DESC:Field of Invention
The present invention related to nutraceutical composition comprising fixed dose combination of at least one NMDA receptor antagonist and cholecalciferol and process of preparation thereof.
Background of Invention
NMDA receptors are an ionotropic glutamate receptors, which are involved in several physiologic functions and any disruption in their function is thus susceptible of resulting in the manifestation of neuropsychotic or neurological pathologies. These receptors are abundantly distributed throughout the brain and are fundamental to excitatory neurotransmission and critical for normal CNS functions. NMDA receptors require both binding of glutamate and postsynaptic depolarization for their activation, and that mediates Ca2+ entry when they are activated. The ion-channel integral to the NMDA receptor is voltage-dependently blocked by Mg2+, and depolarization removes this block. Under pathological conditions the Mg2+ block and causes an excessive amount of Ca2+ influx into the nerve cell, which then triggers a variety of process which leads to the manifestation of neuropsychotic or neurological pathologies.
Overactivation of NMDA receptors thus results in excessive Ca2+ influx through the receptor’s associated ion channel which can lead to Exitotoxic cell death. Exitotoxicity happens due to excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. It is implied to be involved in multiple neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease etc. Thus blocking of NMDA receptors could therefore, be useful in treating such diseases.
Another disorder associated with over activation of NMDA receptor is depression. Depression is one of the most prevalent mood disorders, affecting more than 300 million people worldwide. It is associated with an increased number of suicide attempts and increase lethality. A plethora of studies have supported the growing evidence of the contribution of a dysfunctional NMDA receptor in depression related disorders. Data generated during the last 4 decades of research on the neurobiological basis of depression suggests that abnormalities within glutamaterigic transmission, especially NMDA receptor over activation, are associated with more generalized mechanisms of brain dysfunction that leads to depressive disorders. Clinical studies have already demonstrated that NMDA receptor antagonists, particularly ketamine, have rapid antidepressant effects.
Thus Excitotoxicity and/or overactication of NMDA receptors represent a potential target for treating multiple neurodegenerative disorders. But the challenge faced in the usage of NMDA receptor antagonist to combat Excitotoxicity and/or overactivation is that the same process that in higher levels leads to cell death due to excitoxicity, at lower or normal levels, are also absolutely necessary for proper neural functioning. Thus a suitable NMDA antagonist will be the one which blocks the excessive NMDAr activity and at the same time allows the functioning of the normal physiological NMDAr activity.
NMDA receptors can be inhibited by competitive antagonist or uncompetitive antagonist with vast divergent detrimental or beneficial outcomes [Lipton, Stuart A.“Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond.” Nature Reviews Drug Discovery 5 (2006): 160-170.]. Competitive antagonist directly competes with glutamate and glycine (NMDA agonist) at the agonist binding site. Thus drugs that directly compete with glutamate and glycine will also block normal functioning of the healthy area of the brain. Competitive antagonists will thus result in intolerable side effects and consequently has failed in clinical trials. [Kemp, J.A. & McKernan, R.M. NMDA Receptor pathway as drug targets. Nat. Neurosci. 5(Suppl.), 1039-1042 (2002); Lipton, S.A. Prospects of clinically tolerated NMDA antagonists: open channel blocker and alternative redox states of nitric oxide. Trends Neurosci 16, 527-532(1993)]. In contrast, uncompetitive inhibitors or open-channel blockers preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Examples of Uncompetitive inhibitors are MK-801, mementine and admantine, which have faster binding and unbinding properties that lead to these compounds spare normal synaptic transmission but diminish excessive activation of the receptor.
