WO2023244502A1 - Methods of using low dose naltrexone to treat chronic pain - Google Patents
Methods of using low dose naltrexone to treat chronic pain Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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Definitions
- CRPS Complex regional pain syndrome
- CRPS Complex regional pain syndrome
- CRPS is a chronic neurological condition that can cause severe pain.
- CRPS is a rare, orphan chronic pain disorder affecting fewer than 200,000 individuals each year and is a rare or orphan disease.
- the characteristic feature of CRPS is hypersensitivity to stimulus resulting in pain, including allodynia, pain due to a stimulus that does not usually provoke pain, and hyperalgesia, increased pain from a stimulus that usually provokes pain.
- CRPS is a neuroinflammatory condition and patients frequently experience autonomic, sensory, vasomotor, and motor dysfunction (such as pain in their limbs and dystonia).
- CRPS is divided into two categories. CRPS Type 1 (also known as reflex sympathetic dystrophy or RSD) occurs in the absence of confirmed nerve injury. CRPS Type 2 (previously known as causalgia) occurs with confirmed nerve injury.
- TLR4 Toll-like receptors
- cytokines cytokines that play key roles in the mechanistic pathway.
- the TLR4 receptor is believed to be upregulated during neuroimmune activation, which triggers the production of proinflammatory cytokines, leading to allodynia and hyperalgesia.
- One example embodiment is directed to various methods of using low dose naltrexone to treat chronic pain in a patient.
- the methods of using low' dose naltrexone to treat chronic pain includes administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent.
- Figure 1 discloses a release profile for an example embodiment in a simulated stomach.
- Figure 2 discloses a dissolution profile of an example embodiment in uncoated form.
- Figure 3 discloses a dissolution profile of an example embodiment in coated form demonstrating the biphasic release of naltrexone.
- Naltrexone is approved for use in the treatment of alcohol use disorders (AUD) and other addictions, such as opioid dependence, e.g., a daily 50 mg tablet or weekly 380 mg extended-release suspension.
- naltrexone functions as an opioid antagonist having a competitive binding affinity for p-opioid receptors.
- naltrexone includes (but is not limited to) naltrexone, its metabolites, including 6p-Naltrexol, enantiomers, including (+)-naloxone, isomers and racemic mixtures of same, in both free base and salt forms.
- CRPS chronic myelogenous pulmonary disease .
- inflammatory cytokines that circulate along the patient's body. These inflammatory cytokines are known to cause some of the specific symptoms that result from CRPS including edema, swelling, hypersensitivity to touch, allodynia, vasomotor and pseudo motor changes, and regulation of the inflammatory cytokine release.
- Low-dose naltrexone is believed to down-regulate inflammatory cytokine release, which is important in patients who have complex regional pain syndrome (CRPS).
- Low- dose naltrexone’s affect on cytokine release, in particular, is beneficial to CRPS.
- naltrexone is an antagonist to opioid receptors and has the highest affinity to the mu-opioid receptor and, it is an antagonist of Toll-like receptors (TLR). TLRs lead to production of pro-inflammatory cytokines when they are activated, so antagonizing TLRs decreases the activation of pro-inflammatory' cytokines.
- Pro-inflammatory cytokines increase inflammation, and this is a hallmark of the disease of CRPS because you see inflammation, hypersensitivity to touch, and allodynia which all occur as a result of CRPS. So by blocking this, we are actually treating what likely is tire mechanism of action specific to this particular disease state. This is counterintuitive as Naltrexone typically antagonizes opioids which are typically used to treat pain.
- Naltrexone in higher doses functions as an opioid antagonist targeting the mu and delta opioid receptors.
- Off-label uses of naltrexone have explored its use at lower doses through a different mechanism for the treatment of inflammatory, rheumatological, and neurological conditions. These conditions include multiple sclerosis, fibromyalgia, Crohn’s disease, chronic fatigue syndrome (CFS), and — more recently — CRPS.
- CFS chronic fatigue syndrome
- CRPS chronic fatigue syndrome
- TLR4 Tolllike receptor 4
- naltrexone leads to transient opioid receptor blockade, which triggers a positive feedback mechanism that increases the production of endogenous opioids (endogenous endorphins and enkephalins) and opioid signaling. Together, these mechanisms may work to alleviate pain associated with CRPS.
- naltrexone treat the pain symptom of CRPS, but it can also treat the disease process and disease cascades, since patients who suffer from CRPS have not only increased neuro-inflammation and inflammatory cytokines, but also a decrease in endorphin and enkephalin circulation compared to the average patient. Increasing endogenous enkephalins and endorphins would help from a symptomatic standpoint. Blocking the Toll-like receptors would help the entire cascade of the disease, decreasing the production of pro-inflammatory cytokines, and attenuation of the microglia and glial cells in the central and peripheral nervous system. It may actually treat the underlying disease state, which would be extremely beneficial to the patient.
- Glial cell activation, inflammatory cytokines, and neuro-inflammation are hallmarks of the disease of CRPS.
- the toll-like receptor activity is very important when looking at complex regional pain syndrome specifically.
- naltrexone reduces toll-like TOR signaling in glial cell activation.
- Naltrexone is an antagonist of TOR.
- TOR activation leads to the production of NF-KB, which is an inflammatory signaling pathway.
- NF-KB is a tumor growth factor, but this is also important in the inflammatory signaling pathway. This results primarily in a reduction of inflammatory cytokines, but also reduces neuro -inflammation.
- This mechanism of action of low-dose naltrexone is particularly important in patients experiencing CRPS. CRPS patients suffer from severe debilitating pain, with even light touch or benign stimulation eliciting extreme amounts of pain. Microglial cells and glial cells are oftentimes involved in this pain-signaling pathway, and reduction in glial cell activation can help treat this pain syndrome.
- low-dose naltrexone increases endogenous enkephalins and endorphins which are the body’s natural pain killers.
- endorphins and endorphins which are the body’s natural pain killers.
- the short-acting low-dose naltrexone binds to receptors, leading to a brief blockade of opioid receptors between 2:00 a.m. and 4:00 a.m. This blockade is believed to up-regulate vital life elements of the body and cause an increase in endorphin and enkephalin production. This increase in endorphins and enkephalins causes a decrease in patient pain.
- the first amount of naltrexone is administered to the patient directly or within an immediate-release agent in a manner allowing for uptake of the first amount of naltrexone by the patient within a short period of time (e.g. less than two hours in one example embodiment; less than 30 minutes in another example embodiment).
- the first amount of naltrexone may be selected based on the weight, sex or age of a given patient or various other factors.
- Various types of immediate-release agents may be used to administer the first amount of naltrexone.
