Patent Description:
An opioid overdose is toxicity due to excessive opioids. Symptoms include, but are not limited to, insufficient breathing, small pupils, and unconsciousness. Among individuals who initially survive an opioid overdose, medical complications can include, but are not limited to, rhabdomyolysis, pulmonary edema, compartment syndrome, and permanent brain damage. See, e.g.,<NPL>). Risk factors for opioid overdose include, but are not limited to, opioid dependence, injecting opioids, using high doses of opioids, mental disorders, and use of opioids together with alcohol, benzodiazepines, or cocaine. See, e.g., <NPL>). Opioid use disorders resulted in <NUM>,<NUM> deaths globally in <NUM>, up from <NUM>,<NUM> deaths in <NUM>. See, e.g., GBD <NUM> Mortality and Causes of Death Collaborators, <NPL>). Further, the rate of opioid overdoses has tripled since <NUM> and more deaths were reported in the United States in <NUM> than in any previous year on record. In <NUM>, opioid overdose deaths accounted for <NUM>,<NUM> deaths in the United States. See, e.g., <NPL>).

Initial treatment of an individual exhibiting symptoms of opioid overdose involves supporting the individual's breathing and providing oxygen. See, e.g., <NPL>). Naloxone is then recommended among those who are not breathing in order to reverse the opioid effects. Among individuals who refuse to go to a hospital following reversal, the risks of a poor outcome in the short term appear to be low. See, e.g., <NPL>).

Naloxone, also known as N-allylnoroxymorphone or <NUM>-allyl-<NUM>,5α-epoxy-<NUM>,<NUM>-dihydroxymorphinan-<NUM>-one, is a lipophilic compound that acts as a non-selective and competitive opioid receptor antagonist. Naloxone is a synthetic morphinan derivative derived from oxymorphone. Naloxone is highly lipophilic, which allows naloxone to rapidly penetrate the brain and to achieve a higher brain-to-serum ratio than that of morphine. See, e.g., <NPL>). Naloxone base has the following structure:
<CHM>.

Naloxone hydrochloride is currently available at many pharmacies as (Narcan®) a spray formulation for intranasal (IN) administration and as an intramuscular injection (IM) using an autoinjector (Evzio®). However, the high cost per dosage unit of Narcan® and Evzio® relegates use mainly to first responders, i.e., police or EMT personnel. Typically, the IN and IM are administered by first responders arriving at the scene, the time for which can vary from <NUM> to <NUM> minutes and up to <NUM> minutes after an individual suffering from opioid overdose has been found unconscious and emergency services have been contacted. Consequentially, an individual exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose may live or die simply depending upon when the first-responders reach the individual's physical location.

Further, given the expense of the currently marketed naloxone dosage forms, naloxone can be a budget buster for municipalities, making availability a problem even among first responders. A more affluent municipality may supply Narcan® IN to first responders, while a less affluent, adjacent municipality may not have sufficient revenue to supply Narcan® IN to first responders. Thus, there is a long-felt need for a lower cost alternative, which can be more widely available.

Narcan® IN became the first FDA approved non-injectable naloxone product for the treatment of opioid overdose. EMS programs have now moved toward intranasal administration of naloxone to avoid needle stick risks because many patients needing naloxone are injection drug users and <NUM>% of this patient population in large metropolitan areas is Hepatitis C or HIV positive.

Narcan® IN is supplied in <NUM> or <NUM> dosage strength metered sprays of <NUM> milliliter volume. The current Narcan® IN formulation includes inactive ingredients including benzalkonium chloride (preservative), disodium ethylenediaminetetraacetate (stabilizer), sodium chloride, hydrochloric acid to adjust pH, and purified water. The pH range for Narcan® IN is <NUM> to <NUM>. Such a pH range of <NUM> to <NUM> is highly acidic and may irritate the nasal mucosa. Further, because Narcan® is available in nasal spray dispenser form, the formulation may drip out of the nasal cavity resulting in the dosage being swallowed and not available for treating respiratory arrest.

Further, in many circumstances intranasal administration may not be suitable for persons unresponsive due to opioid overdose. Examples include cases involving damage to, or obstruction of, the nasal mucosa or cavity from habitual snorting of cocaine, opioids, or other substances of abuse. In a study by Barton et al. , it was shown that <NUM> out of <NUM> subjects (<NUM>%) who received intranasal naloxone for suspected opioid overdose were unresponsive to the treatment. See, e.g.,<NPL>.

