Gummies For Good Health: Enhancing TB Treatment with Isoniazid Oral Gummies

Tuberculosis (TB) is a human disease caused by Mycobacterium tuberculosis (MTB), primarily affecting the lungs. Pulmonary disease is the most common manifestation of TB. However, other organ systems, including the respiratory, gastrointestinal, lymphoreticular, skin, central nervous, musculoskeletal, reproductive, and liver systems, can also be affected [1]. TB transmission occurs through airborne transmission when individuals with pulmonary TB cough, sneeze, or spit, releasing germs that can infect others [2]. Symptoms of TB disease typically include persistent cough, chest pain, weakness, weight loss, fever, and night sweats. These symptoms can remain mild for months, leading to delayed medical attention and increased transmission risk [2]. Approximately 25% of the global population is infected with TB bacteria, with 10 million new cases reported annually [3]. Despite being preventable and treatable, TB claims 1.5 million lives each year, making it the world's leading infectious killer [4][2]. In 2022, an estimated 13 million household contacts of individuals with confirmed pulmonary TB were reported worldwide [5]. Notably, TB is the leading cause of death among individuals with HIV [2]. Timely diagnosis, proper treatment, and preventive therapy can effectively prevent many TB-related deaths. TB infections can result in either latent TB infection (LTBI) or potentially fatal TB disease if left untreated [4]. Among the 1.7 billion individuals globally estimated to have latent MTB infection, identifying and treating those at risk of progressing to active disease is crucial [6]. Preventive measures targeting both fatal tuberculosis and latent tuberculosis are essential. Prompt diagnosis and effective treatment are necessary for individuals with active tuberculosis infections, reducing the risk of MTB transmission. Tuberculosis Preventive Treatment (TPT) is recommended by the World Health Organization (WHO) for individuals with HIV, family members in close contact with TB patients, and other at-risk groups [5]. Identifying and treating latent TB infection (TBI) is critical to global TB elimination initiatives. TPT is provided to populations at high risk of TB exposure or progression from infection to active TB disease [7]. Priority should be given to individuals with HIV infection and close contacts of those recently diagnosed with infectious TB, as they face higher risks and require urgent preventive therapy. Tuberculosis (TB) has consistently shown a much higher annual mortality rate than HIV or any other infection. This is due to an array of events that begins with the virulence of Mycobacterium tuberculosis, the highly contagious and persistent bacterium responsible for TB infection. Another contributing factor is the ability of these bacteria to develop genetic mutations that confer resistance to a number of formerly effective antibiotics. The World Health Organization (WHO) estimated about 480,000 cases of multiple-drug resistant (MDR-) TB detected worldwide in 2013. MDRTB and its more resistant sibling, extensively-drug resistant (XDR-) TB, have become increasingly common since successful antibiotic treatments of TB were discovered. Ominously, some experts predict that MDRTB will replace non-resistant TB as the most common form of the disease in the next 50 years [1]. However, there has been a great success in developing effective techniques for preventative care, treatment, and infection control. The annual mortality rate of TB has dropped almost 50% since 1990, and global health organizations are poised to build upon this positive momentum. It has even been stated that after a decade of public health programs and research, “2015 is a watershed moment in the battle against tuberculosis” [2]. Proven care and management methods combined with promising new techniques for better detection and treatment of TB will enable healthcare professionals to continue to make enormous strides in this high-stakes battle. Despite this success, funding for TB control falls far short of that for other infectious diseases. It is clearly evident that present funding and communication gaps are stagnating prevention and control efforts; however targeted investments will pay off in huge dividends in the global campaign to eradicate this debilitating disease [2]. High-quality research evidence is critical for improving global health and health equity, and for achieving the World Health Organization (WHO)’s objective of the attainment of the highest possible level of health by all peoples [1]. This need is most apparent when responding to complex epidemics such as tuberculosis (TB). TB is the leading killer among diseases caused by an infectious agent worldwide, the leading killer of people with HIV infection and a leading cause of death from airborne anti-microbial resistant infections, taking heavy tolls on human lives, communities and health systems at large [2, 3]. WHO estimates that TB caused illness in 10 million people and claimed an estimated 1.6 million lives in 2017 alone [2]. The WHO End TB Strategy, in the context of the Sustainable Development Goals (SDGs), lays ambitious goals and milestones to end the epidemic by reducing incidence and mortality by 80% and 90% in 2030 compared to 2015: such reductions can only be achieved if there are major technological breakthroughs by 2025 [4]. Critical research is needed to acquire rapid point-of-care TB diagnostics, including for drug resistance; shorter, safer and simpler regimens effective against drug-susceptible and drug-resistant TB, as well as latent TB infection (LTBI) that are appropriate for treatment of TB/HIV co-infection; and a new TB vaccine that is effective both before and after exposure. These require scientific advances in the discovery and development of new biomedical tools, together with innovative delivery mechanisms to effectively adapt and adopt new technologies and optimise the necessary linkages and integrations with other health services and sectors. For this reason, “Intensified research and innovation” has been identified as one of the three essential pillars of the End-TB Strategy. This editorial summarises the research questions identified through recent WHO TB policy guidance to increase the quality of evidence for policy-making. Based on evidence arising from research, WHO is mandated to produce recommendations to guide clinical practice and public health policy for TB prevention and care in response to demand from public health decision makers. WHO guideline development groups (GDGs), which include researchers, the health workforce, civil society, as well as end-users of the guidelines, such as policymakers from government, professional associations and other constituencies, are appointed by WHO to develop policy guidelines [5]. A GDG meets with the primary objective of agreeing on the scope of recommendations by reviewing evidence, structured according to the standard framework of population, intervention, control, outcomes (PICO). This permits a systematic study of relevant evidence, the formulation of recommendations and the identification of knowledge gaps that need to be addressed through high quality research conducted in various epidemiological, demographic and geographic settings. The research questions highlighted in this document arose because the respective GDGs agreed they were critical for increasing the certainty/strength of existing recommendation, and/or for stimulating the development or optimisation of new recommendations that can lead to improvement in patient health and welfare. This step is an integral part of the WHO guideline development process (see, for example, the discussion section of FALZON et al. [6]). Among the major challenges facing global policy guidance development in TB are the shortage of good quality evidence exacerbated, for example, by lack of sufficient clinical trials with direct evidence of clinical benefit or improvement in an established surrogate for clinical benefit; data inaccessibility including for programmatic experiences of benefits and safety of interventions in real world setting; or when the evidence being presented does not address broader questions of values and priorities that go beyond medical interventions (e.g. acceptability, feasibility, resource distribution and health equity). Evidence obtained from well-designed, large scale multidisciplinary studies with robust testing of interventions are therefore needed to improve the strength of future guidance. The most up-to-date WHO policy guidance documents for TB prevention and care are summarised in a Compendium of TB Guidelines and Associated Standards [7, 8]. Using this compendium as a reference, we compiled a list of 155 research questions across the continuum of TB prevention, diagnosis, treatment and care (also summarised in table 1): three related to early detection; 35 related to diagnosis of TB disease, 10 related to the diagnosis and management of latent TB infection, 38 related to treatment of TB disease, including drug-resistant TB; 38 related to the management of TB/HIV and malnutrition; and 31 related to childhood TB management [10]. Because these research questions are limited in scope to needs identified during guideline development processes, the majority of the questions highlight gaps at the policy/implementation interface (figure 1). Systematically linking such research questions to public health goals requires collaboration among funders, researchers and end users to ensure that funded research

