carbon atom; it has two enantiomers. Ketamine is metabolized in the liver by N-demethylation and ring hydroxylation pathways, and the main metabolites are norketamine and its hydroxylated derivatives. The formulation may include a pharma- ceutically acceptable salt of ketamine. The formulations may include any form of ketamine, which is an NMDA antagonist and / or a modulator of AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors). The formulations may include ketamine enantiomers, derivatives and / or metabolites. The formulations described herein (for oral administration) may be metabolized in the body to one or more ketamine metabolites. The formulation may include ketamine hydrochloride, a non-competitive NMDA receptor antagonist. The formulation may include racemic (R,S) ketamine hydrochloride. By way of example, the formulations described herein may contain one or both of the R- / S-ketamine stereoisomers. For example, the formulations may contain either R-ketamine or S-ketamine. The term "ketamine metabolites" may include the following compounds: 2R,6R-hydroxynorketamine hydrochloride (increases AMPA currents; decreases D-serine (NMDA coagonist); does not have ketamine-related side effects) 2S,6S-hydroxynorketamine hydrochloride (reduced D-serine (NMDA coagonist); antidepressant) cis-6-hydroxynorketamine hydrochloride (increases AMPA currents; is an antidepressant) (S)-(+)-Ketamine hydrochloride (NMDA receptor antagonist; enantiomer of ketamine hydrochloride with neuroprotective effects) Norketamine hydrochloride (potent noncompetitive NMDA antagonist; antinociceptive) (R)-Norketamine hydrochloride (NMDA receptor modulator and analgesic) (S)-Norketamine hydrochloride (NMDA receptor modulator and analgesic). As used hereinafter, the terms "ketamine" or "active ingredient" are intended to refer to and encompass all of the above-mentioned ketamine forms, salts, derivatives, enantiomers and / or metabolites.

[0011] The formulation may contain any suitable amount of ketamine. For example, the formulation may contain 1% to 70% (v / v%) of ketamine hydrochloride based on the total volume of the formulation provided by the present invention. For example, the formulation may contain 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or 65% (v / v%) of ketamine hydrochloride. For example, a formulation of the present disclosure may contain about (e.g., + / - 1, 2, 3, 4 or 5% (v / v%)) 8% (v / v%) ketamine hydrochloride.

[0012] The formulation further comprises one or more excipients, diluents and / or carriers. Excipients, diluents and / or carriers can be selected based on their functionality. For example, the formulations described herein may include the following excipients: (i) a diluent; (ii) Carrier. (iii) Solvent (iv) Plasticizers (v) Surfactants (vi) Lubricants (vii) Dispersants (viii) Viscosity modifier (ix) Bioavailability modifiers (x) Emulsifier (xi) Transdermal absorption enhancers (xii) Release modifier (xiii) Gelling agent (xiv) Stabilizer (xv) Antioxidants (xvi) pH adjusters / acidity regulators; and (xvii) Thermal stability / cure modifiers. The exact amount (e.g., volume (v / v %)) of each excipient, diluent and / or carrier may vary depending on the desired properties of the formulation. For example, the inventors have found that the release rate of the active agent can be adjusted (e.g., increased or decreased) by adjusting the relative amounts of any carrier compound and any viscosity modifier present in the formulation. In some embodiments, the amount of carrier agent used in the formulation may be less than the amount of viscosity modifier used in the formulation. In other embodiments, the amount of carrier agent used in the formulation may be greater than the amount of viscosity modifier used in the formulation. One of skill in the art will understand that a useful formulation must contain an active pharmaceutical ingredient (API, in this case ketamine as described herein) in an amount sufficient to achieve the desired dosage, while at the same time maintaining a level of any viscosity modifier to ensure abuse resistance, and a sufficient concentration of carrier excipients to ensure that the formulation can be successfully processed. The formulations described herein meet these criteria.

[0013] In one embodiment, a formulation of the present disclosure may include an amount of ketamine along with one or more excipients, which may include, for example, various carrier compounds / compositions, viscosity modifiers, and optionally antioxidants. Suitable carriers may include, for example, copolymers (including those selected from the group consisting of triglycerides, poloxamers, polysorbates, polyethoxylates, polyethylene glycols, and polyglycerides).Suitable carriers may include, for example, poloxamer 124, polysorbate 80, polysorbate 20, Corifol EL, Corifol RH40, polyethylene glycols 1000, 1500, 2000, 6000, and 8000, Corifol HS15, Gelucia 44 / 14, Gelucia 48 / 16, Gelucia 50 / 13.Suitable carriers for use in the formulations of the present invention may include, for example, polyethylene glycols (PEG).For example, useful carriers may include low molecular weight PEGs, such as PEG1500 or PEG6000. When the formulation includes PEG 1500, the formulation may include about 1% to 50% (v / v%) PEG 1500. For example, useful formulations may include about 7%, 8%, 9%, 10%, 15%, 20%, 25%, 26%, 27%, 30%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48% or 49% (all "%" values ​​are v / v%) PEG 1500. For example, formulations used may include 9.19% (v / v%), 27.57% (v / v%) or 45.95% (v / v%) PEG 1500. The formulation may contain PEG 6000; for example, the formulation may contain about 1% to 20% (v / v%) PEG 6000. For example, useful formulations may contain about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 17% or 19% (all "%" values ​​are v / v%) PEG 6000. For example, the formulations used may contain 4.6% (v / v%) or 9.19% (v / v%) PEG 6000. Formulation testing has revealed that an amount of PEG in the formulation prevents tampering and / or abuse of the formulation. One of skill in the art will appreciate that the actual amount of PEG 1500 and / or 6000 used will depend on (i) the desired properties of the formulation (e.g., the desired viscosity, stability, dissolution and / or abuse deterrent level (of the active ingredient: ketamine)), and (ii) the amount (v / v %) of the active ingredient and / or any other excipients / carriers and / or diluents used.

