Claims:We Claim:

1. A formulation for the treatment of Coronavirus disease 2019 (COVID-19) comprises:
50% (± 30%) of Andrographis paniculata extract, 12.5 % (± 30%) of Glycyrrhiza glabra extract, 25% (± 30%) of Phyllanthus niruri extract and 12.5 % (± 30%) of Picrorhizakurroa extract.

2. The formulation for the treatment of Coronavirus disease 2019 (COVID-19) as claimed in claim 1, wherein the composition is in the form of capsules or tablets.

3. The formulation for the treatment of Coronavirus disease 2019 (COVID-19) as claimed in claim 1, wherein the composition is spurified extracts.

, Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:

'A FORMULATION FOR THE TREATMENT OF CORONA VIRUS DISEASE 2019 (COVID-19)'

2. APPLICANT:

(A) AVANCE PHYTOTHERAPIES PVT. LTD.
(B) Indian
(C) 33, The Chamber, Nr. Grand Bhagvati Hotel,
S.G. Highway, Bodakdev, Ahmedabad - 380054,
Gujarat, India.

3. PREMABLE TO THE DESCRIPTION:
PROVISIONAL
The following specification
describes the invention. þ COMPLETE
The following specification particularly
describes the invention and the manner
in which it is to be performed.

The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates to aformulation acting in relieving symptoms of, and thereby helpful in treatment of Coronavirus disease 2019 (Covid-19). More particularly, it describes a formulation in form of capsule which comprises of a mixture of herbal extracts containingAndrographis paniculata, Glycyrrhiza glabra, Phyllanthus niruri and Picrorhizakurroa in defined concentrations.

Background of the Invention
A novel coronavirus-induced pneumonia, which was later called coronavirus disease 2019 (COVID-19), has rapidly increased to an epidemic scale and affected whole human population globally. Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) has become a pandemic hazard to global public health worldwide. Coronaviruses (CoVs) are large viruses comprising of four genera, namely alpha, beta, gamma, and delta. The beta-coronavirus class includes severe acute respiratory syndrome (SARS) virus (SARS-CoV), Middle East respiratory syndrome (MERS) virus (MERS-CoV), and the COVID-19 causative agent SARS-CoV-2.Most people infected with the COVID-19 virus experience mild to moderate respiratory illness and recover without requiring special treatment. Older people and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness.

The present conventional strategy of the disease control includes isolation of cases and tracing their contacts, providing optimal care to these infected cases, reducing chances of secondary infections by early diagnosis, and rapid development of effective diagnostic, preventive and therapeutic strategies, including vaccines. The treatment approach for COVID-19 is supportive care, which is supplemented by the combination of broad-spectrum antibiotics, antivirals, corticosteroids and convalescent plasma. Scientists are working hard to develop effective treatments.Considering the current situation, various treatment modalities have been well-thought-out, including traditional medicine, which has been widely used during the past epidemic outbreaks, including SARS and H1N1 influenza.

In the Prior Art, GB2425476A, it relates tomulti-herb medicament for the treatment of SARS. More particularly it relates to pharmaceutical compositions exhibiting antiviral activity against Coronavirus, and more particularly still against those viruses responsible for severe acute respiratory syndrome (SARS).The use of a multi-herb medicament comprising ethanolic extract obtained from a species of the genus Scutellaria for the treatment of a patient with a SARS-CoV infection. The extract is selected from Scutellariabaicalensis, S. amoena, S. barbata, S. discolour, S. hypercifolia, S. inbica, S. likiangenesis, S. orthocalyx, S. rehderiana, S. scissiliflora and S. viscidula. In this prior art, the applicant has found that a composition shows dose dependant activity against SARS-CoV in cell culture tests. According to the prior art there is provided the use of a botanical raw material (BRM), a botanical drug substance (BDS), or one or more botanical ingredients, obtainable from a species of the genus Scutellaria in the manufacture of an anti-viral medicament. Preferably, the medicament is for the treatment of patients infected by a positive strand RNA virus, more particularly SARS-CoV. However, well-founded concerns that an outbreak of SARS had re-occurred and added impetus to a search for effective therapies.

Various compositions for the treatment of such SARS-CoV-2 disease and processes for the preparation thereof are also known in the prior art. The article refers to Prevention and treatment of COVID-19 using Traditional Chinese Medicine (TCM). The review analyzes and summarizes the prevention and treatment of the novel coronavirus disease (COVID-19) with Traditional Chinese Medicine. The effective method of TCM prevention is by the traditional aromatherapy method with herbs such as Atractylodes lanceolata, Phellodendronamurense, and Artemisia argyi, which have apreventive effect. In addition, the herbs can be made into a sachet toavoid poisonous gas but this particular treatment is effective in prevention of illness while there is a certain need to obtain a natural and an effective combination of highly effective plant based composition which not only prevents but also cures the disease.

