WO2020188496A1

WO2020188496A1 - Stable liquid naltrexone compositions

Info

Publication number: WO2020188496A1
Application number: PCT/IB2020/052461
Authority: WO
Inventors: Moshe Rogosnitzky
Original assignee: Moshe Rogosnitzky
Priority date: 2019-03-18
Filing date: 2020-03-18
Publication date: 2020-09-24

Abstract

The present invention relates to a liquid pharmaceutical composition comprising about 0.1 to 100mg of naltrexone hydrochloride and propylene glycol, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride, oral or transdermal dosage forms thereof and their uses for treating subjects in need thereof. The present invention also relates to a liquid pharmaceutical composition comprising about 0.1 to 100mg of naltrexone hydrochloride and glycerin, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride, oral or transdermal dosage forms thereof and their uses for treating subjects in need thereof.

Description

STABLE LIQUID NALTREXONE COMPOSITIONS

BACKGROUND TO THE INVENTION

[0001] Naltrexone is an opioid antagonist first described in 1965 and approved for human use in 1984 as its hydrochloride salt. The product is indicated for opioid use disorder and alcoholism and sold as 25, 50mg, and lOOmg oral tablets. More recently, a long acting microsphere suspension of naltrexone base in PLG has been approved for similar indications.

[0002] In recent years, there has been increasing interest in the use of naltrexone for a wide variety of conditions including allergies, ALS, anxiety, arthritis, autism spectrum disorder, chronic fatigue syndrome, chronic inflammatory skin disease, Crohn's disease, fibromyalgia, HIV, lupus, osteoarthritis, Parkinson's disease and rheumatoid arthritis at doses, typically up to 5mg, much lower than the approved product’s dosages.

[0003] Although wide interest in the community exists for the use of low dose naltrexone, no product has ever been approved by a health authority which allows for accurate dosing at these levels. Rather, patients rely on compounding pharmacies to provide either capsule formulations or aqueous drops derived from the approved tablet dosages.

[0004] Whilst naltrexone is insoluble in water, its hydrochloride salt is soluble to lOOmg/ml.

However, aqueous compositions of naltrexone hydrochloride suffer from instability and have a shelf life at room temperature of 30 days and only 60 days at refrigerated conditions, resulting in the product’s limited availability. Attempts to improve the stability of aqueous compositions of naltrexone hydrochloride by the addition of further excipients, such as preservatives, have generally been met with concern by the anticipated patient population who remain very wary about the possible

pharmacological effects of these additional ingredients on their conditions.

[0005] Given that typical doses of low-dose naltrexone therapy can be as low as 0.25mg and patients often have to titrate their therapy to an effective dose, there is a need for a stable liquid composition of naltrexone which can provide for accurate, small volume, but variable dosing. Surprisingly, it has now been identified that dissolving naltrexone hydrochloride in the liquid carriers propylene glycol and glycerine allow for stable liquid pharmaceutical compositions with an extended shelf life, which do not suffer from either the stability concerns or bitter taste associated with aqueous compositions of naltrexone and without the need for additional excipients. SUMMARY OF THE INVENTION

[0006] The present invention relates to a liquid pharmaceutical composition comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride, oral or transdermal dosage forms thereof and their uses for treating subjects in need thereof.

[0007] The present invention also relates to a liquid pharmaceutical composition

comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerin, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride, oral or transdermal dosage forms thereof and their uses for treating subjects in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0008] In the present disclosure the singular forms“a,”“an,” and“the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a compound” is a reference to one or more of such compounds and equivalents thereof known to those skilled in the art, and so forth. The term“plurality”, as used herein, means more than one. When a range of values is expressed, another embodiment includes from the one particular and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

[0009] When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. As used herein, "about X" (where X is a numerical value) preferably refers to ± 10% of the recited value, inclusive. For example, the phrase "about 8" refers to a value of 7.2 to 8.8, inclusive; as another example, the phrase "about 8%" refers to a value of 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of "1 to 5" is recited, the recited range should be construed as including ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. In addition, when a list of alternatives is positively provided, such a listing can also include embodiments where any of the alternatives may be excluded. For example, when a range of "1 to 5" is described, such a description can support situations whereby any of 1, 2, 3, 4, or 5 are excluded; thus, a recitation of "1 to 5" may support "1 and 3-5, but not 2", or simply "wherein 2 is not included."

