Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(See sections 10 & rule 13)
1. TITLE OF THE INVENTION
“CHEWABLE TABLET FORMULATION COMPRISING CARICA PAPAYA LEAF EXTRACT AND PREPARATION METHOD THEREOF”
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
FIDO PHARMA PRIVATE LTD Indian
SCO 45,2ND Floor, Sector 4, Panchkula - 134112 (Haryana) India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention in general relates to a chewable tablet formulation comprising phytosomes of carica papaya leaf extract along with pharmaceutically acceptable inert excipients for dengue treatment and a preparation method thereof.

BACKGROUND OF INVENTION
Dengue is the severe arthropod- born viral disease which is shown mainly in tropic or equatorial areas and that may be caused by morbidity and mortality in human beings. Dengue is a severe viral infection with disastrous complication. Disease caused by dengue virus Aedes mosquitoes which is also called as female mosquitos. Mosquitoes belongs to Aedes aegypti is a genus that are found in tropical and subtropical zones, but now found in all continents except Antarctica.

Dengue virus belongs to family Flaviviridae. Flavivirus is the primary or chief vector which is responsible for spread the dengue between the human. It was confirmed by the world health organization (WHO) that 40% of population (approximately 2.5 billion people) among in the world are infected by the dengue. Dengue fever first time derived from “water poison” which is directly co-relate with flying insects in a Chinese medical encyclopaedia at 992 from the Jin Dynasty (265-420 AD). There is no any delicate remedial treatment so it can be cure with proper supervision of supportive care or medicaments and keeping careful watch for possible danger or difficulties or different phases of patient that can be also treatment by the vigilant fluid administration.

After bite of Aedes mosquito’s main complication is show in the patient is haemorrhagic fever and plasma leakage (protein and fluid component of blood leak from blood vessels). It is come out when the actuation the contagious monocytes and T-calls, therefore it will show endothelial cell dysfunction (in small arteries, inner layer will not able to perform its normal functions) and resulting in plasma leakage in dengue patient. Now this plasma leakage hampers the blood clotting therefore resulting in death of the patient. Simply it is found that dengue patient having low platelet count if platelet count will increase then rate of dengue patient death will be reduced.

Bites of female Aedes aegypti mosquito carrying Dengue virus (DENV) member of the genus Flavivirus, family Flaviviridae is significant human pathogen causing dengue fever (DF), Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). There are four dengue virus genotypes; DENV-1, DENV-2, DENV-3 and DENV-4 causes similar disease with no different clinical conditions.

Dengue infection can lead to a wide range of symptoms, which can vary from mild to severe. The incubation period (time between infection and appearance of symptoms) typically ranges from 4 to 10 days. Common symptoms include sudden onset of high fever, severe headaches, pain behind the eyes, joint and muscle pain, fatigue, skin rash, and mild bleeding (e.g., nose or gums). In some cases, the disease can progress to severe Dengue, also known as Dengue hemorrhagic fever (DHF) or Dengue shock syndrome (DSS), which can be life-threatening. Warning signs of severe dengue fever which is a life-threatening emergency can develop quickly. The warning signs usually begin the first day or two after your fever goes away, and may include severe stomach pain, persistent vomiting, bleeding from your gums or nose, blood in your urine, stools or vomit, bleeding under the skin, which might look like bruising, difficult or rapid breathing, fatigue, irritability or restlessness.

Dengue fever is caused by any one of four types of dengue viruses. Dengue fever is spread through mosquito bites. The two types of mosquitoes that most often spread the dengue viruses are common both in and around human lodgings. When a mosquito bites a person infected with a dengue virus, the virus enters the mosquito. Then, when the infected mosquito bites another person, the virus enters that person's bloodstream and causes an infection. After you've recovered from dengue fever, you have long-term immunity to the type of virus that infected but not to the other three dengue fever virus types. This means we can be infected again in the future by one of the other three virus types. Risk of developing severe dengue fever increases if you get dengue fever a second, third or fourth time.

Dengue is diagnosed through a combination of clinical symptoms, travel history, and laboratory tests. Blood tests, such as PCR (Polymerase Chain Reaction) or serological tests, are used to detect the presence of the virus or the antibodies produced in response to the infection.

Currently, there is no specific antiviral treatment for Dengue. The focus is on managing the symptoms and providing supportive care. Patients are advised to rest, drink plenty of fluids, and take pain relievers (e.g., paracetamol) to reduce fever and pain. Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin should be avoided, as they can increase the risk of bleeding. In severe cases, hospitalization may be required for close monitoring and intravenous fluids.

