Claims:WE CLAIM:
1. A herbal composition comprising:
a. tagar extract an amount ranging from 10.0 to 20.0 w/w%;
b. jatamansi extract in an amount ranging from 10.0 to 18.0 w/w%;
c. ashwagandha extract in an amount ranging from 25.0 to 35.0 w/w%;
d. nutmeg extract in an amount ranging from 0.5 to 5.0 w/w%;
e. bramhi extract in an amount ranging from 10.0 to 18.0 w/w%; and
f. shankhpushpi extract in an amount ranging from 20.0 to 30.0 w/w%;
wherein, said composition enhances mean sleep efficiency of the subject being administered with said composition in the range of 75.0 to 95.0%.
2. The herbal composition as claimed in claim 1, wherein said composition further comprises one or more pharmaceutically acceptable excipients/s.

3. The herbal composition as claimed in claim 1, wherein said composition provides at least one of
a. reduces Pittsburg Sleep Quality Index of the subject being administered with said composition by at least 50%;
b. reduces Insomnia Severity Index of the subject being administered with said composition by 10 to 70%; and
c. reduces mean time to sleep onset of the subject being administered with said composition by at least 30 mins.
4. The herbal composition as claimed in claim 1, wherein
a. tagar extract is obtained froma plant partusinga solution of water and ethanol,particularly,70% ethanol+ 30% water-as extracting solvent;
b. jatamansi extract is obtained from roots using a solution of water and ethanol, particularly,50% ethanol+ 50% water-as extracting solvent;
c. ashwagandha extract is obtained from roots using a solution of water and ethanol, particularly, 70% ethanol+ 30% water-as extracting solvent;
d. nutmeg extract is obtained from roots using a solution of water and ethanol, particularly, 50% ethanol+ 50% water-as extracting solvent;
e. brahmi extract is obtained from whole plant using water as extracting solvent; and
f. shankhpushpi extract is obtained from roots using a solution of water and ethanol, particularly, 70% ethanol+ 30% water-as extracting solvent.