Another such prior art CN111789918A describes traditional Chinese medicine composition, which can be used for the treatment of coronavirus diseases. The Chinese medicinal composition or Chinese medicinal preparation contains Chinese medicinal materials ephedra, bitter almonds, gypsum, coix seed, atractylodes, patchouli, polygonum cuspidatum, verbena, reed root, mulberry, orange red, artemisia annua and licorice. The traditional Chinese medicine composition of the present invention may also contain suitable additives, which are known in the art, such as emulsifiers, fragrances, solubilizers, anti-caking agents, defoamers, adhesives, buffers, pH adjustments Agents, propellants, chelating agents and preservatives. Chinese medicine formula is recommended for the treatment of patients with new coronary pneumonia whose syndromes manifest as dampness toxins and stagnation of the lung. The formula is a decoction (water decoction), but the diagnosis and treatment plan did not disclose the specific composition of the decoction and its preparation method, nor did it disclose other dosage forms of the formula and whether it had any effect on other coronaviruses other than the new coronavirus without damaging other organs of the body.

Therefore, there is an unmet need for Indian medicinal compositions that can effectively treat such coronavirus diseases. The Indian Traditional System of Medicine is one of the oldest systems of medical practice in the world and has played an essential role in providing health care service to human civilization, right from its inception. India has the exclusive distinction of its own recognized traditional medicine, Ayurveda, Yoga, Unani, Siddha, and Homoeopathy. The basic treatment approach of all these systems is holistic and the pharmacological modalities are based on natural products of plants, animals, or mineral origin. Given this, there is a resurgence of interest in herbal systems, which have helped the nation in the pandemic crisis due to plague, cholera, Spanish flu, etc. in the past. However, there is a requirement of ideal combination of herbal products or extracts in the capsule formulation which can be easily consumed. The need for composition of herbal extracts which has powerful antiviral properties and has tremendous fast healing properties when consumed puts the patient to ease and comfort. In conclusion, the technique of the prior art mentioned above fails to provide solutions to the existing problems, thus necessitates an improvement in the concerned technical field.

Since the immune status of patients plays an essential role in COVID-19 infection, an herbal medicine, which has an immunomodulatory effect, could have potential as a preventive measure and even therapeutic agent for patients with COVID-19 infection. With this aim, the present invention concentrates on providing an herbal formulation with anti-inflammatory, antiviral, and antiallergic properties that contains natural herbalextracts and is effective against severe acute respiratory syndrome-related coronavirus (SARS-CoV-2).

Object of the Invention
The main object of the present invention is to provide a formulation for the treatment of Coronavirus disease 2019 (COVID-19).

Another object of the present invention is to provide a formulation having herbal extracts in the definite quantity that is given in the form of capsule and suitable for all kinds of patient showing COVID-19 symptoms.

Another object of the present invention is to provide aformulation which has powerful antiviral, antioxidant and immune-modulating properties intreating COVID-19.

Yet another object of the present invention is to provide a formulation which give influential synergistic effect.

Further object of the present invention is to provide a formulation which capitulate strong activity in inhibiting spike glycoprotein which play as target receptor of COVID-19.

Another object of the present invention is to provide a formulation that does not contain any components ultimately harmful to the human body.

Another object of the present invention is to provide a formulation that is effective, affordable and easy to absorb.

Yet an object of the present invention is to provide a formulation which prevents from causing adverse effects and do not interfere with ongoing treatments in Co-morbid patients.

Further object of the present invention is to provide a formulation which prevents COVID-19 that causes serious symptoms of respiratory, enteric and central nervous system.

Summary of the Invention
The present invention relates to aformulation for the treatment of coronavirus disease 2019(COVID-19). It particularly relates to herbal extracts in the form of capsule. The herbal formulation comprises Andrographis paniculata, Glycyrrhiza glabra extract, Phyllanthus niruri extract and Picrorhizakurroa extract as active ingredients particularly useful as effective antiviral and immune-modulator for treating COVID-19. The present invention gives essential synergistic effect in order torelieve symptoms and provide quick recoveryfrom COVID-19. The formulation having the composition of the present invention can be administered orally. The formulation may be delivered in a single bolus dose or multiple doses.