Carica papaya leaf (CPL) extract contains alkaloids, flavonoids, saponins, tannins, glycosides and anthraquinones. CPL extract exhibits anti-dengue activity. Studies have shown Carica papaya upregulate the ALOX 12 and PTAFR gene thereby leading to an increased production and its conversion into platelets. Clinical evidence shows that Carica papaya extract increases ALOX 12 activity 15-fold and PTAFR activity 13.42-fold which is responsible for the increase in platelet production. It also has antimalarial and antiplasmodial activity. The CPL extract tea demonstrated cancer cell growth inhibition by boosting the production of key signalling molecules called Th1-cytokines, which helps to regulate the immune system. It also used as an antipyretic, for the treatment of anemia, appetite stimulation.

Tablets are the most commonly used dosage form. Because, during large manufacturing simplicity and economic condition need to be considered. Therefore, recently Micro Lab Limited and many other companies have introduced C. papaya leaves tablet in the market. Despite several advantages sometimes, certain herbal substances resist compression pressure and need a special formulation technique for improving bioavailability. For avoiding these problems, punching pressure or percentage of excipients is increased. However, high punching pressure may degrade the thermolabile active components of herbal extract, and the excess binding agent may slow the dissolution and disintegration of the formulation. However, similarly, the recently marketed C. papaya leaves tablet (Caripill) might have faced these problems during the manufacturing process. Therefore, the company did not reveal any formulation process to the public. The use of excipients, punching pressure and phytochemical protection was also not mentioned. The problem related to the conventional tablets of C. papaya leaf extract tablets available in the market is its size. This size of the tablet which is due to high dose of CPL extract (3300mg/day) makes its problematic for geriatric and pediatric patients to swallow in intact form. One of the major reasons for poor patient compliance is the bitter taste of the drug which is not sufficiently masked in the currently available formulations which in turns make the formulation unpalatable and tablets after consumption produce bitter after taste which occurs in the mouth when the patient burps, leaving behind a nauseatic and vomiting feeling.

An article entitled, ‘Formulation and Evaluation of Carica Papaya Leaves Aqueous Extract Chewable Tablets’ by G. Lakshmi Devi, K. S. Murali Krishna, Priyanka Mishra, Sana Afreen, Sravya Maddukuri in Asian Journal of Research in Chemistry and Pharmaceutical Sciences 2019 discloses formulation and evaluation of Carica papaya leaves aqueous extract chewable tablets. Carica papaya leaves aqueous extract exhibited potential activity against Dengue fever.

Marketed formulation ‘Carican Tablets’ includes Carica Papaya Leaf Extract (1100 mg), Tinospora Cordifolia, Goat Milk Powder & Vitamin E Tablets. It is useful in the treatment of Dengue, increase platelet count, boosts immunity and aids metabolism.

Marketed formulation ‘Caripill Tablet’ contains Carica papaya leaf extract as the active ingredient. It helps in the process of digestion and treats digestive disorders, aids in the treatment of stomach ulcers, increases low blood count and helps to fight dengue, improves symptoms of dengue such as fever and pain.

To overcome the limitations of conventional film coated C. papaya leaf extract tablet such as high dose, large tablet size, unpalatable taste, bitter and noxious after-taste and poor patient compliance. There is still a need for formulating a chewable tablet formulation comprising phytosomes of CPL extract that would help in taste masking and increasing the bioavailability of CPL extract.

OBJECTS OF THE INVENTION
Main object of the present invention is to provide a chewable tablet formulation comprising phytosomes of carica papaya leaf extract along with pharmaceutically acceptable inert excipients.

Another object of the present invention is to provide a process for the preparation of chewable tablet formulation.

SUMMARY OF THE INVENTION
In an embodiment, the present invention relates to a chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract; and
b) Pharmaceutically acceptable inert excipients.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are diluent, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent, glidant, lubricant and solvent.

In an aspect of the embodiment, the phytosomes of Carica papaya leaf extract is present in a concentration of 550 mg of the total formulation.

In another aspect of the embodiment, the diluent is mannitol and microcrystalline cellulose.

In another aspect of the embodiment, the binder is polyvinylpyrrolidone.

In another aspect of the embodiment, the saliva stimulating agent is citric acid.

In another aspect of the embodiment, the sweetener is aspartame and sucralose.

In another aspect of the embodiment, the cooling agent is menthol.

In another aspect of the embodiment, the flavouring agent is Lemongrass oil.

In another aspect of the embodiment, the lubricant and glidant are talc and silica dioxide.

In another aspect of the embodiment, the solvent is Isopropyl alcohol.

In another embodiment, the present invention relates to a chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract in a concentration of 61.35 % w/w;
b) Diluent in a concentration of 27.88 % w/w; and
c) Binder in a concentration of 1.67 % w/w;
d) Saliva stimulating agent in a concentration of 0.11 % w/w;
e) Sweetener in a concentration of 4.83 % w/w;
f) Cooling agent in a concentration of 0.29 % w/w;
g) Flavouring agent in a concentration of 0.0034 % v/w;
h) Lubricant and Glidant in a concentration of 3.84 % w/w;
i) Solvent in a concentration of 0.045 % v/w.
wherein the percentages are with respect to total weight of the formulation.