Five (<NUM>%) of the nine non-responders had epistaxis (n=<NUM>), nasal mucus (n=<NUM>), trauma (n=<NUM>), or septal abnormality (n=<NUM>), while none of the intranasal naloxone responders had any nasal abnormalities. In addition, excess mucus production and changes in mucociliary clearance rates may also affect bioavailability. During a common cold or sinus congestion, the efficacy of intranasal medication is frequently compromised. Accordingly, a route of administration aside from intramuscular and intranasal is an unmet need for out-of-hospital management of opioid overdose. Accordingly, there remains an unmet need in opioid overdose therapy. If new, safe, less expensive and effective liquid, gel, or semi-solid formulations of naloxone for sublingual and/or buccal administration could be developed, this would represent a useful contribution to the art. Further, if new methods could be found of treating known or suspected opioid overdoses by administering sublingually and/or buccally a liquid, gel, or semi-solid formulation containing naloxone, this would also represent a useful contribution to the art and save thousands of lives. <CIT> discloses a sublingual spray formulation comprising naloxone, water, a co-solvent, and an antioxidant. <CIT> discloses a composition comprising buprenorphine and naloxone for gastrointestinal delivery.

In an embodiment, the present disclosure provides a liquid, gel or semi-solid pharmaceutical comprising from <NUM>% to <NUM>% of naloxone base by the total mass of the composition; and from <NUM>% to <NUM>% of one or more non-aqueous solvents selected from the group consisting of oleic acid, liquid polyethylene glycol, propylene glycol, and ethanol, or mixtures thereof, by the total mass of the composition; wherein the composition is free of water; wherein the naloxone base is completely and homogeneously dissolved in the one or more non-aqueous solvents; and wherein the composition is a sublingual or buccal dosage form. In some embodiments, the composition further comprises from <NUM>% to <NUM>% of a viscosity adjusting agent, by the total mass of the composition.

The pharmaceutical compositions may comprise the naloxone base in an amount of from <NUM> to <NUM>; and the one or more non-aqueous solvents in a combined amount of from <NUM> to <NUM>.

For clarification, naloxone base is completed dissolved in this non-aqueous solvent system or vehicle to form a true single-phase solution. As such, this vehicle composition does not include emulsifiers or surfactants, which would result in two-phase systems such as an emulsion, dispersion, or liquid crystalline systems or precursors to such systems, e.g., self-emulsifying drug delivery systems.

The pharmaceutical compositions may further comprise from <NUM>% to <NUM>% one or more viscosity adjusting agents selected from the group consisting of calcium silicate, acacia, carbomers, carboxymethylcellulose sodium, silicon dioxide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycols or mixtures thereof, by the total mass of the composition.

In some embodiments, the pharmaceutical composition provides a plasma concentration of naloxone of at least about <NUM> ng/mL within about <NUM> minutes following sublingual or buccal administration of the pharmaceutical composition to an individual.

In some embodiments, the individual is exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose.

In some embodiments, the pharmaceutical compositions are configured to be administered sublingually or buccally to an individual from a single unit dosage form container selected from the group consisting of a spray dispenser, an oral syringe, or a blow-fill-seal unit dose dispenser.

In yet another embodiment, the present disclosure provides a pharmaceutical composition as described above for use in the treatment of an individual exhibiting symptoms of respiratory depression associated with known or suspected opioid overdose that can include the steps of: (a) providing a single unit dosage form including a solution of naloxone base, or a derivative thereof, as a completely, homogeneously dissolved solute in one or more non-aqueous solvents; and (b) administering the single unit dosage form sublingually or buccally to the individual.

In some embodiments, the single unit dosage form further includes one or more viscosity adjusting agents.

In some embodiments, the treatment further includues the step of: (c) repeating step (b) if the individual does not recover from respiratory depression within about <NUM> to <NUM> minutes following the administering of step (b).

In some embodiments, the plasma concentration of naloxone in the individual is at least about <NUM> ng/mL within about <NUM> minutes (e.g., within about <NUM> minutes) following the administering step (b).