[0010] As used herein, the terms“component,”“composition,”“composition of

compounds,”“compound,”“drug,”“pharmacologically active agent,”“active agent,” “therapeutic,”“therapy,”“treatment,” or“medicament” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a human subject induces a desired pharmacological and/or physiologic effect by local and/or systemic action.

[0011] As used herein, the terms“treatment” or“therapy” (as well as different forms thereof) include preventative (e.g., prophylactic), curative or palliative treatment. As used herein, the term“treating” includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder.

[0012] As employed above and throughout the disclosure the term“effective amount” refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired result with respect to the treatment of the relevant disorder, condition, or side effect. It will be appreciated that the effective amount of components of the present invention will vary from patient to patient not only with respect to the particular compound, component or composition selected, the route of administration, and the ability of the components to elicit a desired result in the individual, but also with respect to factors such as the disease state or severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, metabolic rate of the individual, the state of being of the patient, and the severity of the pathological condition being treated, concurrent medication or special diets then being followed by the particular patient, and other factors which those skilled in the art will recognize, with the appropriate dosage being at the discretion of the attending physician. Dosage regimes may be adjusted to provide improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.

[0013] The present invention relates to a liquid pharmaceutical composition comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride.

[0014] As used herein, the terms‘naltrexone’ or‘naltrexone base’ refer to the compound 17-(Cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphinan-6-one and the term ‘naltrexone hydrochloride’ refers to said compound’s hydrochloride salt. [0015] As used herein, the term‘propylene glycol’ refers to the compound Propane-1, 2- diol in either an undiluted form or as diluted in water. The amount of water in which the propylene glycol is dissolved is typically represented by a percentage, thus, for example, the term‘100% propylene glycol’ would refer to undiluted propylene glycol and the term‘50% propylene glycol’ would refer to a 50% (v/v) propylene glycol solution in 50% (v/v) water.

[0016] In one embodiment of the invention, the propylene glycol is undiluted. In another embodiment of the invention, the propylene glycol is diluted by being dissolved in water. In a preferred embodiment of the invention, the propylene glycol comprises at least 20% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 25% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 30% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 35% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 40% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 45% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 50% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 55% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 60% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 65% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 70% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 75% water. In another preferred embodiment of the invention, the propylene glycol comprises at least 80% water.

[0017] In one embodiment of the invention, the propylene glycol is undiluted and contains no water. In another embodiment of the invention, the propylene glycol comprises about 20% water. In another embodiment of the invention, the propylene glycol comprises about 25% water. In another embodiment of the invention, the propylene glycol comprises about 30% water. In another embodiment of the invention, the propylene glycol comprises about 35% water. In another embodiment of the invention, the propylene glycol comprises about 40% water. In another embodiment of the invention, the propylene glycol comprises about 45% water. In another embodiment of the invention, the propylene glycol comprises about 50% water. In another

embodiment of the invention, the propylene glycol comprises about 55% water. In another embodiment of the invention, the propylene glycol comprises about 60% water. In another embodiment of the invention, the propylene glycol comprises about 65% water. In another embodiment of the invention, the propylene glycol comprises about 65% water. In another embodiment of the invention, the propylene glycol comprises about 70% water. In another embodiment of the invention, the propylene glycol comprises about 75% water. In another embodiment of the invention, the propylene glycol comprises about 80% water. In a more preferred embodiment of the invention, the propylene glycol comprises about 50% water.

[0018] In one embodiment of the invention, the liquid pharmaceutical composition

comprises about 0.1 to lOOmg of naltrexone hydrochloride and undiluted propylene glycol. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 20% water. In another embodiment of the invention, the

composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 25% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 30% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 35% water. In another embodiment of the invention, the

composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 45% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 45% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 50% water. In another embodiment of the invention, the

composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 55% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 60% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 65% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 70% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 75% water. In another embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises at least 80% water.

[0019] In one embodiment of the invention, the liquid pharmaceutical composition

comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 20% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 25% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 30% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 35% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 40% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 45% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 50% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 55% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 60% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 65% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 70% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 75% water. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 80% water. In a more preferred embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol comprises about 50% water.