[0014] Other (or additional) carriers used may include Gelucia 44 / 14, Polysorbate 80 and / or Gelucia 48 / 16. Gelucia 44 / 14 may be used in an amount equal to about 5% to 70% (v / v%). For example, useful formulations may contain about 6%, 7%, 8%, 9%, 10%, 15%, 19%, 20%, 21%, 30%, 35%, 40%, 45%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 65% or 70% (all "%" values ​​are v / v%) of Gelucia 44 / 14. For example, the formulations used may contain 20.68% (v / v%), 50.55% (v / v%), 55.14% (v / v%) or 59.74% (v / v%) of Gelucia 44 / 14. One of skill in the art will appreciate that the actual amount of Gelucia 44 / 14 used will depend on (i) the desired properties of the formulation (viscosity, stability, dissolution of the active ingredient (ketamine), and / or level of abuse deterrence), and (ii) the amount (v / v %) of the active ingredient and / or any other excipients / carriers and / or diluents used. Polysorbate 80 may be used in an amount equal to about 1% to 30% (v / v%). For example, useful formulations may contain about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 17%, 20%, 22%, 25%, 27% or 29% (all "%" values ​​are v / v%) of polysorbate 80. For example, formulations used may contain 4.6% (v / v%), 11.49% (v / v%) or 13.79% (v / v%) of polysorbate 80. One of skill in the art will appreciate that the actual amount of polysorbate 80 used will depend on (i) the desired properties of the formulation (viscosity, stability, dissolution and / or level of abuse deterrence of the active ingredient (ketamine)), and (ii) the amount (v / v %) of the active ingredient and / or any other excipients / carriers and / or diluents used. Gelucia 48 / 16 may be used in an amount equal to about 10% to 70% (v / v%). For example, useful formulations may contain about 11%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 49%, 50%, 51%, 52%, 55%, 60%, 65% or 69% (all "%" values ​​are v / v%) of Gelucia 48 / 16. For example, the formulation used may contain 50.55% (v / v%) of Gelucia 48 / 16. Those skilled in the art will understand that the actual amount of Gelucia 48 / 16 used will depend on (i) the desired properties of the formulation (viscosity, stability, dissolution and / level of abuse resistance of the active ingredient (ketamine)), and (ii) the amount (v / v%) of the active ingredient and / or any other excipients / carriers and / or diluents used.

[0015] As mentioned above, the formulations of the present disclosure may include a viscosity modifier, such as a gum, such as gellan gum with two acyl substituted acetates and glycerates (average content of one saccharide per repeat and one acetate every third repeat). Useful gums have two acyl substituents and are approximately at least 5×10 5 , 7×10 5 Dalton, 1×10 6 Daltons, or preferably about 1-2×10 6It may be a high acyl gellan gum with a typical weight average molecular weight in Daltons (one skilled in the art will appreciate that the molecular weight of gellan gum may be determined by any suitable method, including that disclosed in U.S. Pat. No. 6,242,035, the contents of which are incorporated herein by reference). Suitable gums may comprise repeating units of a tetrasaccharide polymer consisting of two residues of D-glucose and one residue each of L-rhamnose and D-glucuronic acid. The tetrasaccharide repeat has the following structure: [D-Glc(β1→4)D-GlcA(β1→4)D-Glc(β1→4)L-Rha(α1→3)] n For example, the gum (and thus the formulation according to the invention) may comprise Kelcogel® CGHA™ or Kelcogel® LT100 (manufactured by CP Kelco). Useful gellan gums may have a setting temperature of 30-50°C. Kelcogel CGHA may be used in an amount equal to about 20% to 50% (v / v%) or about 25% to 40% (v / v%). For example, useful formulations may contain about 21%, 25%, 30%, 35%, 40%, 45%, 40%, 45%, 49%, 50%, 51%, 52%, 55%, 60%, 65% or 69% (all "%" values ​​are v / v%) of Kelcogel CGHA. For example, the formulations used may contain 27.57% (v / v%) or 32.17% (v / v%) of Kelcogel CGHA. One of ordinary skill in the art will appreciate that the actual amount of Kelcogel CGHA used will depend on (i) the desired properties of the formulation (viscosity, stability, dissolution of the active ingredient (ketamine), and / or level of abuse deterrence), and (ii) the amount (v / v %) of the active ingredient and / or any other excipients / carriers and / or diluents used.

[0016] When combined with certain excipients, ketamine (i.e., API) is prone to some degradation. Degradation in the presence of selected excipients (e.g., PEG 1500, PEG 6000, Gelucia 44 / 14, Poloxamer 124, Corifol RH 40, Corifol EL, Polysorbate 20, Polysorbate 80, Miglyol 812N) was observed after a storage period (e.g., 4 weeks) at a certain temperature / humidity (40°C / 75% RH). The inventors have observed that in the presence of certain excipients, the API (ketamine) is prone to oxidation. Thus, the formulations disclosed herein may include antioxidants. Suitable antioxidants may include, for example, butylated hydroxytoluene (BHT). Formulations containing butylated hydroxytoluene (BHT) may use, for example, about 0.01% to about 20% (v / v%). For example, useful formulations may contain about 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or 19% (all "%" values ​​are v / v %) of butylated hydroxytoluene (BHT). For example, the formulation used may contain 0.1% (v / v %) of butylated hydroxytoluene (BHT). Those skilled in the art will understand that the actual amount of butylated hydroxytoluene (BHT) used will depend on (i) the desired properties of the formulation (viscosity, stability, dissolution, and / or abuse-proof level of the active ingredient (ketamine)), and (ii) the amount (v / v %) of the active ingredient and / or any other excipients / carriers and / or diluents used. In all cases, an amount that inhibits oxidation of BHT should be used. The formulations described herein may be contained within a capsule shell. For example, the formulations of the present disclosure may be contained within a capsule comprising gelatin or hypromellose (HPMC).