5. The herbal composition as claimed in claim 2, wherein the pharmaceutically acceptable excipient is selected from the group consisting of disintegrating agents, diluents, gliding agents, lubricating agents, film forming agents, plasticizing agents, coloring agents, opacifying agents, anti-caking agent and preservatives.
6. The herbal composition as claimed in claim 5, wherein
i. the disintegrating agent is selected from the group consisting of crospovidone, sodium starch, croscarmelose sodium, maize starch, and pregelatinised starch;
ii. the diluent is selected from the group consisting of microcrystalline cellulose glycolate, mannitol, dibasic calcium phosphate, sorbitol, and lactose;
iii. the gliding agent is selected from the group consisting of micronised silica, colloidal silicondioxide, talc, and magnesium carbonate;
iv. the lubricating agent is selected from the group consisting of magnesium stearate, stearic acid, and sodium stearyl fumarate;
v. the film forming agent is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, iron oxide yellow, polyvinyl alcohol, polyethylene glycol, and polysorbate 80;
vi. the plasticizing agent is selected from the group consisting of polyethylene glycol 4000, glycerine, propylene glycol, and diethyl phthalate;
vii. the coloring agent is selected from the group consisting of iron yellow oxide, brilliant blue, allura red, erythrosine, and sunset yellow;
viii. the opacifying agent is titanium dioxide;
ix. the anti-caking agent is selected from the group consisting of talc, colloidal silicon dioxide, and magnesium stearate; and
x. the preservative is selected from the group consisting of methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, citric acid, and sodium citrate.
7. A tablet composition comprising:
i. 9.0 to 11.0 w/w% of tagar extract;
ii. 8.0 to 10.0 w/w% of jatamansi extract;
iii. 19.0 to 21.0 w/w% of ashwagandha extract;
iv. 1.0 to 3.0 w/w% of nutmeg extract;
v. 8.0 to 10.0 w/w% of bramhi extract;
vi. 15.0 to 17.0 w/w% of shankhpushpi extract;
vii. 9.0 to 11.0 w/w% of crospovidone;
viii. 8.0 to 10.0 w/w% of sodium starch glycolate;
ix. 12.5 to 14.5 w/w% of microcrystalline cellulose;
x. 0.02 to 0.04 w/w% methyl paraben;
xi. 0.001 to 0.006 w/w% of propyl paraben;
xii. 0.5 to 2.0 w/w% of micronized silica;
xiii. 0.8 to 1.0 w/w% of magnesium stearate;
xiv. 1.5 to 2.0 w/w% of hydroxypropyl methyl cellulose;
xv. 0.2 to 0.4 w/w% of polyethylene glycol 4000;
xvi. 0.03 to 0.05 w/w% of titanium dioxide;
xvii. 0.03 to 0.05 w/w% of talc; and
xviii. 0.1 to 0.3 w/w% of coloring agent.
8. A composition comprising:
i. 13.0 to 15.0 w/w% of tagar extract;
ii. 12.0 to 14.0 w/w% of jatamansi extract;
iii. 27.0 to 30.0 w/w% of ashwagandha extract;
iv. 2.0 to 4.0 w/w% of nutmeg extract;
v. 12.0 to 14.0 w/w% of bramhi extract;
vi. 21.0 to 24.0 w/w% of shankhpushpi extract;
vii. 2.0 to 10.0 w/w% of microcrystalline cellulose;
viii. 0.5 to 1.5 w/w% of croscarmellose sodium;
ix. 0.02 to 0.04 w/w% methyl paraben;
x. 0.003 to 0.008 w/w% of propyl paraben;
xi. 0.4to 1.0 w/w% anhydrous colloidal silica;and
xii. 0.5to 1.5w/w% magnesium stearate.
9. The stable herbal composition as claimed in claims 7 and 8, wherein said composition provides at least one of
a. enhances mean sleep efficiency of the subject being administered with said composition in the range of 75.0 to 95.0%;
b. reduces Pittsburg Sleep Quality Index of the subject being administered with said composition by at least 50%;
c. reduces Insomnia Severity Index of the subject being administered with said compositionby 10 to 70%; and
d. reduces mean time to sleep onset of the subject being administered with said composition by at least 30 mins.
10. A process for preparing the tablet composition claimed in claim 7, said process comprising the steps of:
a. obtaining a mixture of a) 9.0 to 11.0 w/w% of tagar extract; b) 8.0 to 10.0 w/w% of jatamansi extract, c) 19.0 to 21.0 w/w% of ashwagandha extract, d) 1.0 to 3.0 w/w% of nutmeg extract, e) 8.0 to 10.0 w/w% of bramhi extract, f) 15.0 to 17.0 w/w% of shankhpushpi extract,8.0 to 10.0 w/w% of microcrystalline cellulose, 7.0 to 10.0 w/w% of crospovidone and6.0 to 8.0 w/w% of sodium starch glycolate;
b. adding a solution of isopropyl alcohol, 0.02 to 0.04 w/w% methyl paraben and 0.001 to 0.006 w/w% of propyl paraben and kneading till the granules are formed, with optional addition of water;
c. drying the granules at a temperature ranging from 25 to 60 oC till loss on drying is in the range of 3.0 to 4.0 w/w%;
d. sifting the granules to obtain uniform sized granules;
e. lubricating the granules by mixing with 2.0 to 4.0 w/w% of crospovidone, 2.0 to 4.0 w/w% of sodium starch glycolate, 2.0 to 4.0 w/w% of microcrystalline cellulose, 0.5 to 2.0 w/w% of micronized silica to obtain lubricated granules;
f. compressing lubricated granules to obtain a tablet of predetermined shape and size; and
g. coating the tablet with a coating suspension obtained by mixing isopropyl alcohol, 0.2 to 0.4 w/w% of polyethylene glycol, 1.5 to 2.0 w/w% of hydroxypropyl methyl cellulose, 0.03 to 0.05 w/w% of titanium dioxide, 0.03 to 0.05 w/w% of talc, 0.1 to 0.3 w/w% of coloring agent and methylene chloride.
11. A process for preparing the composition claimed in claim 8, said process comprising the steps of:
i. obtaining a mixture of a) 13.0 to 15.0 w/w% of tagar extract; b) 12.0 to 14.0 w/w% of jatamansi extract, c) 27.0 to 30.0 w/w% of ashwagandha extract, d) 2.0 to 4.0 w/w% of nutmeg extract, e) 12.0 to 14.0 w/w% of bramhi extract, f) 21.0 to 24.0 w/w% of shankhpushpi extract, 2.0 to 10.0 w/w% of microcrystalline cellulose, and 0.5 to 1.5 w/w% of croscarmellose sodium;
ii. adding a solution of isopropyl alcohol, 0.02 to 0.04 w/w% methyl paraben and 0.003 to 0.008 w/w% of propyl paraben and kneading till the granules are formed, with optional addition of water;
iii. drying the granules at a temperature ranging from 25 to 60 oC till Loss on Drying (LOD) is in the range of 3.0 to 4.0 w/w%;
iv. sifting the dried granules to obtain uniform sized granules; and
v. lubricating the uniformed sized granules by mixing 0.4 to 1.0 w/w% anhydrous colloidal silica, 0.5 to 1.5 w/w% magnesium stearate to obtain the composition and optionally filling into a capsule shell or a pouch or a sachet or a box.
, Description:FIELD OF THE INVENTION:
The present invention relates to a herbal composition for addressing insomnia and insomnia related symptoms and the process for preparing the same. The present invention further relates to a combination of herbal extracts which are used in the herbal composition.
BACKGROUND OF THE INVENTION:
Insomnia is most frequent disorder of sleep. It consists of the inability to get sleep and stay asleep and/or obtain the adequate duration and quality of sleep to restore normal states of energy and wakefulness. Due to improper sleep, subjects with insomnia do not feel refreshed leading to fatigue and other symptoms.
One of the ways of addressing insomnia is to administer synthetically prepared drugs. The problem associated with the administration of the drug is that it is likely to cause side effects and have possibility of being habit forming and can be used for abuse. In order to avoid such side effects, persons suffering from insomnia tend towards herbal or ayurvedic treatment which are perceived to have no known side effects. Ayurvedic texts merely lists out a minimum of 39plants which would be beneficial in sleep and sleep related condition. They are Acorus calamus, Alistonia scholaris, Anacardium occidentale, Areca catechu, Artabotrys hexapetalus, Artemesia capillaries, Azadirachta india, Bacopa monnieri, Boswellia serrata, Calophyllumino phyllum, Canabis sativa, Canscora decussate, Catharanthus roseus Linn, Carviacallosa (Nees) Bremek, Cassia fistula Linn, Cedrusdeodara Roxb, Celastrus paniculatus Willd, Centella asiatica Linn, Cissus repens Lamk, Clerodendrum phlomidis Linn, Convolvulus prostrates Forssk, Clitoria ternatea Linn, Cymbopogon citratus Stapf, Cyperus rotundus Linn, Derris indica Lamk, Delphinium denudatum Wall, Diploknema butyracea Roxb(Ethanolic extract of the seeds), Erithrina indica Lam, Nardostachys jatamansi DC, Nelumbo nucifera Gaertn, Valeriana Jatamansi Jones, Withania somnifera Linn, Papaver somniferum Linn, Piper nigrum Linn, Myristica fragrans Houtt, Nyctanthes arbortristis Linn, and Rauvolfia serpentine.
These texts do not disclose or suggest the number of plant extracts to be combined and the proportion of individual component that would be best suited in a combination for inducing sleep and providing relief in loss of health due to sleep. Sleep is induced due to multiple factors and a polyherbal preparation acting of different pathways would be best suited to induce sleep than a single herb.
A combination of herbal extracts can be a remedy for addressing insomnia and related to sleep disorder. However, which type of extract of which plant would be most suitable for the desired effected is not mentioned or suggested in the available literature. A combination of herbal extract per se is not stable as itis extremely hygroscopic and does not have requisite flow properties to make them suitable for use as such in any pharmaceutical acceptable dosage form. Further, the extracts may be incompatible either with each other or with pharmaceutical excipients.
Additionally, the herbal or ayurvedic ingredients are also not easy to process into modern dosage form as tablets and capsules for the reason that the tablets and the capsules prepared using these ingredients have least disintegration properties and hence do not release ingredients responsible for pharmacological action.
Therefore, there is a need of stable herbal or ayurvedic composition comprising one or more herbal extracts which obviates rebound of insomnia and addresses insomnia related symptoms.
