Muscle, Bone and Joint Pain/Muscle Relaxants:
Cyclobenzaprine:
Cyclobenzaprine is a muscle relaxant. It works by blocking nerve impulses (or pain sensations) that are sent to your brain. Cyclobenzaprine is used together with rest and physical therapy to treat skeletal muscle conditions such as pain or injury. See Drugs.com
Metaxalone (5-[(3,5-dimethylphenoxy)methyl]-2-oxazlidinone):
Introduction:
Metaxalone is used as a skeletal muscle relaxant. The mechanisms of action of metoxalone in humans has not been established but may be due to general central nervous system depression. It was approved by the FDA in 1962 as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions, such as muscles in spasm. (Mutual Pharmaceutical Company, Inc., US7,122,566).
Metaxalone is used short-term to relieve muscle, bone, and joint pain. It seems to relax muscles by affecting nerve activity in the spinal cord. Common side effects include dizziness and drowsiness. Do not drive or do other activities that require alertness or coordination until you know how metaxalone affects you. Dosage is in 400 mg, 800 mg oral tablets. The 800 mg tablets often contain ingredients such as alginic acid, corn starch, ferric oxide red, magnesium stearate, povidone, and pregelatinized starch.
Metaxalone should be stored at room temperature, between 68 F to 77 F (20 C to 25 C). It can be exposed to temperatures between 59 F to 86 F (15 C to 30 C) for shorter periods of time, such as when transporting it. Store in a cool, dry place.
Metaxalone can cause serotonin syndrome when it is taken alone or with other medicines that affect serotonin.
Metaxalone has poor solubility in aqueous buffers but improved dissolution in the presence of surfactant (SLS). Studies indicate that at low pH (1.5), dissolution is minimal (often <10%), while in pH 4.5 media, it generally passes, indicating pH-dependent solubility.
Based on the United States Pharmacopeia (USP) Monograph for Metaxalone Tablets (with revisions, including those around 2022/2023, often referred in 2025 USP publications as Test 1, Test 2, and Test 3), is the dissolution testing for Metaxalone tablets.
Interaction with other substances:
Metaxalone can interact with other active agents. Mutual Pharmaceutical Company, Inc., US 2007/0088065; US 2007/0088066; US7,122,566) for example discloses a method of informing a user that metaxalone affects activity cytochrome p450 isozyme.
(US 2008/0292584, Mutual Pharmaceutical Company, Inc) disclsoes a methods that includes tdermining that a patient in need of metaxalone therapy is taking a substance that is an inhbitor or an inducer of a cytochrome p450 isozyme and adjusting administration to the patient of metaxalone or the substance to avoid an adverse event associated with metaxalone. Also disclsoed is a method of preventing sedation in a patient in need of metaxalone that includes determining a dosing regimen for metaxalone to be administered, determining that a substance that is a known inhibitor of a cytochorme P450 enzyme is currently administered or will be administered to the patient, and altering dosing of metaxalone administered to the patient from the determiend dosing regimen while the known inhibitor of the cytochrome P450 isozyme is coadminstiered to the patent to prevent sedation.
Bioavaiability:
Bioavailability of certain drugs, el.g., essentially water insoluble drugs can be limited when adminsitered orally. Typically, manufacturers recommend that essentially water insoluble drugs be taken along with food to enhance the bioavailability of the drugs. Metaxalone is hydrophobic, essentially water-insolubel powder, which demonsotrates limited absorption from teh gastrointestinal tract (GIT) when adminsitered orally in the form of Skelaxin tablets containing 400 mg metaxalone and other inert compression tableting excipients. Thus, methods have been disclosed to improve the oral bioavaiability of metaxalone from Skelaxin tablet formulation by administering Skelaxin tablets with food. (US 20050276844)
(Zalit, US 2007/0249694) discloses pharmaceutical compositions that include more than 400 mg of metaxalone, ast lesat one binder and at least one disintegrant , wherein the weight ratio between the disintegrant and metaxalone is in the range of about 0.5 percent to about 10 percent. The invention reduces the food effect by increasing the disintegraiton capabity of a metaxalone formulation.
Hall (US 2024/0382464) discloses methods of making metaxalone tablets having consistent dissolution proerpties and bioavailability which includes steps such as compressing a plurality of tablet prototypes at a plurality of hardness values (e.g., 6-35 kp) from a first batch quanity and a first batch quanitity of a second grade of metaxalone as well as a first excipient quatity and providing a first dissolution specification for the protoptyes and determining from the first testing hardness for the protoypes that complies with the first dissolution specification.