[0020] The present invention also relates to a liquid pharmaceutical composition

comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerine, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride.

[0021] As used herein, the term‘glycerine’ refers to the compound Propane-1, 2, 3-triol in a form diluted in water. The amount of water in which the glycerine dissolved is typically represented by a ratio, thus, for example, the term‘glycerine 9:1’ would refer to a solution of 9 parts (v/v) of glycerine dissolved in 1 part (v/v) of water and the term ‘glycerine 1:1’ would refer to a solution of 1 part (v/v) of glycerine dissolved in 1 part (v/v) of water.

[0022] In one embodiment of the invention, the glycerine comprises glycerine 9:1. In

another embodiment of the invention, the glycerine comprises glycerine 8:1. In another embodiment of the invention, the glycerine comprises glycerine 7:1. In another embodiment of the invention, the glycerine comprises glycerine 6:1. In another embodiment of the invention, the glycerine comprises glycerine 5:1. In another embodiment of the invention, the glycerine comprises glycerine 4:1. In another embodiment of the invention, the glycerine comprises glycerine 3:1. In another embodiment of the invention, the glycerine comprises glycerine 2:1. In another embodiment of the invention, the glycerine comprises glycerine 1:1. In another embodiment of the invention, the glycerine comprises glycerine 1:2. In another embodiment of the invention, the glycerine comprises glycerine 1:3. In another embodiment of the invention, the glycerine comprises glycerine 1:4. In another embodiment of the invention, the glycerine comprises glycerine 1:4. In another embodiment of the invention, the glycerine comprises glycerine 1:5. In another embodiment of the invention, the glycerine comprises glycerine 1:6. In another embodiment of the invention, the glycerine comprises glycerine 1:7. In another embodiment of the invention, the glycerine comprises glycerine 1:7. In another embodiment of the invention, the glycerine comprises glycerine 1:8. In another embodiment of the invention, the glycerine comprises glycerine 1:9. In a more preferred embodiment of the invention, the glycerine comprises glycerine 1:1.

[0023] In one embodiment of the invention, the liquid pharmaceutical composition

comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine. In a more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 9:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 8:1. In a more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 7:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 6:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 5:1. In a more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 4:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 3:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 2:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:1. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:2. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:3. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:4. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:5. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:6. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:7. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:8. In another more preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:9. In a most preferred embodiment of the invention, the composition comprises about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:1.

[0024] In one embodiment of the invention, the liquid pharmaceutical composition

comprises about 0.1 to lOOmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 25mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 15mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lOmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 4.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 4mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 3.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 3mg of naltrexone hydrochloride.

In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 2.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises 0.1 to 2mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 1.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to lmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.1 to 0.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 4.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 4mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 3.5mg of naltrexone

hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 3mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 2.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 2mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 1.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to lmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition comprises about 0.25 to 0.5mg of naltrexone hydrochloride. In a more preferred embodiment of the invention, the liquid

pharmaceutical composition comprises about 0.25 to 4.5mg of naltrexone

hydrochloride.

[0025] The present invention also relates to a liquid pharmaceutical composition consisting of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride.

[0026] In one embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and undiluted propylene glycol. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 20% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 25% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 30% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 35% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 45% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 45% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 50% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 55% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 60% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 65% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 70% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 75% water. In another embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of at least 80% water.

[0027] In one embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 20% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 25% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 30% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 35% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 40% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 45% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 50% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 55% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 60% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 65% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 70% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 75% water. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 80% water. In a more preferred embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol and said propylene glycol consists of about 50% water.

[0028] In one embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 25mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 15mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 4.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 4mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 3.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 3mg of naltrexone hydrochloride.

In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 2.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of 0.1 to 2mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 1.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to 0.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 4.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 4mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 3.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 3mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 2.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 2mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 1.5mg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to lmg of naltrexone hydrochloride. In another embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 0.5mg of naltrexone hydrochloride. In a more preferred embodiment of the invention, the liquid pharmaceutical composition consists of about 0.25 to 4.5mg of naltrexone hydrochloride.

[0029] The present invention also relates to a liquid pharmaceutical composition consisting of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride.