[0017] The formulation according to the present disclosure comprises: (i) PEG1500; (ii) PEG6000; (iii) Guercia 44 / 14; (iv) Polysorbate 80; (v) Guercia 48 / 16; (vi) Kelcogel CGHA; and (vii) Butylated hydroxytoluene (BHT) The composition may comprise ketamine hydrochloride together with one or more excipients, carriers or diluents selected from the group consisting of: A suitable formulation is ketamine hydrochloride, as well as (i) Kelcogel CGHA; (ii) Guercia 44 / 14; and (iii) Butylated hydroxytoluene (BHT) may include: A suitable formulation is ketamine hydrochloride, as well as (i) Kelcogel CGHA; (ii) PEG6000 (iii) Guercia 44 / 14 (iv) Polysorbate 80; and (v) Butylated hydroxytoluene (BHT) may include: A suitable formulation is ketamine hydrochloride, as well as (i) Kelcogel CGHA; (ii) PEG6000 (iii) Guercia 44 / 14; and (iv) Butylated hydroxytoluene (BHT) may include: A suitable formulation is ketamine hydrochloride, as well as (i) Kelcogel CGHA; (ii) PEG1500; (ii) Polysorbate 80; and (iv) Butylated hydroxytoluene (BHT) may include: A suitable formulation is ketamine hydrochloride, as well as (i) Kelcogel CGHA; (ii) PEG1500; (iii) Guercia 48 / 16; and (iv) Butylated hydroxytoluene (BHT) may include: A suitable formulation is ketamine hydrochloride, as well as (i) Kelcogel CGHA; (ii) PEG1500; (iii) Guercia 44 / 14; (iv) Polysorbate 80; and (vi) Butylated hydroxytoluene (BHT) may include: A suitable formulation is ketamine hydrochloride, and (i) Kelcogel CGHA (ii) Guercia 44 / 14 (iii) BHT may include: A suitable formulation is ketamine hydrochloride, and (i) Kelcogel CGHA (ii) Guercia 44 / 14 (iii) Polysorbate 80 (iv) BHT may include: A suitable formulation is ketamine hydrochloride, and (i) Kelcogel CGHA (ii) PEG1500 (iii) Guercia 44 / 14 (iv) BHT may include: A suitable formulation is ketamine hydrochloride, and (i) Kelcogel CGHA (ii) PEG1500 (iii) Guercia 44 / 14 (iv) Polysorbate 80 (v) BHT may include: A suitable formulation is ketamine hydrochloride, and (i) Kelcogel CGHA (ii) PEG1500 (iii) Guercia 44 / 14 (iv) BHT may include: A suitable formulation is ketamine hydrochloride, and (i) Kelcogel CGHA (ii) PEG1500 (iii) Guercia 44 / 14 (iv) Polysorbate 80 (v) BHT may include:

[0018] A series of exemplary (but non-limiting) formulations are detailed in the following tables. Each table details six different ketamine hydrochloride-based formulations. In each case, the formulation is specified in terms of the amount (v / v %) of each component. [Table 1] [Table 2]

[0019] As mentioned above, the formulations disclosed herein are designed to be abuse-deterrent. In other words, the disclosed formulations include (or exhibit) abuse-deterrent properties. The term "abuse" can include any intended non-therapeutic use of a drug product or substance to obtain a desired psychological or physiological effect. For example, a subject who abuses a drug product, such as a prescribed drug product, may attempt to crush or dissolve the drug product and snort, smoke, or inject the crushed or dissolved drug product. For example, in the area of ​​opioid drugs, abuse is common, and opioid-addicted subjects attempt to extract the opioid component from the opioid drug in a form that can be, for example, injected, snorted, or smoked. The formulations described herein contain one or more technologies designed to deter abuse. For example, the formulation may contain a chemical barrier that limits drug release from the formulation and / or makes it difficult (or impossible) to process the formulation into a form that can be injected or snorted. For example, a chemical barrier (such as a viscosity modifier) ​​can limit the release of the active agent (in this case ketamine) even after processing (crushing, sieving, heating, etc.).

[0020] The efficacy or potency of any particular formulation depends on the active drug that dissolves, for example, in the gastrointestinal fluids. The dissolution rate is important because it determines how much of the active drug is released and can be used to treat and / or prevent diseases and / or disorders. The formulations described herein may be immediate release formulations. Various formulations have now been tested for dissolution, and the inventors have found that all formulations achieve the required dissolution level. A suitable dissolution rate requires that a certain percentage of the active drug (in this case, ketamine hydrochloride) is recovered after a certain time. For example, about 1-100% of the active drug can be recovered in the dissolution test. For example, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% of the active drug (ketamine hydrochloride) can be recovered under the dissolution test. Note that in the context of the dissolution test, the term "x%" refers to the percentage of the total amount of active drug put into the formulation. For example, any given formulation may be considered to contain (prior to dissolution testing) an amount equal to 100% active drug. Under dissolution testing conditions, the amount of active drug released is measured and expressed as a percentage of the total amount of active drug originally provided in the formulation. As mentioned above, the dissolution profile of any given formulation can be evaluated over a period of time, e.g., from about 1 minute to about 60 minutes. The dissolution profile can be evaluated over, e.g., about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, or about 55 minutes. An acceptable dissolution profile can be, for example, 80% recovery of active drug (ketamine hydrochloride) after 30-45 minutes.

[0021] Thus, the formulations described herein may be oral administration formulations. The formulations described herein have significantly different PK and pharmacokinetic profiles than other (prior art) ketamine formulations. Formulations containing ketamine formulated for nasal, IV or IM administration tend to be absorbed into the bloodstream and avoid early first-pass metabolism. When administered orally, ketamine has a much lower bioavailability and undergoes first-pass metabolism to many different metabolites. Furthermore, the formulations avoid the metallic taste characteristic of some formulations. Ketamine metabolites are hypothesized to be important in causing ketamine's pain relief, as well as antidepressant and anti-suicide effects.

[0022] The formulations provided by the present disclosure can have a variety of clinical applications. Thus, certain aspects of the present disclosure provide one or more of the formulations described herein for use in medicine or as a medicament. For example, the various formulations may be applied (ie, used) in the treatment or prevention of one or more of the following indications: The formulations described herein may be used in the management, treatment and / or prevention of pain. Additionally, one or more of the disclosed formulations may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with pain. It should be noted that the term "pain" encompasses any pain associated with mental health, neurological disorders, skin disorders, psychiatric disorders, trauma, minor surgery, perioperative pain; inflammatory disorders, cancer, asthma, chronic obstructive airways disease, painful procedures (e.g. in emergency departments), and emergency surgery in trauma situations or field conditions in war zones. The formulations described herein may be used in the management, treatment or prevention of post-surgical pain; opioid use; hyperalgesia; neuropathic pain; ischemic limb pain; peripheral neuropathy; complex regional pain syndrome types I and II; phantom limb pain; post-herpetic neuralgia; chronic ischemic neuropathy due to critical limb ischemia; peripheral ischemic neuropathy; ischemic neuropathy associated with diabetes; complex pain across both inflammatory and neuropathic indications; clinical characteristics across indications including hyperalgesia, allodynia, central sensitization, wind-up pain, dysesthesias, dysesthesias, paroxysmal pain, neuropathic pain and tolerance (to other medications), as well as pain that is inadequately controlled by existing drug treatments. Formulations of the present disclosure may be used for pain relief in patients requiring elevated blood pressure, maintenance of airway reflexes / skeletal muscle tone, or who can benefit from the bronchodilatory properties of ketamine. A further aspect provides a method of treating pain (or suicidal thoughts and / or behaviors associated therewith), comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to any of the above pain indications) ketamine in a formulation described herein.