Early detection of TB 

Systematic screening for active tuberculosis: principles and recommendations

Diagnosing TB disease

Xpert MTB/RIF and Ultra assays for the diagnosis of pulmonary and extrapulmonary TB in adults and children and WHO Meeting Report of a Technical Expert Consultation: non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF The use of loop-mediated isothermal amplification (TB-LAMP) for the diagnosis of pulmonary tuberculosis. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV: policy update. The use of molecular line probe assays for the detection of resistance to isoniazid and rifampicin. Molecular line probe assays for the detection of resistance to second-line anti-tuberculosis drugs: policy guidance

Diagnosing and treating latent TB infection

Treating TB

Treatment of drug-susceptible tuberculosis and patient care: 2017 update 8 4.2 WHO treatment guidelines for isoniazid-resistant TB WHO treatment guidelines for drug-resistant tuberculosis: 2016 update

TB/HIV and other comorbidities

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (this is an HIV guideline and the two research questions were those relevant to TB) Integrating collaborative TB and HIV services within a comprehensive package of care for people who inject drugs: consolidated guidelines WHO policy on collaborative TB/HIV activities See ref. [9] Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy (this is an HIV guideline and the 4 research questions were those relevant to TB) Nutritional care and support for patients with tuberculosis

Managing TB in children

Guidance for national tuberculosis programmes on the management of tuberculosis in children represents value for money, not only through the generation of new knowledge but also by contributing to health and economic outcomes. There are several ways of accomplishing that. The National Institute for Health Research Public Health Research Programme (NIHR PHR Programme) in the UK, for example, includes public health decision makers in its decision-making committee, and subsequently, the research it funds has been shown to align with priorities highlighted in national guidelines [11]. However, this is not the practice across all research funders. An exploratory qualitative study of funding strategy among five high-profile public health research funding organisations showed limited involvement from end users/ policymakers in the prioritisation of research questions for funding [12]. Considering the need for well-funded, timely and high-quality research for policy, funders should capitalise on opportunities to strengthen participation of policymakers and other end users in generating priority-driven research funding streams. At a time when there are many competing demands on limited resources, the WHO and its partners, countries, civil society and affected communities have a joint responsibility to ensure that TB research investments help achieve the goals and targets of the End TB Strategy and the SDGs. In recognition of this need, a TB resolution adopted at the World Health Assembly in May 2018 requested WHO to develop a global strategy for TB research and innovation, “to make further progress in enhancing cooperation and coordination in respect of tuberculosis research and development” [13]. Considering the significant funding gap for TB research (USD 1.3 billion gap in 2017 when benchmarked against the targets outlined in the Global Plan to End TB 2016–2020: the Paradigm Shift), such coordination and collaboration is envisioned to help direct time and resources to the most urgent evidence needs faced by TB policymakers [14–16]. Isoniazid has been one of the first-line antitubercular drugs used to treat both active tuberculosis (TB) and latent TB infection (LTBI) for several years [1]. Isoniazid is associated with numerous types of adverse drug reactions (ADRs) affecting the central and peripheral nervous system, such as insomnia, headache, muscle twitching, optic neuropathy, peripheral neurotoxicity, psychosis, and restlessness [2]. Isoniazid may cause psychiatric ADRs that include symptoms such as delusions, hallucination, abnormal behaviour, disor have found an association between the development of psychosis and isoniazid use in the treatment and prophylaxis of TB [5, 6]. Several mechanisms have been hypothesized for isoniazid-induced psychosis. One mechanism involves the marginal inhibition of monoamine oxidase (MAO) by isoniazid, which results in elevated levels of monoamines [7, 8]. Another mechanism is the lack of vitamin B6/pyridoxine, a cofactor necessary to produce numerous neurotransmitters, including gamma-aminobutyric acid (GABA) [9]. When isoniazid is metabolized, it produces hydrazine and its metabolites (reactive nitrogen species), which bind with pyridoxal phosphate, an active form of pyridoxine. This binding inhibits the enzymes dependent on pyridoxal phosphate, including transaminases and those involved in amino acid metabolism, leading to a functional pyridoxine deficiency [10]. In addition, isoniazid is linked to increased oxidative stress caused by increased production of reactive oxygen species (ROS), which lowers the density of N-methyl-Disparate (NMDA) receptors in the hippocampus. ROS are hypothesized to be produced more often, and subsequently, glutathione levels are depleted [11]. The incidence of isoniazid-induced psychosis has not yet been established. The risk factors for the occurrence of psychosis induced by isoniazid include older age, malnourishment, alcohol consumption, diabetes mellites, uraemia, present, past, and family history of psychiatric illness, hepatocellular dysfunction, and neurological disorder [12–14]. Additionally, the isoniazid dose (> 5 mg/ kg) and N acetyltransferases (NAT2) slow acetylators status might contribute to the risk of developing psychosis secondary to isoniazid intake [13]. To our knowledge, no epidemiological studies focused on psychosis due to isoniazid for TB treatment and/or LTBI, and most of the available literature includes case reports and case series. Despite its clinical importance, there is a limited understanding regarding the demographic, social, and clinical determinants of isoniazid-induced psychosis in patients with TB and LTBI. Our systematic review focused on the in-depth clinical profiling of patients who developed isoniazid-induced psychosis. In this systematic review, we assessed the occurrence of isoniazid-induced psychosis based on patient demographics, social factors, and clinical determinants. We investigated whether there were specific periods during which psychosis was more likely to occur in TB and LTBI patients. This review also provides an overview of the pharmacological management of isoniazid induced psychosis.