- the first amount of naltrexone ranges between approximately 1.5 mg to 5 mg. In another example embodiment, the first amount of naltrexone ranges between approximately 0.25 mg to 5 mg. In another example embodiment, the first amount of naltrexone ranges between approximately 0.25 mg to 2.00 mg. In another example embodiment, the first amount of naltrexone is approximately 1.5 mg. hi another example embodiment, the first amount of naltrexone is approximately 1.0 mg. In another example embodiment, the first amount of naltrexone is approximately 2 mg.
- the second amount of naltrexone is administered to the patient within a modified- release agent to allow uptake of the second amount of naltrexone to the patient over an extended period of time (e.g. in one example embodiment the extended period of time is two or more hours; in another example embodiment the extended period of time is greater than 30 minutes; in another example embodiment the extended period of time is between 30 minutes to two hours).
- the second amount of naltrexone is administered to the patient after the first amount of naltrexone has been administered to the patient.
- the second amount of naltrexone is administered to the patient while at least a portion of the first amount of naltrexone is being administered to the patient.
- the second amount of naltrexone may be selected based on the weight, sex or age of a given patient or various other factors.
- the modified-release agent releases the second amount of naltrexone over a 30 minute to 24 hour period of time. In one exampl e embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 4 hour period of time. In another example embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 1 hour period of time. In another example embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 3 hour period of time.
- the second amount of naltrexone ranges between approximately 1.5 mg to 5 mg. In another example embodiment, the second amount of naltrexone ranges between approximately 1 mg to 5 mg. In another example embodiment, the second amount of naltrexone ranges between approximately 0.25 mg to 5 mg. In another example embodiment, the second amount of naltrexone is approximately 1.5 mg. In another example embodiment, the second amount of naltrexone is approximately 1.0 mg. In another example embodiment, the second amount of naltrexone is approximately 2 mg.
- the modified-release agent is comprised of a slow-release agent. In another embodiment, the modified-release agent is comprised of a controlled release agent. In another embodiment, the modified-release agent is comprised of a sustained release agent.
- modified-release agents may be used to administer the second amount of naltrexone.
- the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that is a low-dosage of naltrexone. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that does not exceed 10 mg daily for a patient. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that does not exceed 5 mg daily for a patient. In another example embodiment, the total amount of naltrexone administered to the patient daily ranges between approximately 1 mg to 5 mg.
- the total amount of naltrexone administered to the patient daily is approximately 4.5 mg. In another example embodiment, the total amount of naltrexone administered to the patient daily is approximately 2 mg. In another example embodiment, the total amount of naltrexone administered to the patient is approximately 2 mg per day for approximately 4 weeks followed by 4 mg per day after the initial 4 weeks to treat the chronic pain disorder (e.g. CRPS). It can be appreciated that the initial period of time for treating the patient may exceed or be less than 4 weeks.
- the chronic pain disorder e.g. CRPS
- the total amount of naltrexone administered to the patient is approximately 2 mg per day for approximately 4 weeks followed by 4 mg per day after the initial 4 weeks to treat the chronic pain disorder (e.g. CRPS).
- the chronic pain disorder e.g. CRPS
- the first amount of naltrexone in the immediate-release agent and the second amount of naltrexone in a modified-release agent may be administered to a patient in one of various methods such as orally (e.g. pill, liquid, suspension), transdermally (e.g. transdermal patch), topically, via injection, e.g., intravenous or intramuscular, inhalation, rectally, or the like.
- orally e.g. pill, liquid, suspension
- transdermally e.g. transdermal patch
- injection e.g., intravenous or intramuscular, inhalation, rectally, or the like.
- the first amount of naltrexone and the second amount of naltrexone are administered simultaneously via a pill ingested by the patient.
- the first amount of naltrexone and the second amount of naltrexone are administered via a biphasic pill ingested by the patient.
- the pill is comprised of a bilayer pill with a first layer for the first amount of naltrexone and a second layer for the second amount of naltrexone.
- the pill is comprised of an inner portion with the second amount of naltrexone within the modified-release agent surrounded by an outer layer with the first amount of naltrexone within the immediate- release agent.
- the first amount of naltrexone in the immediate-release agent and the second amount of naltrexone in a modified-release agent may be administered simultaneously to the patient (e.g. via a pill, liquid solution).
- the first amount of naltrexone in the immediate-release agent and the second amount of naltrexone in a modified-release agent may be administered to the patient at separate times with the second amount of naltrexone administered shortly after the first amount of naltrexone is administered to the patient.
- the first amount of naltrexone and the second amount of naltrexone are administered to the patient in accordance with the patient’s sleep cycle. In on such embodiment, the first and second amounts of naltrexone are administered approximately 30 minutes to 3 hours prior to the patient going to sleep. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone axe administered to the patient just prior to the patient going to sleep.
- naltrexone works in part by stimulating endogenous endorphins (the body’s natural pain killers) which are only produced by body in significant quantities beginning approximately 3 - 4 hours into the sleep cycle.
- the first amount of naltrexone and the second amount of naltrexone are administered to the patient in a manner that maintains a concentration of naltrexone in the patient’s circulatory system within an effective range over a twenty four hour period.
- a biphasic pill system is used to administer the naltrexone to the patient with a lower dosage of naltrexone for a first period of time followed by an increased dosage of naltrexone after the first period of time.
- a first total amount of naltrexone is administered to the patient daily for a first period of time and after the first period of time a second total amount of naltrexone is administered to the patient daily on a continuous basis to treat the chronic pain condition.
- the second total amount of naltrexone is higher than the first total amount of naltrexone.
- the second total amount of naltrexone is higher than the first total amount of naltrexone by at least two times.
- the first total amount of naltrexone is substantially equal to the second total amount of naltrexone.
- One example method of using low-dose naltrexone to treat chronic pain disorders generally comprises administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent.
- chronic pain disorders include, but are not limited to, complex regional pain syndrome (CRPS), fibromyalgia, or neuropathic pain.
- CRPS complex regional pain syndrome
- fibromyalgia fibromyalgia
- neuropathic pain neuropathic pain.
- a first total amount of naltrexone is administered to tire patient daily for an initial period of time (e.g. approximately 4 weeks) followed by a second total amount of naltrexone per day after the initial period of time to treat the chronic pain disorder wherein the second total amount of naltrexone is higher than the first total amount of naltrexone.
- the naltrexone may be administered to a patient in one of various methods such as orally (e.g. pill, multilayered pill, liquid, suspension), transdermally (e.g. transdermal patch), topically, via injection, e.g., intravenous or intramuscular, inhalation, rectally, or the like.
- the first total amount of naltrexone administered to the patient daily is comprised of the first amount of naltrexone at approximately 1 mg and the second amount of naltrexone at approximately 1 mg for the initial period of time (e.g. approximately 4 weeks), and then the second total amount of naltrexone administered to the patient daily after the initial period of time is comprised of the first amount of nal trexone at approximately 2 mg and the second amount of naltrexone at approximately 2 mg to treat the chronic pain disorder.