[0023] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of certain psychiatric disorders. Psychiatric disorders that can be treated with any of the formulations described herein include, for example, bipolar disorder, cyclothymic disorder, severe mood dysregulation disorder, dysthymia, major depressive disorder, premenstrual dysphoric disorder, seasonal affective disorder (SAD), mania, hypomania, treatment-resistant depression, postpartum depression, atypical depression (AD), melancholic depression, major psychotic depression, catatonic depression, bipolar depression, depressive personality disorder, depression not otherwise specified; recurrent brief depression; minor depressive disorder; bipolar disorder-bipolar I, bipolar II, cyclic bipolar disorder; substance-induced mood disorder, intoxication and withdrawal symptoms (e.g., alcohol, benzodiazepines); mood disorders secondary to other medical conditions (e.g., dementia, metabolic disorders, endocrine disorders, thyroid disorders, cardiovascular disease (heart attack), pulmonary disease (chronic obstructive pulmonary disease), cancer and autoimmune diseases. Each of the various formulations described herein may also be used in the treatment and / or prevention (control) of suicidal thoughts and behaviors associated with any of the above-mentioned psychiatric disorders. A further aspect provides a method of treating a psychiatric disorder (including any of the psychiatric disorders described above: (or suicidal thoughts and / or behaviors associated therewith) comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to any of the psychiatric disorders described above) ketamine in a formulation as described herein.

[0024] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of certain mental health disorders.Mental health disorders that can be treated with any of the formulations described herein include, for example, post-traumatic stress disorder, severe and acute anxiety, eating disorders; neurodevelopmental disorders, personality disorders, psychotic disorders, and substance use disorders. Each of the various formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with any of the above mental health disorders. A further aspect provides a method of treating a mental health disorder (including any of the psychiatric disorders (or suicidal thoughts and / or behaviors associated therewith) comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to any of the mental health disorders) ketamine in a formulation as described herein.

[0025] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of certain neurological disorders. Neurological disorders that may be treated with any of the formulations described herein include, for example, various forms of paralysis, paralysis / writing and inflammation associated with Parkinson's disease, side effects of Parkinson's disease medications, multiple sclerosis, Parkinson's plus disease, migraine headaches, Alzheimer's disease, epilepsy, L-dopa-induced dyskinesia and movement disorders. Each of the various formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with any of the above neurological disorders. A further aspect provides a method of treating a neurological disorder (including any of the neurological disorders described above: (or suicidal thoughts and / or behaviors associated therewith) comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to any of the neurological disorders described above) ketamine in a formulation as described herein.

[0026] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of certain skin disorders.Skin disorders that can be treated with any of the formulations described herein include, for example, trauma; trigeminal nerve root injury, diabetic truncal radiculopathy, nerve lesion skin and immune conditions, carpal tunnel syndrome, shingles, neuropeptides, trigeminal neurotrophic syndrome, shingles infection, carpal tunnel syndrome, trigeminal neurotrophic syndrome, sarcoidosis, vasculitis syndrome, mononeuritis or asymmetric sensorimotor neuropathy, polyarteritis nodosa, Churg-Strauss syndrome, Wegener's granulomatosis, and cryoglobulinemia. Each of the various formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with any of the above skin health disorders. A further aspect provides a method of treating a skin disorder (including any of the above skin disorders: (or suicidal thoughts and / or behaviors associated therewith) comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to any of the above skin disorders) ketamine in a formulation as described herein.

[0027] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of erythromelalgia, a rare genetic clinical syndrome characterized by intermittent red, burning and painful extremities that usually manifests in the lower extremities (mainly the feet), but may also affect the upper extremities (mainly the hands) and, rarely, the face at the same time. Each of the various formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with erythromelalgia. A further aspect provides a method of treating erythromelalgia (or suicidal thoughts and / or behaviors associated therewith), comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to erythromelalgia) ketamine in a formulation described herein.

[0028] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of epidermolysis bullosa (EB), a group of rare genetic disorders characterized by blistering and scarring as a result of minor mechanical trauma. The major types of EB include epidermolysis bullosa simplex, hemidesmosomal epidermolysis bullosa, junctional epidermolysis bullosa, and recessive (dystrophic) epidermolysis bullosa (RDEB). Each of the various formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with EB. A further aspect provides a method of treating EB (or suicidal thoughts and / or behaviors associated therewith), comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to EB) ketamine in a formulation described herein.

[0029] One or more of the formulations described herein may be used in the treatment, prevention, control and / or management of brachioradial pruritus, a neurogenic pruritic condition characterized by itching of one or both upper extremities. Each of the various formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors associated with brachioradial pruritus. A further aspect provides a method of treating brachioradial pruritus (or suicidal thoughts and / or behaviors associated therewith), comprising administering to a subject in need thereof (e.g., a subject suffering from or susceptible to brachioradial pruritus) ketamine in a formulation described herein.

[0030] Successful treatment of any of the above conditions (i.e., successful treatment, prevention, control or management of any one of the above-mentioned conditions or disorders) can be determined by changes in the level, activity and / or expression of one or more biomarkers. Biomarkers that can be used to determine the level of treatment, prevention, management and / or control include: Psychological / cognitive biomarkers - pre- and post-treatment levels of anhedonia, apathy, attention disorders, motor disorders, and reward disorders Levels of specific cell types; e.g., natural killer, leukocyte, neutrophil and other immune and inflammatory cell levels Pathway markers including proteins, steroids, pathways - dopamine levels, mu and delta opioid, NMDA, AMPAR, sigma, receptor pathway regulatory changes, immunological markers, and intracellular signaling interleukin, cytokine, tumor necrosis factor and inflammatory pathway marker levels.