Types Of Tuberculosis

Pulmonary

Pulmonary TB affects the lungs. The lungs are the primary site of TB in up to 87 in 100Trusted Source cases. Pulmonary TB may be latent or active, and around 10 in 100 people develop symptoms. Around one-third of people may develop respiratory symptoms with pulmonary TB, but prolonged fever is the most common symptom.

• Affects the lungs
• Most common and contagious form
• Symptoms: persistent cough, blood in sputum, fever, night sweats

Extrapulmonary TB affects organs and tissues outside of the lungs. Extrapulmonary TB accounts for around 15 in 100 of all TB cases.

People with a weakened immune system may develop extrapulmonary TB, such as people with HIV.

• Affects organs other than the lungs (e.g., lymph nodes, bones, brain, kidneys)
• Not usually contagious

Common types:

• Lymph Node TB (most common form of EPTB)
• Bone and Joint TB (Pott’s disease)
• Meningeal TB (affects the brain)
• Abdominal TB (affects intestines and peritoneum)

TB lymphadenitis affects the lymph nodes and is the most common form of extrapulmonary TB. Symptoms of TB lymphadenitis include:

• enlarged lymph nodes, which may appear as painless lumps on both sides of the head and neck
• fever
• night sweats
• fatigue

1.1.4 Skeletal TB

Skeletal TB is a type of TB that has spread to the bones. Around Source Trusted in extrapulmonary TB cases are skeletal TB. The most commonly affected area for skeletal TB is the thoracic spine, which is the middle section of the spine.

Symptoms of skeletal TB include:

• pain
• weakness or changes in movement and muscle function
• other TB symptoms, such as fever and malaise

1.1.5 Miliary TB

Miliary TB is a form of both Trusted Source pulmonary and extrapulmonary TB. Miliary TB appears as millet-seed-like lesions on the lungs and other organs in the body.

Miliary TB may affect the blood, bones, lymphatic system, central nervous system, or organs.

Symptoms of miliary TB depend on which organs it affects, but people can experience general symptoms such as:

• weakness
• fever
• cough
• unexplained weight loss
• lack of energy

1.1.6 Genitourinary TB

Genitourinary TB affects the genitals, urinary tract, or kidneys. Bladder TB usually occurs after a TB infection in the kidneys. Genital TB is rare, but in females, it may cause infertility. Genitourinary TB does not usually cause any symptoms

Liver TB usually affects those with an advanced HIV infection or other immunodeficiency. Liver TB may appear as multiple, small nodules on imaging scans.

1.1.8 Gastrointestinal TB

Gastrointestinal TB affects the gastrointestinal tract. TB is rare in the intestines but more common in the ileocecal area, between the end section of the small intestine and the beginning of the large intestine.

Intestinal TB may share similar symptoms and features with Crohn’s disease. Complications include intestinal obstructions and perforations.

TB meningitis is an infection of the meninges, the membranes covering the spinal cord and brain.

The TB infection may travel Trusted Source from the lungs through the lymph nodes to reach the meninges.

TB meningitis causes symptoms of meningitis, including:

• headache
• fever
• change in mental status
• facial palsy

Peritoneal TB affects the peritoneum, which is the lining of the abdomen. Peritoneal TB usually occurs   alongside other types of abdominal TB. Peritoneal TB may cause ascites, which is a buildup of fluid in the abdomen.

1.1.1.2.  TB pericarditis

TB pericarditis affects the pericardium, which is the membrane surrounding the heart. TB pericarditis affects around 1–2%Trusted Source of people with pulmonary TB.

Symptoms of TB pericarditis include:

• chest pain
• fever
• difficulty breathing
• cough

 1.1.1.3. Cutaneous TB

Cutaneous TB affects the skin and is a rare form of TB. Around 1–2%Trusted Source of all extrapulmonary TB cases are cutaneous TB. It is more common in people with HIV or other immunodeficiency.