In view of the above need the present inventions envisages a herbal composition for addressing insomnia and insomnia related symptoms.
OBJECTIVE OF THE INVENTION:
It is an objective of the present invention to provide a composition directed towards inducing sleep.
It is another objective of the present invention to provide a composition for maintenance of sleep which promotes quality and restful sleep.
It is further objective of the present invention to provide a composition which alleviates insomnia related symptoms such as daytime fatigue, daytime mood, ability to function at work, concentration and memory.
It is still further objective of the present invention to provide a composition which obviates rebound of insomnia and insomnia related symptoms.
It is still further objective of the present invention to provide a process for preparing the composition directed towards inducing sleep.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a herbal composition that is effective in promoting sleep thereby inducing a person to fall asleep and maintain sleep.
The present invention provides a herbal composition which comprises plurality of extracts in a very specific proportion effective to provide at least one of the effect selected from the group of promote sleep, relieve pain, and obviate rebound of insomnia and insomnia related symptoms even after the administration of the herbal composition is stopped.
The present invention also provides a stable herbal composition in which the herbal extracts remain stable without deteriorating in its quality and quantity.
DETAILED DESCRIPTION OF THE INVENTION:
To achieve the above mentioned objectives, the present invention provides a herbal composition comprising a) tagar extractin amount ranging from 10.0 to 20.0 w/w%; b) jatamansi extract in an amount ranging from 10.0 to 18.0 w/w%; c) ashwagandha extract in an amount ranging from 25.0 to 35.0 w/w%; d) nutmeg extract in an amount ranging from 0.5 to 5.0 w/w%; e) bramhi extract in an amount ranging from 10.0 to 18.0 w/w%; and f) shankhpushpi extract in an amount ranging from 20.0 to 30.0 w/w.
The herbal composition may further comprise one or more pharmaceutically acceptable excipients/s.
The herbal composition of the present invention induces sleep wherein the mean sleep efficiency of the subject being administered with said composition is enhanced by 75.0 to 95.0%.
The herbal composition of the present invention has a positive impact on enhancing the quality of sleep which is realised by reduction of at least one of the following;
a. Pittsburg Sleep Quality Index;
b. Insomnia Severity Index; and
c. mean time to sleep onset.
In one embodiment reduction in Pittsburg Sleep Quality Index of the subject being administered with the composition of the present invention is at least by 50%.
In another embodiment reduction in Insomnia Severity Index of the subject being administered with the composition of the present invention is at least by 10 to 70%.
In yet another embodiment reduction in mean time to sleep onset of the subject being administered with the composition of the present invention is at least by 30 mins.
The plant part and the solvent used for extraction can be critical to the composition. The plant part used for extracting the herbal extracts useful for the purpose of the present invention can be root, branch, stem, bark, flower, fruit, leaves, shots, twigs and combinations thereof.
In one embodiment tagar extract used in the composition of the present invention is obtained from roots using a solution of water and ethanol, particularly, 70% ethanol+ 30% water-as extracting solvent.
In one embodiment jatamansi extract used in the composition of the present invention is obtained from roots using a solution of water and ethanol, particularly, 50% ethanol+ 50% wateras extracting solvent.
In one embodiment ashwagandha extract used in the composition of the present invention is obtained from roots using a solution of water and ethanol, particularly, 70% ethanol+ 30% water-as extracting solvent.
In one embodiment nutmeg extract used in the composition of the present invention is obtained from roots using a solution of water and ethanol, particularly, 50% ethanol+ 50% water as extracting solvent.
In one embodiment brahmi extract used in the composition of the present invention is obtained from whole plant using water as extracting solvent.
In one embodiment shankhpushpi extract used in the composition of the present invention is obtained from roots using a solution of water and ethanol, particularly, 70% ethanol+ 30% water-as extracting solvent.
The extracts of these herbs are usually not stable in the composition and therefore to arrive at a stable composition either in a form of tablet or capsule can be a challenge. The inventors of the present invention used the pharmaceutically acceptable excipient which includes but is not limited to disintegrating agents, diluents, gliding agents, lubricating agents, film forming agents, plasticizing agents, coloring agents, opacifying agents, anti cacking agent and preservatives in specific proportion to arrive, after several unsuccessful attempts, at the stable composition.
Non-limiting examples of the disintegrating agent include crospovidone, sodium starch glycolate, croscarmelose sodium, maize starch, and pregelatinised starch.
Non-limiting examples of the diluents include microcrystalline cellulose glycolate, mannitol, dibasic calcium phosphate, sorbitol, and lactose.
Non-limiting examples of the gliding agent include micronised silica, colloidal silicondioxide, talc, and magnesium carbonate.
Non-limiting examples of the lubricating agent include magnesium stearate, stearic acid, and sodium stearyl fumarate.
Non-limiting examples of film forming agent include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, iron oxide yellow, polyvinyl alcohol, polyethylene glycol, and polysorbate 80.
Non-limiting examples of the plasticizing agent include polyethylene glycol 4000, glycerine, propylene glycol, and diethyl phthalate.
Non-limiting examples of the coloring agent include iron yellow oxide, brilliant blue, allura red, erythrosine, and sunset yellow.
Non-limiting examples of the opacifying agent is titanium dioxide.
Non-limiting examples of the anti-caking agent include talc, colloidal silicon dioxide, and magnesium stearate.
Non-limiting examples of the preservative include methyl paraben, propyl paraben, sodium benzoate, potassium sorbate, citric acid, and sodium citrate.
In one embodiment, a stable herbal composition of the present invention is in the form of a tablet comprising:
i. 9.0 to 11.0 w/w% of tagar extract;
ii. 8.0 to 10.0 w/w% of jatamansi extract;
iii. 19.0 to 21.0 w/w% of ashwagandha extract;
iv. 1.0 to 3.0 w/w% of nutmeg extract;
v. 8.0 to 10.0 w/w% of bramhi extract;
vi. 15.0 to 17.0 w/w% of shankhpushpi extract;
vii. 9.0 to 11.0 w/w% of crospovidone;
viii. 8.0 to 10.0 w/w% of sodium starch glycolate;
ix. 12.5 to 14.5 w/w% of microcrystalline cellulose;
x. 0.02 to 0.04 w/w% methyl paraben;
xi. 0.001 to 0.006 w/w% of propyl paraben;
xii. 0.5 to 2.0 w/w% of micronized silica
xiii. 0.8 to 1.0 w/w% of magnesium stearate;
xiv. 1.5 to 2.0 w/w% of hydroxypropyl methyl cellulose;
xv. 0.2 to 0.4 w/w% of polyethylene glycol 4000;
xvi. 0.03 to 0.05 w/w% of titanium dioxide;
xvii. 0.03 to 0.05 w/w% of talc; and
xviii. 0.1 to 0.3 w/w% of coloring agent.
In another embodiment, a stable herbal composition of the present invention is in the form of a comprising:
i. 13.0 to 15.0 w/w% of tagar extract;
ii. 12.0 to 14.0 w/w% of jatamansi extract;
iii. 27.0 to 30.0 w/w% of ashwagandha extract;
iv. 2.0 to 4.0 w/w% of nutmeg extract;
v. 12.0 to 14.0 w/w% of bramhi extract;
vi. 21.0 to 24.0 w/w% of shankhpushpi extract;
vii. 2.0 to 10.0 w/w% of microcrystalline cellulose;
viii. 0.5 to 1.5 w/w% of croscarmellose sodium;
ix. 0.02 to 0.04 w/w% methyl paraben;
x. 0.003 to 0.008 w/w% of propyl paraben;
xi. 0.4 to 1.0 w/w% anhydrous colloidal silica; and
xii. 0.5 to 1.5 w/w% magnesium stearate.
The stable herbal composition of the present invention has a positive impact on enhancing the quality of sleep which is realised by reduction of at least one of the following;
a. Pittsburg Sleep Quality Index;
b. Insomnia Severity Index; and
c. mean time to sleep onset.
In one embodiment reduction in Pittsburg Sleep Quality Index of the subject being administered with the stable herbal composition of the present invention is at least by 50%.
In another embodiment reduction in Insomnia Severity Index of the subject being administered with the stable herbal composition of the present invention is at least by 10 to 70%.
In yet another embodiment reduction in mean time to sleep onset of the subject being administered with the stable herbal composition of the present invention is at least by 30 mins.
The present invention also relates to a process for preparing a stable herbalcomposition in a tablet or a fill able powder in a capsule shell or a pouch or a sachet or a box. The process for preparing the stable herbal composition in a tablet form is described herein after.
Initially, a mixture of a) 9.0 to 11.0 w/w% of tagar extract; b) 8.0 to 10.0 w/w% of jatamansi extract, c) 19.0 to 21.0 w/w% of ashwagandha extract, d) 1.0 to 3.0 w/w% of nutmeg extract, e) 8.0 to 10.0 w/w% of bramhi extract, f) 15.0 to 17.0 w/w% of shankhpushpi extract, 8.0 to 10.0 w/w% of microcrystalline cellulose, 7.0 to 10.0 w/w% of crospovidone and6.0 to 8.0 w/w% of sodium starch glycolate is obtained.
To the mixture, a solution of isopropyl alcohol, 0.02 to 0.04 w/w% methyl paraben and 0.001 to 0.006 w/w% of propyl paraben is added followed by kneading till the granules are formed. Water may be added to prepare granules, if required.