[0031] Those skilled in the art will understand that there are assays and tests that can be used to determine pain levels. For example, neuropathic pain can be assessed using verbal rating scales, visual analog scales and graphic rating scales, numeric rating scales, picture scales or face scales, Descriptor Differential Scale of Pain Intensity (DDSI), behavioral measures, LANSS (Leeds Assessment of Neuropathic Symptoms and Signs: Neuropathic Pain Questionnaire (NPQ), Quantitative Sensory Testing (QST), Somatosensory Evoked Potentials (SEP), Standard Assessment of Pain (StEP): Brief Pain Questionnaire, Clinical Global Impression Scale, McGill Pain Questionnaire, Palliative Care Outcome Scale. Depression levels can be assessed using depression rating scales such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Scale, Raskin Depression Rating Scale, Beck Depression Scale, self-report scales, Geriatric Depression Scale (GDS), Tsang Self-Rating Depression Scale, Patient Health Questionnaire (PHQ), Patient Health Questionnaire-9 (PHQ-9), Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Examination Questionnaire, Beck Depression Scale; Clinically Useful Depression Outcome Scale, Depressive Symptoms Scale, Mood and Feelings Questionnaire, and Brief Depressive Symptoms Scale. In terms of suicide, suicidal thoughts and behaviors can be assessed using the Suicidal Thoughts and Behaviors Assessment Tool (SIBAT).

[0032] The formulations provided by the present disclosure may be used alone or in conjunction with (e.g., simultaneously or prior and / or subsequent to) other medications. For example, any of the formulations described herein may be used (concurrently) with opioids to manage otherwise intractable pain; concurrently with psychotherapy to manage mood, mental health and psychiatric disorders; concurrently with addictive substances to support cessation, and / or concurrently with medications for a disease / disorder to manage the pain.

[0033] One or more of the formulations described herein may be used in the treatment of "treatment-resistant depression." Treatment-resistant depression (TRD) may be defined as an episode of depression (or a condition or disease associated therewith) in which one or more therapeutic interventions have failed, particularly when the interventions are used for a sufficient duration and at an appropriate dose. By way of example, TRD may be defined as (i) failure to respond to one or more (pharmacological or non-pharmacological) antidepressant therapies; or (ii) failure to respond to two or more currently available antidepressants at appropriate doses and durations in a current episode of depression. The formulations described herein may be used in the treatment and / or prevention (or control) of suicidal thoughts and behaviors, respectively, associated with TRD. Further aspects provide methods of treating TRD (or suicidal thoughts and / or behaviors associated therewith), comprising administering to a subject in need thereof (e.g., a subject suffering from or having a history of TRD) ketamine in a formulation described herein.

[0034] In a further aspect, the present invention provides a method of making any one of the formulations described herein, the method comprising administering ketamine hydrochloride (in a suitable and / or therapeutically effective amount) to a subject in need thereof, (i) PEG1500; (ii) PEG6000; (iii) Guercia 44 / 14; (iv) Polysorbate 80; (v) Guercia 48 / 16; (vi) Kelcogel CGHA; and (vii) Butylated hydroxytoluene (BHT) The composition includes a composition comprising the compound of claim 1, in combination with one or more excipients, carriers or diluents selected from the group consisting of: The formulations prepared by the methods described herein may use or utilise an amount of one or more of the active agents, excipients, carriers or diluents described above. In terms of amounts, the manufacturing methods may utilise any of the amounts or quantities defined for the first aspect of the invention. The present disclosure will be described in detail with reference to the following figures. [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 is a graph showing the dissolution profile of Replicate 1 formulation. [Diagram 2] FIG. 2 is a graph showing the dissolution profiles of replicate 2 formulations. [Diagram 3] FIG. 3 is a graph showing initial inhalation results for additional test formulations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Example 1 Preparation of filled capsules The compositions of a number of exemplary formulations are detailed in Tables 1 and 2. Gelcia 44 / 14 was preheated in a lab oven at 60-70°C and formulated while still molten. All excipients were weighed directly into labeled glass bottles with the masses recorded in the lab notebook, except for Kelcogel CGHA and BHT. First, the BHT was weighed into a weigh boat and then added to the glass bottle containing the other excipients. The formulation was then placed in a lab oven at 60-70°C to maintain a molten mixture. Ketamine hydrochloride was added directly to the molten formulation and immediately stirred with a microspatula until completely wetted. Finally, Kelcogel was slowly added to the mixture while stirring. Each sample was high shear mixed. The samples were highly sheared for up to 3 minutes until the API appeared well dispersed in the excipients and the formulation was visually homogenous. The temperature of the formulation along with the duration of mixing was recorded before and after high shear mixing. After high shear mixing, the formulation was again kept in an oven at 60-70°C. Each formulation was hand-filled into white size 1 gelatin Conis snap capsules. Capsules were filled to a fill mass of 500 mg ± 7.5%. Gelatin banding solution was prepared by weighing gelatin and water into a stainless steel pot. The solution was hand-stirred until sufficiently homogenous and ready for use and kept in an oven at 60-70°C. The filled capsules were banded before being allowed to dry overnight. The banded capsules were then vacuum tested using a vacuum chamber and visually inspected for any signs of leakage or defects.

[0037] Abuse prevention: needle passage The abuse resistance of the formulations was evaluated by needle penetration test using a mortar and pestle. One banded capsule was weighed and placed in a mortar. The capsule shell was crushed using the pestle. The samples were crushed with the pestle for 2 minutes, applying uniform pressure for the duration of the crushing. Care was taken to remove large pieces of shell and to secure as much of the formulation as possible and separate it from the capsule shell fragments. 5 mL of solvent was then added to the mortar and all formulations were tested with sterile water followed by 40% ethanol solution (1 capsule per solvent). A 3 mL syringe was used with a 23 gauge needle to attempt to extract as much material as possible from the milled formulation. The volume of sample drawn into the syringe was measured. If necessary, multiple fills of one syringe were performed with one sample. Material was expelled from the syringe directly into a volumetric flask and measured by mass. Material collected in the volumetric flask was saved for analysis by assay to determine ketamine content.