<FIG> depicts the free naloxone plasma concentration over time following administration of naloxone compositions prepared according to an embodiment of the present invention as compared to intramuscular ("IM") and intranasal ("IN") administration of commercially available formulations of naloxone.

The present invention provides naloxone compositions for use in methods of treatment of opiate overdose induced respiratory depression. In certain embodiments, the present invention provides pharmaceutical formulations for rapid transmucosal delivery of naloxone base, by sublingual or buccal administration at or near physiological pH.

Transmucosal delivery includes, but is not necessarily limited to, the oral, tongue, esophagus, and nasal mucosa. Buccal administration is a topical route of administration by which a drug held or applied in the buccal area (i.e., in the oral cavity, between the gum and the cheek of an individual) permeates through the oral mucosa and enters directly into the bloodstream. Sublingual administration is a transmucosal route of administration by which a drug product is placed under the tongue of an individual and permeates through the oral mucosa and enters directly into the bloodstream.

The physiological pH values of the various transmucosal membranes vary considerably. The physiological pH of the gastrointestinal tract increases along its length from about pH <NUM> in the stomach to about pH <NUM> in the colon. Saliva has a pH of about <NUM>. The pH of nasal fluids ranges from about <NUM> to about <NUM>. Without being bound by theory, the present invention is designed to provide rapid transmucosal absorption of naloxone base in the pH range specific to the target mucosal tissue, which avoids local irritation. Accordingly, transmucosal absorption of liquid, gel, and semi-solid formulations of naloxone base, according to embodiments of the present invention, occurs independently of local pH as naloxone base is insoluble in water and therefore cannot change the pH of saliva or mucosal tissue. Without being bound by theory, transmucosal delivery of liquid, gel, and semi-solid formulations of naloxone base, according to embodiments of the present invention, requires only the development of a hydration or dielectric gradient from water in the saliva. This results in the formation of a supersaturated naloxone solution as water from saliva interacts with the non-aqueous drug vehicle, which increases the driving force for transmucosal drug absorption.

Naloxone hydrochloride is not natively amenable to sublingual delivery even though it is soluble in water. This is supported by the low naloxone plasma levels obtained from Suboxone®, a combination buprenorphine/naloxone hydrochloride sublingual tablet (SLT). Naloxone's mean absolute bioavailability from Suboxone® SLT is approximately <NUM>%. Mean peak naloxone plasma levels (Cmax) averaged <NUM>. 28ng/mL for the <NUM> naloxone strength Suboxone® (Suboxone® Tablet <NUM> Patient Package Insert).

The <NUM> naloxone composition described in the Examples below, when administered sublingually, had peak naloxone levels of <NUM> ng/mL, or <NUM> times greater when dose adjusted to the <NUM> naloxone strength Suboxone® SLT. This pharmacokinetic (PK) data substantiated that this novel drug delivery technology significantly increases naloxone's bioavailability over Suboxone®.

In certain embodiments, the present invention provides, inter alia, processes for preparing rapid onset transmucosal naloxone delivery systems (or isomers or derivatives thereof).

Compounding the liquid, gel, or semi-solid formulation, according to embodiments of the present invention, includes forming a homogeneous solution of naloxone base and a solvent vehicle including one or more non-aqueous solvents, in which naloxone is a completely dissolved solute. In certain embodiments, the liquid, gel, or semi-solid formulation may further include one or more viscosity adjusting agents. Without being bound by theory, increasing the drug vehicle viscosity increases the residence time in the oral cavity and thereby minimizes the amount of naloxone that will be swallowed. For clarification, naloxone base is completed dissolved in this non-aqueous solvent system or vehicle to form a true single-phase solution. As such, this vehicle composition does not include emulsifiers or surfactants, which would result in two-phase systems such as an emulsion, dispersion, or liquid crystalline systems or precursors to such systems, e.g., self-emulsifying drug delivery systems.

In embodiments of the present invention, the non-aqueous solvent system including one or more non-aqueous solvents may include one or more solvents selected from the group consisting of oleic acid, polyethylene glycol, propylene glycol, ethanol, or mixtures thereof. Polyethylene glycols that are liquids under ambient conditions may be used as solvents in the non-aqueous solvent systems of embodiments of the present invention and may be selected from the group consisting of PEGs having a molecular weight of <NUM> or less, e.g., PEG <NUM>, PEG <NUM>, PEG <NUM>, and PEG <NUM>.

