Claims:1. A pharmaceutical composition comprising Acetyl carnitine, Vitamin E and Palmitoylethanolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of powder, granules, pellets, tablets, caplets, mini- tablets, and sachets.

3. The pharmaceutical composition as claimed in claim 1, wherein the acetyl carnitine or pharmaceutically acceptable salts thereof is present in at least 75% by total weight of the composition.

4. The pharmaceutical composition as claimed in claim 1, wherein the palmitoylethanolamide or pharmaceutically acceptable salts thereof is present in at least 20% by total weight of the composition

5. The rapidly dispersible pharmaceutical composition as claimed in claim 1, wherein the Vitamin E or pharmaceutically acceptable salts thereof is present in at least 15% by total weight of the composition.

6. A process for preparing a pharmaceutical composition as claimed in claim 1, the process comprising mixing Acetyl carnitine, Vitamin E and palmitoylethanolamide or pharmaceutically acceptable salts thereof with one or more other pharmaceutically acceptable excipients.

7. A process for the preparation of a pharmaceutical composition of Acetyl carnitine, Vitamin E and palmitoylethanolamide or pharmaceutically acceptable salts thereof, the process comprising:
(a) preparing a blend of Acetyl carnitine, Vitamin E and palmitoylethanolamide or pharmaceutically acceptable salts thereof, one or more sweetener/s, one or more flavoring agent/s and optionally one or more pharmaceutically acceptable excipients; (b) granulating the blend of step (a) using water to form granules; and (c) formulating the granules prepared in step (b) into a suitable dosage form, wherein the composition is free of any organic/inorganic acid.

8. The pharmaceutical composition as claimed in claim 11, wherein the Acetyl carnitine, Vitamin E and palmitoylethanolamide or pharmaceutically acceptable salts thereof comprises about 83.33% by weight of the tablet.

9. A method of treating fibromyalgia, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising Acetyl carnitine, Vitamin E and palmitoylethanolamide or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