The granules are dried at a temperature ranging from 25 to 60oC till Loss on Drying (LOD) is in the range of 3.0 to 4.0 w/w% at 105 oC. The dried granules are sifted to obtain uniform sized granules. Then the uniformed sized granules are lubricated by mixing 2.0 to 4.0 w/w% of crospovidone, 2.0 to 4.0 w/w% of sodium starch glycolate, 2.0 to 4.0 w/w% of microcrystalline cellulose, and 0.5 to 2.0 w/w% of micronized silica to obtain lubricated granules which are compressed to obtain a tablet of predetermined shape and size.

Finally, the tablet is coated with a coating suspension obtained by mixing isopropyl alcohol, 0.2 to 0.4 w/w% of polyethylene glycol, 1.5 to 2.0 w/w% of hydroxypropyl methyl cellulose, 0.03 to 0.05 w/w% of titanium dioxide, 0.03 to 0.05 w/w% of talc, 0.1 to 0.3 w/w% of coloring agent and methylene chloride.
The process for preparing the stable herbal composition in a fill able powder in a capsule shell or a pouch or a sachet or a box as described herein after.
Initially, a mixture of a) 13.0 to 15.0 w/w% of tagar extract; b) 12.0 to 14.0 w/w% of jatamansi extract, c) 27.0 to 30.0 w/w% of ashwagandha extract, d) 2.0 to 4.0 w/w% of nutmeg extract, e) 12.0 to 14.0 w/w% of bramhi extract, f) 21.0 to 24.0 w/w% of shankhpushpi extract,2.0 to 10.0 w/w% of microcrystalline cellulose, and 0.5 to 1.5 w/w% of croscarmellose sodium is obtained.

To the mixture, a solution of isopropyl alcohol, 0.02 to 0.04 w/w% methyl paraben and 0.003 to 0.008 w/w% of propyl paraben is added followed by kneading till the granules are formed. Water may be added to prepare granules, if required.

The granules are dried at a temperature ranging from 25 to 60 oC till Loss on Drying (LOD) is in the range of 3.0 to 4.0 w/w% at 105 oC. The dried granules are sifted to obtain uniform sized granules. Then the uniformed sized granules are lubricated by mixing 0.4 to 1.0 w/w% anhydrous colloidal silica and 0.5 to 1.5 w/w% magnesium stearate to obtain the composition. The composition is then optionally filled into a capsule shell or a pouch or a sachet or a box.

GEOGRAPHICAL SOURCE OF BIOLOGICAL MATERIAL:
The plant and plant parts used for the purpose of the present invention were obtained from India.

The present invention shall now be described with the help of the following non-limiting examples.

Examples:
1. Trials
Trial 1:To prepare tablets by direct compression and evaluate it on the basis of physical and chemical parameters.

Sr. no. Ingredient Unit Formula (mg/tablet)
1. Jatamansi extract (Nordostachysjatamansi) 70.000
2. Tagar extract (Vallerianawallichi) 75.000
3. Ashwagandha 1.5% powdered extract
(Withaniasomnifera) 150.00
4. Nutmeg extract (Myristicafragrans) 15.000
5. Bramhi extract (Bacopa monierri) 70.000
6. Shankhpushpi extract (Convolvulus pluricaulis) 120.00
7. Crospovidone 25.000
8. Sodium Starch Glycolate 25.000
9. Microcrystalline Cellulose 193.0
10. Magnesium Stearate 7.00
13. Hydroxypropyl methyl cellulose 6CPS 14.00
12. Polyethylene glycol 4000 1.760
13. Titanium dioxide 0.300
14. Purified talc 0.300
15. Iron oxide yellow 1.640
16. Purified water* q.s.
Total 768
# 30% overages to be taken to compensate process loss
*Does not appear in the final product

Conclusion: The tablets obtained by direct compression failed due to poor flow of blend. Also non compressibility of blend was observed.

Trial II: To prepare tablets by wet granulation and evaluate it on the basis of physical & chemical parameters.

Sr. no. Ingredient Unit Formula (mg/tablet)
1. Jatamansi extract (Nordostachysjatamansi) 70.000
2. Tagar extract (Vallerianawallichi) 75.000
3. Ashwagandha 1.5% powdered extract
(Withaniasomnifera) 150.00
4. Nutmeg extract (Myristicafragrans) 15.000
5. Bramhi extract (Bacopa monierri) 70.000
6. Shankhpushpi extract (Convolvulus pluricaulis) 120.00
7. Crospovidone 25.000
8. Sodium Starch Glycolate 25.000
9. Microcrystalline Cellulose 193.0
10. Methyl Paraben 0.20
11. Propyl Paraben 0.04
12. Purified Water q.s.
10. Magnesium Stearate 7.00
13. Hydroxypropyl methyl cellulose 6CPS 14.00
12. Polyethylene glycol 4000 1.760
13. Titanium dioxide 0.300
14. Purified talc 0.300
15. Iron oxide yellow 1.640
16. Purified water* q.s.
Total 768
# 30% overages to be taken to compensate process loss
*Does not appear in the final product

Conclusion: The tablets prepared by wet granulation process failed as it resulted in very sticky, black coloured mass.

Trial III: To prepare tablets by wet granulation by nonaqueous solvent and evaluate it on the basis of physical and chemical parameters.

Sr. no. Ingredient Unit Formula (mg/tablet)
1. Jatamansi extract(Nordostachysjatamansi) 70.000
2. Tagar extract (Vallerianawallichi) 75.000
3. Ashwagandha 1.5% powdered extract
(Withaniasomnifera) 150.00
4. Nutmeg extract (Myristicafragrans) 15.000
5. Bramhi extract (Bacopa monierri) 70.000
6. Shankhpushpi extract (Convolvulus pluricaulis) 120.00
7. Crospovidone 25.000
8. Sodium Starch Glycolate 25.000
9. Microcrystalline Cellulose 193.0
10. Methyl Paraben 0.20
11. Propyl Paraben 0.04
12. Isopropyl alcohol q.s.
10. Magnesium Stearate 7.00
13. Hydroxypropyl methyl cellulose 6CPS 14.00
12. Polyethylene glycol 4000 1.760
13. Titanium dioxide 0.300
14. Purified talc 0.300
15. Iron oxide yellow 1.640
16. Purified water* q.s.
Total 768
# 30% overages to be taken to compensate process loss
*Does not appear in the final product

Conclusion: The wet granulation by nonaqueous solvent was found to be satisfactory. However,the desired disintegration was not achieved.

Trial IV: To prepare Serene Tablets by addition of sodium starch glycolate (superdistegrant) for DT and MCC and evaluate it on the basis of physical and chemical parameters.

Sr. no. Ingredient Unit Formula (mg/tablet)
1. Jatamansi extract(Nordostachysjatamansi) 70.000
2. Tagar extract (Vallerianawallichi) 75.000
3. Ashwagandha 1.5% powdered extract
(Withaniasomnifera) 150.00
4. Nutmeg extract (Myristicafragrans) 15.000
5. Bramhi extract (Bacopa monierri) 70.000
6. Shankhpushpi extract (Convolvulus pluricaulis) 120.00
7. Crospovidone 25.000
8. Sodium Starch Glycolate 25.000
9. Microcrystalline Cellulose 82.76
10. Methyl Paraben 0.20
11. Propyl Paraben 0.04
12. Isopropyl alcohol q.s.
10. Microcrystalline cellulose 20.00
11. Crospovidone 50.00
12. Sodium Starch Glycolate 40.00
13. Magnesium Stearate 7.00
14. Hydroxypropyl methyl cellulose 6CPS 14.00
15. Polyethylene glycol 4000 1.760
16. Titanium dioxide 0.300
17. Purified talc 0.300
18. Iron oxide yellow 1.640
19. Purified water* q.s.
Total 768
# 30% overages to be taken to compensate process loss
*Does not appear in the final product

Conclusion: The granulation and compression by this process was found to be satisfactory. However, the tablet absorbs environmental moisture and swells.