[0030] In one embodiment of the invention, the glycerine consists of glycerine 9:1. In

another embodiment of the invention, the glycerine consists of glycerine 8:1. In another embodiment of the invention, the glycerine consists of glycerine 7:1. In another embodiment of the invention, the glycerine consists of glycerine 6:1. In another embodiment of the invention, the glycerine consists of glycerine 5:1. In another embodiment of the invention, the glycerine consists of glycerine 4:1. In another embodiment of the invention, the glycerine consists of glycerine 3:1. In another embodiment of the invention, the glycerine consists of glycerine 2 1 In another embodiment of the invention, the glycerine consists of glycerine 1:1. In another embodiment of the invention, the glycerine consists of glycerine 1 2 In another embodiment of the invention, the glycerine consists of glycerine 1:3. In another embodiment of the invention, the glycerine consists of glycerine 1:4. In another embodiment of the invention, the glycerine consists of glycerine 1:4. In another embodiment of the invention, the glycerine consists of glycerine 1:5. In another embodiment of the invention, the glycerine consists of glycerine 1:6. In another embodiment of the invention, the glycerine consists of glycerine 1:7. In another embodiment of the invention, the glycerine consists of glycerine 1:7. In another embodiment of the invention, the glycerine consists of glycerine 1:8. In another embodiment of the invention, the glycerine consists of glycerine 1:9. In a more preferred embodiment of the invention, the glycerine consists of glycerine 1:1.

[0031] In one embodiment of the invention, the liquid pharmaceutical composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine. In a more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 9:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 8:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 7:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 6:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 5:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 4:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 3:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 2:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:1. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:2. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:3. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:4. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:5. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:6. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:7. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:8. In another more preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:9. In a most preferred embodiment of the invention, the composition consists of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine 1:1.

[0032] In one embodiment of the invention, the liquid pharmaceutical composition of the invention comprises about 10 to 20mg/ml of naltrexone hydrochloride.

[0033] In one embodiment of the invention, the liquid pharmaceutical composition is in the form of drops. In one embodiment of the invention, said drops have a volume of about 0.025ml. In a preferred embodiment of the invention, said drops have a volume of about 0.05ml. In another preferred embodiment of the invention, the liquid pharmaceutical composition comprises 0.25 to 0.5mg of naltrexone hydrochloride per drop.

[0034] In one embodiment of the invention, the liquid pharmaceutical compositions can be in the form of an oral dosage form. In a preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are oral liquid dosage forms comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol. In another preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are oral liquid dosage forms consisting of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol. In a more preferred embodiment of the invention, the propylene glycol of said oral liquid dosage forms comprise about 50% water. In another preferred embodiment of the invention, the oral liquid dosage forms comprise about 10 to 20mg/ml of naltrexone hydrochloride. In another preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are oral liquid dosage forms comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerine. In yet another preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are oral liquid dosage forms consisting of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine. In a more preferred embodiment of the invention, the glycerine of said oral liquid dosage forms comprise glycerine 1:1. In another preferred embodiment of the invention, the oral liquid dosage forms comprise about 10 to 20mg/ml of naltrexone hydrochloride.

[0035] In one embodiment of the invention, the liquid pharmaceutical compositions can be in the form of a transdermal dosage form. In a preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are transdermal liquid dosage forms comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol. In another preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are transdermal liquid dosage forms consisting of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol. In a more preferred embodiment of the invention, the propylene glycol of said transdermal liquid dosage forms comprise about 50% water. In another preferred embodiment of the invention, the transdermal liquid dosage forms comprise about 10 to 20mg/ml of naltrexone hydrochloride. In another preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are transdermal liquid dosage forms comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerine. In yet another preferred embodiment of the invention, the liquid pharmaceutical compositions of the invention are transdermal liquid dosage forms consisting of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine. In a more preferred embodiment of the invention, the glycerine of said transdermal liquid dosage forms comprise glycerine 1:1. In another preferred embodiment of the invention, the transdermal liquid dosage forms comprise about 10 to 20mg/ml of naltrexone hydrochloride.

[0036] In one embodiment of the invention, the liquid pharmaceutical compositions also comprise a bitterness blocking agent. Examples of bitterness blocking include, but are not limited to, essential oils of tarragon (e.g., Artemesia dracunculus) and/or basil (e.g., Ocium basilicum), salts of glycyrrhizin, and sucralose.