[0038] Dissolution Test Six capsules of each formulation were dissolved in acidic medium. The pot was filled with 250 mL of 0.01 M HCl and equilibrated to 37° C.±0.5° C. using a thermometer. A single pre-weighed capsule was placed in the sample holder, which is a glass reciprocating cylinder with a plastic mesh screen at the bottom. The sample holder itself was then screwed into the corresponding position on the instrument. 1 mL aliquots were taken at 5, 10, 15, 20, 30 and 45 min for HPLC assay.

[0039] Inhalation Test To further differentiate the abuse-deterrent performance between the designed prototypes, additional inhalation tests were performed. Prior to inhalation testing, an initial evaluation was made as to whether pre-heat treatment of the capsules was necessary. One filled capsule for each formulation was used and the shell was removed using a scalpel; then the capsule fill was immediately ground in a coffee grinder for 5 minutes. For any given formulation, pre-heat treatment was deemed not necessary during additional testing after the product was ground to a size of less than 1 mm. If not, the pre-heat treatment was used in subsequent analyses. If pre-heat treatment was required, the capsules were frozen in a -20°C freezer for at least 24 hours prior to testing. Five capsules were shelled using a scalpel and then ground in a coffee grinder for 1 minute. The particle size distribution of the five capsule contents was determined by passing them through the following sieve assemblies: 1000, 500, 250, and 106 microns. An attempt was made to further remove any large particles by manual crushing using hands. The sieves were mechanically vibrated for 5 minutes to allow the appropriate particle size of the formulation to pass through. Any material that passed through each sieve was weighed. The material on each sieve was analyzed and the approximate total capsule mass was used to calculate API recovery.

[0040] Results and Discussion Preparation of filled capsules The compounded masses for Replicate 1 and Replicate 2 formulations are detailed in Table 3. All capsules were hand filled to the desired fill mass of 500 mg ± 7.5%. The capsules were banded, dried overnight, and vacuum tested at <-25" Hg for 20 minutes. A visual evaluation of the capsules was performed and none of the capsules were leaking or had any defects. [Table 3]

[0041] Abuse prevention: needle passage A "needle passage" test (as an abuse prevention measure) was performed using 5 mL of solvent, a 23 gauge needle, and a 3 mL syringe. Tests were terminated using both ethanol and sterile water. The results, shown in Table 4, indicate the mass of material excreted and the corresponding amount of ketamine recovered from the assay. For studies performed with sterile water, some of formulation 5.1 could be drawn into the syringe and expelled through the needle. For studies performed with 40% ethanol, for all formulations, some material could be drawn into the syringe and expelled. Formulations 2.1 and 3.1 had the most API recovered, while formulations 1.1 and 4.1 had the lowest expulsion values. [Table 4]

[0042] Dissolution Test Dissolution screening was performed on capsules of each formulation from Replicate 1. The HPLC analysis results of the dissolution samples are detailed in Table 5. Capsules from each formulation were analyzed in duplicate and the average of the six results was recorded. All six formulations met the immediate release criterion of 80% recovery in 45 minutes. The slowest release was observed for Formulation 2.1 and Formulation 3.1 with 80% recovery measured at 30 minutes. Formulation 4.1 and Formulation 6.1 had the fastest dissolution profiles with 80% release within 15 minutes. [Table 5]

[0043] Consideration From the needle passage results obtained, formulations 1.1 and 4.1 showed the greatest potential for abuse-deterrent formulations. The dissolution data generated showed that formulations 4.1 and 6.1 released API the fastest, with room for increased abuse deterrent properties, while maintaining immediate release dissolution performance. For these formulations, the inclusion of relatively high levels of either or both PEG 1500 and Gelucia 44 / 14 could produce favorable needle passage and / or dissolution results. Formulations with higher Gelucia 44 / 14 levels tended to have slower release profiles, but were better for abuse deterrent screening. Formulations containing PEG 1500 had desirable dissolution release times; abuse deterrent properties were variable. For formulations 1.1, 4.1 and 6.1, minor adjustments were made to their compositions to improve either or both the dissolution profile and abuse deterrence. Three new formulations were designed to measure the effect of various levels of PEG 1500, Gelucia 44 / 14 and Polysorbate 80 on, for example, abuse deterrence and dissolution. The objective was to identify a formulation that exhibited acceptable abuse deterrence but retained a usable drug dissolution profile.

[0044] Example 2 (Modifications of Formulations 1.1, 4.1 and 6.1) Preparation of filled capsules The compounded mass for the second replicate formulation is detailed in Table 6. All capsules were hand filled to 500 mg ± 7.5%. Gelatin banding solution #1268 / 114 / 03 was prepared. Capsules were banded, dried overnight, and vacuum tested. A visual evaluation of the capsules was performed and none were leaking or had any defects. [Table 6]

[0045] Abuse prevention: needle passage An abuse-resistant needle passage test was performed using 5 mL of solvent, a 23 gauge needle, and a 3 mL syringe. Tests were completed using both ethanol and sterile water. The results shown in Table 7 show the mass of material expelled and the corresponding ketamine measurements recovered from the assay. No material was drawn into the syringe for any of the formulations using water as the solvent, so only the results using 40% ethanol as the solvent were used to differentiate the formulations. The differences between the formulations were not as great as those prepared in Example 1, but formulations 1.2 and 7.1 performed best in this round of testing. Although there was some variability between the performance of the formulations tested, all exhibited desirable injection resistance, particularly with no extraction with water (presumably the solvent for preparation of suitable injectable formulations by abusers). [Table 7]

[0046] Dissolution Test The results of the HPLC analysis of the dissolution samples are detailed in Table 8. Capsules were analyzed in duplicate for each formulation and the average of the six results was recorded. All six formulations met the criteria for immediate release with 80% recovery at 45 minutes. The fastest release was observed for formulations 4.2, 6.2 and 8.1 with 80% recovery measured by 15 minutes. Formulation 1.2 had the slowest release profile. Note that the difference between the fastest and slowest formulations was much smaller than replicate 1. All six profiles were deemed to meet the criteria for an immediate release product. [Table 8]

[0047] Observation (Example 2) The needle passage results suggested that all formulations were abuse-deterrent, with the formulations with higher Gelucia 44 / 14 levels generally being better. All formulations were able to prevent any material from being drawn into the syringe when water was used as the solvent, supporting the abuse-deterrent properties of the formulations. The dissolution profiles of the new formulations were significantly improved from those tested in Example 1, with all six formulations releasing greater than 80% by the 20 minute time point. Thus, all formulations met the immediate release profile. The results of Examples 1 and 2 show some useful formulations. The positive needle passage data lent credibility to the abuse-deterrent classification of many of the formulations evaluated. The dissolution profiles for most of the formulations are typical of immediate release products, and the data collected to date suggests high reproducibility and low relative standard deviations. The seven best formulations were selected as the critical formulations and were prepared again. To strengthen the abuse deterrence data already collected, capsules were prepared for further needle passage testing. More capsules were tested to eliminate any discrepancies in the results. In addition to further needle passage testing, an initial inhalation test of the capsules was performed prior to the full abuse deterrence screening process.