Brief Description of the Drawings
The present invention is readily understood with reference to the following specifications and attached drawings wherein:
Figure 1 shows RT-PCR infographic study on 7 different individuals indicating reduced CT value with 3 different samples with average patient discharge days and average age of individual after being treated with formulation of the present invention respectively.
Figure 2 shows C-reactive protein infographic levels on 7 different individuals with four different series demonstrating lowest CRP level at 4th seriesafter being treated with formulation of the present invention respectively.
Figure 3 shows a meta-analysis conducted to evaluate on the 7 patients treated with formulation and the association between D-dimer levels and severe COVID-19 disease respectively.

Detailed Description of the Invention
The nature of the invention and the manner in which it is performed is clearly described in the specification. The invention has various components and clearly described in the following pages of the complete specification. The preferred embodiments of the herbal formulation used for treatment of coronavirus disease 2019 (COVID-19) are described for a better understanding of the invention without any limitations.

The structural and distinctive properties of the invention and all advantages introduced shall be understood more clearly by virtue of the description given below and therefore evaluation should be performed taking this detailed description into consideration.

The formulation of the present invention is a synergistic composition of the herbal extracts in combination has potential use as adjuvants in the treatment of early/mild common flu symptoms of COVID-19thanthe individual ingredients. The advantage of the synergism is the significant recovery from mild to moderate respiratory illness infected with the COVID-19. Optimal quantities of each individual ingredient couldpotentially be administered in combination to achieve the desired therapeutic effect.

A formulation for treating COVID-19 comprising of herbal extracts which have antimicrobial or antiviral, anti-inflammatory, and immunostimulatory activities, helps to accelerate in relieving symptoms. These herbal extracts are assumed to have the capacity to modulate the immune response and, therefore, they are believed to have beneficial effects on preventing or treating COVID-19.

The present invention comprises balanced, ideal combination of carefully selected, highly
standardized and effective herbal/natural extracts which are successfully practiced without any adverse effect as they are very well tolerated by human body. For the purposes of the application the term "plant extract" refers to the extracts obtained by separation of medicinally active portions of plant from the inert components by using selective solvents in standard extraction procedures. These include classes of preparations known as infusions, fluid extracts, tinctures, pilular (semisolid) extracts and powdered extracts.

The present disclosure comprises following active ingredients which are as follows:

Andrographispaniculata extract(Kalmegh) is from the (family Acanthaceae) and it is the medicinal plant possessing several photochemical constituents with interesting and unique biological properties. The extract and pure compounds of the plant have been known for their anti-microbial, cytotoxicity, anti-protozoan, anti-inflammatory, antioxidant, immunostimulant, anti-diabetic, anti-infective, anti-angiogenic, hepato-renal protective, liver enzymes modulation insecticidal and toxicity activities.The aerial parts, roots and whole plant of A. paniculata have been used for centuries in Asia as traditional medicine for the treatment of stomachaches, inflammation, pyrexia, and intermittent fevers.In addition, Andrographolide is the most abundant diterpene lactone in the leaves and stems of A.paniculata and is a dietary supplement widely used in herbal medicine because of its diverse biological activities. Andrographolide exhibits antiviral activity against the human immunodeficiency virus, herpes simplex virus, influenza virusand Epstein–Barr virusvia different mechanisms.

Glycyrrhiza glabraL. (Licorice)extractis a small perennial herb that has been traditionally used to treat many diseases, such as respiratory disorders, hyperdipsia, epilepsy, fever, sexual debility, paralysis, stomach ulcers, rheumatism, skin diseases, hemorrhagic diseases, and jaundice. The herb’s root is used as medicine. The chemicals contained in licorice are believed to decrease swelling, thin mucus secretions, decrease cough, and increase the chemicals in our body that heal ulcers.Licorice root contains glycyrrhizin, which is also called glycyrrhizic acid.Glycyrrhizic acid (GA) is a triterpene glycoside found in the roots of licorice plants (Glycyrrhiza glabra).It is used for eczema, swelling (inflammation) of the liver (hepatitis), mouth sores, and many other conditions. GA is the most important active ingredient in the licorice root and possesses a wide range of pharmacological and biological activitiescoupled with glycyrrhetinic acid and 18-beta-glycyrrhetic acid acts as an anti-inflammatory, antiviral, and antiallergic drug.The powerful anti-inflammatory capabilities of GA make it effective in the treatment of various types of hepatitis like viral hepatitis and nonalcoholic hepatitis. GA was found to inhibit the replication of the SARS-associated virus.