Uncompetitive inhibitors like mementine and admantine mimics the physiological function of Mg2+ as channel blocker. [Chen H-S, V. & Lipton S.A. The chemical biology of clinically tolerated NMDA receptor antagonist. Journal of Neurochemistry. 97. 1611-1626, (2006)]. Magnesium ion blocks the ion channel of the NMDA receptor and prevents its excessive activation. Liu et al., reported the modulation of NMDA receptor when Mg2+ and Ketamine were used in combination. Liu and his colleagues found that Mg2+ and Ketamine decrease the half-maximal inhibitory effect concentration >90% at the receptor. But they also reported that in the clinical setting the administration of ketamine with Mg2+ is also exhibited dose-dependent side effects [Liu HT, Hollmann MW, Liu WH, Hoenemann CW, Durieux ME. Modulation of NMDA receptor function by ketamine and magnesium: Part I. Anesth Analg. 92(5):1173-81 (2001)]. Felsby et al. also compared the effect of ketamine and Magnesium in NMDA receptor blockage for treatment of chronic neuropathic pain. Two mechanism of NMDA receptor blockade were investigated: (1) a physiological one using Mg2+ to block the ion channel coupled to NMDA receptor and (2) a blocked for phencyclidine site by ketamine. They reported that while ketamine reduced ongoing pain and the area of allodynia significantly, but Mg2+ failed to reduce pain. It was proposed that the in-effectivity of Magnesium in reducing pain may be due to the concentration of Mg2+ which was too low to produce a sufficient additional lock of the NMDA receptor. [ S. Felsby; J. Nielsen; L. Arendt-Nielsen; T.S. Jensen. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. , 64(2), 0–291. doi:10.1016/0304-3959(95)00113-1(1996)].
Decollogne et al. explored the effect of elevation of the plasma Mg2+ level on several pharmacological and behavioural tests in which the activity of NMDA antagonist has been documented. The results from their study indicated that increasing Mg2+ level in biological fluids has psychopharmacological consequences resembling those achieved after MK-801 administration.
Bartlomiej et al. demonstrated in their study the antidepressent -like activity of magnesium in the animal model of anhedonia, thus indicating the possible involvement of the NMDA/glutamatergic receptors in this activity [Bartlomiej P et al, Antidepressant-like activity of magnesium in the chronic mild stress model in rats: alterations in the NMDA receptor subunits, International Journal of Neuropsychopharmacology, Volume 17, Issue 3, March 2014, Pages 393–405]
Mg2+ thus seems to be a potential antagonist of NMDA receptors which can be used in place of the existing non-competitive NMDA antagonist drug molecules. Several studies have already reported the equivalent action of Mg2+ with the known NMDA antagonist like MK-801 and ketamine.
In vitro, this blockade operates at extracellular Mg2+ concentrations of less than 1mM, which are within the range of those found in the cerebrospinal fluid (CSF) and plasma of humans and animals. It has thus been assumed that at membrane potentials close to resting, NMDA receptors are totally inhibited by Mg2+ present in the extracellular fluids. However experimental data indicate that raising the concentration of Mg2+ above physiological levels causes further antagonism of response to NMDA.
Vitamin D plays critical role in maintaining and regulating normal brain functions and it has been reported that low level of serum vitamin D3 is connected with depression [Y Milaneschi et. al., The association between low vitamin D3 and depressive disorders, Molecular Psychiatry (2013), Pages 1–8]. Behnaz Abiri et.al. studied the effect of vitamin D in obese women with mild to moderate depressive symptoms and reported that supplementing vitamin D significantly lowers the depression score and has a beneficial effect on mood. [Behnaz Abiri et.al., Randomized study of the effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammation, and SIRT1 in obese women with mild to moderate depressive symptoms, Abiri and Vafa Trials (2020) pages 1-7]
Y Milaneschi et. al. compared the level of serum 25-hydroxyvitamin-D [25(OH)D] in patients having remitted and current depression with healthy person and observed that patients with depression have low serum 25(OH)D as compared with healthy person. [Y Milaneschi et. al., The association between low vitamin D and depressive disorders, Molecular Psychiatry (2013), Pages 1–8]
Bogdan Stefanowski et. al., reviewed the effect of vitamin D3 deficiency on the incidence and severity of depressive symptoms and reported that low level of vitamin D3 is likely to be critical link in patients suffering from depression and providing an effective dose of vitamin D3 3,000–6,000 IU per day have a significant antidepressant effect. [Bogdan Stefanowski et.al. The effect of vitamin D3 deficiency on the severity of depressive symptoms. Overview of current research, Psychiatr. Pol. 2017; page 437–454]
Provided the anti-depressant activity of NMDA receptor antagonist and cholecalciferol, it can be used as a potential supplement for ameliorating depressive disorders.