–Using Food to Increase: (US6407128 & US 6,407,128) Elan Pharmaceuticals, Inc) and (King Pharmaceuticals Research Development, Inc) discloses the unexpected finding that administration of metaxalone with food increases both the rate and extent of absorption via the oral dosage form in human subjects. A method is disclosed of increasing the oral bioavailability of metaxalone to a patient receiving metaxalone therapy by administering to the patent a therapeutically effective amount of metaxalone in a pharmacuetical composition with food.
SKELAXIN (400 mg strenght) was approved by the FDA under NDA #13-217, prior to Jan. 1, 1982. In 2002, supplemental NDA #13-217/S-044 (400 mg) and NDA#13-217/S-036 (800 mg), which related to administering SKELAXIN with food were approved.
–Crystalling forms:
(US 2007/0185177A1, Dabur Pharma LTD) discloses crystalling forms of Metaxalone.
(US 2013/0158083, Holland) disclsoes new cocrystals of metaxalone including: a 1:1 metaxalone adipic acid cocrystal, a 1:0.5 metaxalone fumaric acid cocrystal, a 1:1 metaxalone salicyclic acid cocryasl, a 1:0.5 metaxalone succinic acid cocrystal and a 1:0.5 metaxalone maleic acid cocrysalt.
–Nanoparticulate compositions:
(20050063913, Elan Pharma International, Ltd.) discloses nanoparticulate compositions that include metaxalone and at elast one surface stabilizer. The nanoparticulate metaxalone particles have an effective average particle size of less than about 2 microns. The particles offer faster onset of action, potential decrease in the frequency of dosing, smaller doses to obtain the same pharmacological effect, icnreased bioavailability and dissolution and improved performance characteristics for oral, intravenous, subcutaneous or intramuscular injection.
–Controlled Release Compositions:
Controlled release drug delivery systems deliver drug to the body so as to establish therapeutically effective blood levels of the active inredient and once these blood levels are acheived they continue to maintain constant blood dlevels for long duration. By avoiding peaks and troughs in blood levels asociated with conventional dosage forms, they lower the incidence of adverse effects. (US2005/1063839, Sun Pharmaceutical Industries Limited)
(US2005/1063839, Sun Pharmaceutical Industries Limited) discloses an oral controlled release pharmaceutical composition that includes metaxalone. The metaxalone may include any solid particulate form of metaxalone. Crystalline metaxalone when used is preferably micronised.
–Micronized formulations:
(US 2016/0159756, Iceutica Inc.) discloses dosage forms of metaxalone containing submicron particles of metaxalone and uses thereof. The submicron forms have improved bioavaiability compared to certain conventional metaxalone dosage forms. The metaxalone particles can be prepared by dry milling metaxalone in a mill with milling bodies and a gridning matrix.
WO2004/019937 discloses a pharmaceutical composition of metaxalone containing the drug in a micronized form wherein the metaxalone particles are reduced to levels below 10 micrometers of particle diameter, which yealed metaxalone 400 mg tablets with enhanced oral bioavailability asc ompared to SKELAXIN 400 mg tablets.
(US 2006/0167069A1, Sun Pharmaceutical Industries Ltd) discloses a pharmaceutical composition that include metaxalone with enhanced bioavailability as compared to conventional pharmaceutical compositions commercially available. The improved form includes micronised metaxalone, salt form of metaxalone, high-energy crystalling form of metaxalone or amorphous metaxalone. Micronised metaxalone may be obtained either by crystalisation of metaxalone or spray drying or by the use of covnentional milling techniques. Where milling is employed, metaxalone may be micronized to the desired particle size range by milling in mills such as a ball, rod or hammer mill.
(Dodd, US 2012/0160944A1; US 2012/0202694; US 2012/0263760A1) discloses methods for producing nanoparticle and microparticle powders using dry milling processes.
Commercial Formulations:
–Skelaxin (metaxalone): Metaxalone has been marketed under the brand name SKELAXIN in 400 mg and 800 mg tablets. The general dosage for adults and children over 12 years of age is two 400 mg tablets (800 mg) or one 800 mg tablet, three to four times a day. (Elan Pharma International, Ltd). Skelaxin is a brand-name prescription muscle relaxant. It has been made by Upsher-Smith Laboratories, LLC, a U.S. pharmaceutical company. The active ingredient in Skelaxin is metaxalone.