As described herein, the formulations comprise one or more non-aqueous solvents and are therefore substantially free of water; however, the formulations may comprise a small amount of water, such as incidental water content due to absorption of water from the environment, including from use of excipients that contain an incidental amount of water. For example, some commercially available PEGs may contain up to about <NUM>% water.

In certain embodiments of the present invention, the liquid, gel, or semi-solid formulations may include one or more viscosity adjusting agents selected from the group consisting of calcium silicate, acacia, carbomers, carboxymethylcellulose sodium, silicon dioxide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol or mixtures thereof. Polyethylene glycols that are solids under ambient conditions may be used as viscosity adjusting agents in the non-aqueous solvent vehicle of embodiments of the present invention, and may be selected from the group consisting of PEGs having a molecular weight of greater than <NUM>, e.g., PEG <NUM>, <NUM>, <NUM>. Although one or more viscosity adjusting agents are within the purview of the present invention any functionally equivalent to one or more viscosity adjusting agents selected from the group consisting of calcium silicate, acacia, carbomers, carboxymethylcellulose sodium, silicon dioxide, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and mixtures thereof.

In various embodiments, the present invention is directed to a liquid, gel, or semi-solid formulation including: naloxone base in an amount of from <NUM>% to <NUM>% of the total mass of the formulation; and one or more non-aqueous solvents in a collective amount of from <NUM>% to <NUM>% of the total mass of the formulation. Optionally, the formulation may further comprise from about <NUM>% to about <NUM>% of one or more viscosity adjusting agents.

In various embodiments, the formulation comprises from <NUM>% to about <NUM>% or from <NUM>% to about <NUM>% of naloxone base, by the total mass of the formulation. In various embodiments, the formulation comprises a collective amount of from about <NUM>% to <NUM>%, from about <NUM>% to <NUM>%, or from about <NUM>% to <NUM>% of one or more non-aqueous solvents, by the total mass of the formulation. In other various embodiments, the formulation comprises a collective amount of from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, or from about <NUM>% to about <NUM>% of one or more non-aqueous solvents, by the total mass of the formulation. And in yet other various embodiments, the formulation comprises a collective amount of from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, from about <NUM>% to about <NUM>%, or from about <NUM>% to about <NUM>% of one or more non-aqueous solvents, by the total mass of the formulation. In various embodiments, the formulation comprises from about <NUM>% to about <NUM>% or from about <NUM>% to about <NUM>% of the one or more viscosity adjusting agents, by the total mass of the formulation.

In a preferred embodiment of the liquid, gel, or semi-solid formulation, the one or more non-aqueous solvents are selected from the group consisting of oleic acid and ethanol. In another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes oleic acid in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation. In yet another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes ethanol in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation. In one embodiment, the formulation includes naloxone base in an amount from <NUM>% to about <NUM>% of the total mass of the formulation. In one embodiment, the formulation includes naloxone base in an amount from about <NUM>% to about <NUM>% of the total mass of the formulation.

In another embodiment, the present invention is directed to a liquid, gel, or semi-solid formulation including: naloxone base in an amount of from <NUM>% to about <NUM>% of the total mass of the formulation; one or more non-aqueous solvents in a collective amount of from about <NUM>% to about <NUM>% of the total mass of the formulation; and optionally one or more viscosity adjusting agents in a collective amount of from about <NUM>% to about <NUM>% of the total mass of the formulation.

In one preferred embodiment of the liquid, gel, or semi-solid formulation, the one or more non-aqueous solvents are selected from the group consisting of oleic acid and ethanol and a combination thereof. In another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes oleic acid in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation. In yet another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes ethanol in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation. In another embodiment of the liquid, gel, or semi-solid formulation, the one or more viscosity adjusting agents is silicon dioxide. In yet another embodiment of the liquid, gel, or semi-solid formulation, the formulation includes silicon dioxide in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation.