[0048] Example 3 Additional needle passage and inhalation testing Preparation of filled capsules The formulation weights of capsules prepared for further testing are detailed in Table 9. All capsules were hand filled to 500 mg ± 7.5%. Gelatin banding solutions #1268 / 128 / 01 and #1268 / 129 / 01 were prepared. Capsules were banded using a Qualiseal benchtop banding machine, dried overnight, and vacuum tested for 20 minutes at <-25" Hg. A visual evaluation of the capsules was performed and none of the capsules were leaking or had any defects. [Table 9]

[0049] Abuse-proof needle passage An abuse-resistant needle passage test was performed using 5 mL of solvent, a 23 gauge needle, and a 3 mL syringe. Since the formulations had previously been tested with sterile water and no formulation was drawn into the syringe, testing was completed on three capsules per formulation using ethanol only. The results, shown in Table 10, show the mass of material expelled and the corresponding ketamine recovered from the assay. [Table 10]

[0050] Initial inhalation testing Capsules of each additional test formulation were evaluated for inhalation, as well as powder-filled ketamine capsules. The test results are shown in Table 11. Compared to the powdered ketamine capsules, all six abuse-deterrent formulations had a lower ability to pass through sieves of decreasing mesh size. Three formulations (Formulation 6.1, Formulation 7.1, and Formulation 9.1) were unable to pass through the largest mesh size, and the total content of the milled formulation was collected on the first sieve. As these formulations did not pass through any sieve, the recovered API content was not measured, and therefore the theoretical 100.00% API recovery applies. For formulations in which some milled particles pass through some sieves, only very small amounts of ketamine were recovered. The smallest sieve used has a mesh size of 0.106 mm, which corresponds approximately to the particle size that can pass through the nasal mucosa where inhalation occurs. None of the milled abuse-deterrent formulations were able to pass through this sieve size, indicating a limit for inhalation. More than 80.00% of the powder-filled capsules passed through all sieves and were collected at the bottom of the sieves. This result suggests that the powder-filled ketamine capsules can be inhaled and that the majority of the particles are below the smallest mesh size. As an abuse-deterrent formulation, the powder-filled capsules were insufficient. The total API recovered for each formulation, excluding that which did not pass through any mesh, represents the amount collected and analyzed relative to the total maximum ketamine possible. In the inhalation testing process, some material is inevitably lost during transfer. This explains why the total for each formulation does not necessarily equal 100.00%. The methods for crushing and transferring the formulations are intended to mimic those that abusers may apply. [Table 11] * Theoretical recovery - none of the formulation passed through the largest sieve and therefore the formulation was not analyzed.

[0051] summary Needle passage analysis performed on the formulations suggested that each formulation had abuse deterrent properties and reduced recovery of ketamine for each dose. Formulations 1.2 and 4.1 had the lowest % API recovery of the seven formulations tested. Inhalation analysis was used to further differentiate the formulations. In the inhalation test, all formulations had good abuse deterrence, suggesting that none or very few of the formulations were broken down into small particle sizes. This confirms the abuse deterrence of these formulations. All formulations produced favorable results during testing, but the three formulations whose particles did not pass through the sieve showed the greatest likelihood that the formulations would not break down into smaller particles.

[0052] conclusion Abuse-resistant ketamine formulations were designed and prepared. In Example 1, many of the formulations showed promising needle passage and dissolution results. The results suggested that PEG1500 and Gelucia 44 / 14 content may contribute to favorable needle passage and / or dissolution results. Formulations with higher Gelucia 44 / 14 levels tended to have slower release profiles, but performed better in abuse-resistant screening. Formulations containing PEG1500 produced desirable dissolution release times, but different levels in the formulation composition affected the abuse-resistant properties of the formulations. In Example 2, minor adjustments were made to the compositions of Formulation 1.1, Formulation 4.1, and Formulation 6.1 to generate three new formulations. In general, the dissolution profiles improved, with all six formulations releasing more than 80% by the 20 minute time point. All formulations showed desirable injection resistance, as they were not extractable with water (a solvent for the preparation of suitable injections by abusers). The results of Examples 1 and 2 demonstrated several useful formulations.

Claims

1. (i) (a) ketamine or a pharma- ceutically acceptable salt or enantiomer thereof; (b) 2R,6R-hydroxynorketamine hydrochloride; (c) 2S,6S-hydroxynorketamine hydrochloride; (d) cis-6-hydroxynorketamine hydrochloride; (e) norketamine hydrochloride; (f) (R)-norketamine hydrochloride; and (g) (S)-Norketamine hydrochloride; an active agent selected from the group consisting of: (ii) (a) Gelucia 44 / 14; (b) Gelucia 48 / 16 and PEG 1500; and (c) Polysorbate 80 and PEG 1500; one or more carrier compounds / compositions selected from the group consisting of: (iii) a viscosity modifier that is a gum containing repeating units of a tetrasaccharide polymer consisting of two D-glucose residues and one residue each of L-rhamnose and D-glucuronic acid; and (iv) optionally an antioxidant; 16. An encapsulated composition for oral administration comprising:

2. The encapsulated composition of claim 1, wherein the active agent is selected from the group consisting of ketamine hydrochloride, racemic (R,S) ketamine hydrochloride, R-ketamine, S-ketamine, and (S)-(+)-ketamine hydrochloride.