Skelaxin is from the class of medicines called skeletal muscle relaxant and is used to treat symptoms of skeletal muscle conditions such as pain or injury. It is thought to work by blocking nerve impulses (or pain sensations) in the brain. Skelaxin is used together with rest and physical therapy. Skelaxin (metaxalone) was originally marketed by King Pharmaceuticals, but the brand and then by Pfizer, though the 400mg strength is discontinued, with generics available from companies like Lannett and Teva. While Pfizer’s website lists the brand, the original manufacturer’s rights transferred, and now generic metaxalone is common.
The “food effect” with metaxalone (Skelaxin®) means that taking the medication with food—especially a high-fat meal—dramatically increases how much of the drug your body absorbs. When metaxalone is taken on an empty stomach there is lower absorption whereas when it is taken with food, much higher blood levels are achieved. In fact, taking it with a high fat meal can increase the peak concentration (Cmax) to about 2–3 times higher with overall exposure Area Under the Curve (AUC): about 1.5–2 times higher. The downside of this is that with food, the patient is more likely to experience some of the known side effects known to be associated with taking metaxalone such as drowsiness, sedation and impaired coordination. When patients say that “took the same dose as usual, why do I feel so much more sedated?” the answer is often due to the “food effect”. Accordingly, there is a tradeoff dilemma. Taking it with food will increase effectiveness but it will also increase side effects such as drowsiness. It is often recommend to take without a heavy meal if daytime use.
Tizanidine (Zanaflex®):
Tizanidie is a Alpha-2 adrenergic agonist (central acting). It works in the works in the spinal cord and brain to reduce nerve signals that trigger muscle tone.
(US 2019/0060287, Adare Pharmaceuticals, Inc) discloses pharmaceutical compositions that include Tizanidine or a pharmaceutically acceptable salt thereof which controllably modulate the onset of at lest one secondary effect associated with Tizanidine administration. In particular embodiments, the composition includes at elast 3 different compoents: an iimmedaite release component comprising tizanidine, or a phamraceutically aceceptable salt thereof, a first delayed release component that includes tizandidine and a seocnd delaeyd release component that includes tizanidine.
Tizanidine works as an α2-adrenergic agonist (similar family to clonidine). Because of this brain mechanism, it commonly causes sleepiness. In fact, Tizanidine is usually worse for drowsiness than metaxalone. As a result of this side effect, it is often used at night specifically because it makes people sleepy. It is still prescribed because It can be more effective for spasticity (neurologic muscle tightness). Food can also make Tizanidine feel stronger and more sedating, similar in direction to metaxalone
Methocarbamol
Methocarbamol is a carbamate derivative of guaifenesin. Its full chemical name is 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate.
Methocarbamol is a prescription skeletal muscle relaxant used for acute muscle spasms, back/neck strain and muscule pain from injuries. It works centrally in the nervous system to reduce muscle over-activity, but it is not a sedative-hypnotic like tizanidine. Unlike Metaxoline it does not have a huge food effect. However, drowsiness is still a known side-effect.
Pain Signalling Pathways involving Sodium Channels:
Ournavx (suzetrigine -Vertex Pharmaceuticals) 50 milligram oral tablets, a first-in-class non-opioid analgesic, has recently been FDA approved to treat moderate to severe acute pain in adults. Journavx reduces pain by targeting a pain-signaling pathway involving sodium channels in the peripheral nervous system, before pain signals reach the brain. Taken as a pill, it is approved to relive short term pain that typically stems from tissue injury as a result of trauma or surgery.
Tolperisone:
Tolperisone is a centrally-acting muscle relaxant that ahs been used for symptomatic treatment of spaticity and muscle spasm. It has also been used in the treamtent of conditions, which include dysmenorrhea, climacteric compliants, lockjaw, and neurolatyrism. (US 2020/3090754, Nuerana Pharmaceuticals)
Generally, centrally acting muscle relaxants reduce the increased muscle tonus and are typically sedative when used. For example, physicians cite drawsiness as their most common concern when prescribing skeletal muscle relaxants, like cyclobenzaprine hydrochloride (sold under the names FLEXERIL and AMRIX).
US 2020/3090754, Nuerana Pharmaceuticals) disclsoes that tolperisone adminsitration surprisngly had a positive effect on cognitive functio and improves a subject’s alertness when tested, such as when driving performance is tested and reation time is measured. One might expect that the reaciton time following adminsitration of tolperisone would be superior to the reaciton time following adminstiration of cyclobenzaprine. However, it was unexpected that tolperisone demonstrated a superior reaciton time result versus treatment with placebo.