Trial V: To prepare tablets by addition of micronized silica at lubrication stage and evaluate it on the basis of physical and chemical parameters.

Sr. no. Ingredient Unit Formula (mg/tablet)
1. Jatamansi extract(Nordostachysjatamansi) 70.000
2. Tagar extract (Vallerianawallichi) 75.000
3. Ashwagandha 1.5% powdered extract
(Withaniasomnifera) 150.00
4. Nutmeg extract (Myristicafragrans) 15.000
5. Bramhi extract (Bacopa monierri) 70.000
6. Shankhpushpi extract (Convolvulus pluricaulis) 120.00
7. Crospovidone 25.000
8. Sodium Starch Glycolate 25.000
9. Microcrystalline Cellulose 82.76
10. Methyl Paraben 0.20
11. Propyl Paraben 0.04
12. Isopropyl alcohol q.s.
10. Microcrystalline cellulose 20.00
11. Crospovidone 50.00
12. Micronized silica 9.00
13. Sodium Starch Glycolate 40.00
14 Magnesium Stearate 7.00
15. Hydroxypropyl methyl cellulose 6CPS 14.00
16. Polyethylene glycol 4000 1.760
17. Titanium dioxide 0.300
18. Purified talc 0.300
19. Iron oxide yellow 1.640
20. Purified water* q.s.
Total 768
# 30% overages to be taken to compensate process loss
*Does not appear in the final product

Conclusion: The granulation and compression by above process was found to be satisfactory. However, during coating tablet was being peeled and turn rough.

Trial VI:To prepare tablets by use of nonaqueous coating system and evaluate it on the basis of physical and chemical parameters.

Sr. no. Ingredient Unit Formula (mg/tablet)
1. Jatamansi extract(Nordostachysjatamansi) 70.000
2. Tagar extract (Vallerianawallichi) 75.000
3. Ashwagandha 1.5% powdered extract
(Withaniasomnifera) 150.00
4. Nutmeg extract (Myristicafragrans) 15.000
5. Bramhi extract (Bacopa monierri) 70.000
6. Shankhpushpi extract (Convolvulus pluricaulis) 120.00
7. Crospovidone 25.000
8. Sodium Starch Glycolate 25.000
9. Microcrystalline Cellulose 82.76
10. Methyl Paraben 0.20
11. Propyl Paraben 0.04
12. Isopropyl alcohol q.s.
10. Microcrystalline cellulose 20.00
11. Crospovidone 50.00
12. Micronized silica 9.00
13. Sodium Starch Glycolate 40.00
14 Magnesium Stearate 7.00
15. Hydroxypropyl methyl cellulose 6CPS 14.00
16. Polyethylene glycol 4000 1.760
17. Titanium dioxide 0.300
18. Purified talc 0.300
19. Iron oxide yellow 1.640
20. Isopropyl Alcohol* q.s.
21 Methylene Chloride* q.s.
Tablet 768
# 30% overages to be taken to compensate process loss
*Does not appear in the final product

Conclusion: All the parameters of this batch found to be satisfactory. It was considered as optimized formulation.

2. Stability study of the composition obtained in Trial VI:
Tablet (Stability Study up to 6 months)
Result of Analysis for tablets packed in HDPE bottle and Alu-Alu Blister pack.

Tests
Description DT Assay
*** NMT 30 min Total Polyphenol(NLT 2.0%)
Initial *** 10-11 min 7.30
HDPE Bottles
(120 cc/38 mm CT closure with induction seal) 25oC/60% RH 3M *** 11-12 min 6.02
6M *** 16-17 min 6.04
30oC/75% RH 1M *** 13-14 min 6.39
2M *** 11-12 min 6.09
3M *** 15-16 min 5.78
6M *** 18-19 min 6.07
40oC/75% RH 1M *** 12-13 min 7.20
2M *** 12-13 min 6.33
3M *** 18-19 min 5.82
6M *** 20-21 min 5.75
Alu-Alu blister 25oC/60% RH 3M *** 15-16 min 6.29
6M *** 20-21 min 6.04
30oC/75% RH 1M *** 13-14 min 6.64
2M *** 12-13 min 6.07
3M *** 15-16 min 6.20
6M *** 20-21 min 6.07
40oC/75% RH 1M *** 13-14 min 7.18
2M *** 12-13 min 6.00
3M *** 16-17 min 6.40
6M *** 23-24 min 5.75

*** Reddish brown coloured, film coated, biconvex tablet, breakline on one side and plain
on other side.
Conclusion:
The product subjected to stability condition for 6 months in packing as specified above confirms that the results are meeting the laid down specifications.
3. General Process of the preparation of a tablet composition:
STEP 1: DRY MIXING AND WET GRANULATION:
a. Sifted jatamansi extract, tgar extract, ashwagandha extract, nutmeg dry extract, bramhi extract, and shankhpushpi extract, microcrystalline cellulose ,crospovidone , and sodium starch glycolatewas mixed for 10 min to obtain a powder mixture.
b. A clear solution of isopropyl alcohol, methyl paraben and propyl paraben was added to the powder mixture for 4-5 min to obtain slurry.
c. The slurry was kneaded for 5-6 minutes till end point of granule formation is observed. Water was added if required.

STEP 2: DRYING:
a. The granules obtained in step 1 were dried at a temperature ranging from 25 to 60 oC till LOD of 3.0 -4.0% w/w at 105 oC is achieved.

STEP 3: SIFTING & SIZE REDUCTION:
a. The dried granules were sifted using vibratory sifter and granules passed through 2.4 mm perforated S.S. screen were retained to obtain uniform sized granules.

STEP 4: LUBRICATION:
a. The uniform sized granules were blended with crospovidone, sodium starch glycolate , microcrystalline cellulose, and micronized silica for 10 min.
b. Magnesium stearate was mixed.
c. The lubricated blend was unloaded and subjected to compression.

STEP 5: COMPRESSION:
a. The lubricated blend was compressed to obtain uncoated tablet having the following parameters:
Average Weight: 750 mg ± 3% (727.50 mg – 772.50 mg);
Weight Variation: Avg. weight ± 5.0%
Thickness: 6.20 ± 0.30mm
Hardness: 100-120 N Friability NMT 1.0%w/w
Disintegration time: NMT 15 minutes

STEP 6: COATING:
a. Isopropyl alcohol was taken into suitable S.S. vessel fitted with stirrer.
b. Polyethylene glycol was added to isopropyl alcohol with stirring for 15 min to obtain uniform dispersion.
c. HPMC 6 CPS was added to the above solution and stir for 15 min to obtain uniform dispersion.
d. Titanium dioxide, purified talc, iron oxide of yellow, and methylene chloride were added to the dispersion with intermittent stirring to obtain the coating suspension which was passed through colloidal mill for 20 min and strained through nylon cloth.
e. Uncoated the tablets were coated until average weight gain is about 25.0 mg to obtain the coated tablet having the following parameters:
Average Weight: 768 mg ± 3% (744.96 mg – 791.04 mg)
Uniformity of weight: Avg. weight ± 5.0%
Thickness: 6.30 ± 0.30mm
Disintegration time: NMT 30minutes
STEP 7: PACKING
a. The coated tablets were packed in a bottle