In another embodiment, the present invention relates to a process for preparation of chewable tablet formulation comprises steps of;
a) Weighing and mixing phytosomes of Carica papaya leaf extract, diluents, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent and solvent to form a dough;
b) Sieving and drying the dough to obtain dried granules;
c) Mixing the dried granules with glidant and lubricant to obtain uniform granules;
d) Compressing the uniform granules using single punch tablet machine to form chewable tablet formulation.

BRIEF DESCRIPTION OF THE DRAWINGS
Reference will be made to embodiments of the invention, examples of which may be illustrated in accompanying figures. These figures are intended to be illustrative, not limiting. Although the invention is generally described in the context of these embodiments, it should be understood that it is not intended to limit the scope of the invention to these particular embodiments.
• Figure 1 shows Size distribution study of CPL extract phytosomes.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention is all about a chewable tablet formulation comprising phytosomes of carica papaya leaf extract along with pharmaceutically acceptable inert excipients for dengue treatment and a preparation method thereof.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The term "a" and "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. The information provided in this document, and particularly the specific details of the described exemplary aspects, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood from there.

As used herein, the term "about" means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, "about" means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

As used herein, the terms "treat," or "treatment" mean both therapeutic treatment or prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease.

As used herein, the term “Chewable tablet formulation” refers to a type of pharmaceutical oral dosage form intended to be chewed and then swallowed by the patient rather than swallowed whole. They should be designed to be palatable and be easily chewed and swallowed.

The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical formulation other than the active and which are approved by regulatory authorities or are generally ‘regarded as safe’ for human or animal use. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

Main embodiment of the present invention relates to a chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract; and
b) Pharmaceutically acceptable inert excipients.

Carica papaya leaf (CPL) extract contains alkaloids, flavonoids, saponins, tannins, glycosides and anthraquinones. CPL extract exhibits anti-dengue activity. Studies have shown Carica papaya upregulate the ALOX 12 and PTAFR gene thereby leading to an increased production and its conversion into platelets. Clinical evidence shows that Carica papaya extract increases ALOX 12 activity 15-fold and PTAFR activity 13.42-fold which is responsible for the increase in platelet production. It also has antimalarial and anti-plasmodial activity. It also used as an antipyretic, for the treatment of anemia, appetite stimulation. Carica papaya phytosomes which avoided the gastric acid degradation of the flavonoids and other essential chemical constituents. The phytosomes provides rapid absorption and better bioavailability of the drug in the systemic circulation.

In an aspect of the embodiment, the phytosomes of Carica papaya leaf extract is present in a concentration of 550 mg of the total formulation.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are diluent, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent, glidant, lubricant and solvent.

Diluents, also known as fillers, are inactive ingredients used in pharmaceutical formulations to increase the bulk volume of a tablet or capsule. They serve several purposes, including facilitating the manufacturing process, aiding in the uniform distribution of active pharmaceutical ingredients (APIs), improving the flow properties of powders during processing, and ensuring dose uniformity. Diluents are typically inert substances that do not react chemically with other components of the formulation. Common examples of diluents are Lactose. Microcrystalline cellulose (MCC), Dicalcium phosphate (DCP), Mannitol, Sorbitol, Starch, Calcium carbonate, Xylitol, Maltodextrin, Dextrose, Fructose, etc.

In another aspect of the embodiment, the diluent is mannitol and microcrystalline cellulose.

Mannitol is a sugar alcohol commonly used as a diluent in pharmaceutical formulations, including chewable tablets. Mannitol serves as a bulking agent, increasing the volume of the tablet formulation. This helps in achieving the desired tablet size and weight while ensuring dose uniformity. Mannitol has a sweet taste, which can help improve the palatability of chewable tablets, especially for pediatric or geriatric patients who may be sensitive to bitter or unpleasant tastes. Mannitol contributes to the texture and mouthfeel of chewable tablets, providing a smooth and pleasant experience for the patient upon chewing and ingestion.

In another aspect of the embodiment, the mannitol is present in the concentration of 22.31 % w/w.

Microcrystalline cellulose (MCC) is a commonly used diluent in chewable tablet formulations. It is a purified, partially depolymerized cellulose derived from natural wood pulp. MCC is widely preferred in pharmaceutical applications due to its excellent compressibility, flowability, and compatibility with active pharmaceutical ingredients (APIs). MCC possesses excellent compressibility, allowing it to be easily formed into tablets with consistent hardness and durability. This is crucial for chewable tablets to maintain their integrity while being chewed. MCC has good flow properties, which aids in the manufacturing process by ensuring uniform distribution of the API and other excipients in the tablet blend. Although chewable tablets are designed to be chewed and dissolved in the mouth, MCC can help facilitate disintegration by breaking down into smaller particles when exposed to saliva, thus aiding in the release of the API.