3. (i) 1% to 50% (v / v %) of the active agent; or (ii) 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% (v / v%) ketamine hydrochloride; 3. The encapsulated composition of claim 1 or 2, comprising:

4. said one or more carrier compounds being (i) copolymers; (ii) triglycerides; (iii) poloxamer; (iv) polysorbate; (v) polyethoxylates; (vi) polyethylene glycol; (vii) polyglycerides; (viii) poloxamer 124; (ix) Polysorbate 80; (x) Polysorbate 20; (xi) Coryfor EL; (xii) Coryphor RH40; (xiii) polyethylene glycol (PEG) 1000; (xiv) PEG1500; (xv) PEG2000; (xvi) PEG6000; (xvii) PEG8000; (xviii) Coryphor HS15; (xix) Gelucia 44 / 14; (xx) Gerucia 48 / 16; and (xxi) Gelucia 50 / 13; and / or The antioxidant is butylated hydroxytoluene (BHT); The encapsulated composition of any one of claims 1 to 3.

5. said one or more carrier compounds being (i) 1% to 50% (v / v%) PEG 1500; (ii) 7%, 8%, 9%, 10%, 15%, 20%, 25%, 26%, 27%, 30%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48% or 49% (v / v%) PEG 1500; (iii) 9.19% (v / v%) PEG 1500; (iv) 27.57% (v / v%) PEG1500; (v) 45.95% (v / v%) PEG1500; (vi) PEG 6000 from 1% to 20% (v / v%); (vii) 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 17% or 19% (v / v%) PEG 6000; (viii) 4.6% (v / v%) PEG 6000; and (ix) 9.19% (v / v%) PEG 6000; The encapsulated composition of any one of claims 1 to 4, selected from the group consisting of:

6. The encapsulated composition of any one of claims 1 to 5, wherein the carrier compound comprises 5% to 70% (v / v%) Gelucia 44 / 14, and the carrier compound may comprise 20.68% (v / v%) Gelucia 44 / 14, 50.55% (v / v%) Gelucia 44 / 14, 55.14% (v / v%) Gelucia 44 / 14 or 59.74% (v / v%) Gelucia 44 / 14.

7. The encapsulated composition of any one of claims 1 to 5, wherein the carrier compound comprises polysorbate 80 at 1% to 30% (v / v%), and the carrier compound may comprise 4.6% (v / v%) polysorbate 80; 11.49% (v / v%) polysorbate 80 or 13.79% (v / v%) polysorbate 80.

8. The encapsulated composition of any one of claims 1 to 5, wherein the carrier compound comprises Gelucia 48 / 16 at 10% to 70% (v / v%), and optionally the carrier compound comprises Gelucia 48 / 16 at 50.55% (v / v%).

9. The viscosity modifier is (i) Gellan gum with two acyl substituted acetate and glycerate; (ii) Gum from Sphingomonas elodea; (iii) a high acyl gellan gum having two acyl substituents; and (iv) Kelcogel® CGHA or Kelcogel® LT100; The encapsulated composition of any one of claims 1 to 8, selected from the group consisting of:

10. 10. The encapsulated composition of any one of claims 1 to 9, wherein the viscosity modifier comprises Kelcogel® CGHA at 20% to 50% (v / v %), and optionally the viscosity modifier comprises 27.57% (v / v %) or 32.17% (v / v %) Kelcogel® CGHA.

11. Ketamine hydrochloride, (i) PEG1500; (ii) PEG6000; (iii) Gelucia 44 / 14; (iv) Polysorbate 80; (v) Gelucia 48 / 16; (vi) Kelcogel® CGHA; and (vii) Butylated hydroxytoluene (BHT) 10. The encapsulated composition of claim 1, comprising one or more excipients, carriers or diluents selected from the group consisting of:

12. (i) Ketamine hydrochloride; Kelcogel® CGHA; Gelucia 44 / 14; and butylated hydroxytoluene (BHT); (ii) Ketamine hydrochloride; Kelcogel® CGHA; PEG 6000; Gelucia 44 / 14; Polysorbate 80; and butylated hydroxytoluene (BHT); (iii) Ketamine hydrochloride; Kelcogel® CGHA; PEG 6000; Gelucia 44 / 14; and butylated hydroxytoluene (BHT); (iv) Ketamine hydrochloride; Kelcogel® CGHA; PEG 1500; Polysorbate 80; and butylated hydroxytoluene (BHT); (v) Ketamine hydrochloride; Kelcogel® CGHA; PEG 1500; Gelucia 48 / 16; and butylated hydroxytoluene (BHT); (vi) Ketamine hydrochloride; Kelcogel® CGHA; PEG 1500; Gelucia 44 / 14; Polysorbate 80; and butylated hydroxytoluene (BHT); (vii) ketamine hydrochloride; Kelcogel® CGHA; Gelucia 44 / 14; Polysorbate 80 and butylated hydroxytoluene (BHT); or (viii) Ketamine hydrochloride; Kelcogel® CGHA; PEG 1500; Gelucia 44 / 14 and butylated hydroxytoluene (BHT); 12. The encapsulated composition of claim 11 comprising:

13. (i) the management, treatment and / or prevention of pain; (ii) the treatment and / or prevention of suicidal thoughts and behaviors associated with pain; (iii) the treatment and / or prevention of mental disorders; (iv) the treatment and / or prevention of mental health disorders; (v) treatment and / or prevention of certain neurological disorders; (vi) treatment and / or prevention of skin disorders; (vii) treatment and / or prevention of erythromelalgia; (viii) treatment and / or prevention of epidermolysis bullosa (EB); (ix) treatment and / or prevention of brachioradial pruritus; or (x) treatment of treatment-resistant depression; An encapsulated composition according to any one of claims 1 to 12 for use in

14. (i) encapsulated in a hard capsule; and / or (ii) the capsule comprises gelatin; The encapsulated composition of any one of claims 1 to 13.

15. The encapsulated composition of any one of claims 1 to 12 and 14, which is an abuse-deterrent composition.

16. The encapsulated composition of any one of claims 1 to 12 and 14, exhibiting immediate release of the active agent.

17. 15. The encapsulated composition of any one of claims 1 to 12 and 14, wherein elution of the active agent from the composition is equivalent to 80% recovery of the active agent after 30 to 45 minutes.

Images