- the first total amount of naltrexone administered to the patient daily in a multilayered pill is comprised of the first amount of naltrexone at approximately 1 mg in an immediate-release agent and tire second amount of naltrexone at approximately 1 mg in a modified-release agent for the initial period of time (e.g. approximately 4 weeks), and then the second total amount of naltrexone administered to the patient daily after the initial period of time is comprised of the first amount of naltrexone at approximately 2 mg in an immediate-release agent and the second amount of naltrexone at approximately 2 mg in a modified-release agent to treat the chronic pain disorder.
- the first total amount of nal trexone o f approximately 2 mg is administered daily to the patient daily for the initial time period (e.g. 4 weeks) via a multilayered pill having an inner portion (or inner layer) with the second amount of naltrexone of approximately 1 mg with in the modified-release agent surrounded by an outer layer with the first amount of naltrexone of approximately 1 mg within the immediate-release agent.
- the second total amount of naltrexone of approximately 4 mg is administered daily to the patient daily after initial time period (e.g.
- the modified-release agent may be a controlled release agent, a sustained release agent or a slow-release agent.
- a method is disclosed of administering daily to the patient a first total amount of naltrexone for an initial period of time, wherein the first total amount of naltrexone is less than 3 mg.
- the method is disclosed of administering daily to the patient a second total amount of naltrexone after the initial period of time, wherein the second total amount of naltrexone is less than 5 mg, and wherein the second total amount of naltrexone is greater than the first total amount of naltrexone.
- the second total amount of naltrexone is approximately two times greater than the first total amount of naltrexone.
- the first total amount of naltrexone is comprised of a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent
- the second total amount of naltrexone is comprised of a third amount of naltrexone in an immediate- release agent and a fourth amount of naltrexone in a modified-release agent.
- the first amount of naltrexone is approximately 1 mg
- the second amount of naltrexone is approximately 1 mg
- the third amount of naltrexone is approximately 2 mg
- the fourth amount of naltrexone is approximately 2 mg.
- the first amount of naltrexone and the second amount of naltrexone are administered via a first pill ingested by the patient, wherein the first pill is comprised an inner layer with the second amount of naltrexone and an outer layer with the first amount of naltrexone, tire third amount of naltrexone and the fourth amount of naltrexone are administered via a second pill ingested by the patient, wherein the second pill is comprised an inner layer with the fourth amount of naltrexone and an outer layer with the second amount of naltrexone.
- the method comprises administering daily to the patient a first pill having a first total amount of naltrexone for an initial period (e.g. approximately four weeks), wherein the first total amount of naltrexone is comprised of a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent, ⁇ wherein the first amount of naltrexone is approximately 1 mg, wherein the second amount of naltrexone is approximately 1 mg, wherein the first amount of naltrexone and the second amount of naltrexone are administered via a first pill ingested by the patient, and wherein the first pill is comprised an inner layer with the second amount of naltrexone and an outer layer with the first amount of naltrexone.
- the method further comprises administering daily to the patient a second pill having a second total amount of naltrexone after the initial period of time, wherein the second total amount of naltrexone is comprised of a third amount of naltrexone in an immediate-release agent and a fourth amount of naltrexone in a modified-release agent, wherein the third amount of naltrexone is approximately 2 mg, wherein the fourth amount of naltrexone is approxi mately 2 mg, wherein the third amount of naltrexone and the fourth amount of naltrexone are administered via at least one second pill ingested by the patient, wherein the at least one second pill is comprised an inner layer with the fourth amount of naltrexone and an outer layer with the third amount of naltrexone.
- One variation of this preferred embodiment includes where the second total amount of naltrexone is administered to the patient via two pills ingested by the pill, wherein each of the two pills are comprised of half the fourth amount of naltrexone (e.g. approximately 1 mg) in the modified-release agent in an inner layer and half the third amount of naltrexone (e.g. approximately 1 mg) in the immediate- release agent of an outer layer surrounding the inner layer.
- half the fourth amount of naltrexone e.g. approximately 1 mg
- half the third amount of naltrexone e.g. approximately 1 mg
- a biphasic pill is used to orally administer to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified- release agent.
- the total amount of naltrexone is orally administered to the patient daily in a multilayered pill comprised of the first amount of naltrexone at approximately 1 mg in the immediate-release agent in an outer coating of the biphasic pill and the second amount of naltrexone at approximately 1 mg in the modified-release agent in a core of the biphasic pill surrounded by the outer coating to treat the chronic pain disorder.
- the approximate 1 mg of naltrexone in the outer coating is delivered immediately to the patient with the approximate 1 mg of naltrexone in the core of the biphasic pill delivered in a sustained release manner over a period of approximately 3-4 hours.
- Table 1 below discloses an example embodiment of components and composition for one biphasic pill dosage for the core and the coating surrounding the core:
- Glyceryl Dibenhenate is basically like a wax which results in the sustained release of the naltrexone.
- the Methocel KI 5 is a sustained release agent (basically Like cellulose) and causes the slower release of the naltrexone.
- Citric Acid is included to create a porous structure in the inner core matrix which allows for faster dissolution.
- the Microcrystalline Cellulose is an excipient that acts as a filler for the biphasic pill.
- the Magnesium Stearate acts as a lubricant during the manufacturing of the biphasic pill to prevent the core mixture from sticking to the metal press during compression of the core material to form the core wi thin a metal press.
- immediate release naltrexone that releases within 0 to 15 minutes is mixed with a suitable pill coating material such as OP ADRY® which is a one-step film coating system which combines a polymer, plasticizer and pigment (as required) in a dry concentrate.
- OPADRY® is manufactured and sold by BPSI Holdings LLC d/b/a Colorcon. After the inner core of the biphasic pill is formed, the inner core is then coated with the outer coating by spraying a layer of the outer coating over the entire exterior surface of the inner core.
- the total weight of the biphasic tablet is approximately 55.0 mg with an outer diameter of approximately 4.0 mm and an approximate hardness of about 11 kP.
- the average weight of the biphasic pills are approximately 49.5 to 60.5 mg with a target weight of approximately 55.0 mg.
- the biphasic pill has a hardness of approximately 3.0 to 6.0 kP.
- the biphasic pill has an approximate 50% release of the total amount of naltrexone within approximately 5 to 15 minutes (i.e. approximately 1 mg of naltrexone released), approximately 60% release of the second amount of naltrexone in approximately 90 minutes (i.e.
- naltrexone HC1 was included in the outer coating while naltrexone base was included in the core to provide a sustained release profile.
- Naltrexone HC1 is comprised of naltrexone mixed with hydrochloric acid which is a weak acid that allows for the immediate release of naltrexone (the amount of hydrochloric acid is negligible based on weight and volume).