In another aspect of the embodiment, the microcrystalline cellulose is present in the concentration of 5.57 % w/w.

Binders are substances used to impart cohesive properties to the powdered ingredients of a tablet, ensuring that the tablet remains intact after compression and does not crumble. Binders used to help hold the active pharmaceutical ingredients (APIs) and other excipients together while still allowing the tablet to disintegrate easily in the mouth. The choice of binder in chewable tablets is critical to ensure proper texture, palatability, and structural integrity. Examples of binders are Hydroxypropyl cellulose (HPC), Hydroxypropyl methylcellulose (HPMC), Methylcellulose (MC), Polyvinylpyrrolidone, Corn starch, Pregelatinized starch Sorbitol, Mannitol, Xylitol, Povidone (PVP), etc.

Polyvinylpyrrolidone (PVP) is commonly used as a binder in chewable tablet formulations due to its excellent binding properties and compatibility with other tablet ingredients. PVP has strong binding properties, which help hold the tablet ingredients together, ensuring the tablet maintains its shape and integrity during handling and consumption. PVP is highly water-soluble, which means it dissolves readily in the mouth when the tablet is chewed. This property facilitates the disintegration of the tablet, allowing for easy administration and ingestion. PVP exhibits good adhesive properties, aiding in the cohesion of tablet particles and promoting uniform distribution of the active ingredients throughout the tablet matrix.

In another aspect of the embodiment, the binder is polyvinylpyrrolidone is in the concentration of 1.67 % w/w.

A saliva-stimulating agent is a substance that helps increase the production of saliva in the mouth. Saliva plays a crucial role in maintaining oral health by lubricating the mouth, aiding in chewing and swallowing, neutralizing acids, and protecting against tooth decay and oral infections. Saliva-stimulating agents work by stimulating the salivary glands to produce more saliva, thus alleviating symptoms of dry. Saliva-stimulating agents can be incorporated into chewable tablet formulations to provide relief for dry mouth symptoms while offering the convenience of a chewable dosage form. Examples of saliva stimulating agents are Xylitol, Citric Acid, Sour Candy or Citrus Flavors, herbal extracts, such as licorice root extract or marshmallow root extract, etc.

In another aspect of the embodiment, the saliva stimulating agent is citric acid is in concentration of 0.11% w/w.

Sweeteners are substances added to pharmaceutical products to enhance sweetness. In chewable tablet formulations, sweeteners are often included to improve palatability and mask the taste of active pharmaceutical ingredients (APIs) or other bitter-tasting excipients. Examples of sweeteners are Aspartame, Sucralose, Saccharin, Acesulfame potassium, Neotame, Xylitol, Sorbitol, Mannitol, Erythritol, Sucrose (table sugar), Fructose, Glucose, Maltose, etc.

In another aspect of the embodiment, the sweetener is aspartame and sucralose.

Aspartame is a commonly used artificial sweetener in various food and beverage products due to its intense sweetness and low-calorie content. It is composed of two amino acids, aspartic acid and phenylalanine, and is approximately 200 times sweeter than sucrose (table sugar) on a weight basis. Aspartame is often used in chewable tablet formulations to improve taste and palatability while minimizing the caloric content of the product. Aspartame is virtually calorie-free, making it suitable for use in products intended for individuals who are monitoring their calorie intake or managing conditions like diabetes.

In another aspect of the embodiment, the aspartame is present in concentration of 3.35 % w/w.

Sucralose is approximately 400-700 times sweeter than sucrose (table sugar), allowing for the use of very small amounts to achieve the desired level of sweetness in chewable tablets. Since sucralose is not metabolized by the body for energy, it provides sweetness without adding calories to the formulation. This is particularly beneficial for individuals who need to monitor their calorie intake. Sucralose is heat-stable and remains unchanged under a wide range of processing and storage conditions, making it suitable for use in pharmaceutical formulations where stability is crucial. Sucralose has a clean, sweet taste profile without any bitter aftertaste, which can help improve the overall palatability of chewable tablets.

In another aspect of the embodiment, the sucralose is present in concentration of 1.48 % w/w.

Cooling agents are substances that impart a cooling sensation when consumed orally. While they are more commonly associated with products like chewing gum, lozenges, or confectionery, they can also be used in chewable tablet formulations to enhance the sensory experience and provide a refreshing effect. Examples of cooling agents used in chewable tablets are Menthol, Peppermint oil, Eucalyptus oil, Camphor, etc.

In another aspect of the embodiment, the cooling agent is menthol is in a concentration of 0.29 % w/w.

Menthol is a natural compound derived from peppermint oil or other mint oils. It produces a cooling sensation by activating cold-sensitive receptors in the mouth and throat. Menthol is often used in chewable tablets for its pleasant flavor and cooling effect, providing relief for sore throat or nasal congestion.

