DESC:FIELD OF THE INVENTION
The present invention relates to synergistic phytoconstituent of sugar free dry syrup for cough &cold. Further invention relates to process for preparation of sugar free dry syrup comprising phytoconstituents with or without other pharmaceutical acceptable excipients.

BACKGROUND OF THE INVENTION
Herbal ingredients play an important role in respiratory disease. Stability is main drawback in herbal syrup and hence high concentration of antioxidant and preservative should be added and it is not safe for longer period of time. To overcome this problem, present invention compliance with synergy phytoconstituents basedDry Syrup formulation and a method for preparation thereof for providing treatment in chronic respiratory disorders such as cold, cough, allergic, asthma, seasonal allergic rhinitis, pharyngitis, laryngitis, bronchitis and the like and which is nonalcoholic, non-sedating and chemical free in nature.

Phytochemical investigation of the herbal drugs or their extracts reveals the presence of several chemical compounds. Through all the ingredients do not possess specific therapeutic activity, it is believed that the different chemical compounds present in the plant or its extract act in harmonious manner and possibly due to synergistic effect of the compounds, some ingredients potentiate the therapeutic activity of the main active ingredient or even retard the undesirable actions of the main compound because individual compounds may not be as effective as that of the mixture of compounds present in the plant. Multi-ingredient therapy is preferred over single drug therapy since the therapy is more effective.

In conventional marketed syrup, Sugar as a base is drawback of syrup especially in cough cold, and respiratory disease and all. Artificial sweetener and flavor also cause dryness of mouth and throat allergy. Active constituent concentration may not target due to high concentration of additives and hence effectiveness is poor. Keep that in mind, we innovate super-soluble excipientless dry syrup blend with multiple phytoconstituents synergistic effect to solve multiple health benefits in respiratory condition.

OBJECTIVE OF INVENTION
The present invention relates to asynergy phytoconstituent based composition which is non-alcoholic, non-sedating and non-freezing, high soluble, non-palatable, excipientless, preservative free with no artificial flavor dry syrup in the treatment of chronic respiratory disorders such as cold, cough, allergic asthma, seasonal allergic rhinitis, pharyngitis, laryngitis, bronchitis and the like and a process for preparing the same.

SUMMARY OF THE INVENTION
The present invention relates to synergistic phytoconstituent blend of sugar free dry syrup for cough & cold.

Further invention relates to process for preparation of sugar free dry syrup comprising phytoconstituents with or without other pharmaceutical acceptable excipients.

Yet, another embodiment of present invention relates to the process of manufacturing of herbal extracts is as follows:
1. Individual Phytoconstituent as per mentioned specification cross check by suitable analytical technique.
2. Except Glycyrrhiza GlaberaIndividual extract reprocesses with granulation to improve palatability and micromeritics property. Granulation blend process are as follow.
(a) Synergy form of Curcumin mixed with Black piper, Lavang and Saponin blend of Liquorice for Anti-inflammatory effect by improve its poor characteristics.
(b) Synergy form of Ajwain, Ginger, Cinnamon mixed for synergy bronchodilation and Antihistaminic effect.
(c) Synergy form of Betel leaf, Kakamachi and Lindipiper mixed for cough, cold and expectorant
(d) Synergy blend of Puskarmool, Tulsi and Vasaka mixed for its Antiviral, Anti-bacterial activity
3. Dry all blend of Phytoconstituents at 40-55 0C in tray dryer or fluidized bed dryer for 30-60 min.
4. Pulverized it in sieve number 80-100.
5. Check flowability of individual as per free flow compliance and mixed all in synergy form.
6. Continue mixing of all improvised granules for 30-45 min and then add natural blend of Mentha Spicata extract 4-8% and again mix for 20-30 minutes.
7. At last mixed Glycyrrhiza Glabera with optimized concentration in above blend and mixed it for 15-20 min.
8. Viscosity adjusted with Natural gum of Phytoconstituents blend.
DETAILED DESCRIPTION OF THE DRAWINGS:
Graph 1: Percent subjects with daytime cough
Graph 2: Percent subjects with night cough
Graph 3: Percent subjects with Throat irritation
Graph 4: Percent subjects with Chest Pain
Graph 5: Percent subjects with Wheezing and shortness of breath
Graph 6: Percent subjects with throat clearing & Sore throat
Graph 7: Percent subjects relieved from cough and throat irritation within 15 min
Graph 8: Percent subjects relieved from symptoms within 4 hrs