[0037] In one embodiment of the invention, the liquid pharmaceutical compositions also comprise a flavoring agent. Examples of flavoring agents include, but are not limited to, essential oils (e.g. lemon oil), sweeteners (e.g. sugars or sugar substitutes), vanilla extract, peppermint extract, wintergreen extract, eucalyptus extract, cinnamon, chocolate extract and rum extract, glutamates, esters and aldehydes, stevia or steviosides, and succralose.

[0038] In one embodiment of the invention, therapeutically effective amounts of the liquid pharmaceutical compositions of the invention can be administered to a subject, in need thereof, to treat conditions responsive to low dose naltrexone therapy. In a preferred embodiment, said conditions include acantholytic skin disease, adenoid cystic carcinoma, alcoholism, allergies, alopecia, ALS, anxiety, aplastic anemia, arthritis, autism spectrum disorder, benign fasciculation syndrome, bipolar disorder, breast cancer, burning mouth syndrome, cervical dystonia, chronic fatigue syndrome,

cholangiocarcinoma, chronic back pain, chronic inflammatory skin disease, colon cancer, chronic constipation, Crohn's disease, complex regional pain syndrome, common variable immune deficiency, Darier disease, dementia, depression, dermatitis herpetiformis, dermatomyositis, diabetes, diabetic neuropathy, dissociative disorder, Ehlers-Danos syndrome, endometriosis, Epstein-Barr, erythmodermic psoriasis, esophageal carcinoma, fibromyalgia, glioma, gulf war illness, hailey-hailey disease, Hashimoto's, hepatitis C, hepatoblastoma, HIV, hypertension, hypothyroidism, irritable bowel syndrome, inflammatory bowel disease, infertility, interstitial cystitis, lichen planopilaris, lichen sclerosus, liver cancer, lung cancer, lupus, lyme disease, lymphoma, mast cell activation syndrome, mesenteric panniculitis, monoclonal gammopathy of undetermined significance, multiple sclerosis, neuroblastoma, neuropathic corneal pain, osteoarthritis, ovarian cancer, chronic pain, pancreatic cancer, pancreatitis, Parkinson's disease, parotid carcinoma, polymyalgia rheumatica, postural orthostatic tachycardia, post-polio syndrome, premenstrual syndrome, pruritus, psoriasis, psoriatic arthritis, PTSD, Raynaud's disease, reactive hypoglycemia, renal cell carcinoma, restless legs syndrome, rheumatoid arthritis, sarcoidosis, seropositive arthritis, sexual dysfunction, small intestinal bacterial overgrowth, sinusitis, Sjogren’s, skin cancer,

spondyloarthropathy, stickler syndrome, substance abuse, systemic sclerosis, torn anterior cruciate ligament, transverse myelitis, ulcerative colitis and uterine sarcoma.

[0039] In one embodiment of the invention, the liquid pharmaceutical compositions are stable and have a shelf life of at least 12 months. In another embodiment of the invention, the liquid pharmaceutical compositions have a shelf life of at least 18 months. In another embodiment of the invention, the liquid pharmaceutical compositions have a shelf life of at least 24 months. In another embodiment of the invention, the liquid pharmaceutical compositions have a shelf life of at least 30 months. In another embodiment of the invention, the liquid pharmaceutical compositions have a shelf life of at least 36 months.

[0040] As used herein, the terms‘stable’ and‘shelf life’ shall be understood according to the definitions accepted by the US Food and Drug Agency (FDA) as provided within the International Council on Flarmonization’s guidance documents (ICH) Ql(A-F) and Q5C.

[0041] This invention will be better understood by reference to the Examples, which follow.

Those of skill in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

EXAMPLES

Example 1 : Naltrexone hydrochloride stability in propylene glycol

[0042] Samples of naltrexone hydrochloride were introduced to volumes of 100%

propylene glycol, 50% propylene glycol and water and stirred until dissolution. The solutions were each assayed by HPLC and the naltrexone content was calculated as a function of the area of the eluting peak. The samples were then placed on stability testing protocols at room temperature, 37^°C and 60^°C for 9 days. Further HPLC analyses were performed at 48 hours and after 9, 47 and 116 days. The results of the testing are shown in Table 1.