4. A capsule composition of the present invention:

Sr.
No.
Ingredients Unit composition
(mg/cap)
1 Jatamansiextract(Nordostachysjatamansi) 70.000
2 Tagar extract(Vallerianawallichi) 75.000
3 Ashwagandha 1.5% powdered extract (Withaniasomnifera) 150.00
4 Nutmeg extract (Myristicafragrans) 15.000
5 Bramhi extract (Bacopa monierri) 70.00
6 Shankhpushpi extract
(Convolvulus pluricaulis) 120.00
7 Microcrystalline Cellulose 16.02
8 Croscarmellose Sodium
(AC-DI-SOL)/Primalose 5.00
9 Methyl Hydroxybenzoate (Methyl Paraben) 0.15
10 Propyl Hydroxybenzoate
(Propyl Paraben) 0.030
12 Isopropyl alcohol* q.s.
14 Colloidal Silicon dioxide
(Aerosil 200) 3.50
16 Magnesium Stearate 5.30
Total 530
17 E. HPMC CAPSULE. Size “00” white opaque body / White opaque cap 1 No.

5. General Process for the preparation of a capsule composition:
STEP 1: DRY MIXING:
a. Sifted Jatamansi extract (Nardostachysjatamansi), Tagar extract (Vallerianawallichi), Aswagandha extract (Withaniasomnifera), Nutmeg Dry extract (Myristicafragrans), Bramhi extract (Bacopa monierri), and Shankhapushpi extract (Convolvulus pluricaulis); and microcrystalline cellulose, croscarmellose sodium were mix for 15 minutes to obtain a mixture.

b. A solution of isopropyl alcohol, methyl paraben and propyl paraben was added to the mixture and stirred till granulation is observed.

STEP 2: DRYING:
a. Granules were dried at a temperature between 60oC – 70oC till it achieves LOD of 4.5% w/w at 105oC.

STEP 3: SIZE REDUCTION:
a. The dried granules werepassed through 2.0 – 2.5 mm perforated S.S screen on multimill to obtain granules of uniform size.

STEP 4: BLENDING AND LUBRICATION:
a. To the uniform sized granules, colloidal anhydrous silica was mixed for 10 minutes,and then magnesium stearate was added lubricated for 5 minutes.
STEP 5: CAPSULE FILLING:
a. The lubricated granules were filled in capsule shells having the following parameters

Sr. No. Parameters Limits
1. Appearance Brownish powder filled in size “00” HPMC capsules with White opaque cap and white opaque body
2. Theoretical fill weight of capsule 530.00 mg± 7.5%
3. Theoretical fill weight of blend in 20 capsules [A] 10.6 gm ± 3%
4. Average weight of 20 Empty Capsules [B] 2.40 gm ± 0.14 gm
5. Average weight of 20 Filled Capsules [A + B] 13.00 gm
6. Average weight of filled capsule E = [A + B/20] 0.650 gm ± 5.0%
7. Uniformity of weight Average weight± 7.5%
8. Locking Length 23.2 mm ± 0.3 mm

STEP 6: CAPSULE POLISHING:
a. Capsules filled with the lubricated granules were polish by polishing machine.

STEP 7: CAPSULE SORTING:
a. Empty capsules or lower weight filled capsules were sorted by capsule sorting machine.

STEP 8: PACKING:
a. Capsules were packed in a suitable container.

6. Preparation of extracts for the composition of the present invention:

Selection of Optimum Solvent for Extraction

Plant % yield in Solvent
Aqueous 30% Alcohol 50% Alcohol 70% Alcohol Only Alcohol
tagar Root 8.00 12.00 18.00 25.61 6.00
ashvagandha Root 12.00 11.00 15.00 12.75 18.00
shankhapushpi Whole Plant 5.00 6.00 8.00 9.46 7.85
brahmiWhole Plant 6.92 12.00 14.00 16.00 18.00
jatamansi Root 5.00 7.00 6.62 8.40 8.80
nutmeg Fruit 3.00 5.00 5.80 6.00 7.00

Conclusion:
For tagar extract, actives were maximum in extract obtained by using a solution of 70% alcohol + 30% water. Therefore, the solution of 70% alcohol + 30% water was selected as extracting solvent for obtaining tagar extract.

For ashvagandha extract, though extraction in other solventshas better yield, the actives were maximum in exatract obtained by using a solution of 70% alcohol + 30% water extract and toxic ingredients were absent. Therefore, the solution of 70% alcohol + 30% water was selected as extracting solvent for obtaining ashvagandha extract.

For shankhapushpi extract, yield and actives were maximum in extract obtain by using a solution of 70% alcohol + 30% water. Therefore, the solution of 70% alcohol + 30% water was selected as extracting solvent for obtaining shankhapushpi extract.

For brahmi extract, though yield was less, maximum actives were present in extract obtained by using water. Therefore, water was selected as extracting solvent for obtaining brahmi extract.

For jatamansi extract, though yield was less, maximum actives were present in extract obtained by using 50% alcohol + 50% water. Therefore, the solution of 50% alcohol + 50% water was selected as extracting solvent for obtaining jatamansi extract.

For nutmeg extract, maximum actives were present inextract obtained by using 50% alcohol + 50% water and toxic ingredients were absent. Therefore, the solution of 50% alcohol + 50% water was selected as extracting solvent for obtaining nutmeg extract.

7. Clinical Trials:
A randomized, double blind, placebo controlled, comparative, interventional, multi-centric, prospective, clinical study was carried out to evaluate:
1. Patient-reported total sleep time (as per patient diary).
2. Sleep efficiency (Total sleep time/ time in bed*100) derived from patient diary.
3. Patient-reported time to sleep onset (as per patient diary).
4. Patient- reported number of awakenings (as per patient diary).
5. Patient -reported wake time after sleep onset [Wake Time After Sleep Onset (WASO) is defined as total awakening time from falling asleep to final awakening was subjectively determined based on patient diary)].
6. Severity of Insomnia using Insomnia Severity Index.
7. Daytime fatigue using Fatigue Severity Scale (FSS).
8. Daytime mood, ability to function at work, concentration and memory on a graded scale.
9. Rebound of insomnia on day 35 (as per patient reported diary).
10. Quality of sleep on Pittsburgh Sleep Quality Index (PSQI).
11. Global assessment for overall improvement by investigator and by patient at the end of the study treatment.
12. Tolerability of study drug.
13. Adverse events/ Adverse drug reactions.
14. Laboratory parameters like Liver function tests (LFTs), Renal function tests (RFTs).
15. Lipid profile, Complete blood count (CBC), ESR, Hb% and Urine Examination.

As per computer generated randomization list, subjects were either randomized to drug group or placebo group in 1:1 ratio. Subjects underwent general and systemic examinations. A sleep diary was given to subjects to record time to sleep onset, total sleep time, number of awakenings, wake time after sleep onset (WASO: is defined as total awakening time from falling asleep to final awakening) and sleep efficiency (Total sleep time/ time in bed*100). Subjects were given training how to fill in sleep diary. Subjects were instructed to complete sleep diary every day in the morning. Subjects were evaluated to check whether sleep problem interferes with his/her daily functioning such as daytime mood, ability to function at work, concentration and memory on graded scale (0= Not at all Interfering, 1= A Little, 2= somewhat, 3= Much, 4= Very Much Interfering). Subject’s daytime fatigue (if any) was evaluated using fatigue severity scale. Subject’s quality of sleep was evaluated using Pittsburgh Sleep Quality Index (PSQI). Subjects were advised not to consume alcohol, caffeine, and nicotine during the study period.