- hydrochloric acid is a weak acid that allows for the immediate release of naltrexone (the amount of hydrochloric acid is negligible based on weight and volume).
- 4 parts of OP AD RY® was mixed with 1 part of naltrexone HC1 to form an outer coating mixture.
- the outer coating mixture was sprayed on the core using a spray coater (Freund Vector laboratory development coating system, LDCS) with 5 mg of outer coating mixture being deposited on the tablet such that the final weight of the tablet was 55 mg.
- LDCS Spray Cound Vector laboratory development coating system
- the dissolution profile of the above example embodiment in uncoated form is shown in Figure 2.
- the dissolution profile of the above example embodiment in coated form is shown in Figure 3 below demonstrating the biphasic release (immediate release followed by sustained release of naltrexone).
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Abstract
Methods of using low dose naltrexone to treat chronic pain in a patient. The methods of using low dose naltrexone to treat chronic pain generally includes administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent.
Description
Methods of Using Low Dose Naltrexone to Treat Chronic Pain
BACKGROUND
The described example embodiments in general relate to various methods of using low dose naltrexone to treat chronic pain in a patient.
Complex regional pain syndrome (CRPS) is a chronic neurological condition that can cause severe pain. CRPS is a rare, orphan chronic pain disorder affecting fewer than 200,000 individuals each year and is a rare or orphan disease. The characteristic feature of CRPS is hypersensitivity to stimulus resulting in pain, including allodynia, pain due to a stimulus that does not usually provoke pain, and hyperalgesia, increased pain from a stimulus that usually provokes pain. CRPS is a neuroinflammatory condition and patients frequently experience autonomic, sensory, vasomotor, and motor dysfunction (such as pain in their limbs and dystonia).
CRPS is divided into two categories. CRPS Type 1 (also known as reflex sympathetic dystrophy or RSD) occurs in the absence of confirmed nerve injury. CRPS Type 2 (previously known as causalgia) occurs with confirmed nerve injury.
The cause of CRPS is likely multifactorial and the exact mechanism is still unclear. However, evidence suggests that Toll-like receptors (TLR4) and inflammatory cytokines play key roles in the mechanistic pathway. The TLR4 receptor is believed to be upregulated during neuroimmune activation, which triggers the production of proinflammatory cytokines, leading to allodynia and hyperalgesia.
Because of the rarity of CRPS, little high-quality research has been performed to evaluate optimal management strategies. Currently, there is no FDA approved treatment for CRPS and it is an unmet medical need. Current treatment of CRPS includes physical and occupational therapy, pharmacotherapies, and interventional procedures. Pharmacologic treatments focus on traditional medicines for pain management, including steroids and
opioids. Much of the current research is inconclusive as to the efficacy of opioid treatment for CRPS.
SUMMARY
One example embodiment is directed to various methods of using low dose naltrexone to treat chronic pain in a patient. The methods of using low' dose naltrexone to treat chronic pain includes administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent.
There has thus been outlined, rather broadly, some of the embodiments of the present disclosure in order that the detailed description thereof may be better understood, and in order that the present contribution to the art may be better appreciated. There are additional embodiments that will be described hereinafter and that will form the subject matter of the claims appended hereto. In this respect, before explaining at least one embodiment in detail, it is to be understood that the various embodiments are not limited in its application to the details of construction or to the arrangements of the components set forth in the following description or illustrated in the drawings. Also, it is to be understood that tire phraseology and terminology employed herein are for the purpose of the description and should not be regarded as limiting.
To better understand the nature and advantages of the present disclosure, reference should be made to the following description and the accompanying figures. It is to be understood, however, that each of the figures is provided for the purpose of illustration only and is not intended as a definition of the limits of the scope of the present disclosure. Also, as a general rule, and unless it is evidence to the contrary from the description, where elements in different figures use identical reference numbers, the elements are generally either identical or at least similar in function or purpose.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 discloses a release profile for an example embodiment in a simulated stomach.
Figure 2 discloses a dissolution profile of an example embodiment in uncoated form.
Figure 3 discloses a dissolution profile of an example embodiment in coated form demonstrating the biphasic release of naltrexone.
DETAILED DESCRIPTION
A. Overview.
1. Naltrexone.
Naltrexone is approved for use in the treatment of alcohol use disorders (AUD) and other addictions, such as opioid dependence, e.g., a daily 50 mg tablet or weekly 380 mg extended-release suspension. At standard dosage, naltrexone functions as an opioid antagonist having a competitive binding affinity for p-opioid receptors. As used herein, naltrexone includes (but is not limited to) naltrexone, its metabolites, including 6p-Naltrexol, enantiomers, including (+)-naloxone, isomers and racemic mixtures of same, in both free base and salt forms.
The disease state of CRPS involves inflammatory cytokines that circulate along the patient's body. These inflammatory cytokines are known to cause some of the specific symptoms that result from CRPS including edema, swelling, hypersensitivity to touch, allodynia, vasomotor and pseudo motor changes, and regulation of the inflammatory cytokine release.
Low-dose naltrexone is believed to down-regulate inflammatory cytokine release, which is important in patients who have complex regional pain syndrome (CRPS). Low- dose naltrexone’s affect on cytokine release, in particular, is beneficial to CRPS.
From a mechanistic standpoint, naltrexone is an antagonist to opioid receptors and has the highest affinity to the mu-opioid receptor and, it is an antagonist of Toll-like receptors (TLR). TLRs lead to production of pro-inflammatory cytokines when they are activated, so antagonizing TLRs decreases the activation of pro-inflammatory' cytokines. Pro-inflammatory cytokines increase inflammation, and this is a hallmark of the disease of CRPS because you see inflammation, hypersensitivity to touch, and allodynia which all occur as a result of CRPS. So by blocking this, we are actually treating what likely is tire mechanism of action specific to this particular disease state. This is counterintuitive as Naltrexone typically antagonizes opioids which are typically used to treat pain.
Naltrexone in higher doses functions as an opioid antagonist targeting the mu and delta opioid receptors. Off-label uses of naltrexone have explored its use at lower doses through a different mechanism for the treatment of inflammatory, rheumatological, and neurological conditions. These conditions include multiple sclerosis, fibromyalgia, Crohn’s disease, chronic fatigue syndrome (CFS), and — more recently — CRPS. At the low doses used for these conditions, naltrexone is thought to act as an immune modulator. Some speculate that this mechanism is caused by reduced neuroinflammation in the case of disorders like CFS. Evidence suggests that, at low doses, naltrexone antagonizes TLR4 on activated glial cells without the previously mentioned function as a mu opioid receptor antagonist. Thus, low-dose naltrexone presents a promising therapeutic avenue for the treatment of CRPS, a condition in which TLR4 upregulation is a primary pathway through attenuation of glial cell activation and direct targeting of TLR4 activity.