Thus there exist in the art a need for further providing combination which acts synergistically and compliments each other functions thereby providing nutraceutical composition with established safety and tolerability. The synergistic combination of the present invention i.e. at least one magnesium salt and cholecalciferol provides synergistic effects – i) by blocking of NMDA receptors and controlling the excessive Ca2+ influx and ii) by increasing the level of vitamin D respectively.
Object of Invention
The object of the present invention is to provide a nutraceutical composition comprising combination of at least one NMDA receptor antagonist and cholecalciferol for anti-depressant effect and process of preparation thereof. The NMDA receptor antagonist is selected from magnesium (Mg2+) salt wherein salt form is being preferred owing to increased bioavailability.
In particular, the present invention provides a nutraceutical composition comprising a single dose combination of Mg2+ salt(s) and cholecalciferol to have a beneficial effect on depression and ameliorate mood and behaviour.
Another object of the present invention is to provide oral composition comprising a combination of Mg2+ salt and cholecalciferol and pharmaceutically acceptable excipients wherein dual combination of Mg2+ salt is being preferred.
Summary of the Invention
The present invention provides a nutraceutical composition comprising fixed dose combination of magnesium (Mg2+) and cholecalciferol and process of preparation thereof wherein magnesium is present in salt form to improve its bioavailability. The composition of the present invention provides an oral dosage form comprising magnesium salt and cholecalciferol wherein the composition provides anti-depressant effect and have beneficial effect on mood and behaviour. The oral composition of the present invention is in the dosage form of a tablet, capsule, or pills
Detailed Description of the invention
The present invention provides a synergistic nutraceutical composition comprising at least one NMDA receptor antagonist and cholecalciferol for improving mood and have anti-depressant effect. In one embodiment NMDA receptor antagonist is selected from magnesium (Mg2+) salt wherein salt form is being preferred owing to increased bioavailability.
In another embodiment the nutraceutical composition of present invention comprises combination of magnesium salt and cholecalciferol acts synergistically – i) by blocking of NMDA receptors and controlling the excessive Ca2+ influx and ii) by increasing plasma level of vitamin D respectively. The composition may further contain pharmaceutical or nutraceutical acceptable excipients. In one embodiment of the present invention, the composition is present in form of oral dosage form.
In another embodiment of the present invention, the composition is a solid dosage form preferably tablet, capsule, granules, powder, pills or lozenges. In most preferred embodiment, the solid dosage form is tablet.
In one embodiment magnesium is present in salt form to improve its bioavailability wherein Mg2+ salt is selected from sulphate, chloride, oxide, gluconate, citrate, aspartate, glycinate, lactate, malate, threonate, stearate, taurate and combinations thereof. In most preferred embodiment Mg2+ salt is present as l-threonate and/or acetyl taurate.
In one embodiment cholecalciferol is present to supplement vitamin D deficiency in person suffering from depression.
In one embodiment the magnesium salt present in an amount from 5 to 90 %w/w based on total weight of the formulation and preferably in an amount from 5 to 80 %w/w based on total weight of the formulation.
In an another embodiment the present invention provides a tablet composition comprises Magnesium-L-threonate as magnesium salt between 100-300 mg most preferably one tablet comprises 250 mg Magnesium-L-threonate.
In an another embodiment the present invention provides composition comprises Magnesium Taurate as an aditional magnesium salt between 50-100 mg most preferably 75 mg.
In one embodiment cholecalciferol present in an amount ranging 100 to 2,000 IU per serving and preferably in an amount from ranging from 200 to 1,000 IU per serving most preferably 400 IU per serving.