As per computer generated randomization list, subjects of Group Awere given “the tablet comprising the composition of the present invention” or and subjects of Group B were given placebo. Subjects were given medication packed in HDPE bottle (each containing 30 tablets). Subjects were advised to take given medication in a dose of 2 capsules/ tablets orally after evening/night meal with water for 28 days. Cognitive behavioral therapy for insomnia (CBT-I) was advised to subjects in both the groups in addition to study treatment. CBT-I consists of five treatment components: sleep education, stimulus control, sleep restriction, relaxation techniques, and cognitive therapy.
After 28 days, subjects were advised to stop taking study medication and come for follow up after 7 days to check rebound insomnia. Subjects were called for follow up on day 7, day 14, day 21, day 28, and day 35. Subjects who continuously missed dosing for >3 consecutive days or total missed doses >6 days during the study period were treated as drop outs. Subjects were allowed to come for follow up either 3 days prior or after the scheduled follow up visit, provided subject continued the given treatment.
On every follow up visit, subjects underwent general and systemic examinations. Filled in sleep diary was collected from subjects and data were recorded in the clinical report file. A sleep diary was given to subject to record time to sleep onset, total sleep time, number of awakenings, wake time after sleep onset (WASO: is defined as total awakening time from falling asleep to final awakening) and sleep efficiency (Total sleep time/ time in bed*100). Subjects were evaluated to check whether sleep problem interferes with his/her daily functioning such as daytime mood, ability to function at work, concentration and memory on graded scale (0= Not at all Interfering, 1= A Little, 2= somewhat, 3= Much, 4= Very Much Interfering). Subject’s daytime fatigue (if any) was evaluated using fatigue severity scale. On day 14, Subject’s severity of insomnia was evaluated using Insomnia Severity index.
On day 28, subject’s global evaluation for overall improvement and Investigator’s global evaluation for overall improvement were done. Subject’s severity of insomnia was evaluated Clinical Study Report, using Insomnia Severity index. Tolerability of the study drugs was assessed by the investigator and patient at the end of the study. All the subjects were closely monitored for any adverse events/ adverse drug reactions from baseline visit till the end of the study. On day 28, subject’s investigations [viz. CBC, ESR, Hb% LFT, RFT, Lipid profile, Urine examinations, UPT (only for fertile females)] were done. Subject’s ECG was done. Subjects were asked to stop trial medication after completion of 28 days and ask to come for follow up on day 35 to check rebound insomnia. On day 28 subjects were given sleep diary to record time to sleep onset, total sleep time, number of awakenings, wake time after sleep onset (WASO: is defined as total awakening time from falling asleep to final awakening) and sleep efficiency (Total sleep time/ time in bed*100). On day 35, filled in sleep diary was collected from subjects and data were noted in the CRF. Subjects were evaluated to check whether sleep problem interferes with his/her daily functioning such as daytime mood, ability to function at work, concentration and memory on graded scale (0= Not at all Interfering, 1= A Little, 2= somewhat, 3= Much, 4= Very Much Interfering). Subject’s daytime fatigue (if any) was evaluated using fatigue severity scale. Subjects were advised to take investigator’s advice for further treatment.
Observation:
The present study was conducted to evaluate safety and efficacy of the tablet of the present invention in comparison with placebo tablets in patients suffering from primary insomnia. The study was conducted in four centres in India. As per computer generated randomization list, subjects were randomized to one of the two study groups i.e. group A (the tablet of the present invention) or group B (Placebo tablet) in 1:1 ratio. Subjects were advised to take given medication in a dose of 2 tablets orally after evening/night meal with water for 28 days. After stoppage of medication, subjects were called on day 35 to check rebound insomnia. A total of 61 subjects suffering from primary insomnia were screened for recruitment in the study. 01 subject did not fulfil the inclusion /exclusion criteria and hence was not enrolled in the study. Total 60 subjects were recruited in the study. Out of 60 recruited subjects, all the 60 subjects (30 subjects in each group) completed the study. There were no dropouts in the study.
In subjects of group A, the mean total sleep time significantly improved by 1.16 hours at the end of 28 days as compared to reduction in mean total sleep time by 49 minutes at the end of 28 days in subjects of group B. The mean sleep efficiency increased significantly from 77.07% (day 7) to 91.82% on day 28 in subjects of group A, whereas the mean sleep efficiency reduced significantly from 72.53% (day 7) to 66.11% on day 28 in subjects from group B. It was observed that significant improvement in the mean total sleep time and mean sleep efficiency was observed from 7 days onwards till day 28 in subjects of group A. After stoppage of treatment post 28 days, though slight decline in mean total sleep time and mean sleep efficiency was observed on day 35 in subjects of group A, but the mean total sleep time and mean sleep efficiency significantly increased from baseline values suggesting there is no significant relapse after stoppage of treatment for 7 days. From these results it is evident that the tablet of the present invention is significantly superior to placebo tablet in terms of improving total sleep time and sleep efficiency in subjects suffering from primary insomnia.
The mean time to sleep onset significantly reduced from 93.00 minutes on day 7 to 31.00 minutes on day 28 in subjects of group A. The mean time to sleep onset significantly increased from 113.00 minutes on day 7 to 137.67 minutes on day 28 in subjects of group B. The mean number of total awakenings significantly reduced from 3.03 on day 7 to 0.47 on day 28 in subjects of group A, however the mean number of total awakenings significantly increased from 2.97 on day 7 to 3.23 on day 28 in subjects of group B. The mean wake time after sleep onset (WASO) significantly reduced from 81.33 minutes to 12.67 minutes on day 28 in subjects from group A. The mean wake time after sleep onset (WASO) significantly increased from 62.00 minutes to 72.83 minutes on day 28 in subjects from group B. Even after stoppage of treatment for 7 days, the mean time to sleep onset, the mean number of total awakenings and WASO significantly reduced from baseline to day 35 in subjects of group A, suggesting there is no significant relapse in these symptoms.
On day 28, the mean insomnia severity index significantly reduced from baseline visit by 30.7% in subjects of group A, whereas the mean insomnia severity index insignificantly increased from baseline visit by 0.8% on day 28 in subjects of group B. At the beginning of the study, subjects of group A were in moderate clinical insomnia category as per insomnia severity index. After 28 days of treatment almost all the subjects were in no clinically significant insomnia category as per insomnia severity index. Subjects from group B remained in moderate clinical insomnia category during the entire study period. This suggests that the tablet of the present invention is superior to placebo in terms of reducing severity of insomnia in subjects suffering from primary insomnia.
Quality of sleep was evaluated using Pittsburgh Sleep Quality Index (PSQI) at baseline visit and on day 28. The mean global PSQI score reduced significantly from 14.23 on baseline visit to 3.33 on day 28 in subjects from group A, however the score increased from 14.70 on baseline visit to 15.77 on day 28 in subjects from group B. This suggests that the quality of sleep was significantly improved in group consuming the tablet of the present inventionthan that of the group consuming placebo tablet.
Significant improvement was observed in symptoms such as fatigue, daytime mood, ability to function at work, concentration and memory on day 28 in subjects from group A, however no significant improvement was observed in these symptoms on day 28 in subjects from group B. Overall improvement in primary insomnia was assessed by subjects and physician at the end of the study. It was observed that 86.7% subjects from group A reported very much improvement, whereas 90% subjects from group B reported no change in primary insomnia at the end of the study.
The superiority of the tablet of the present invention in improving primary insomnia over placebo tablet can be attributed to the unexpected and surprising effect of the ingredients present in it.