Cutaneous TB can appear as any type of skin lesion, such as:

• papules
• nodules
• ulcers
• pustules
• verrucous plaques

1.1.1.4.  Tests for TB

Tests for TB include Trusted Source the following:

• Mantoux tuberculin skin test (TST): A doctor will inject a substance — tuberculin — into the skin on the arm to see if it creates a reaction, which can indicate whether a TB infection is present or not.
• Blood tests: Doctors use blood tests known as interferon-gamma release assays (IGRAs) to test whether TB infection is present.
• X-ray or CT scan: A doctor may carry out additional imaging scans if they think a TB infection is present in the lungs.
• Sputum tests: A sputum test examines mucus that people cough up to see if a TB infection is present.

1.1.1.5. Transmission

TB spreads through the air when an infected person coughs, sneezes, or talks. People in close contact with TB patients, such as family members or healthcare workers, are at higher risk of infection. However, not everyone infected with TB bacteria becomes sick—this is known as latent TB infection (LTBI), which can later develop into active TB disease if the immune system weakens.

Modes of TB Transmission:

1. Airborne Transmission (Most Common)

When an infected person exhales droplets into the air, others nearby can inhale the bacteria into their lungs.

High-risk environments: Crowded places like hospitals, prisons, shelters, and poorly ventilated homes.

2. Direct Contact with Infected Secretions (Rare)

Handling sputum, saliva, or other bodily fluids from an infected person may pose a risk in healthcare settings.

3. Congenital TB (Rare)

A mother with active TB can pass TB to her baby during pregnancy or birth.

1.1.1.6. Who is at Higher Risk?

• Close contacts of TB patients (family, healthcare workers)
• People with weakened immune systems (HIV/AIDS, diabetes, malnutrition)
• Smokers, alcoholics, and drug users
• Elderly and young children

1.1.1.7.  TB is NOT spread by:

• Sharing food, drinks, or utensils
• Handshakes or hugs
• Casual contact (e.g., touching surfaces)

1.1.1.8. How to Prevent TB Transmission?

• Early detection & treatment of active TB cases
• Wearing masks & covering coughs/sneezes
• Proper ventilation in crowded places
• BCG vaccination (for children in high-risk areas)

 1.1.1.9 Symptoms

5. Persistent cough lasting more than 3 weeks
5. Chest pain
5. Coughing up blood or sputum
5. Fever and chills
5. Night sweats
5. Unexplained weight loss
5. Fatigue and weakness

Diagnosis of Tuberculosis (TB)

The diagnosis of tuberculosis (TB) involves several steps and tests. Here's an overview of the common methods used:

1. Medical History & Physical Examination:

A detailed medical history is taken, focusing on symptoms like cough, weight loss, fever, night sweats, and chest pain.

Physical examination to check for signs like abnormal lung sounds, swollen lymph nodes, or signs of extrapulmonary TB.

2. Tuberculin Skin Test (TST) / Mantoux Test:

Involves injecting a small amount of tuberculin (a protein from the TB bacteria) under the skin. A raised bump is checked after 48–72 hours.

A positive result indicates exposure but not necessarily active TB.

3. Chest X-ray:

Used to identify lung abnormalities indicative of active TB, such as cavitary lesions, infiltrates, or lung scarring.

X-rays help assess the severity of the disease and its spread.

4. Sputum Tests:

Sputum Smear Microscopy: A sample of mucus from the lungs is examined under a microscope for the presence of acid-fast bacilli (AFB), which are indicative of TB bacteria. Sputum Culture: A more sensitive test that involves growing the TB bacteria in a laboratory. This confirms the diagnosis and helps test for drug resistance.

Polymerase Chain Reaction (PCR): Molecular tests that detect TB bacteria’s genetic material in sputum samples.

5. Blood Tests:

Interferon-gamma release assays (IGRAs), such as QuantiFERON-TB, measure the immune response to TB bacteria. It is especially useful in diagnosing latent TB.

6. Other Tests:

If extrapulmonary TB (outside of the lungs) is suspected, tests such as biopsy, lumbar puncture (for TB meningitis), or urine tests (for TB in the kidneys) may be conducted.
Treatment of Tuberculosis

The treatment of TB depends on whether it is active or latent, and whether it is drug-sensitive or drug-resistant.

1. Active TB (Drug-Sensitive)

• The standard treatment for drug-sensitive TB is a combination of four first-line antibiotics:

• Isoniazid (INH)
• Rifampin (RIF)
• Pyrazinamide (PZA)
• Ethambutol (EMB)

• This treatment regimen is typically followed for 6 months:
• 2 months of intensive treatment (INH, RIF, PZA, EMB) followed by 4 months of continuation therapy (INH and RIF).
• Adherence to the treatment plan is crucial to prevent resistance, relapse, and the spread of the disease.

2. Latent TB

Isoniazid or Rifampin may be prescribed for 6–9 months to reduce the risk of latent TB becoming active. Directly Observed Therapy (DOT) may be recommended to ensure that patients take their medication regularly.