Phyllanthus niruriextract is from a genus of plant Phyllanthusused in herbal medicine. The plant extract is touted as natural remedies for a variety of health problems.They can help treat high blood pressure and also used as a diuretic.P. niruri is an important plant of Indian Ayurvedic system of medicine which is used in the problems of stomach, genitourinary system, liver, kidney and spleen. It is bitter, astringent, stomachic, febrifuge and antiseptic. Phyllanthus niruri has been also known as an immunomodulator and possess an antiviral activity against several RNA viruses, such as hepatitis B virus and hepatitis C virus by inhibiting viral entry and replication.

Picrorhizakurroa extract is from a plant that grows in the Himalayan mountains. As an ayurvedic medicine, the root and rhizome (underground stem) of the plant are used for treatment of liver problems, fever, allergy, and many other conditions. Picrorhiza contains chemicals that stimulate the immune system, kill cancer cells, and relieve inflammation (swelling).Kutkin is the active principal of Picrorhizakurroa and is comprised of kutkoside and the iridoid glycoside picrosides I, II, and III. Other active constituents are apocynin, drosin, and nine cucurbitacin glycosides. Apocynin is a catechol that has been shown to inhibit neutrophil oxidative burst in addition to being a powerful anti-inflammatory agent, while the curcubitacins have been shown to be highly cytotoxic and possess antitumor effects. Different pharmacological activities of P. kurroa is also known which includes anti-microbial, anti-oxidant, anti-bacterial, anti-mutagenic, cardio-protective, hepato-protective, anti-malarial, anti-diabetic, anti-inflammatory, anti-cancer, anti-ulcer, and nephro-protective activities were recorded from this plant. It demonstrates antioxidant and protective effects of Picrorhizakurroa against oxidative damage of macromolecules such as DNA, protein, and lipids.

Further the production of the said formulation is described by adding and mixing above said herbal extracts (active ingredients) in a predetermined sequence to get the product. The composition of the present invention is a mixture of plant extracts and is administered orally or by any clinically/medically accepted methods which is effective in the treatment of Coronavirus disease (COVID-19).

Andrographis paniculata extract used in the composition of present disclosure helps in neutralizing free radicals, increase bile flow and has anti-inflammatory activity.Glycyrrhiza glabraextract used in the composition of present disclosure prevents lipid peroxidation and also acts as an anti-viral agent. It also increases endogenous?- interferons. The antiviral mechanisms of Glycyrrhizic acid (GA) includes the inhibition of viral replication and immunity regulation.Phyllanthus niruri extract used in the composition of present disclosure act as an anti-viral agent and by evaluating the activity of phyllanthin and hypophyllanthin, isolated from Phyllanthus niruri is used in inhibiting spike glycoprotein (6LZG) and main protease (5R7Y) which play as target receptors of COVID-19.Picrorhizakurroaextract used in the composition of present disclosure has high antimalarial activity, itis considered to be effective among the high-risk coronavirus population because of its constituent kutkin which is useful for its antiviral, anti-asthmatic, and immune boosting properties.

The abnormal coagulation function has been proven to be involved in the disease progression of COVID-19. The test for detecting the coronavirus disease is related to the Nucleic acid-based testing and is often called PCR. The said molecular test detect the virus genetic material (nucleic acids).The association between D-dimer levels, C-reactive protein levels and the severity of COVID-19 arealso linked. The clinical study was aimed to examine the association between D-dimer levels, C-reactive protein levels and the severity of COVID-19 based on a cohort study and meta-analysis.

In certain embodiments, the composition of herbal formulation comprising 50% (± 30%) of Andrographis paniculate extract, 12.5 % (± 30%) of Glycyrrhiza glabra extract, 25% (± 30%) of Phyllanthus niruriextractand 12.5 % (± 30%) of Picrorhizakurroaextract.

The foregoing materials are formed to create a capsule. The herbal composition of the present invention is a synergistic composition which constituent herbal extracts in combination has far higher antiviral activity than the individual ingredients. The advantage of the synergism is the significant increase in treating Coronavirus disease 2019.

The invention is illustrated more in detail in the following example. The example describes and demonstrates embodiments within the scope of the present invention. This example is given solely for the purpose of illustration and is not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope.

Example 1:

Materials and methods:
Demographic and clinical data of all confirmed cases with COVID-19 on admission to Hospital from December 18, 2020, to June 16, 2021, were collected and analyzed, and coagulation function parameters were described and average between patients with different age were analyzed.

Preparation of the composition:
To prepare the composition of present invention, the following extracts of each ingredient are mixed: 200 mg (± 60 mg) of Andrographis paniculataextract; 50 mg (± 15 mg) of Glycyrrhiza glabraextract; 100 mg (± 30 mg) of Phyllanthus niruriextract; and 50 mg (± 15 mg) of Picrorhizakurroa extract. The said composition can be formulated to a 400 mg capsule.