Flavouring agents are substances added to pharmaceutical products to impart or enhance taste or aroma. In pharmaceuticals, flavoring agents are often used to improve the palatability of oral dosage forms such as chewable tablets. These agents help mask the unpleasant taste of active pharmaceutical ingredients (APIs) and other excipients, making the medication more palatable and easier to administer. Common examples of flavouring agents are Fruit flavours such as cherry, orange, lemon, raspberry, and grape, Mint flavours, including peppermint and spearmint, lemongrass oil, sweet flavours such as vanilla, chocolate, caramel, and butterscotch.

In another aspect of the embodiment, the flavouring agent is Lemongrass oil is in concentration of 0.0034 % w/w.

Lemongrass oil is indeed used as a flavouring agent in various products, including pharmaceuticals, food, and beverages. Lemongrass (Cymbopogon citratus) is a tropical plant commonly cultivated for its citrus-like flavour and aroma. Lemongrass oil is extracted from the leaves of the plant and possesses a distinctive lemony scent and flavour. It adds a refreshing and citrusy taste that can help mask the bitterness or medicinal flavour of active ingredients.

Lubricants are substances added to pharmaceutical powders or granules to reduce friction between particles and between the powder/granules and the surfaces of the processing equipment. This helps prevent adhesion and ensures smooth flow during tableting. Glidants are substances added to improve the flow properties of powders or granules by reducing interparticle friction and promoting uniform particle distribution. Glidants help prevent the formation of agglomerates and ensure consistent flow during processing and filling operations. Common examples of lubricant and glidant are Magnesium stearate, Calcium stearate, Stearic acid, Sodium stearyl fumarate, Polyethylene glycol (PEG), Talc, Colloidal silicon dioxide (e.g., Aerosil), Corn starch, Microcrystalline cellulose (MCC), etc.

In another aspect of the embodiment, the lubricant and glidant are talc and silica dioxide.

In another aspect of the embodiment, the silica dioxide is present in concentration of 2.88 % w/w.

In another aspect of the embodiment, the silica dioxide is present in concentration of 0.96 % w/w.

Solvents are substances capable of dissolving solutes to form a solution. In pharmaceutical formulations, solvents are used for various purposes, including dissolving or dispersing active pharmaceutical ingredients (APIs) and excipients, adjusting the concentration of components, and aiding in the manufacturing process. Examples of solvents are water, alcohols such as ethanol and isopropyl alcohol, Glycerin, Propylene Glycol, Polyethylene Glycol, etc.

In another aspect of the embodiment, the solvent is Isopropyl alcohol is in concentration of 0.045% v/w.

In another embodiment, the present invention relates to a chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract in a concentration of 61.35 % w/w;
b) Diluent in a concentration of 27.88 % w/w; and
c) Binder in a concentration of 1.67 % w/w;
d) Saliva stimulating agent in a concentration of 0.11 % w/w;
e) Sweetener in a concentration of 4.83 % w/w;
f) Cooling agent in a concentration of 0.29 % w/w;
g) Flavouring agent in a concentration of 0.0034 % v/w;
h) Lubricant and Glidant in a concentration of 3.84 % w/w;
i) Solvent in a concentration of 0.045 % v/w.
wherein the percentages are with respect to total weight of the formulation.

In another embodiment, the present invention relates to a process for preparation of chewable tablet formulation comprises steps of;
a) Weighing and mixing phytosomes of Carica papaya leaf extract, diluents, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent and solvent to form a dough;
b) Sieving and drying the dough to obtain dried granules;
c) Mixing the dried granules with glidant and lubricant to obtain uniform granules;
d) Compressing the uniform granules using single punch tablet machine to form chewable tablet formulation.

EXAMPLES
Example 1– Preparation of Phytosomes of CPL extract
1) Phytosomes were prepared using modified solvent evaporation method.
2) CPL extract and Phospholipon 90H in a molar ratio 1:1 was dissolved in 20ml dichloromethane.
3) The RBF was then attached to a rotary evaporator maintaining the temperature at 40°C and at 50 rpm to get a thin film formed on the inner surface of RBF.
4) 10ml of n-Hexane was added to the RBF and subjected to continuous stirring at specified time, temperature and rpm.
5) The resultant mixture was centrifuged at 15000 rpm for 30 minutes.
6) The supernatant was discarded and the residue was subjected to drying at 40 °C.
7) The residue obtained after drying was sieved and stored in airtight amber colored bottle.

Phytosomal
Formulation code X1
Time (min) X2
Temperature (°C) X3
RPM (rpm)
P1 5 40 50
P2 20 40 50
P3 5 55 50
P4 20 55 50
P5 5 40 100
P6 20 40 100
P7 5 55 100
P8 20 55 100
Table no. 1 - 23 factorial design for optimization of developed phytosomes formulation

Design expert 7.0.0 software was used for optimization. Screening designs are used to screen the important factors during method optimization. Most significant factors were identified and taking those factors into consideration the factors design 2 level 3 factor (23) was designed and used for selection of the optimized batch. Time (X1), Temperature (X2) and RPM (X3) were selected as independent variables and entrapment efficiency was selected as dependent variable.