In contrast with standard-dose naltrexone (i.e. 50 mg or higher), low-dose naltrexone is believed to exert its mechanism of action through interaction with and antagonism of Tolllike receptor 4 (TLR4). TLR4 has been shown to be a key mediator of microglial cell activation, which has been identified as a causal mechanism of neuropathic pain in CRPS. Microglial cell activation is associated with the release of pro -inflammatory cytokines, reactive oxygen species, and prostaglandins, which amplify the inflammatory response.
Another potential mechanism of action of low-dose naltrexone treatment is a paradoxical upregulation of opioid signaling. Low-dose naltrexone leads to transient opioid receptor blockade, which triggers a positive feedback mechanism that increases the production of endogenous opioids (endogenous endorphins and enkephalins) and opioid signaling. Together, these mechanisms may work to alleviate pain associated with CRPS.
Not only does low-dose naltrexone treat the pain symptom of CRPS, but it can also treat the disease process and disease cascades, since patients who suffer from CRPS have not only increased neuro-inflammation and inflammatory cytokines, but also a decrease in endorphin and enkephalin circulation compared to the average patient. Increasing endogenous enkephalins and endorphins would help from a symptomatic standpoint. Blocking the Toll-like receptors would help the entire cascade of the disease, decreasing the production of pro-inflammatory cytokines, and attenuation of the microglia and glial cells in the central and peripheral nervous system. It may actually treat the underlying disease state, which would be extremely beneficial to the patient.
2. Central Nervous System.
Glial cell activation, inflammatory cytokines, and neuro-inflammation are hallmarks of the disease of CRPS. The toll-like receptor activity is very important when looking at complex regional pain syndrome specifically.
In the central nervous system, low-dose naltrexone reduces toll-like TOR signaling in glial cell activation. Naltrexone is an antagonist of TOR. TOR activation leads to the production of NF-KB, which is an inflammatory signaling pathway. NF-KB is a tumor growth factor, but this is also important in the inflammatory signaling pathway. This results primarily in a reduction of inflammatory cytokines, but also reduces neuro -inflammation. This mechanism of action of low-dose naltrexone is particularly important in patients experiencing CRPS. CRPS patients suffer from severe debilitating pain, with even light touch or benign stimulation eliciting extreme amounts of pain. Microglial cells and glial
cells are oftentimes involved in this pain-signaling pathway, and reduction in glial cell activation can help treat this pain syndrome.
3. Peripheral Nervous System.
Low-dose naltrexone also has effects in the peripheral nervous system where low- dose naltrexone can modulate T and B lymphocyte production. In the periphery nervous system, low-dose naltrexone can also reduce interleukin 6, interleukin 12, and tumor necrosis factor alpha. This is very important in patients who suffer from CRPS, specifically. Patients who have CRPS often have an increase in inflammatory cytokines and may often note an increase in interleukin 6, interleukin 12, and tumor necrosis factor alpha. By reducing these inflammatory cytokines back to what would be a more normal state, it is likely that we would be able to treat the actual disease state of complex regional pain syndrome.
4. Endogenous Enkephalins and Endorphins.
Another important part of low-dose naltrexone is that it increases endogenous enkephalins and endorphins which are the body’s natural pain killers. For example, it is also noted that when taken at bedtime, the short-acting low-dose naltrexone binds to receptors, leading to a brief blockade of opioid receptors between 2:00 a.m. and 4:00 a.m. This blockade is believed to up-regulate vital life elements of the body and cause an increase in endorphin and enkephalin production. This increase in endorphins and enkephalins causes a decrease in patient pain.
B. First Amount of Naltrexone.
The first amount of naltrexone is administered to the patient directly or within an immediate-release agent in a manner allowing for uptake of the first amount of naltrexone by the patient within a short period of time (e.g. less than two hours in one example embodiment; less than 30 minutes in another example embodiment). The first amount of naltrexone may be selected based on the weight, sex or age of a given patient or various
other factors. Various types of immediate-release agents may be used to administer the first amount of naltrexone.
In one example embodiment, the first amount of naltrexone ranges between approximately 1.5 mg to 5 mg. In another example embodiment, the first amount of naltrexone ranges between approximately 0.25 mg to 5 mg. In another example embodiment, the first amount of naltrexone ranges between approximately 0.25 mg to 2.00 mg. In another example embodiment, the first amount of naltrexone is approximately 1.5 mg. hi another example embodiment, the first amount of naltrexone is approximately 1.0 mg. In another example embodiment, the first amount of naltrexone is approximately 2 mg.
C. Second Amount of Naltrexone.
The second amount of naltrexone is administered to the patient within a modified- release agent to allow uptake of the second amount of naltrexone to the patient over an extended period of time (e.g. in one example embodiment the extended period of time is two or more hours; in another example embodiment the extended period of time is greater than 30 minutes; in another example embodiment the extended period of time is between 30 minutes to two hours). In one example embodiment, the second amount of naltrexone is administered to the patient after the first amount of naltrexone has been administered to the patient. In another example embodiment, the second amount of naltrexone is administered to the patient while at least a portion of the first amount of naltrexone is being administered to the patient. The second amount of naltrexone may be selected based on the weight, sex or age of a given patient or various other factors.
In one example embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 24 hour period of time. In one exampl e embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 4 hour period of time. In another example embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 1 hour period of time. In another example
embodiment, the modified-release agent releases the second amount of naltrexone over a 30 minute to 3 hour period of time.
In one example embodiment, the second amount of naltrexone ranges between approximately 1.5 mg to 5 mg. In another example embodiment, the second amount of naltrexone ranges between approximately 1 mg to 5 mg. In another example embodiment, the second amount of naltrexone ranges between approximately 0.25 mg to 5 mg. In another example embodiment, the second amount of naltrexone is approximately 1.5 mg. In another example embodiment, the second amount of naltrexone is approximately 1.0 mg. In another example embodiment, the second amount of naltrexone is approximately 2 mg.
In one embodiment, the modified-release agent is comprised of a slow-release agent. In another embodiment, the modified-release agent is comprised of a controlled release agent. In another embodiment, the modified-release agent is comprised of a sustained release agent. Various types of modified-release agents may be used to administer the second amount of naltrexone.
D. Combined Total Amount of Naltrexone.
In one example embodiment, the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that is a low-dosage of naltrexone. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that does not exceed 10 mg daily for a patient. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that does not exceed 5 mg daily for a patient. In another example embodiment, the total amount of naltrexone administered to the patient daily ranges between approximately 1 mg to 5 mg. In another example embodiment, the total amount of naltrexone administered to the patient daily is approximately 4.5 mg. In another example embodiment, the total amount of naltrexone administered to the patient daily is approximately 2 mg.