Excellent tolerability of both the drugs was reported by subjects and physician at the end of the study. No significant post treatment change in any of the lab investigations was observed in both the groups. Also no significant post treatment change in vitals such as pulse rate, blood pressure, body temperature and respiratory rate was observed in both the groups, suggesting both the drugs were safe in subjects suffering from primary insomnia. Thus,the tablet of the present invention is safe and effective in subjects suffering from primary insomnia.

Results:
1. Demographic Data:
In the present study, there were 30 completers in group A and 30 completers in group B. There were 15 males and 15 females in group A. The mean age of the subjects in group A was 42.27 ±11.92 years. There were 13 males and 17 females in group B. The mean age of the subjects in group B was 40.40 ±13.61 years.
2. Patient reported total sleep time:
In group A subjects, total sleep time (as per patient diary) on day 7 was 5.75 ± 0.84 hrs, which significantly increased to 6.91 ± 0.79 on day 28 and 6.52 ± 0.68 on day 35. In group B subjects, total sleep time (as per patient diary) on day 7 was 5.47 ± 0.76 hrs, which significantly reduced to 4.98 ± 0.87 on day 28 and 5.05 ± 0.82 on day 35.
2. Sleep efficiency:
Sleep efficiency was calculated by formula- Total sleep time/ time in bed*100. In group A subjects, sleep efficiency on day 7 was 77.07 ± 9.39, which significantly increased to 91.82 ± 5.99 on day 28 and 87.41 ± 5.15 on day 35.In group B subjects, sleep efficiency on day 7 was 72.53 ± 7.32, which significantly reduced to 66.11 ± 6.82 on day 28 and 66.89 ± 7.17 on day 35.
3. Patient-reported time to sleep onset:
In group A subjects, the mean patient-reported time to sleep onset was 93.00 ± 41.20 mins on day 7, which significantly reduced to 31.00 ± 18.86 mins on day 28. In group B subjects, the mean patient-reported time to sleep onset was 113.00 ± 37.34 mins on day 7, which significantly increased to 137.67 ± 44.85 mins on day 28.
4. Patient- reported number of awakenings:
In group A subjects, the mean patient-reported total number of awakenings on day 7 was 3.03± 1.43, which significantly reduced to 0.47 ± 0.68 on day 28. In group B subjects, the mean patient-reported total number of awakenings on day 7 was 2.97 ± 1.40, which increased significantly to 3.23 ± 1.74 on day 28.
5. Patient -reported wake time after sleep onset (WASO):
In group A subjects, the mean patient-reported wake time after sleep onset (WASO) on day 7 was 81.33 ± 45.01 mins, which significantly reduced to 12.67 ± 20.54 on day 28. In group B subjects, the mean patient-reported wake time after sleep onset (WASO) on day 7 was 62.00 ± 31.20 mins, which significantly increased to 72.83 ± 36.52 on day 28.
6. Severity of Insomnia assessed using Insomnia Severity Index:
In group A subjects, the mean severity of Insomnia assessed using Insomnia Severity Index on baseline visit was 19.00 ± 2.00, which significantly reduced to 05.70 ± 4.23 on day 28. In group B subjects, the mean severity of Insomnia assessed using Insomnia Severity Index on baseline visit was 18.87 ± 1.91, which increased significantly to 20.20 ± 2.72 on day 28.
7. Daytime fatigue assessed using Fatigue Severity Scale (FSS):
In group A subjects, the mean daytime fatigue assessed using Fatigue Severity Scale (FSS) on baseline visit was 47.03 ± 7.83, which significantly reduced to 24.07 ± 6.34 on day 28. In group B subjects, the mean daytime fatigue assessed using Fatigue Severity Scale (FSS) on baseline visit was 47.00 ± 6.34, which significantly increased to 48.60 ± 7.30 on day 28.
8. Daytime mood, ability to function at work, concentration and memory:
Maximum subjects from group A did not have problems in mood, ability to function at work, concentration and memory from day 21 till day 35. Mild to moderate grade problems in mood, ability to function at work, concentration and memory were reported in subjects from group B even on day 28 and 35.
9. Quality of sleep assessed using Pittsburgh Sleep Quality Index (PSQI):
In group A subjects, the mean quality of sleep assessed using Pittsburgh Sleep Quality Index on baseline visit was 14.23 ± 2.03, which significantly reduced to 3.33 ± 2.02 on day 28. In group B subjects, the mean quality of sleep assessed using Pittsburgh Sleep Quality Index on baseline visit was 14.70 ± 1.95, which significantly increased to 15.77 ± 1.33 on day 28.
10. Global assessment for overall improvement by investigator and by patient:
As per investigator’s and subject’s assessment, 86.7% subjects of group A reported very much improvement in overall condition of insomnia at the end of the study. As per investigator’s and subject’s assessment, 90.0% subjects of group B reported no change in overall condition of insomnia at the end of the study.
11. Tolerability of study drugs:
As per investigator’s and subject’s assessment, all the subjects from group A and group B reported excellent tolerability to the respective study drug at the end of the study.
12. Adverse events/ adverse drug reactions:
Nine subjects from group A and 11 subjects from group B reported to have adverse events during the study period. These adverse events were mild in nature and resolved during the study period. Most of these adverse events did not have causal relationship with the study drug.
13. Laboratory parameters and vitals:
All the safety laboratory parameters were within normal limits both at baseline visit and at the end of the study visit. No significant change in any of the vitals was observed at the end of the study.

Conclusion:
1. The tablet of the present invention is significantly effective in improving total sleep time and sleep efficiency in subjects suffering from insomnia.
2. The improvement in total sleep time and sleep efficiency continued even after stoppage of the treatment for 7 days, suggesting no evidence of rebound insomnia.
3. The tablet of the present invention is significantly effective in reducing sleep onset and total number of awakenings in subjects suffering from insomnia.
4. The tablet of the present invention is significantly effective in reducing wake time after sleep onset in subjects suffering from insomnia.
5. The tablet of the present invention is significantly effective in reducing severity of insomnia in subjects suffering from insomnia.
6. The tablet of the present invention is significantly effective in reducing fatigue, problems in daytime mood, ability to function at work, concentration and memory in subjects suffering from insomnia.
7. The tablet of the present invention is significantly effective in improving quality of sleep in subjects suffering from insomnia.
8. No significant change in any of the safety laboratory parameters and vitals was observed after treatment with the tablet of the present invention, suggesting safety of the drug.
9. Even after stoppage of consumption of the tablet of the present invention, for seven days, no rebound of insomnia was observed in any of the subject.
Thus,the tablet of the present invention issafe and effective medicine for the treatment of insomnia.

Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, or step or group of steps, but not the exclusion of any other element or step, or group of elements or steps.

The use of expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more desired objects or results.

Any discussion of the documents, acts, links, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the invention as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to contrary.