3. Drug-Resistant TB

• For multidrug-resistant TB (MDR-TB), where the bacteria are resistant to at least Isoniazid and Rifampin, treatment becomes more complex:
• A combination of second-line drugs is used, including fluoroquinolones, injectable agents like amikacin, kanamycin, or capreomycin, and other newer drugs like bed aquiline or dexaminid.
• Treatment duration is extended to 18–24 months or longer.
• In cases of extensively drug-resistant TB (XDR-TB), where there is resistance to first-line drugs and some second-line drugs, treatment can be more challenging and may require newer agents and individualized 2

 2.1 Oral gummies

• In recent years, there has been an increasing demand for functional foods that promote healthy lifestyle and improve overall well-being.
• This growing interest from consumers in enhancing their quality of life has had a significant impact on the confectionery market.
• To meet the expectations of discerning consumers, confectionary manufacturers have been incorporating new ingredients into their products that cater to these needs [1].
• Gummy candies, being hugely popular across all age groups, are suitable matrix for the addition of functional ingredients [2].
• Traditionally, gummy candies are made using a combination of sugar, water, and gelatin [3].
• However, to improve candy formulations, there are several common techniques employed such as substituting the gelling agent for gelatin, utilizing natural colorants, incorporating plant extracts, vitamins, or fruit derivatives, and substituting sugar with other sweeteners [4].
• Gelatin is often used in gummy candies because it provides a strong and transparent texture to the final product that is desirable to consumers.
• But since pigskin is the primary source of gelatin in the global market, it is often controversial for religious believers [5].
• Therefore, it is imperative to use a suitable substitute for gelatin in the production of gummy candies.
• Modified starch is widely used, alone or in combination with other gelling agents, for making gummy candies due to their good gelling properties [6].
• They can be added in varying amounts to achieve the desired texture.
• Sugar is another key ingredient in gummy candies formulations, but it may not be suitable for individuals with diabetes or other health conditions that require them to limit their sugar consumption.
• Stevia, as a natural, zero-calorie sweetener, can be used as a sugar substitute in food formulations. It is a suitable option for individuals looking to reduce their sugar intake [7].
• Recently, plant extracts have been used to add flavour, aroma, and nutritional value to various food products [8].
• By formulating gummy candies with plant extracts, manufacturers can offer consumers a tasty snack with added health benefits. The use of plant extracts in gummy candies formulation has been the subject of numerous studies.
• For example, a study in 2019 investigated the use of eggplant peel extract in gummy candies. It found that adding 1.5 % of free extract and spray dried powder improves the colour properties and acceptability of the product [9].

2.1.1 Types of Oral Gummies

• Jelly Babies.
• Bears.
• Cola Bottles.
• Rings.
• Red frogs.
• Roadkill gummies.
• Teeth gummies.
• Worm gummies.

Teeth Gummies

Gummy teeth look like the real teeth and gum and are very sweet and look silly. They are suitable for dental related occasions and are packed 40 pieces in every pound. Ingredients; Carnauba Wax and Bees Wax, Beef Gelatin, Acidulant (citric acid), Palm Oil, Artificial Flavors, Sugar, Colours, Corn Syrup. Teeth gummies can be stored at room temperature and last a period of up to 1 year before they expire.

Fig: - 7 Teeth Gummies

2.1.1.   Gummy Alligators

Fig: - 8 Gummy alligators

Gummy alligators are flavourful dimensional candies usually made in green or a combination of colours. They are made to look like the real swampy creatures. Gummy alligators can be used in occasions like kids’ birthdays or reptilian-themed celebrations.

Ingredients; gelatin, natural flavours, sorbitol, carnauba wax, canola oil, lecithin, water, corn syrup, rosemary extract, sugar, citric acid, vegetable oil. Gummy alligators should not be used by vegetarians because it contains gelatin.

2.1.2. Gummy bears

Fig: - 9 Gummy Bears

Gummy bears are small, fruity candies, almost similar to the jelly baby gummy in other countries. These gummies are about 2 cm long and look like a bear. They can be used for occasions like bear beach party.

Ingredients; sugar, glucose syrup, food colouring, starch, gelatin, flavouring, and citric acid.

The ingredients can differ depending on the consumers. Gummy bears can stick to the teeth hence can cause tooth decay.

 2.1.3. Gummy body parts

Fig: - 10 Gummy Body Parts

Gummy body parts are candies that are designed in the shapes of body parts such as ear, eyeball, finger, foot, brain. These candies are suitable for parties meant to freak out friends.

Ingredients; Marple syrup, Sorbitol, Water, Sodium Citrate, Carnauba Wax, Artificial Flavors, Gelatin, Sugar, Malic Acid, Colours and Citric Acid. Gummy body parts are suitable for handing out to trick-or-treaters parties but should not be consumed in large quantities.

 2.1.4. Gummy Bunny

Fig: - 11Gmmy Bunny

Gummy bunny is soft and delicious and really juicy since it is made with natural fruit juice.  This candy is also fat-free made in variety of colours and flavours. They can be used as snacks or toping in kids’ birthday parties.

Ingredients; Marple Syrup, Gelatin, Potato Starch, Natural Flavors, Sugar, Citric Acid, Rice Syrup, Apple Juice Concentrate, Sodium Citrate, Coconut Oil, Vegetable Juice, Spirulina Extract, Beta-Carotene, Carnauba Wax, fat, Pectin.

 2.1.5 Gummy Candy Corn

Fig: -12 Gummy Candy Corn

Gummy candy corn is a gummy version which is lightly covered with sugar with a soft texture in different flavours. They are suitable to be used as a treat for friends or for decorating Halloween Cupcakes or for other beautiful Halloween decorations.

Ingredients; Sugar, Tapioca Dextrin, Fumaric Acid, Corn Syrup, Maltodextrin, candy Glaze (Shellac), Salt, Malic Acid, Citric Acid, Sodium Citrate, Gelatin, Honey, Acacia, Sesame Oil, Artificial Flavors and colours.

2.1.6. Gummy flowers

Fig: - 13 Gummy Flower

Gummy flowers are made of tasty flavours like strawberries, lemon and orange all in one candy. They come in small sizes but they are irresistible. Gummy flowers are used for baking decorations and perfect for eating on the go. Ingredients; Water, Sodium Citrate, Glucose Syrup, Sweeteners, Marple Starch, Gelatin, food Acid, Flavors, and Colours. This candy type is also packed in the same way cereals containing gluten, peanuts are packed.