Characterization of Phytosomes of CPL extract –
• Morphology
The CPL extract phytosomes were observed under microscope having round shape, unilamellar and also bilamellar. No crystals were found. The diameter of the phytosomes was in the range of 3.24µm to 14.5µm.

• Particle size and Zeta potential
The z-average of CPL extract phytosome was 6474.6nm. (Fig 1) The zeta potential for CPL extract phytosomes was found to be -57.4 mV.

• Entrapment Efficiency
The entrapment efficiency of 8 formulation (P1-P8) by 23 factorial design was found in the range of 86.17±0.03% to 92.44±0.02%.

Phytosomal formulation code % Entrapment efficiency* ± SD
P1 88.47 ± 0.03
P2 90.33 ± 0.04
P3 86.17 ± 0.03
P4 89.16 ± 0.02
P5 86.88 ± 0.04
P6 89.95 ± 0.04
P7 92.44 ± 0.02
P8 87.88 ± 0.03
Table no. 2 - Entrapment efficiency of CPL extract phytosomes in 23 factorial designs

• In-vitro Dissolution study of Phytosome
The results indicated the release of 16.57 % in 0.1N Hydrochloric acid and 11.00% in phosphate buffer pH 6.8 at the end of first hour because of the presence of unentrapped CPL extract in the CPL extract phytosomal powder. The phytosomal complex showed sustained release of CPL extract from vesicles. The drug release was 81.33% and 72.65% at the end of 24 hrs in 0.1N hydrochloric acid and phosphate buffer pH 6.8. The sustained release of CPL extract may improve its absorption and lowers the elimination rate with increase in the bioavailability.

Time (hrs) % Cumulative drug release ± SD
0.1 N Hydrochloric acid Phosphate buffer pH 6.8
0.5 13.25 ± 0.023 8.92 ± 0.034
1 16.57 ± 0.112 11.00 ± 0.131
2 17.6 ± 0.132 12.65 ± 0.114
3 20.29 ± 0.139 13.29 ± 0.319
4 24.22 ± 0.19 17.78 ± 0.21
5 29.05 ± 0.23 20.52 ± 0.376
6 46.64 ± 0.32 23.95 ± 0.42
24 81.33 ± 0.41 72.65 ± 0.33
Table no. 3 - Dissolution study of CPL extract phytosome

Example 2 - CPL extract chewable tablet according to the invention

S.N. Ingredients (mg/ml) F1 F2 F3 F4 F5 F6 F7 F8
1 CPL extract Phytosomes 1100 1100 1100 1100 550 550 550 550
2 Mannitol 350 200 200 200 200 200 200 200
3 PVP K30 11 11 11 11 11 11 11 15
4 MCC 102 20 20 20 50 - 50 50 50
5 Aspartame 20 20 20 20 20 20 - 30
6 Sucralose - - - - - - 25 13.3
7 Menthol 0.1 1 1 1 1 1 1 2.6
8 Citric acid 1 1 1 1 1 1 1 1
9 Peppermint oil 0.02 0.02 - - - - - -
10 Lemongrass oil - - 0.02 0.02 0.02 0.02 0.02 0.03
11 Isopropyl Alcohol 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4
12 Methyl Salicylate 0.1 0.1 0.1 - - - - -
13 Camphor 0.02 - - - - - - -
14 Thymol 0.02 - - - - - - -
15 Talc 5 - - 13.83 8.83 8.83 8.88 8.62
16 Aerosil 200 4 13.53 13.53 13.83 13.83 26.49 26.64 25.86
17 Magnesium Stearate 10 13.53 13.53 20.74 - - - -
Table no. 4 – Formulation of CPL extract chewable tablet according to the invention

Among all the batches, Batch F8 formulation was selected as optimized formulation due to increase in PVP K30 concentration to improve the hardness of the CPL extract tablet as well as the concentration of lemongrass oil and menthol was increased to improve the flavouring and cooling property. Aerosil 200 and Talc was added to improve the flow property and the stability of the granules formulated.

Manufacturing process of CPL extract chewable tablet –
1) All the ingredients were mixed homogeneously and prepared a dough using a suitable granulating agent.
2) The prepared dough was passed through sieve no. 16 and allowed to dry at 50° C for 60 minutes.
3) The dried granules were passed through sieve no. 20. The obtained granules were mixed with lubricant and glidant.
4) Accurately weighed quantity of formulated granules were subjected to compression on single punch tablet machine (Royal Artist) using 16mm flat faced punch.

Characterization of CPL extract chewable tablet –
a) Pre-compression parameters
Drug containing granules ready for compression were subjected to study the flow properties of granules to achieve uniformity of weight. The result of all the pre-compression parameters is given in Table 5.