In another embodiment the present invention provides a tablet composition comprising synergistic combination of:
• 250 mg Magnesium-L-Threonate and;
• 75 mg Magnesium Taurate and;
• 400 IU Cholecalciferol
In another embodiment the composition may further comprises pharmaceutically or nutraceutical acceptable excipients selected from the group consisting of diluents, binders, disintegrants, lubricants, glidants, colorant, solvent or anti-adherent and combinations thereof.
Examples of diluents used in the present invention are cellulose derivatives, such as microcrystalline cellulose or wood cellulose, lactose, lactose anhydrous, sucrose, starch, pregelatinized starch, dibasic calcium phosphate, dextrose, mannitol, fructose, xylitol, sorbitol, com starch, modified com starch and combinations thereof. In a preferred embodiment the diluents are selected from microcrystalline cellulose and dibasic calcium phosphate.
Examples of binders used in the present invention are corn starch, polyvinyl pyrrolidone (PVP K12, K17, K25, K30, K60, K90, or K120), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like ethyl cellulose, hydroxymethylcellutose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth and combinations thereof. In a preferred embodiment the binder is Polivinylpyrrolidone (PVPK 30).
Examples of disintegrants used in the present invention are polyvinylpyrrolidone, sodium starch glycolate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, partially pregelatinized starch, carboxymethylsutyl sodium, pregelatinized starch and combinations thereof. In a preferred embodiment the disintegrant is crosscarmellose sodium.
Examples of lubricants used in the present invention are sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, talcum. Silicon dioxide, povidone, Sodium croscarmellose and colloidal anhydrous silica and combinations thereof.
Examples of glidants used in the present invention are colloidal silicon dioxide, talc, starch, starch derivatives and combination thereof. In a preferred embodiment glidant is talc.
In an embodiment the present invention comprises anti-caking agent is Magnesium Aluminometasilicate and antisticking agent is magnesium stearate.
Examples of colorants used in the present invention are iron oxides such as red oxide of iron, yellow oxide of iron, and black oxide of iron; titanium oxide; beta-carotene; Ponceau, Brilliant blue and combinations thereof.
In one embodiment the tablet of present invention may be optionally sugar coated or film coated.
In a preferred embodiment the uncoated tablet was coated with film coating wherein film coating agent is hydroxypropyl methylcellulose (HPMC E15) and coating solvent comprises methylene chloride and isopropyl alcohol.
The nutraceutical compositions of the present invention are prepared by dry or wet processing methods. In a preferred embodiment the tablet composition is prepared by wet granulation.
In an embodiment the present invention provides method of preparation of tablet composition comprising:
• Dry mixing magnesium salts with other excipients;
• Preparing binder preparation by mixing binder with IPA
• Granulating dry mixture with binder solution to obtain wet granulation
• Drying the wet granules and
• Lubricating the dry granules, Cholecalciferol and other excipients with magnesium stearate
• Compressing the lubricated granules and coating the uncoated tablet with film coating.
Methods for compression of tablets are known to a skilled person and may be elected appropriately without undue effort. For example, after mixing of ingredients (in case of direct compression), the powder blend may be directly compressed to obtain a tablet. Methods for compression of granules into tablets are also known to a skilled person, wherein granules are subsequently compressed into tablets. The compression is preferably carried out by either by single punch machine (stamping press) or by multi station machine (rotary press).