, Description:Field of the Invention
The present invention relates to a pharmaceutical dosage form comprising Acetyl L Carnitine, Palmitoylethanolamide and Vitamin E and phamaceutically acceptable excipients for the treatment of Fibromyalgia and neuropathic pain. This invention also relates to methods for preparing the immediate release dosage form of Acetyl L Carnitine, Palmitoylethanolamide and Vitamin E or its pharmaceutically acceptable salts.
Background of the Invention
Neuropathic pain is often defined as a shooting or burning pain and often is the consequence of nerve damage or a malfunctioning nervous system. The effect of nerve damage is a variation in nerve function both at the site of the injury and areas around it. Symptoms of Neuropathic Pain may include shooting and burning pain, Tingling and numbness.
Fibromyalgia is also called fibromyalgia syndrome. People with fibromyalgia experience aches and pain all over the body, fatigue (extreme tiredness that does give better sleep or rest), and problems in sleeping. Fibromyalgia may be caused by a problem in the brain with nerves and pain signals. In other words, in people with fibromyalgia, the brain misunderstands everyday pain and other sensory experiences, making the person more sensitive to pressure, temperature (hot or cold), bright lights, and noise compared to people who do not have fibromyalgia (Hudson JI, Pope HG. The concept of affective spectrum disorder: relationship to fibromyalgia and other syndromes of chronic fatigue and chronic muscle pain. Baillieres Clin Rheumatol 1994; 8(4): 839–856).
Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory and mood issues. Researchers believe that fibromyalgia amplifies painful sensations by affecting the way your brain processes pain signals.
Chronic (long-term), widespread pain is the most common symptom of fibromyalgia. The pain may feel like a deep muscle ache, or it may throb or burn. Other symptoms of fibromyalgia include:Extreme tiredness, called fatigue, that does not get better with sleep or rest, Cognitive and memory problems (sometimes called “fibro fog”), Trouble sleeping, Mood problems, Morning fatigue, Muscle fatigue, Headaches, Irritable bowel syndrome (IBS), Painful menstrual periods, Numbness or tingling of hands and feet, Restless legs syndrome, Temperature sensitivity, Sensitivity to loud noises or bright lights and Depression or anxiety. Women with fibromyalgia often have more morning fatigue, pain all over the body, and IBS symptoms than men with fibromyalgia.
Symptoms of fibromyalgia include: Widespread pain, Fatigue and Cognitive difficulties. Fibromyalgia often co-exists with other painful conditions, such as: Irritable bowel syndrome, Migraine and other types of headaches, Interstitial cystitis or painful bladder syndrome and Temporomandibular joint disorders (Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014; 311(15): 1547–1555).
Palmitoylethanolamide (PEA) belong to endocannabinoid family, a group of fatty acid amides. PEA has been proven to have analgesic and anti-inflammatory activity and has been used in several controlled studies focused on the management of chronic pain among adult patients with different underlying clinical conditions.
Palmitoylethanolamide (PEA) is a cannabimimetic compound and lipid messenger hypothesized to reduce pain through a variety of endocannabinoid driven activities that were discussed earlier or reducing inflammation. PEA does not bind the classical cannabinoid receptors but may indirectly stimulate the effects of both phyto- or endocannabinoids, either by its role as an agonist of the transient receptor potential vanilloid type 1 (TRPV1), peroxisome proliferator-activated receptor-a (PPAR-a) and the cannabinoid receptors. PEA’s analgesic actions may be due to its agonism of peroxisome proliferatoractivated receptor-a (PPAR-a) which has been shown to have a pivotal role in the PEA pharmacodynamic mechanisms for pain relief. PEA plays an important role in suppression of inflammation by reducing the activity of the pro-inflammatory enzymes such as COX, eNOS, and iNOS and by reducing mast cell activation (Clinical applications of palmitoylethanolamide in pain management: protocol for a scoping review, Maria Beatrice Passavanti et al., Systematic Reviews volume 8, Article number: 9 (2019).
Palmitoylethanolamide is used for pain, neuropathic pain, fibromyalgia, multiple sclerosis (MS), carpal tunnel syndrome, infections of the airway, and many other conditions, but there is no good scientific evidence to support these uses.
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, an analog of the endocannabinoid anandamide (AEA), that belongs to the family of N-acylethanolamines (NAE). NAEs are released from cells in response to noxious stimuli. As all NAEs, also the PEA has a local effect, and its tissue levels are closely regulated through the balance of production and degradation activity. Two intracellular amidases, expressed in the inflammatory cells, have been involved in lipid amide degradation: fatty-acid amide hydrolase (FAAH) and N-acylethanolamine hydrolyzing acid amidase (NAAA).
The effects of the PEA are due to its interaction with several pathways: at first, it reduces, via the peroxisome proliferator-activated receptor alpha (PPARa), the recruitment and activation of mast cells at sites of nerve injury and the release of pro-inflammatory mediators from these cells; secondly, it inhibits the microglia activation and the recruitment of mast cells into spinal cord after peripheral nerve injury, as well as following spinal neuroinflammation or spinal cord injury. In the beginning, PEA was also supposed to be an agonist of the cannabinoid type II receptor (CB2); subsequently, in their research, Sugiura et al. have demonstrated that PEA has just a very low affinity for this receptor, clarifying why CB2 antagonists do not inhibit some of its anti-inflammatory effects. Anyhow, PEA indirectly activates CB2 and the cannabinoid receptor type 1 (CB1), down-modulating fatty acid amide hydrolase (FAAH), the enzyme responsible of the degradation of the anandamide (AEA), a CB1 agonist.