Table 1

Example 2 : Naltrexone hydrochloride stability in glycerine [0043] Samples of naltrexone hydrochloride were introduced to volumes of glycerine 9:1, glycerine 1:1 and water and stirred until dissolution. The solutions were each assayed by HPLC and the naltrexone content was calculated as a function of the area of the eluting peak. The samples were then placed on stability testing protocols at room temperature, 37^°C and 60^°C for 9 days. Further HPLC analyses were performed at 24 hours and after 9, 47 and 116 days. The results of the testing are shown in Table 2.

Table 2

Example 3 : Naltrexone hydrochloride oral antimicrobial stability in propylene glycol and glycerine

[0044] Samples of 20mg/ml naltrexone hydrochloride in water, 30% propylene glycol or 30% glycerine (glycerine 3:7) were assayed (MCS Laboratories, Derbyshire, UK) according to the European Pharmacopeia 10^th edition’s efficacy of antimicrobial preservation assay for oral products (5.1.3-3). The results of the testing are shown in Table 3.

Table 3

Example 4 : Naltrexone hydrochloride topical antimicrobial stability in propylene glycol and glycerine

[0045] Samples of 20mg/ml naltrexone hydrochloride in water, 30% propylene glycol or 30% glycerine (glycerine 3:7) were assayed (Oxford Biosciences, Oxford, UK) according to ISO 11930. The results of the testing are shown in Table 4.

Table 4

Claims

We Claim:

1. A liquid pharmaceutical composition comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol, wherein said composition comprising about 10 to 20mg/ml of naltrexone hydrochloride.

2. The composition of Claim 1, wherein the propylene glycol comprises at least 20% water.

3. The composition of Claim 1, wherein the propylene glycol comprises about 50% water.

4. The composition of Claim 1, comprising 0.25 to 15mg of naltrexone hydrochloride.

5. The composition of Claim 1, comprising 0.25 to 4.5mg of naltrexone hydrochloride.

6. The composition of Claim 1, wherein said composition is in the form of drops.

7. The composition of Claim 1, wherein the composition comprises 0.25 to 0.5mg of naltrexone hydrochloride per drop.

8. The composition of Claim 1 which has a shelf life of at least 12 months.

9. A liquid pharmaceutical composition consisting of about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride.

10. The composition of Claim 9, wherein the propylene glycol comprises about 50% water.

11. An oral liquid dosage form comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol.

12. The dosage form of Claim 11, wherein the propylene glycol comprises about 50% water.

13. The dosage form of Claim 11 comprising about 10 to 20mg/ml of naltrexone hydrochloride.

14. A transdermal liquid dosage form comprising about 0.1 to lOOmg of naltrexone hydrochloride and propylene glycol.

15. The dosage form of Claim 14, wherein the propylene glycol comprises about 50% water.

16. The dosage form of Claim 14 comprising about 10 to 20mg/ml of naltrexone hydrochloride.

17. A method of treating acantholytic skin disease, adenoid cystic carcinoma, alcoholism, allergies, alopecia, ALS, anxiety, aplastic anemia, arthritis, autism spectrum disorder, benign fasciculation syndrome, bipolar disorder, breast cancer, burning mouth syndrome, cervical dystonia, chronic fatigue syndrome, cholangiocarcinoma, chronic back pain, chronic inflammatory skin disease, colon cancer, chronic constipation, Crohn's disease, complex regional pain syndrome, common variable immune deficiency, Darier disease, dementia, depression, dermatitis herpetiformis, dermatomyositis, diabetes, diabetic neuropathy, dissociative disorder, Ehlers-Danos syndrome, endometriosis, Epstein-Barr, erythmodermic psoriasis, esophageal carcinoma, fibromyalgia, glioma, gulf war illness, hailey-hailey disease, Hashimoto's, hepatitis C, hepatoblastoma, HIV, hypertension, hypothyroidism, irritable bowel syndrome, inflammatory bowel disease, infertility, interstitial cystitis, lichen planopilaris, lichen sclerosus, liver cancer, lung cancer, lupus, lyme disease, lymphoma, mast cell activation syndrome, mesenteric panniculitis, monoclonal gammopathy of undetermined significance, multiple sclerosis, neuroblastoma, neuropathic corneal pain, osteoarthritis, ovarian cancer, chronic pain, pancreatic cancer, pancreatitis, Parkinson's disease, parotid carcinoma, polymyalgia rheumatica, postural orthostatic tachycardia, post-polio syndrome, premenstrual syndrome, pruritus, psoriasis, psoriatic arthritis, PTSD, Raynaud's disease, reactive hypoglycemia, renal cell carcinoma, restless legs syndrome, rheumatoid arthritis, sarcoidosis, seropositive arthritis, sexual dysfunction, small intestinal bacterial overgrowth, sinusitis, Sjogren’s, skin cancer, spondyloarthropathy, stickler syndrome, substance abuse, systemic sclerosis, torn anterior cruciate ligament, transverse myelitis, ulcerative colitis or uterine sarcoma comprising administering to a human subject, in need thereof, a therapeutically effective amount of the composition of Claim 1.