Flow properties Results Specified Limits Remark
Angle of Repose 29.82 25-30 Excellent
Bulk Density (BD) 0.526gm/ml - -
Tapped Density (TD) 0.625gm/ml - -
Compressibility Index 15.84 12-16 Good
Hausner’s Ratio 1.18 1.12-1.18 Good
Table no. 5 - Flow properties for optimized granules

b) Post-compression parameters
• Physical Appearance
The appearance of optimized CPL extract chewable tablet is summarized in Table 6.
Parameters Observation
Shape Circular shaped
Color Buffed colored with some small black spots
Surface Flat surfaced
Diameter 16mm
Odor Pleasant
Table no. 6 - Appearance of optimized CPL extract chewable tablet

• Taste masking evaluation
Informed consent was first obtained from eight healthy volunteers and taste evaluation study was carried out. Intact CPL extract chewable tablet was held in mouth of each volunteer for 30 seconds. After expectoration, bitterness level was recorded by using the numerical scale (Score 0-Pleasant, 1-Tasteless, 2-Slightly bitter, 3-Moderately bitter, 4-Extremely bitter).

The taste masking score obtained for optimized CPL extract chewable tablet by Gustatory sensation test was 1 and was found to be tasteless based on the numerical scale for bitterness value.

• Average weight, Hardness and Thickness
Compressed tablets were evaluated to study weight variation, hardness and thickness. The results of evaluation test are mentioned in Table 7.

Test Results Limits
Weight Variation (mg) 904±5.62 More than 324mg 5%
Hardness (kg/cm2) 4±0.023 4 – 8kg/cm2
Thickness (mm) 4.1±0.085 -
% Friability 0.375±0.091 0.5 – 1%
Drug content (%) 99.14% -
Table no. 7 – Results for evaluation parameters of CPL extract chewable tablet

• % Friability
The friability of a sample of 20 tablets was measured using a USP type Roche friabilator. The friability of chewable tablet was found to be 0.375±0.091 %. (Table no. 7)

• Drug content (%)
The % drug content for 10 individual tablets was between 97-100% indicating content uniformity of the formulated tablets. The average drug content was found to be 99.14 %. (Table no. 7)

• In-vitro Disintegration time
The results of optimized CPL extract chewable tablet disintegration time are tabulated in Table 8.

In-vitro Disintegration time (min) 0.1 N hydrochloric acid Phosphate buffer pH 6.8 Distilled water
34.21 25.38 26.33
Table no. 8 - In vitro Disintegration time for of CPL extract chewable tablet

• Stability studies
Stability study results indicated that there was no change in physical appearance, hardness, weight variation and friability of the CPL extract chewable tablet at accelerated conditions. No significant change in the content of active drug was observed. Also, the optimized formulation did not show any significant change in the drug release profile. The optimized formulation was found to be stable. Stability studies of optimized batch of CPL extract are represented in Table 9.
Parameters Period
0 month 1 month 2 months 3 months

Appearance Buffed colored with some small black spots flat surfaced circular tablets
Complies Complies Complies
Average weight 904 ± 0.562 903 ± 0.318 904 ± 0.331 904 ± 0.451
Hardness (kg/cm2) 4 ± 0.023 4.2 ± 0.029 4 ± 0.033 4 ± 0.01
Friability (%) 0.375 ± 0.091 0.376 ± 0.095 0.335 ± 0.01 0.322 ± 0.021
Assay (%) 99.14 99.81 99.52 99.38
Table no. 9 - Stability study results at 40 ± 2°C temperature and 75 ± 5 % Relative humidity

c) Comparative study of the optimized formulation with marketed formulation
The optimized CPL extract chewable tablet was compared with the marketed formulation which is a conventional film coated tablet with result to post-compression parameters, In-vitro disintegration time and In-vitro dissolution study. The results are given in Table 10and 11.

Parameters Optimized CPL extract chewable tablet Marketed formulation
Shape Circular flat surfaced Oblonged with concave surface
Color Buffed color Erythrosine color film coated
Thickness 4.1 ± 0.085 7.2 ± 0.042
Diameter 16 mm (circular) 16mm (oval)
Dose of Drug (mg) 550mg 1100mg
Average weight (mg) 904 ± 0.562 1485 ± 0.0025
Hardness (kg/cm2) 4 ± 0.023 -
Friability (%) 0.375 ± 0.091 -
Assay (%) 99.14 100.24
Table no. 10 - Comparative evaluation of optimized CPL extract chewable tablet and marketed formulation with respect to post-compression parameters

Medium used for In-vitro disintegration study In-vitro disintegration time (min) ± SD
CPL extract chewable tablet Marketed formulation
Distilled water 26.33 ± 1.22 30.21 ± 1.43
0.1 N Hydrochloric acid 34.21 ± 1.35 29.43 ± 2.1
Phosphate buffer pH 6.8 25.38 ± 2.13 33.19 ± 1.23
Table no. 11 - In-vitro disintegration time of optimized CPL extract chewable tablet and marketed formulation (conventional film coated tablet)
We Claim:
1. A chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract; and
b) Pharmaceutically acceptable inert excipients.