DETAILED DESCRIPTION OF THE INVENTION:
In pharmaceutical industry, cough syrup is widely used in respiratory disease especially in allergic cough and cold, bronchitis, Pneumonia, asthma and like that. Active pharmaceutical ingredients contain poor characteristics like unpleasant taste, odour, solubility problem and many more. To improve its poor characteristics excipients to be added either equal or more proportional. Additionally base is sugar, sucrose, sucralose set with artificial sweeteners, flavors and for stability, number of preservatives are incorporate. In ayurvedic syrup, stability, fermentation, microbial growth, palatability and sedimentation is key drawback in number of marketed syrups. In allopathy, Palatability and incompatibility is key issue and to overcome limitation, excipients either in form of additives or preservatives should be incorporate. Its all about present scenario.
Common colds are among the most common infectious diseases, causing millions of doctor visits at a cost of billions of dollars each year. As used in the present disclosure, these symptoms are collectively referred to as “cold symptoms” or the “inflammatory response.” Typically, cold symptoms are caused by some type of picornavirus (usually a rhinovirus), coronavirus, or respiratory syncytial virus. The chronic inflammation causes an associated increase in airway hyper responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, especially at night or in the early morning. These episodes are usually associated with wide spread but variable airflow obstruction that is often reversible either spontaneously or with treatment. Pharmaceutical compositions and methods of using same comprising a non-steroidal anti-inflammatory Phytoconstituents combination and synergy active component selected from an antihistamine, decongestant, cough suppressant (antitussive), expectorant is provided for the relief of cough, cold and cold-like symptoms. The present invention relates to a PhytoPharmaceutical formulation containing a mixture of specified herbal phytoconstituents and a method for preparation thereof for providing treatment in chronic respiratory disorders such as cold, cough, allergic asthma, seasonal allergic rhinitis, pharyngitis, laryngitis, Bronchitis and the like and which is nonalcoholic, non-sedating and non-freezing and super soluble in nature. Further the process for the preparation of Phyto Synergy composition of the present invention does not involve use of pharmaceutically unacceptable and hazardous organic solvents. The process for preparing this composition of the present invention comprises procuring, cleaning, grading of specified herbal extraction as per the standard specification, and design granulation to improve poor palatability and micromeritics property for high disintegrating power and pulverizing separately to form the fine free flow powder.Colds are minor infections of the nose and throat caused by more than 200 different viruses. Rhinovirus is the most common cause, accounting for 10 to 40 percent of colds. Other common cold viruses include coronavirus. A cold may last for about one week, but some colds last longer, especially in children, the elderly and those in poor health. In the United States, colds account for more visits to the doctor than any other condition. Adults get an average of two to four colds per year, mostly between September and May. Young children suffer from an average of six to eight colds per year. Colds are highly contagious. They most often spread when droplets of fluid that contain a cold virus are transferred by touch. These droplets may also be inhaled.
Dry syrup is excipientless, non-alcoholic, non-sedating and non-freezing, non-palatable, preservative free with no artificial flavor, individual Phytoconstituents blend itself replace the role of excipients. Itself phytoconstituents selected for desirable effect for good patients compliance which have capacity of additives as with active therapeutical.

Phytoconstituents Therapeutic Properties
Trachyspermum Ammi ext. It has an anti-inflammatory antibacterial and stimulating expectorant action.
Glycyrrhiza Glabera ext. It has an Anti-inflammatory, demulcent and expectorant action.
Ocimum Sanctum ext. It has an Anti-inflammatory, spasmolytic action and anti- bacterial action.
Piper longum ext. It has an Expectorant, bronchodilator action.
Iris Germanica ext. It has an Expectorant, spasmolytic, bronchodilator action.
Zingiber Officinale ext. It has an Antipyretic action,
Solanum Nigrum ext. It has an Anti-inflammatory, expectorant and antitussive action.
Piper betle ext. It has an Anti-asthmatic and antibacterial action.
Piper nirgum ext. It has an Antibacterial action.
Syzygiumaromaticumext It has an analgesic, anti-inflammatory, and anti-bacterial action.
Cinnamomum verum ext. It has an Anti-inflammatory, Anti-Viral and antihistaminic action.
Curcuma Longa ext. It has an Anti-inflammatory, Anti-Viral, and Anti-Sars-CO2 activity
Adhatodavasacaext It has an antitubercular action.

Further embodiment of present invention is Taste masked, Stable, Fast dissolving, Excipient less, Sugar free, Preservative free, compatible Dry syrup made up with Phytoconstituents and its blend.