Clinical Study:
Dose Administration
The test drug "present composition" of Andrographis paniculata extract, Glycyrrhiza glabra extract; Phyllanthus niruri extract; and Picrorhizakurroa extract were administeredorally in the form of one capsule twice daily.

The formulation has been administered retrospectively in 7 patients including both genders and none of the individuals were vaccinated while they were testedpositive with laboratory confirmation of COVID-19 carried out by real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR) at the time of enrollment.

The composition of the present invention has been evaluated by primary end point i.e., Negative RT-PCR as described in Fig. 1, and secondary end points i.e., CRP reduction and D-Dimer reduction infographics as described in Figs. 2 and 3 respectively.

Observation and Results:

The study was conducted to evaluate the effectiveness of present composition of herbal extracts on 7 different individuals with age range from 43-60 yearsfor 9-14 days of treatment period. The composition in form of capsules can be single administered for relative period of time. The results are observed from the day of hospitalizationwith average patient discharge in 9 days and the average age of individual of 49 years as shown in Fig. 1. The subsequent resultsshowsignificantly reduced levels of C-reactive protein (CRP) and D-Dimer levels (as shown in Figs. 2 and 3) and the negative RT-PCR as shown in Fig. 1.

Observation: The Fig. 1 shows the RT-PCR study of a formulation on 7 different individualsindicatingreduced CT valuewith 3 different samples providingnegative RT-PCR. In a real time, PCR assay a positive reaction is detected by accumulation of a fluorescent signal. The Ct (cycle threshold) is defined as the number of cycles required for the fluorescent signal to cross the threshold (i.e., exceeds background level). Ct levels are inversely proportional to the amount of target nucleic acid in the sample (i.e., the lower the Ct level the greater the amount of target nucleic acid in the sample). The average discharge period from the day of hospitalization is 9 days with an average age group of 49 years including male and female patients.

The Fig. 2 shows C-reactive protein (CRP) levels of 7 different individuals with four different series demonstrating lowest CRP level at 4th series.C-reactive protein (CRP) is a protein made by the liver. CRP levels in the blood increase when there is a condition causing inflammation somewhere in the body. A CRP test measures the amount of CRP in the blood to detect inflammation due to acute conditions or to monitor the severity of disease in chronic conditions. The results in Fig. 2 shows significantly reduced levels of C- reactive protein in all the seven patients. From the above test it is concluded that present formulation is highly efficacious.

The Fig. 3 showsa meta-analysis conducted to evaluate the association between D-dimer levels and severe COVID-19.Patients with severe disease were more likely to exhibit dysregulated coagulation function, and a significantly higher D-dimer level. The 7 patients treated with formulation had drastically lower levels of D-Dimer is observed.

Conclusion:
The individuals treated with present formulation were studied by its clinical characteristics, and coagulation function parameters of patients with confirmed COVID-19.On admission samples were collected and compared between patients from severe infection and those with non-severe infection until the patient is discharged. Further, based on the obtained results, it was concluded that the herbal formulation under present study was able to treat COVID-19 disease and is highly efficacious unlike other hepatotoxic drugs and affordable. The negative RT-PCR test was attained for the patients treated with present formulation.

A formulation for treating COVID-19 was found to be very effective with antiviral properties. Thus, the evidence that patients with lower D-dimer levels and CRP levels is found to be highly efficient. Thus, it is concluded that a present formulation developed is found be effective in treatment of Corona virus disease 2019 (COVID-19).

The present invention further comprising above herbal extracts as active ingredients that has powerful synergistic properties to protect patient from the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and the disease it caused, known as coronavirus disease 2019 (COVID-19). It prevents from mild to severe infection of the COVID-19 disease. The present invention also gives synergistic effect without affecting their therapeutic activities allowing
the quick healing of the patients.

The present invention acting as anantiviral phytoceutical has powerful antiviral properties and synergistically works on individuals affected with Corona virus 2019. It aids in reducing D-dimer and CRP levels, promotes very fast healing havingnegative RT-PCRreport and does not damage other organs of the body. The present invention provides the significant improvement in treating COVID-19 disease acting as an antiviral which results in reduction of D-dimer levels.

While the present invention has been described with respect to what is presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. To the contrary, the invention is intended to cover various modifications and equivalent ranges included within the spirit and scope of those skilled in the art. It is expressly understood, however, that such modifications are within the spirit and scope of the present invention as set forth in the following claims.

Dated this on 6th day of September 2021