In another example embodiment, the total amount of naltrexone administered to the patient is approximately 2 mg per day for approximately 4 weeks followed by 4 mg per day after the initial 4 weeks to treat the chronic pain disorder (e.g. CRPS). It can be appreciated that the initial period of time for treating the patient may exceed or be less than 4 weeks.
In another example embodiment, the total amount of naltrexone administered to the patient is approximately 2 mg per day for approximately 4 weeks followed by 4 mg per day after the initial 4 weeks to treat the chronic pain disorder (e.g. CRPS).
E. Methods and Systems of Administration to Patient.
The first amount of naltrexone in the immediate-release agent and the second amount of naltrexone in a modified-release agent may be administered to a patient in one of various methods such as orally (e.g. pill, liquid, suspension), transdermally (e.g. transdermal patch), topically, via injection, e.g., intravenous or intramuscular, inhalation, rectally, or the like.
In one example embodiment, the first amount of naltrexone and the second amount of naltrexone are administered simultaneously via a pill ingested by the patient. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone are administered via a biphasic pill ingested by the patient. In one example embodiment of the naltrexone delivered via a pill, the pill is comprised of a bilayer pill with a first layer for the first amount of naltrexone and a second layer for the second amount of naltrexone. In another example embodiment of the naltrexone delivered via a pill, the pill is comprised of an inner portion with the second amount of naltrexone within the modified-release agent surrounded by an outer layer with the first amount of naltrexone within the immediate- release agent. One benefit of using a bilayer pill to administer the first amount of naltrexone and the second amount of naltrexone independently is the reduction of lucid dreaming and other side effects that can accompany high dosages of naltrexone.
F. Timing of Administration to Patient.
In one example embodiment, the first amount of naltrexone in the immediate-release agent and the second amount of naltrexone in a modified-release agent may be administered simultaneously to the patient (e.g. via a pill, liquid solution). In another example, embodiment, the first amount of naltrexone in the immediate-release agent and the second amount of naltrexone in a modified-release agent may be administered to the patient at separate times with the second amount of naltrexone administered shortly after the first amount of naltrexone is administered to the patient.
In another example embodiment, the first amount of naltrexone and the second amount of naltrexone are administered to the patient in accordance with the patient’s sleep cycle. In on such embodiment, the first and second amounts of naltrexone are administered approximately 30 minutes to 3 hours prior to the patient going to sleep. In another example embodiment, the first amount of naltrexone and the second amount of naltrexone axe administered to the patient just prior to the patient going to sleep. One believed benefit of administering the low-dosage naltrexone within a few hours before the patient goes to sleep is because naltrexone works in part by stimulating endogenous endorphins (the body’s natural pain killers) which are only produced by body in significant quantities beginning approximately 3 - 4 hours into the sleep cycle.
In another example embodiment, the first amount of naltrexone and the second amount of naltrexone are administered to the patient in a manner that maintains a concentration of naltrexone in the patient’s circulatory system within an effective range over a twenty four hour period.
In one embodiment, a biphasic pill system is used to administer the naltrexone to the patient with a lower dosage of naltrexone for a first period of time followed by an increased dosage of naltrexone after the first period of time. In another example embodiment, a first total amount of naltrexone is administered to the patient daily for a first period of time and after the first period of time a second total amount of naltrexone is administered to the patient
daily on a continuous basis to treat the chronic pain condition. In this example, the second total amount of naltrexone is higher than the first total amount of naltrexone. In one variation of this example, the second total amount of naltrexone is higher than the first total amount of naltrexone by at least two times. In another variation of this example, the first total amount of naltrexone is substantially equal to the second total amount of naltrexone.
G. Example Embodiments.
1. First Example Embodiment.
One example method of using low-dose naltrexone to treat chronic pain disorders generally comprises administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent. Examples of chronic pain disorders include, but are not limited to, complex regional pain syndrome (CRPS), fibromyalgia, or neuropathic pain.
2. Second Example Embodiment.
In a preferred example embodiment, a first total amount of naltrexone is administered to tire patient daily for an initial period of time (e.g. approximately 4 weeks) followed by a second total amount of naltrexone per day after the initial period of time to treat the chronic pain disorder wherein the second total amount of naltrexone is higher than the first total amount of naltrexone. In the preferred embodiment, the naltrexone may be administered to a patient in one of various methods such as orally (e.g. pill, multilayered pill, liquid, suspension), transdermally (e.g. transdermal patch), topically, via injection, e.g., intravenous or intramuscular, inhalation, rectally, or the like.
In a variation of this preferred embodiment, the first total amount of naltrexone administered to the patient daily is comprised of the first amount of naltrexone at approximately 1 mg and the second amount of naltrexone at approximately 1 mg for the initial period of time (e.g. approximately 4 weeks), and then the second total amount of naltrexone administered to the patient daily after the initial period of time is comprised of
the first amount of nal trexone at approximately 2 mg and the second amount of naltrexone at approximately 2 mg to treat the chronic pain disorder.
In another variation of this preferred embodiment, the first total amount of naltrexone administered to the patient daily in a multilayered pill is comprised of the first amount of naltrexone at approximately 1 mg in an immediate-release agent and tire second amount of naltrexone at approximately 1 mg in a modified-release agent for the initial period of time (e.g. approximately 4 weeks), and then the second total amount of naltrexone administered to the patient daily after the initial period of time is comprised of the first amount of naltrexone at approximately 2 mg in an immediate-release agent and the second amount of naltrexone at approximately 2 mg in a modified-release agent to treat the chronic pain disorder.
In this variation of this preferred embodiment, the first total amount of nal trexone o f approximately 2 mg is administered daily to the patient daily for the initial time period (e.g. 4 weeks) via a multilayered pill having an inner portion (or inner layer) with the second amount of naltrexone of approximately 1 mg with in the modified-release agent surrounded by an outer layer with the first amount of naltrexone of approximately 1 mg within the immediate-release agent. In furtherance of this variation of the preferred embodiment, the second total amount of naltrexone of approximately 4 mg is administered daily to the patient daily after initial time period (e.g. after 4 weeks) via two multilayered pills each having an inner portion (or inner layer) with the second amount of naltrexone of approximately 1 mg within the modified-release agent surrounded by an outer layer with the first amount of naltrexone of approximately 1 mg within the immediate-release agent. The modified-release agent may be a controlled release agent, a sustained release agent or a slow-release agent.