Acetyl-L-carnitine improves memory and mental function in older people with some memory loss. It improves feelings of mental and physical tiredness in older people. It also appears to reduce feelings of tiredness after exercise.Acetyl-L-carnitine might slow the rate of disease progression, improve memory, and improve some measures of mental function and behavior in some patients with Alzheimer disease. It is more likely to help those with early-onset Alzheimer disease who are less than 66 years of age and have a faster rate of disease progression and mental decline. It improves memory in 30-60 year-old people with long-term thinking problems due to alcohol use. Acetyl-L-carnitine seems to improve symptoms in people with nerve pain caused by diabetes (Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Malaguarnera M etal. .Scand J Gastroenterol. 2011 Jun;46(6):750-9).
.
Vitamin E is an ingredient in many skincare products; especially those that claim to have anti-aging benefits. Vitamin E supplements may prevent coronary heart disease, support immune function, prevent inflammation, promote eye health, and lower the risk of cancer (Meydani M. Vitamin E. Lancet. 1995;345:170–5).
Vitamin E is a vitamin that dissolves in fat. It is found in many foods including vegetable oils, cereals, meat, poultry, eggs, fruits, vegetables, and wheat germ oil. It is also available as a supplement.
Vitamin E is an important vitamin required for the proper function of many organs in the body. It is also an antioxidant. This means it helps to slow down processes that damage cells.An inherited condition that affects motor control (ataxia with vitamin E deficiency or AVED). The genetic movement disorder called ataxia causes severe vitamin E deficiency. Vitamin E supplements are used as part of the treatment for ataxia.Vitamin E taken along with standard treatment is better than standard treatment alone for reducing pain in people with Rheumatoid arthritis (RA). However, this combination doesn't reduce swelling.
Objective of the Invention
The object of the present invention is to prepare pharmaceutical dosage forms of Acetyl L Carnitine, Palmitoylethanolamide and Vitamin E.
Another objective of the present invention is to provide a pharmaceutical composition comprising Acetyl L Carnitine, Palmitoylethanolamide and Vitamin E for the treatment of Fibromyalgia and neuropathic pain.
Yet another objective of the present invention is to provide a pharmaceutical composition comprising Acetyl L Carnitine, Palmitoylethanolamide and Vitamin E and one or more pharmaceutically acceptable excipientsfor the treatment of Fibromyalgia and neuropathic pain.
In one general aspect, there is provided a solid oral pharmaceutical composition comprising:(a) at least one first component comprising acetyl carnitine or salts thereof and one or more pharmaceutical excipients exhibiting immediate release;(b) at least one second component comprising palmitoylethanolamide or salt thereof and one or more pharmaceutical excipients exhibiting immediate release, and(c) at least one third component comprising vitamin E and one or more pharmaceutical excipients exhibiting immediate release.
In another general aspect, the solid oral pharmaceutical composition is in the form of a multilayer tablet, a bilayer tablet or a tri-layer tablet.
In another general aspect, the amount of acetyl carnitine in the pharmaceutical composition from about 1% to about 20% by total amount of acetyl carnitine or salt thereof in the composition.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides apharmaceutical composition comprising acetyl carnitine, palmitoylethanolamide and vitamin E or its pharmaceutically acceptable salts comprising one or more pharmaceutically acceptable excipients.
Detailed Description of the Invention
The term pharmaceutically acceptable excipients as used in this invention comprise binders, fillers, lubricants, glidants and the like.
Suitable binders according to the present invention are selected from methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, starch, pregelatinized starch, agar, tragacanth or sodium alginate.
Suitable fillers used according to the present invention are selected from calcium phosphate-dibasic, cellulose-microcrystalline, cellulose powdered, calcium silicate, polyols such as mannitol, sorbitol, xylitol, maltitol, sucrose and combinations thereof.
Suitable lubricants according to the present invention are selected from talc, magnesium stearate, stearic acid, zinc stearate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and suitable glidants include colloidal silicon dioxide or talc.
Suitable hydrophilic polymers according to present invention are selected from polyvinylpyrrolidone, alginate or its salts; xanthan gum, cellulose polymer such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, methylcellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose and the like; polyethylene oxide, carbopol, pectin, galactomannan, or polyethylene glycol (PEG).
The present invention provides a simple, non-complex and more economic process for the preparation of an immediate Release dosage form, which comprises the steps of:
i) sifting Vitamin E, Palmitoylethanolamide and acetylcarnitine and fillers,
ii) mixing the sifted materials of step (i) in a rapid mixer granulator,
iii) granulating the blend of step (ii) with a solution of binder,
iv) drying the wet mass of step (iii) in a fluid bed drier,
v) milling the dried granules,
vi) optionally mixing the dried granules with inorganic silicates, polymers and fillers,
vii) lubricating the blend of step (vi) with lubricants and
compressing the lubricated blend of step (vii) to get tablets of Palmitoylethanolamide, Acetyl L carnitine and Vitamin E.
The following examples further exemplify the inventions and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
Example 1
Acetyl L Carnitine 500mg
Palmitoylethanolamide 150mg
Vitamin E 50% 100mg
The processing steps that are involved in examples 1 is
i) sifted Acetyl L Carnitine, Palmitoylethanolamide and Vitamin E, magnesium aluminum silicate, xanthan gum, and carbopol 971 P through #40 mesh,
ii) loaded the material of step (i) in RMG and mixed for 15 minutes,
iii) dissolved hydroxypropyl cellulose in sufficient quantity of IPA:water
iv) added the binder solution of step (iii) to dry mix of step (ii) and continued mixing until granules of uniform consistency were obtained,
v) granules were dried, milled and lubricated,
vi) Granules of step (v) were compressed to form tablets of Palmitoylethanolamide, Acetyl L carnitine and Vitamin E.