Following techniques employed to formulate dry syrup
1. Taste masking achieved by unique granulation.
2. Stability and micromeritics property improved with synergy blend incorporation by granulation.
3. Fast dissolving action
4. Design unique natural super disintegrants involvement during granulation.
5. Sweetness and Taste with good acceptable palatability is design by replacement of sugar or other sweeteners.
6. Synergy blend is compatible and there is no incompatibility, interaction found by physical characterization.
7. Stability is checked for 3 months as per ICH guideline, and it is concluded no instability found, dissolving rate and palatability also remain same.
As per case study, Animal toxicity report and human clinical trials, it is proven safe, and therapeutically proven for cough cold, allergy, bronchitis, asthma, Pneumonia and in viral disease. As per Invitro Sars Cov-2 Antiviral study, Anti- Sars Cov-2 activity found 75% in 24 hrs in VERO E-6 infected cell with more than 95 % cell viability as per Department of Biotechnology report.
The process of manufacturing of herbal extracts is as follows:
1) Individual Phytoconstituent as per mentioned specification cross check by suitable analytical technique.
2) Except Glycyrrhiza GlaberaIndividual extract reprocesses with granulation to improve palatability and micromeritics property. Granulation blend process are as follow.
a. Synergy form of Curcumin mixed with Black piper, Lavang and Saponin blend of Liquorice for Anti-inflammatory effect by improve its poor characteristics.
b. Synergy form of Ajwain, Ginger, Cinnamon mixed for synergy bronchodilation and Antihistaminic effect.
c. Synergy form of Betel leaf, Kakamachi and Lindipiper mixed for cough, cold and expectorant
d. Synergy blend of Puskarmool, Tulsi and Vasaka mixed for its Antiviral, Anti-bacterial activity
3) Dry all blend of Phytoconstituents at 40-55 0C in tray dryer or fluidized bed dryer for 30-60 min.
4) Pulverized it in sieve number 80-100.
5) Check flowability of individual as per free flow compliance and mixed all in synergy form.
6) Continue mixing of all improvised granules for 30-45 min and then add natural blend of Mentha Spicata extract 4-8% and again mix for 20-30 minutes.
7) At last mixed Glycyrrhiza Glabera with optimized concentration in above blend and mixed it for 15-20 min.
8) Viscosity adjusted with Natural gum of Phytoconstituents blend.
Examples:
For the purpose of this invention the Ayurvedic plants constituents are selected from the following group:
Botanical name of Plant Therapeutic Properties Concentration(%)
Trachyspermum Ammi ext. It has an anti-inflammatory antibacterial and stimulating expectorant action. 15-20
Glycyrrhiza Glabera ext. It has an Anti-inflammatory, demulcent and expectorant action. 15-20
Ocimum Sanctum ext. It has an Anti-inflammatory, spasmolytic action and anti- bacterial action. 8-16
Piper longum ext. It has an Expectorant, bronchodilator action. 6-10
Iris Germanica ext. It has an Expectorant, spasmolytic, bronchodilator action. 4.5-9
Zingiber Officinale ext. It has an Antipyretic action, 4-9
Solanum Nigrum ext. It has an Anti-inflammatory, expectorant and antitussive action. 3.5-9
Piper betle ext. It has an Anti-asthmatic and antibacterial action. 3-6
Piper nirgum ext. It has an Antibacterial action. 3-6
Syzygiumaromaticumext It has an analgesic, anti-inflammatory, and anti-bacterial action. 2-6
Cinnamomum verum ext. It has an Anti-inflammatory, Anti-Viral and antihistaminic action. 2-6
Curcuma Longa ext. It has an Anti-inflammatory, Anti-Viral, and Anti-Sars-CO2 activity 1-4
Adhatodavasacaext It has an antitubercular action. 1-4

Pre-formulation study including parameters like husner’s ratio, carr’s index and angle of repose representing flow property are good to excellent after granulation.

Physio-chemical parameters in compatibility study.
Physio-chemical evaluation of Blend
Parameters Dry Syrup when mixed with water
pH 5
Viscosity 650 CP
Sedimentation No
Taste evaluation Satisfactorily

According to following data available it can be concluded that synergic blend when mixed with water shows pH 5, honey-based syrup viscosity is 650 cp, clear solution after storage due to best aqueous solubility and taste is masked via granulation of blend while sweetness is maintained by liquorice. No sedimentation found after settle down it for 24 hours indicates good solubility and dispersibility of solute in dispersion medium.

As dry syrup formulated sugar free, non-alcoholic, non-sedating and non-freezing, non-palatable, preservative free with no artificial flavor shows better patient compliance in comparison with other sugar syrup available in market.