2. The chewable tablet formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are diluent, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent, glidant, lubricant and solvent.

3. The chewable tablet formulation as claimed in claim 1, wherein the phytosomes of Carica papaya leaf extract is present in a concentration of 550 mg of the total formulation.

4. The chewable tablet formulation as claimed in claim 2, wherein the diluent is mannitol and microcrystalline cellulose.

5. The chewable tablet formulation as claimed in claim 2, wherein the binder is polyvinylpyrrolidone.

6. The chewable tablet formulation as claimed in claim 2, wherein the saliva stimulating agent is citric acid.

7. The chewable tablet formulation as claimed in claim 2, wherein the sweetener is aspartame and sucralose.

8. The chewable tablet formulation as claimed in claim 2, wherein the cooling agent is menthol.

9. A chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract in a concentration of 61.35 % w/w;
b) Diluent in a concentration of 27.88 % w/w; and
c) Binder in a concentration of 1.67 % w/w;
d) Saliva stimulating agent in a concentration of 0.11 % w/w;
e) Sweetener in a concentration of 4.83 % w/w;
f) Cooling agent in a concentration of 0.29 % w/w;
g) Flavouring agent in a concentration of 0.0034 % v/w;
h) Lubricant and Glidant in a concentration of 3.84 % w/w;
i) Solvent in a concentration of 0.045 % v/w.
wherein the percentages are with respect to total weight of the formulation.

10. A process for preparing a chewable tablet formulation comprises the steps of:
a) Weighing and mixing phytosomes of Carica papaya leaf extract, diluents, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent and solvent to form a dough;
b) Sieving and drying the dough to obtain dried granules;
c) Mixing the dried granules with glidant and lubricant to obtain uniform granules;
d) Compressing the uniform granules using single punch tablet machine to form chewable tablet formulation.

Dated this: 28th day of March 2024

Vijaykumar Shivpuje
IN/PA-1096
Agent for the Applicants

To
The Controller of Patents
The Patent Office, At Mumbai / Chennai / New Delhi / Kolkata

“CHEWABLE TABLET FORMULATION COMPRISING CARICA PAPAYA LEAF EXTRACT AND PREPARATION METHOD THEREOF”

ABSTRACT

The present invention relates to a chewable tablet formulation comprising phytosomes of carica papaya leaf extract. The formulation further includes diluent, binder, saliva stimulating agent, sweetener, cooling agent, flavoring agent, glidant, lubricant and solvent. The invention also provides a process for preparation of chewable tablet formulation. , Claims:1. A chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract; and
b) Pharmaceutically acceptable inert excipients.

2. The chewable tablet formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are diluent, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent, glidant, lubricant and solvent.

3. The chewable tablet formulation as claimed in claim 1, wherein the phytosomes of Carica papaya leaf extract is present in a concentration of 550 mg of the total formulation.

4. The chewable tablet formulation as claimed in claim 2, wherein the diluent is mannitol and microcrystalline cellulose.

5. The chewable tablet formulation as claimed in claim 2, wherein the binder is polyvinylpyrrolidone.

6. The chewable tablet formulation as claimed in claim 2, wherein the saliva stimulating agent is citric acid.

7. The chewable tablet formulation as claimed in claim 2, wherein the sweetener is aspartame and sucralose.

8. The chewable tablet formulation as claimed in claim 2, wherein the cooling agent is menthol.

9. A chewable tablet formulation comprising
a) Phytosomes of Carica papaya leaf extract in a concentration of 61.35 % w/w;
b) Diluent in a concentration of 27.88 % w/w; and
c) Binder in a concentration of 1.67 % w/w;
d) Saliva stimulating agent in a concentration of 0.11 % w/w;
e) Sweetener in a concentration of 4.83 % w/w;
f) Cooling agent in a concentration of 0.29 % w/w;
g) Flavouring agent in a concentration of 0.0034 % v/w;
h) Lubricant and Glidant in a concentration of 3.84 % w/w;
i) Solvent in a concentration of 0.045 % v/w.
wherein the percentages are with respect to total weight of the formulation.

10. A process for preparing a chewable tablet formulation comprises the steps of:
a) Weighing and mixing phytosomes of Carica papaya leaf extract, diluents, binder, saliva stimulating agent, sweetener, cooling agent, flavouring agent and solvent to form a dough;
b) Sieving and drying the dough to obtain dried granules;
c) Mixing the dried granules with glidant and lubricant to obtain uniform granules;
d) Compressing the uniform granules using single punch tablet machine to form chewable tablet formulation.