In another preferred embodiment of the liquid, gel, or semi-solid formulation, the one or more non-aqueous solvents are selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, and any combination thereof. In another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes polyethylene glycol in an amount of from about <NUM>% to <NUM>% of the total mass of the formulation. In yet another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes propylene glycol in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation. In yet another preferred embodiment of the liquid, gel, or semi-solid formulation, the formulation includes ethanol in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation. In another embodiment of the liquid, gel, or semi-solid formulation, the one or more viscosity adjusting agents is silicon dioxide. In yet another embodiment of the liquid, gel, or semi-solid formulation, the formulation includes silicon dioxide in an amount of from about <NUM>% to about <NUM>% of the total mass of the formulation.

In another embodiment, the liquid, gel, or semi-solid formulation comprises from <NUM>% to <NUM>% of naloxone base, and from about <NUM>% to <NUM>% polyethylene glycol, and optionally from about <NUM>% to about <NUM>% propylene glycol, and optionally from about <NUM>% to about <NUM>% ethanol.

In some embodiments, the formulation is a liquid formulation. In other embodiments, the formulation is a gel formulation. And in yet other embodiments, the formulation is a semisolid formulation.

In some embodiments, the liquid, gel, or semi-solid formulations described herein consist of, or consist essentially of, the components described. For example, in some embodiments the liquid, gel, or semi-solid formulations consist of, or consist essentially of: naloxone base in an amount of from <NUM>% to <NUM>% of the total mass of the formulation; and one or more non-aqueous solvents in a collective amount of from <NUM>% to <NUM>% of the total mass of the formulation; and optionally from about <NUM>% to about <NUM>% of one or more viscosity adjusting agents.

In embodiments of the present invention, the liquid, gel, or semi-solid formulation may be packaged in such manner as to aid in maintaining stability of the formulation in a single-unit dose dispenser. Packaging methods and materials may include, but are not limited to, spray dispensers, oral syringes, blow-fill-seal ("BFS") unit-dose dispensers, and other dosage form containers suitable for direct administration of the liquid, gel, or semi-solid formulations of the present invention to the oral or nasal mucosa. The packaging methods and materials for the liquid, gel, or semi-solid formulations of the present invention employ manufacturing techniques familiar to one versed in the art of formulating and processing pharmaceutical dosage forms.

In embodiments of the present invention, a rapid, bolus, transmucosal dose of naloxone base is provided that is formulated as a liquid, gel, or semi-solid. In certain embodiments, the rapid, bolus, transmucosal dosage form releases naloxone relatively quickly, resulting in transmucosal absorption of naloxone in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minute. In other embodiments, transmucosal absorption of naloxone occurs in less than about <NUM> minutes.

The naloxone liquid, gel, or semi-solid formulations according to embodiments of the present invention are useful in the acute treatment of respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose. Methods of treatment do not form part of the invention.

Such a method of treating respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose can include the steps of:.

More generally, a formulation, composition or dosage described herein may be administered transmucosally to the oral mucosa. For example, the dosage may be administered by a blow-fill-seal unit dose dispenser, oral syringe, or spray delivery.

The process described herein effects a method of treating respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose.

Another method of treating respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose can include the steps of:.

Yet another method of treating respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose can include the steps of:.

The process described herein effects a method of treating respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose. Yet another method of treating respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose can include the steps of:.

Single dosage forms of the liquid, gel, or semisolid formulations according to the embodiments of the present invention including naloxone base may contain an effective amount of naloxone base. The effective amount of naloxone base is sufficient to treat respiratory depression in an individual exhibiting symptoms associated with known or suspected opioid overdose. In certain embodiments of the present invention, a single dosage form may contain naloxone base in an amount of about <NUM> to about <NUM>. In other embodiments of the present invention, a single dosage form may contain naloxone base in an amount of about <NUM> to about <NUM>. In other embodiments of the present invention, a single dosage form may contain naloxone base in an amount of about <NUM>. In other embodiments of the present invention, a single dosage form may contain naloxone base in an amount of about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, about <NUM>, or about <NUM>.