3. Third Example Embodiment.
In another preferred example embodiment, a method is disclosed of administering daily to the patient a first total amount of naltrexone for an initial period of time, wherein the first total amount of naltrexone is less than 3 mg. In furtherance of this preferred
embodiment, the method is disclosed of administering daily to the patient a second total amount of naltrexone after the initial period of time, wherein the second total amount of naltrexone is less than 5 mg, and wherein the second total amount of naltrexone is greater than the first total amount of naltrexone. In one variation of this preferred embodiment, the second total amount of naltrexone is approximately two times greater than the first total amount of naltrexone. In another variation of this preferred embodiment, the first total amount of naltrexone is comprised of a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent, and wherein the second total amount of naltrexone is comprised of a third amount of naltrexone in an immediate- release agent and a fourth amount of naltrexone in a modified-release agent. In another variation of this preferred embodiment, the first amount of naltrexone is approximately 1 mg, wherein the second amount of naltrexone is approximately 1 mg, wherein the third amount of naltrexone is approximately 2 mg, and wherein the fourth amount of naltrexone is approximately 2 mg. In another variation of this preferred embodiment, the first amount of naltrexone and the second amount of naltrexone are administered via a first pill ingested by the patient, wherein the first pill is comprised an inner layer with the second amount of naltrexone and an outer layer with the first amount of naltrexone, tire third amount of naltrexone and the fourth amount of naltrexone are administered via a second pill ingested by the patient, wherein the second pill is comprised an inner layer with the fourth amount of naltrexone and an outer layer with the second amount of naltrexone.
4. Fourth Example Embodiment.
In another preferred example embodiment of the method for treating a chronic pain disorder in a patient, the method comprises administering daily to the patient a first pill having a first total amount of naltrexone for an initial period (e.g. approximately four weeks), wherein the first total amount of naltrexone is comprised of a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent, ■wherein the first amount of naltrexone is approximately 1 mg, wherein the second amount of naltrexone is approximately 1 mg, wherein the first amount of naltrexone and the second amount of naltrexone are administered via a first pill ingested by the patient, and wherein
the first pill is comprised an inner layer with the second amount of naltrexone and an outer layer with the first amount of naltrexone. In furtherance of this preferred embodiment, the method further comprises administering daily to the patient a second pill having a second total amount of naltrexone after the initial period of time, wherein the second total amount of naltrexone is comprised of a third amount of naltrexone in an immediate-release agent and a fourth amount of naltrexone in a modified-release agent, wherein the third amount of naltrexone is approximately 2 mg, wherein the fourth amount of naltrexone is approxi mately 2 mg, wherein the third amount of naltrexone and the fourth amount of naltrexone are administered via at least one second pill ingested by the patient, wherein the at least one second pill is comprised an inner layer with the fourth amount of naltrexone and an outer layer with the third amount of naltrexone. One variation of this preferred embodiment includes where the second total amount of naltrexone is administered to the patient via two pills ingested by the pill, wherein each of the two pills are comprised of half the fourth amount of naltrexone (e.g. approximately 1 mg) in the modified-release agent in an inner layer and half the third amount of naltrexone (e.g. approximately 1 mg) in the immediate- release agent of an outer layer surrounding the inner layer.
5. Fifth Example Embodiment.
In another example embodiment of using low-dose naltrexone to treat chronic pain disorders, a biphasic pill is used to orally administer to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified- release agent. In one example variation of this example embodiment, the total amount of naltrexone is orally administered to the patient daily in a multilayered pill comprised of the first amount of naltrexone at approximately 1 mg in the immediate-release agent in an outer coating of the biphasic pill and the second amount of naltrexone at approximately 1 mg in the modified-release agent in a core of the biphasic pill surrounded by the outer coating to treat the chronic pain disorder. In this example variation of this example embodiment, the approximate 1 mg of naltrexone in the outer coating is delivered immediately to the patient with the approximate 1 mg of naltrexone in the core of the biphasic pill delivered in a sustained release manner over a period of approximately 3-4 hours.
Table 1 below discloses an example embodiment of components and composition for one biphasic pill dosage for the core and the coating surrounding the core:
For the core components. Glyceryl Dibenhenate is basically like a wax which results in the sustained release of the naltrexone. The Methocel KI 5 is a sustained release agent (basically Like cellulose) and causes the slower release of the naltrexone. Citric Acid is included to create a porous structure in the inner core matrix which allows for faster dissolution. The Microcrystalline Cellulose is an excipient that acts as a filler for the biphasic pill. The Magnesium Stearate acts as a lubricant during the manufacturing of the biphasic pill to prevent the core mixture from sticking to the metal press during compression of the core material to form the core wi thin a metal press.
For the outer coating components, immediate release naltrexone that releases within 0 to 15 minutes is mixed with a suitable pill coating material such as OP ADRY® which is a one-step film coating system which combines a polymer, plasticizer and pigment (as
required) in a dry concentrate. OPADRY® is manufactured and sold by BPSI Holdings LLC d/b/a Colorcon. After the inner core of the biphasic pill is formed, the inner core is then coated with the outer coating by spraying a layer of the outer coating over the entire exterior surface of the inner core.
In one example preferred embodiment of the biphasic pill disclosed in Table 1, the total weight of the biphasic tablet is approximately 55.0 mg with an outer diameter of approximately 4.0 mm and an approximate hardness of about 11 kP. hr another example preferred embodiment, the average weight of the biphasic pills are approximately 49.5 to 60.5 mg with a target weight of approximately 55.0 mg. In another example preferred embodiment, the biphasic pill has a hardness of approximately 3.0 to 6.0 kP. In another example preferred embodiment, the biphasic pill has an approximate 50% release of the total amount of naltrexone within approximately 5 to 15 minutes (i.e. approximately 1 mg of naltrexone released), approximately 60% release of the second amount of naltrexone in approximately 90 minutes (i.e. approximately 0.60 mg of the second amount of naltrexone or 1.60 mg of the total amount of naltrexone including the first amount of naltrexone released previously), approximately 90% release of the second amount of naltrexone in approximately 2 hours (i.e. approximately 0.90 mg of the second amount of naltrexone or 1.90 mg of the total amount of naltrexone including the first amount of naltrexone released previously), and approximately 100% release of the total amount of 2 mg of naltrexone in 3 hours. The preferred embodiment release timing prevents dose dumping while still delivering 65-75% of the total naltrexone in the first hour and then the remaining 25-35% of the total naltrexone over hours 2 and 3. Naltrexone has a half-life of approximately 4 horns so the preferred embodiment formula would not cause does stacking of accumulation in the system over time. Figure 1 discloses a release profile of this example embodiment in a simulated stomach based on four separate test results.
To achieve the burst release where over 60% of the naltrexone was delivered within
3 hours, naltrexone HC1 was included in the outer coating while naltrexone base was included in the core to provide a sustained release profile. Naltrexone HC1 is comprised of
naltrexone mixed with hydrochloric acid which is a weak acid that allows for the immediate release of naltrexone (the amount of hydrochloric acid is negligible based on weight and volume). For the outer coating, 4 parts of OP AD RY® was mixed with 1 part of naltrexone HC1 to form an outer coating mixture. The outer coating mixture was sprayed on the core using a spray coater (Freund Vector laboratory development coating system, LDCS) with 5 mg of outer coating mixture being deposited on the tablet such that the final weight of the tablet was 55 mg.