In terms of per and post formulation parameters dry syrup indicates good compliance with pharmacopeia as mentioned in comment 2, 5 and 7. It shows that once mixed with water, clear solution is formed without any sedimentation after few days of storage due to best aqueous solubility.

As per the Figure 1, at Baseline 100% subjects were experiencing daytime cough in both groups. At visit 4, the no. of subjects experiencing cough in test group was less than in placebo group. In test group, 16.7% subjects experienced daytime cough i.e. 83.3% subjects were relieved of cough while in placebo group 50% subjects experienced daytime cough i.e. 50% subjects were relieved of cough.
As describe in Figure No 02, at Baseline 100% subjects were experiencing night cough in both groups. At visit 4, the no. of subjects experiencing cough in test group was less than in placebo group. In test group, 10% subjects experienced night cough i.e. 90% subjects were relieved of cough while in placebo group 50% subjects experienced night cough i.e. 50% subjects were relieved of cough.
As per the Figure 3, at Baseline 100% subjects were experiencing throat irritation in both groups. At visit 4, no subjects experienced throat irritation in test group i.e. 100% subjects were relieved of throat irritation while in placebo group 60% subjects experienced throat irritation i.e. 40% subjects were relieved of cough.
As per Figure No 04, At Baseline 100% subjects were experiencing Chest pain in both groups. At visit 4, no subjects experienced chest pain in test group i.e. 100% subjects were relieved of chest pain while in placebo group 33.3% subjects experienced chest pain i.e. 66.6% subjects were relieved of chest pain.
At Baseline 100% subjects were experiencing wheezing and shortness of breath in both groups. At visit 4, no subjects experienced wheezing and shortness of breath in test group i.e. 100% subjects were relieved of wheezing and shortness of breath while in placebo group 33.3% subjects experienced wheezing and shortness of breath i.e. 66.6% subjects were relieved of wheezing and shortness of breath as describe in Figure No 05.
At Baseline 100% subjects were experiencing throat clearing & Sore throat in both groups. At visit 4, no subjects experienced throat clearing & Sore throat in test group i.e. 100% subjects were relieved of throat clearing & Sore throat while in placebo group 33.3% subjects experienced throat clearing & Sore throat i.e. 66.6% subjects were relieved of throat clearing & Sore throat as describe in Figure No 06.
At Baseline 100% subjects were taking time of 1 hr to get relief of cough and throat pain in both groups. At visit 4, no 100% subjects were relieved cough and throat pain within 15 min while in placebo group 50% subjects took 30 to get min relief of cough and throat pain and 50% subjects were relieved cough and throat pain within 15 min as per figure no 07.
In figure No 08, at Baseline 100% subjects were getting relief from symptoms for 1-2 hrs in both groups. At visit 4, 100% subjects got relief from symptoms for 4 hrswhile in placebo group 50% subjects got relief from symptoms for 3 hrs and 50% subjects got relief from symptoms for 4 hrs.
,CLAIMS:1. A synergistic phytoconstituent blend of sugar free dry syrup for cough & cold.

2. The synergistic phytoconstituent blend as claimed in claim 1, wherein the process for preparation of sugar free dry syrup comprising phytoconstituents without other pharmaceutical acceptable excipients.

3. The synergistic phytoconstituent blend as claimed in claim 1, wherein the process of manufacturing of herbal extracts is as follows:
a. Individual Phytoconstituent as per mentioned specification cross check by suitable analytical technique.
b. Except Glycyrrhiza GlaberaIndividual extract reprocesses with granulation to improve palatability and micromeritics property. Granulation blend process are as follow.
i. Synergy form of Curcumin mixed with Black piper, Lavang and Saponin blend of Liquorice for Anti-inflammatory effect by improve its poor characteristics.
ii. Synergy form of Ajwain, Ginger, Cinnamon mixed for synergy bronchodilation and Antihistaminic effect.
iii. Synergy form of Betel leaf, Kakamachi and Lindipiper mixed for cough, cold and expectorant
iv. Synergy blend of Puskarmool, Tulsi and Vasaka mixed for its Antiviral, Anti-bacterial activity
c. Dry all blend of Phytoconstituents at 40-55 0C in tray dryer or fluidized bed dryer for 30-60 min.
d. Pulverized it in sieve number 80-100.
e. Check flowability of individual as per free flow compliance and mixed all in synergy form.
f. Continue mixing of all improvised granules for 30-45 min and then add natural blend of Mentha Spicata extract 4-8% and again mix for 20-30 minutes.
g. At last mixed Glycyrrhiza Glabera with optimized concentration in above blend and mixed it for 15-20 min.
h. Viscosity adjusted with Natural gum of Phytoconstituents blend.