In certain embodiments of the present invention, the concentration of naloxone base, as completely and homogenously dissolved solute in a non-aqueous solvent system, as a percentage of mass of naloxone base to total mass of solvent system, is from <NUM>% to <NUM>%. In other embodiments of the present invention, the concentration of naloxone base, as completely and homogeneously dissolved solute in a non-aqueous solvent system, as a percentage of mass of naloxone base to total mass of solvent system, is from about <NUM>% to about <NUM>%. In other embodiments of the present invention, the concentration of naloxone base, as completely and homogeneously dissolved solute in a non-aqueous solvent system, as a percentage of mass of naloxone base to total mass of solvent system, is from about <NUM>% to about <NUM>%. In other embodiments of the present invention, the concentration of naloxone base, as completely and homogeneously dissolved solute in a non-aqueous solvent system, as a percentage of mass of naloxone base to total mass of solvent system, is from <NUM>% to about <NUM>%. In other embodiments of the present invention, the concentration of naloxone base, as completely and homogeneously dissolved solute in a non-aqueous solvent system, as a percentage of mass of naloxone base to total mass of solvent system, is from about <NUM>% to <NUM>%. In other embodiments of the present invention, the concentration of naloxone base, as completely and homogeneously dissolved solute in a non-aqueous solvent system, as a percentage of mass of naloxone base to total mass of solvent system, is about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, about <NUM>%, or about <NUM>%.

The term "recover," as used herein, alone or in combination with other terms, unless stated otherwise, means observable amelioration of physical symptoms conventionally associated with respiratory depression, including, but not limited to, reversal of respiratory depression.

The term "effective amount," as used herein, alone or in combination with other terms, means an amount necessary to treat an individual in need thereof.

It will be readily understood that the compositions, ingredients, solvents, agents, formulations, processes, and methods of the present invention, as generally described herein, are arranged and designed in a wide variety of dosage forms and formulations. The compositions, ingredients, solvents, agents, formulations, processes, and methods described herein in the embodiments above may be further understood in connection with the following Examples. In addition, the following non-limiting Examples are intended to illustrate the invention. However, the person skilled in the art will appreciate that it may be necessary to vary the procedures for any given embodiment of the invention, e.g., vary the order or steps of the methods and/or the compositions, ingredients, solvents, agents, and/or formulations used.

In an embodiment, the present invention provides a liquid solution dosage form composition, having a total mass of about <NUM> milligrams ("mg"), including <NUM> of naloxone base, oleic acid, and ethanol. In such an embodiment, naloxone is mixed with oleic acid and ethanol until the naloxone is completely dissolved in the oleic acid and ethanol so as to form a homogeneous solution. An exemplary formulation in accordance with this embodiment includes mass amounts of ingredients according to Table 1A, below.

In an embodiment, the present invention provides a viscous liquid solution dosage form composition, having a total mass of about <NUM> milligrams ("mg"), including <NUM> of naloxone base, oleic acid, ethanol and silicon dioxide. An exemplary formulation in accordance with this embodiment includes mass amounts of ingredients according to Table 1B, below.

In an embodiment, the present invention provides a liquid solution dosage form composition, having a total mass of about <NUM>, including <NUM> of naloxone base, and polyethylene glycol <NUM>. In such an embodiment, naloxone is mixed with polyethylene glycol <NUM> until the naloxone is completely dissolved in the polyethylene glycol <NUM> so as to form a homogeneous solution. An exemplary formulation in accordance with this embodiment includes mass amounts of ingredients according to Table <NUM>, below.

In an embodiment, the present invention provides a liquid solution dosage form composition, having a total mass of about <NUM>, including <NUM> of naloxone base, polyethylene glycol <NUM>, propylene glycol, and ethanol. In such an embodiment, naloxone is mixed with polyethylene glycol <NUM>, propylene glycol, and ethanol until the naloxone is completely dissolved in the polyethylene glycol <NUM>, propylene glycol, and ethanol so as to form a homogeneous solution. An exemplary formulation in accordance with this embodiment includes mass amounts of ingredients according to Table 3A, below.

In an embodiment, the present invention provides a viscous liquid solution dosage form composition, having a total mass of about <NUM>, including <NUM> of naloxone base, polyethylene glycol <NUM>, propylene glycol, ethanol, and silicon dioxide. An exemplary formulation in accordance with this embodiment includes mass amounts of ingredients according to Table 3B, below.