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention. The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Examples 1: Formula for 250mg Magnesium-L-Theronate, 75mg Magnesium Taurate and 400IU Cholecalciferol tablet
S no. Ingredients Role Claim per tablet
1. Magnesium -L-Threonate Active Ingredient 250 mg
2. Magnesium Taurate Active Ingredient 75 mg
3. Microcrystalline Cellulose Diluent ---
4. Dibasic Calcium Phosphate (Anhydrous) Diluent ---
5. Isopropyl Alcohol Solvent For Coating ---
6. Polyvinylpyrrolidone (PVPK 30) Binding Agent ---
7. Cholecalciferol Active Ingredient 400 IU
8. Talcum Glidant ---
9. Magnesium Aluminometasilicate (Neusilin US2) Anti-caking agent ---
10. Crosscarmellose Sodium Disintegrant ---
11. Magnesium Stearate Antisticking ---
12. H.P.M.C. (E15) Coating Agent ---
13. Col Indigo Caramine Lake (Roha Dyechem) NA ---
14. Col Brilliant Blue Fcf Lake NA ---
15. Titanium Di Oxide NA ---
16. Poly Ethylene Glycol (PEG 6000) Vehicle ---
17. Talcum Dusting Powder For Coating ---
18. Methylene Chloride Solvent For Coating ---
19. Isopropyl Alcohol Solvent For Coating ---

Example-2
Process for production of tablet of example-1
Magnesium-L-Threonate, Magnesium taurate, microcrystalline cellulose and Dibasic calcium phosphate were sifted and mix through sieve no. 30 and 40 and dry mixed in rapid mixer granulator. The dry mix obtained was granulated with polyvinylpyrrolidone and isopropyl alcohol solution in rapid mixer granulator to obtain wet granules.
The wet granules were dried in fluidised bed dryer and were sized in multi-mill, the obtained dry granules were mixed with cholecalciferol, talc and magnesium Aluminometasilicate and crosscarmellose sodium and lubricated with magnesium.
The lubricated granules were compressed and coated with film coating solution comprising isopropyl alcohol, hydroxypropyl methylcellulose, isopropyl alcohol, Dichloromethane, Polyethylene glycol, talc, titanium oxide and colorant to obtain a film coated tablet.
,CLAIMS:1. A nutraceutical composition comprising a combination of NMDA antagonist and Cholecalciferol, wherein the NDMA antagonist is Magnesium or salts thereof.
2. The nutraceutical composition as claimed in claim 1 wherein the NDMA antagonist is selected from Magnesium-L-threonate and magnesium taurate or a combination thereof
3. The nutraceutical composition as claimed in claim 1 and 2 comprises Magnesium-L-threonate in the amount of 250mg and Magnesium Taurate in the amount of 75mg.
4. The nutraceutical composition as claimed in claim 1 comprises 400 IU of cholecalciferol.
5. The nutraceutical composition as claimed in claim 1 is in the form of solid dosage form is selected from group consisting of tablets, capsules, granules or caplets.
6. The nutraceutical composition as claimed in claim 5 is preferably a tablet composition comprising 250mg of Magnesium-L-threonate, 75 mg of Magnesium Taurate and 400 IU of cholecalciferol
7. The nutraceutical tablet as claimed in claim 6 further comprises one or more pharmaceutically acceptable excipients selected from one or more diluent, binder, glidant, disintegrant, anti-caking agent.
8. The nutraceutical tablet as claimed in claim 7 comprises one or more pharmaceutically acceptable excipients:
• Microcrystalline cellulose and Dibasic calcium phosphate as diluents and;
• Polyvinylpyrrolidone as a binder and;
• Talc as a glidant and;
• Crosscarmellose sodium as a disintegrant and;
• Magnesium aluminometasilicate as an anti-caking agent and;
• Hydroxypropyl methylcellulose as a coating agent
9. The nutraceutical composition as claimed in any of the above claims provides anti-depressant effect and have beneficial effect on mood and behavior.
10. The nutraceutical composition as claimed in any of the above claims is prepared by following method:
i. Dry mixing magnesium salts with microcrystalline cellulose and Dibasic calcium phosphate and;
ii. Granulating the dry missing with binder solution comprising polyvinylpyrrolidone and isopropyl alcohol and;
iii. Drying the wet granules and lubricate the dry granules, Cholecalciferol, talc, Magnesium Aluminometasilicate, crosscarmellose sodium with magnesium stearate
iv. Compressing the lubricated granules into table and coating the uncoated tablet with film coating.