 2.1.7 Gummy Frogs

Fig: - 14 Gummy Frogs

Gummy frogs are white foamy bellies with lime flavour and they are sweet with some sour taste. Gummy frogs are suitable for frog-based parties or rain forest occasions and they are green in color.

Ingredients: Marple syrup, gelatin, artificial colours, citric acid, sweetener, dextrose, natural flavours, Marple starch, processed coconut oil, beeswax coating, carnauba wax. Each bag has all the three flavours of gummy frogs in different amounts of each.

 2.1.8. Rings

Fig: - 15 Rings

Chapter 2: -Aim & Objectives:

The primary aim of the formulation development and characterization of isoniazid gummies for treating tuberculosis is to create a novel, patient-friendly, and effective dosage form that enhances patient compliance, ensures optimal therapeutic efficacy, and improves the bioavailability of the drugs used in tuberculosis treatment.[22]

The objectives of formulation development and characterization of isoniazid gummies for treating tuberculosis can be outlined as follows:

1. Formulation Development:

• To develop a stable, palatable, and effective gummy formulation that can deliver the required doses of isoniazid for the treatment of tuberculosis.
• To optimize the combination of isoniazid within the gummy matrix, ensuring their stability, compatibility, and bioavailability.
• To select suitable excipients (e.g., gelling agents, sweeteners, stabilizers) that will not affect the therapeutic efficacy of the drugs.
• To design a dosage form with controlled release properties to maintain a therapeutic drug concentration over time and improve patient compliance.
• To ensure ease of manufacturing and scalability for large-scale production of the gummies.                                                                                                     

2. Characterization of Formulation:

• To assess the physical characteristics of the gummies, including appearance, texture, shape, and size, ensuring consistency in each batch.
• To evaluate the drug content uniformity, ensuring each gummy contains the appropriate amounts of isoniazid as per the required therapeutic doses.[23]
• To conduct in vitro release studies to determine the release profile of isoniazid from the gummy matrix.