The pharmacokinetics of a naloxone <NUM> composition of Example 1B was investigated when administered sublingually. The plasma concentration of naloxone following administration are presented in <FIG>. The intramuscular ("IM") and <NUM> composition demonstrated lag times (i.e., the time needed to exceed <NUM> ng/mL) of between <NUM> and <NUM> minutes. The <NUM> dose showed greater naloxone plasma concentration levels at <NUM> minutes compared to that of the intramuscular (i.e., <NUM> ng/mL and <NUM> ng/mL, respectively). The Cmax was greater for sublingual administration, being <NUM> ng/mL vs. <NUM> ng/mL for the IM. Thus, transmucosal absorption of <NUM> composition from administration sublingually exceeded the <NUM> IM administration drug exposure. The pharmacokinetics of a naloxone <NUM> composition of Example 3B were investigated when administered both sublingually and on top of the tongue. The plasma concentration of naloxone following administration of the <NUM> composition sublingually and on the top of the tongue are presented in <FIG>. The intramuscular ("IM") and both <NUM> compositions demonstrated lag times (i.e., the time needed to exceed <NUM> ng/mL) of between <NUM> and <NUM> minutes. Both <NUM> administrations showed greater naloxone plasma concentration levels at <NUM> minutes compared to that of the intramuscular, i.e. <NUM> ng/mL (sublingual), <NUM> ng/mL (on tongue), and <NUM> ng/mL, respectively). The Cmax was greater for administration on top of the tongue, <NUM> ng/mL, vs. <NUM> ng/mL sublingually. The absorption of naloxone took a few more minutes on top of the tongue; however, the maximum plasma concentration of naloxone achieved was greater than for administration sublingually and for intranasal ("IN") spray. Without being bound by theory, these results may be explained by mucosal physiology. The sublingual mucosa is thin (~<NUM>), not keratinized, and has a lower surface area, while the mucosa of the tongue is thicker (~<NUM>), keratinized, and has a greater surface area due to papillae. Thus, transmucosal absorption from administration either sublingually or on top of the tongue provides comparable drug exposure and exceeds the <NUM> IM administration drug exposure.

Pharmacokinetic data from the naloxone <NUM> and <NUM> compositions also demonstrated greater exposure compared to the <NUM> IM injection, thereby exceeding the Reference Listed Drug ("RLD") standard. The <NUM> strength peak naloxone plasma concentration levels were <NUM> times greater than that of the IM injection and <NUM> to <NUM> times greater for the <NUM> strength. The IM and IN pharmacokinetic data used for this comparison were obtained from Narcan® IN spray Clinical Pharmacology Review in <NUM> subjects. A graph of naloxone plasma concentration levels comparing a <NUM> composition (n = <NUM>) to the <NUM> IM injection and <NUM> IN spray with <NUM>% CIis depicted in <FIG>. Naloxone plasma concentration levels beyond the <NUM>-minute time point substantially exceeded the IM plasma concentration levels and the <NUM> strength was comparable to the IN spray plasma concentration levels.

The plasma curve for the <NUM> compositions from sublingual administration is similar to that of the IN spray. The lag time is several minutes longer for the sublingual administration; however, both curves reached <NUM> ng/mL naloxone plasma concentration levels within <NUM> minutes of the other (i.e., <NUM> minutes for the <NUM> composition vs. <NUM> minutes for the intranasal spray). Similarly, the <NUM> ng/mL plasma concentration level is reached at <NUM> minutes for sublingual administration vs. <NUM> minutes for the intranasal spray. Both the <NUM> and <NUM> compositions and the IN spray reach Tmax at <NUM> minutes. The IN spray has a slightly higher Cmax of <NUM> ng/mL compared to <NUM> ng/mL for the <NUM> composition administered sublingually. Prior pharmacokinetic studies with similar formulations have shown good correlation between dose and Cmax. Therefore, a higher Cmax may be expected by increasing the dose of naloxone, should that be deemed desirable.

Claim 1:
A liquid, gel or semi-solid pharmaceutical composition comprising:
from <NUM>% to <NUM>% of naloxone base by the total mass of the composition; and
from <NUM>% to <NUM>% of one or more non-aqueous solvents selected from the group consisting of oleic acid, liquid polyethylene glycol, propylene glycol, and ethanol, or mixtures thereof, by the total mass of the composition;
wherein the composition is free of water;
wherein the naloxone base is completely and homogeneously dissolved in the one or more non-aqueous solvents, and
wherein the composition is a sublingual or buccal dosage form.