18. A liquid pharmaceutical composition comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerine, wherein said composition comprising about 10 to 20mg/ml of naltrexone hydrochloride.

19. The composition of Claim 18, comprising 0.25 to 15mg of naltrexone hydrochloride.

20. The composition of Claim 18, comprising 0.25 to 4.5mg of naltrexone hydrochloride.

21. The composition of Claim 18, wherein said composition is in the form of drops.

22. The composition of Claim 18, wherein the composition comprises 0.25 to 0.5mg of naltrexone hydrochloride per drop.

23. The composition of Claim 18 which has a shelf life of at least 12 months.

24. A liquid pharmaceutical composition consisting of about 0.1 to lOOmg of naltrexone hydrochloride and glycerine, wherein said composition comprises about 10 to 20mg/ml of naltrexone hydrochloride.

25. An oral liquid dosage form comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerine.

26. The dosage form of Claim 25 comprising about 10 to 20mg/ml of naltrexone hydrochloride.

27. A transdermal liquid dosage form comprising about 0.1 to lOOmg of naltrexone hydrochloride and glycerine.

28. The dosage form of Claim 27 comprising about 10 to 20mg/ml of naltrexone hydrochloride.

29. A method of treating acantholytic skin disease, adenoid cystic carcinoma, alcoholism, allergies, alopecia, ALS, anxiety, aplastic anemia, arthritis, autism spectrum disorder, benign fasciculation syndrome, bipolar disorder, breast cancer, burning mouth syndrome, cervical dystonia, chronic fatigue syndrome, cholangiocarcinoma, chronic back pain, chronic inflammatory skin disease, colon cancer, chronic constipation, Crohn's disease, complex regional pain syndrome, common variable immune deficiency, Darier disease, dementia, depression, dermatitis herpetiformis, dermatomyositis, diabetes, diabetic neuropathy, dissociative disorder, Ehlers-Danos syndrome, endometriosis, Epstein-Barr, erythmodermic psoriasis, esophageal carcinoma, fibromyalgia, glioma, gulf war illness, hailey-hailey disease, Hashimoto's, hepatitis C, hepatoblastoma, HIV, hypertension, hypothyroidism, irritable bowel syndrome, inflammatory bowel disease, infertility, interstitial cystitis, lichen planopilaris, lichen sclerosus, liver cancer, lung cancer, lupus, lyme disease, lymphoma, mast cell activation syndrome, mesenteric panniculitis, monoclonal gammopathy of undetermined significance, multiple sclerosis, neuroblastoma, neuropathic corneal pain, osteoarthritis, ovarian cancer, chronic pain, pancreatic cancer, pancreatitis, Parkinson's disease, parotid carcinoma, polymyalgia rheumatica, postural orthostatic tachycardia, post-polio syndrome, premenstrual syndrome, pruritus, psoriasis, psoriatic arthritis, PTSD, Raynaud's disease, reactive hypoglycemia, renal cell carcinoma, restless legs syndrome, rheumatoid arthritis, sarcoidosis, seropositive arthritis, sexual dysfunction, small intestinal bacterial overgrowth, sinusitis, Sjogren’s, skin cancer, spondyloarthropathy, stickler syndrome, substance abuse, systemic sclerosis, torn anterior cruciate ligament, transverse myelitis, ulcerative colitis or uterine sarcoma comprising administering to a human subject, in need thereof, a therapeutically effective amount of the composition of Claim 18.