 Chapter 3: Review Of Literature

1. Emma A. Kean et al. (2023) The shortage of child-friendly formulations is a major challenge in managing tuberculosis in children. Chewable formulations are attractive alternatives to tablets and suspensions due to their taste masking, no need for water, and appealing shapes for kids aged 2 and above. We developed a polymeric gummy drug formulation (P-GDF), named Flex Chew, containing isoniazid using a solid-liquid dispersion and temperature-dependent sol-gel technique. Flex Chew gummies are visually appealing, compact (17.738 mm height, 10.473 mm width, 8.603 mm thickness), lightweight (1.425 g), and mechanically robust (hardness 37.260 N). They are easy to chew (chewiness 30.570 N) and effectively encapsulate isoniazid (101.565%), releasing it nearly completely (≈100% in 75 min) through zero-order and non-Fickian mechanisms. They also provide efficient taste masking and better palatability compared to the placebo.
2.  Oluwatoyin A. Adeleke et al. (2024) Gummy formulations are gaining popularity as alternatives to traditional tablets and capsules due to their chewability, flexibility, and improved drug release. They are particularly appealing for children and enhance patient compliance. However, there is a need for measurable quality parameters for these products.
3. Arvind Natarajan et al (2020) Tuberculosis (TB), which is caused by bacteria of the Mycobacterium tuberculosis complex, is one of the oldest diseases known to affect humans and a major cause of death worldwide. Tuberculosis continues to be a huge peril disease against the human population and according to WHO, tuberculosis is a major killer of the human population after HIV/AIDS. Tuberculosis is highly prevalent among the low socioeconomic section of the population and marginalized sections of the community. In India, National strategic plan (2017–2025) has a national goal of elimination of tuberculosis by 2025. It requires increased awareness and understanding of Tuberculosis. In this review article history, taxonomy, epidemiology, histology, immunology, pathogenesis and clinical features of both pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (EPTB) has been discussed. A great length of detailed information regarding diagnostic modalities has been explained along with diagnostic algorithm for PTB and EPTB. Treatment regimen for sensitive, drug resistant and extensive drug resistant tuberculosis has been summarized along with newer drugs recommended for multi drug resistant tuberculosis. This review article has been written after extensive literature study in view of better understanding and to increase awareness regarding tuberculosis, as a sincere effort that will help eliminate tuberculosis off the face of the earth in near future.
4. Shahinda S R Alsayed et al (2023)¹Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host’s immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bed aquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB—the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years—reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.
5. Yi Huang et al (2022) Diagnosis of tuberculosis, and especially the diagnosis of extrapulmonary tuberculosis, still faces challenges in clinical practice. There are several reasons for this. Methods based on the detection of Mycobacterium tuberculosis (Mtb) are insufficiently sensitive, methods based on the detection of Mtb-specific immune responses cannot always differentiate active disease from latent infection, and some of the serological markers of infection with Mtb are insufficiently specific to differentiate tuberculosis from other inflammatory diseases. New tools based on technologies such as flow cytometry, mass spectrometry, high-throughput sequencing, and artificial intelligence have the potential to solve this dilemma. The aim of this review was to provide an updated overview of current efforts to optimize classical diagnostic methods, as well as new molecular and other methodologies, for accurate diagnosis of patients with Mtb infection.
6. Catherine Vilchèze et al (2019) Isoniazid (INH) was the first synthesized drug that mediated bactericidal killing of the bacterium Mycobacterium tuberculosis, a major clinical breakthrough. To this day, INH remains a cornerstone of modern tuberculosis (TB) chemotherapy. This review describes the serendipitous discovery of INH, its effectiveness on TB patients, and early studies to discover its mechanisms of bacteriocidal activity. Forty years after its introduction as a TB drug, the development of gene transfer in mycobacteria enabled the discovery of the genes encoding INH resistance, namely, the activator (katG) and the target (inhA) of INH. Further biochemical and x-ray crystallography studies on KatG and InhA proteins and mutants provided comprehensive understanding of INH mode of action and resistance mechanisms. Bacterial cultures can harbor subpopulations that are genetically or phenotypically resistant cells, the latter known as persisters. Treatment of exponentially growing cultures of M. tuberculosis with INH reproducibly kills 99% to 99.9% of cells in 3 days. Importantly, the surviving cells are slowly replicating or non-replicating cells expressing a unique stress response signature: these are the persisters. These persisters can be visualized using dual-reporter mycobacteriophages and their formation prevented using reducing compounds, such as N-acetylcysteine or vitamin C, that enhance M. tuberculosis’ respiration. Altogether, this review portrays a detailed molecular analysis of INH killing and resistance mechanisms including persistence. The phenomenon of persistence is clearly the single greatest impediment to TB control, and research aimed at understanding persistence will provide new strategies to improve TB chemotherapy.
7. Kiet A Ly et al (2008) Habitual consumption of xylitol reduces mutans streptococci (MS) levels but the effect on Lactobacillus spp. is less clear. Reduction is dependent on daily dose and frequency of consumption. For xylitol to be successfully used in prevention programs to reduce MS and prevent caries, effective xylitol delivery methods must be identified. This study examines the response of MS, specifically S. mutans/sobrinus and Lactobacillus spp., levels to xylitol delivered via gummy bears at optimal exposures.
8. Rutuja R et al (2022) Abstract: A multivitamin is a medication intended to serve as a salutary supplement with vitamins, salutary minerals, and other nutritive rudiments. Multivitamin formula contains vit C, B2, Zinc, Calcium, Magnesium, Potassium. gummy vitamins are designed to be a further palatable(read sweeter) volition to regular vitamins in the expedients that people will be more inclined to take them. numerous people prefer sticky vitamins to capsules due to their gooey flavours and delicacy- suchlike taste. Dissolvable, chewable, greasepaint or sticky vitamins tend to be easier to digest. Like capsules and capsules, gummies supply the vitamins. Vitamin C and Vitamin B2(riboflavin) are the idol constituents of multivitamin gummies, both gives the antioxidant exertion, Photoprotection, crack mending, ameliorate hair growth and remedial uses on eye related conditions, migraine and exertion on healthy skin/ hair independently. Citric acid have defensive goods in the body. It's used in sticky, can kill bacteria and lower the acid in urine. Agar is extensively used as gelling, thickening, stabilizing and density controlling agent for gummies. Pure honey is a enhancing agent that makes gummies delicious to eat. Orange juice shows antioxidant exertion and gives delicious flavour to sticky.
9. Carol L Wagner et al (2019) The objective of this investigation was to compare bioavailability between single oral dose Vitamin D₃ (vitD₃) gummies vs. tablets in healthy adults. An initial crossover, randomized clinical trial involving healthy adults (n = 9) was conducted followed by a larger, confirmatory study (n = 31). Healthy participants aged 18–45 years with body mass index (BMI) 18–30 without anemia or vitD deficiency were randomized to receive 20,000 international units (IU) vitD₃ as single dose gummies or tablets with serial samples obtained to measure plasma vitD₃ at baseline, 3, 6, 10, 24, and 48 h followed by a 2-week washout period. The same participants then crossed over to receive 20,000 IU vitD₃ in the form not previously given, with sampling at the same time points. Deidentified blood samples were analyzed for vitD₃ concentration by liquid chromatography (LC)-mass spectroscopy. In Study 1, results suggested bioavailability was greater with gummies compared with tablets, (effect size 1.08 at 24 h). In Study 2, the area under the concentration curve (AUC) was higher with gummies than tablets (gummy mean (95% CI): 1474 ng·/mL (1393–1555); tablet mean (95% CI): 774 ng·h/mL (693–855), p < 0.0001). Average peak blood concentration (C_max) values were significantly higher with gummies (gummy: 47.3 ng/mL; tablet: 23.4 ng/mL; p < 0.0001). VitD₃ gummies had greater bioavailability than tablets with higher vitD concentrations over time, which may have implications for achieving vitD sufficiency.