The dissolution profile of the above example embodiment in uncoated form (i.e. without the outer layer) is shown in Figure 2. The dissolution profile of the above example embodiment in coated form (i.e. with the outer layer) is shown in Figure 3 below demonstrating the biphasic release (immediate release followed by sustained release of naltrexone).
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the various embodiments of the present disclosure, suitable methods and materials are described above. All patent applications, patents, and printed publications cited herein are incorporated herein by reference in their entireties, except for any definitions, subject matter disclaimers or disavowals, and except to the extent that the incorporated material is inconsistent with tire express disclosure herein, in which case the language in this disclosure controls. The various embodiments of the present disclosure may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and it is therefore desired that the various embodiments in the present disclosure be considered in all respects as illustrative and not restrictive. Any headings utilized within the description are for convenience only and have no legal or limiting effect.
Claims
1. A method for treatment of a chronic pain disorder in a patient, the method comprising administering to the patient a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified-release agent, wherein the first amount of naltrexone and the second amount of naltrexone combined equal a total amount of naltrexone that is approximately 2 mg.
2. The method of claim 1 , wherein the first amount of naltrexone and the second amount of naltrexone are administered to the patient approximately 1 to 3 hours prior to the patient going to sleep.
3. The method of claim 1, wherein the modified-release agent is a controlled release agent, a sustained release agent or a slow-release agent.
4. The method of claim 1, wherein the second amount of naltrexone is only released to the patient after the first amount of naltrexone has been released to the patient, and wherein the modified-release agent releases the second amount of naltrexone over an extended period of time.
5. The method of claim 1, wherein the modified-release agent releases the second amount of naltrexone over a 30 minute to 2 hour period of time.
6. The method of claim 1, wherein the first amount of naltrexone is approximately 1 mg and wherein the second amount of naltrexone is approximately 1 mg.
7. The method of claim 1 , w'herein the first amount of naltrexone and the second amount of naltrexone are administered concurrently to the patient.
8. The method of claim 1 , wherein the first amount of naltrexone and the second amount of naltrexone are administered via a biphasic pill ingested by the patient.
9. The method of claim 1 , wherein the first amount of naltrexone and the second amount of naltrexone are administered via a pill ingested by the patient, wherein the pill is comprised an inner layer with the second amount of naltrexone and an outer layer with the first amount of naltrexone.
10. The method of claim 1 , wherein the first amount of naltrexone and the second amount of naltrexone are administered via a pill ingested by the patient, wherein the pill is comprised an inner layer with the second amount of naltrexone and an outer layer with the first amount of naltrexone, wherein the first amount of naltrexone is approximately 1 mg, and wherein the second amount of naltrexone is approximately 1 mg.
11. A method for treatment of a chronic pain disorder in a patient, the method comprising administering daily to the patient a biphasic pill having a first amount of naltrexone in an immediate-release agent and a second amount of naltrexone in a modified- release agent, wherein the first amount of naltrexone is approximately 1 mg, wherein the second amount of naltrexone is approximately 1 mg, wherein the first amount of naltrexone and the second amount of naltrexone are administered via a biphasic pill ingested by the patient, and wherein the biphasic pill is comprised an inner core with the second amount of naltrexone and an outer layer surrounding the inner core with the first amount of naltrexone.
12. A method for treatment of a chronic pain disorder in a patient, the method comprising: administering daily to the patient a biphasic pill having an inner core and an outer layer surrounding the inner core; wherein the outer layer is comprised of an amount of coating material and an amount of naltrexone HC1, and wherein the inner core is comprised of an amount of naltrexone base and an amount of citric acid.
13. The method of claim 12, wherein the inner core is comprised of an amount of glyceryl dibehenate.
14. The method of claim 12, wherein the inner core is comprised of an amount of methocel KI 5.
15. The method of claim 12, wherein the inner core is comprised of an amount of microcrystalline cellulose.
16. The method of claim 12, wherein the amount of naltrexone HC1 is approximately 1 mg.
17. The method of claim 16, wherein the amount of naltrexone base is approximately 1 mg.
18. The method of claim 12, wherein the inner core is comprised of approximately 7.5 mg of glyceryl dibehenate, approximately 5 mg of methocel K15, and approximately 33.75 mg of microcrystalline cellulose, wherein the amount of naltrexone base is approximately 1 mg.
19. The method of claim 18, wherein the amount of coating material is approximately 4 mg and wherein the amount of naltrexone HC1 is approximately 1 mg.
20. The method of claim 12, wherein the amount of coating material is approximately 4 mg and wherein the amount of naltrexone HC1 is approximately 1 mg.
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US17/839,453 US20220305004A1 (en) | 2020-12-31 | 2022-06-13 | Methods of Using Low Dose Naltrexone to Treat Chronic Pain |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150110879A1 (en) * | 2001-08-06 | 2015-04-23 | Purdue Pharma L.P. | Opioid agonist formulations with releasable and sequestered antagonist |
US20150110865A1 (en) * | 2013-10-21 | 2015-04-23 | Florida State University Research Foundation | Cns stimulant and opioid receptor antagonist combination as a non-addictive, non-aversive and synergistic anti-obesity treatment |
US20170239239A1 (en) * | 2016-02-18 | 2017-08-24 | Immune Therapeutics Inc. | Method for Inducing a Sustained Immune Response |
WO2019209217A2 (en) * | 2017-12-21 | 2019-10-31 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Modified release formulations of flurbiprofen |
WO2022076470A1 (en) * | 2020-10-06 | 2022-04-14 | Sorrento Therapeutics, Inc. | Oral delayed burst formulation of low-dose naltrexone or naloxone used for|treating fibromyalgia and long covid |
-
2023
- 2023-06-09 WO PCT/US2023/024903 patent/WO2023244502A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150110879A1 (en) * | 2001-08-06 | 2015-04-23 | Purdue Pharma L.P. | Opioid agonist formulations with releasable and sequestered antagonist |
US20150110865A1 (en) * | 2013-10-21 | 2015-04-23 | Florida State University Research Foundation | Cns stimulant and opioid receptor antagonist combination as a non-addictive, non-aversive and synergistic anti-obesity treatment |
US20170239239A1 (en) * | 2016-02-18 | 2017-08-24 | Immune Therapeutics Inc. | Method for Inducing a Sustained Immune Response |
WO2019209217A2 (en) * | 2017-12-21 | 2019-10-31 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Modified release formulations of flurbiprofen |
WO2022076470A1 (en) * | 2020-10-06 | 2022-04-14 | Sorrento Therapeutics, Inc. | Oral delayed burst formulation of low-dose naltrexone or naloxone used for|treating fibromyalgia and long covid |
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