10. Laura L DeMars etval (2001) The texture of gelatin:high-methoxyl pectin gummy gels was quantified by instrumental and sensory techniques and their microstrucuture examined by light and transmission electron microscopy. Gelatin:HM pectin confectionery gels (33.4% sucrose and 29.8% 42 DE corn syrup solids) with 3.0, 4.5, or 6.0% gelatin and 0.0, 0.5, 1.0, or 1.5% HM pectin were formed into oval-shaped samples and fractured in tension. Descriptive sensory evaluation was done on seven of these gels in duplicate by 10 experienced panelists using free choice profiling. The addition of pectin reduced the strain at fracture of gelatin gels. Stress at fracture could be described by upper and lower bound behavior. Microstructural analysis suggested that at high total polymer or pectin concentration, increased phase viscosity and rate of gelation influenced structure by preventing coalescence of the dispersed gelatin-rich phase. Micrographs suggested that gelatin in the pectin-rich phase was concentrated enough to gel and contributed to mixed gel properties. Gels were described variously as soft to firm and brittle to rubbery. Mixed gels were more fruity, sweet, and tart than pure gelatin gels. Gels with a high degree of coalescence of the dispersed phase were described as pulpy. Sensory texture first principal component values correlated with strain at fracture (r=0.90), log [stress at fracture] (r=0.87), and flavor first principal component values (r=0.83).
11. Fatemeh Haidari et al. 2021 Obesity has reached epidemic proportions globally. Among several methods for treating obesity, the use of dietary supplements is common recently. One supplement that can help in this regard might be vitamin B6 in high doses. The objective of this study was to evaluate the effect of pyridoxine hydrochloride supplementation on anthropometric indices, body composition, visceral adiposity index (VAI), and metabolic status in obese and overweight women. In this randomized controlled clinical trial, 44 obese and overweight women aged 18–50 years were selected and divided randomly into 2 groups: an intervention group (receiving 80 mg pyridoxine hydrochloride supplement for 8 weeks) and a control group (receiving placebo for 8 weeks). In the pyridoxine hydrochloride group, weight (p = 0.03), body mass index (p = 0.023), fat mass (p = 0.003), waist circumference (p = 0.005), VAI (p = 0.001), fasting insulin, insulin resistance (homeostasis model assessment of insulin resistance; HOMA-IR), total cholesterol, low-density lipoprotein, triglycerides (TG) and leptin (p < 0.001) decreased whereas adiponectin (p < 0.001) increased in comparison to the baseline values. There was a significant difference in fat mass, VAI, fasting insulin, HOMA-IR, and TG between pyridoxine hydrochloride and control groups following intervention in adjusted models (p < 0.05). The findings suggest that vitamin B6 supplementation may be effective in reducing BMI and improving body composition and biochemical factors associated with obesity.
12. Francesca Aiello et al. 2024 In this work, the peels of red and blonde oranges as well as lemons were efficiently (5.75–9.65% yield) extracted by hydroalcoholic solution with ultrasound assistance and employed as active molecule sources in the preparation of functional gummies. Antioxidant performances of the hydroalcoholic extracts were characterized by colorimetric assays, whereas LC–HRMS analyses identified the main bioactive compounds (phenolic acids and flavonoids). The highest scavenging activity was recorded for lemon extract in an aqueous environment (IC50 = 0.081 mg mL−1). An ecofriendly grafting procedure was performed to anchor polyphenols to gelatin chains, providing macromolecular systems characterized by thermal analysis and antioxidant properties. Scavenger abilities (IC50 = 0.201–0.454 mg mL−1) allowed the employment of the conjugates as functional ingredients in the preparation of gummies with remarkable antioxidant and rheological properties over time (14 days). These findings confirmed the possible employment of highly polluting wastes as valuable sources of bioactive compounds for functional gummies preparation.
13.  Bing Yan et al. 2021Vitamin gummies have gained popularity in recent years due to ease of swallowing, appealing appearance, and tasty flavors. Water-soluble vitamins such as vitamin C are susceptible to degradation when exposed to oxygen, moisture, light, heat, and change in pH during manufacturing and shelf life. Therefore, it is essential to improve vitamin stability and delay the degradation process. In this study, microencapsulation of vitamin C inside casein gel followed by spray drying produced vitamin C capsules in powder form referred to as micro cheese powder (MCP). The Fourier transform infrared spectroscopy results confirmed an increase in hydrogen bonding between vitamin C and casein, as well as vitamin C and the gummy. In addition, Quartz crystal microbalance with dissipation technology was utilized to provide insights into the physical interaction between micellar casein, rennet treated casein, and vitamin C. The storage studies showed that microcapsules integrated into the gummy retained 92% of vitamin C during accelerated tests within a ten-week period, while the unencapsulated vitamin C in the gummy only retained 79%. In addition, compared to the unencapsulated vitamin C in the gummy, encapsulated vitamin C in the gummy showed better retention of vitamin C and color at different temperatures, humidity, and light conditions. MCP showed slower release and better protection of vitamin C from gummy in the simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The developed vitamin C microencapsulation is promising to improve the stability of water-soluble vitamins in gummies during processing and storage.
14.  Santoshi Rawat et al. 2024 Gummies belong to a confectionery category characterized by a hydrocolloid, acting as a stabilizer, forming a network to retain a high-moisture sugar syrup, and hydrocolloids play a key role in shaping the visual appeal, flavour release, and texture of the gel network. This study investigates the potential substitution of gelatin in gummies with plant-based hydrocolloids like agar-agar and guar gum. It is also aimed at optimizing the level of functional ingredients like curcumin and piperine in standardized gummies through incorporation of turmeric and black pepper, respectively. These plant-based gelling agents mimic gelatin’s chewable, firm, and elastic texture, catering to broader consumption and suitability for versatile use. Consumer interest in healthier diets has spurred the transition towards plant-based functional foods, leading to the replacement of gelatin gummies with plant-based alternatives. Agar-agar significantly influences gummy texture by contributing to firmness, elasticity, and stable gel formation, imparting essential strength and consistency. Guar gum, recognized as a plant-based hydrocolloid, enhances gummy texture, consistency, and moisture retention through thickening and stabilization. While agar-agar and guar gum individually fell short in achieving the desired textural attributes in the gummies, their combined use (1% agar-agar and 5.5% guar gum) yielded optimal chewiness (1,455.12 ± 1.75 N), gumminess (2251.11 ± 2.14 N), and high overall acceptability (8.96), resembling gelatin-based gummies. The optimized formulation included 40% sugar, 2% citric acid, 2% turmeric, and 0.6% black pepper. The developed vegan gummies contained 56.9 ± 0.09 mg/100 g total phenols, 37.27 ± 1.4% antioxidant capacity, 0.054 ± 0.0012% curcumin, and 0.02 ± 0.008% Piperine. Consequently, the combined use of agar-agar and guar gum emerged as stable and effective gelling agents, offering an alternative to gelatin for creating turmeric and black pepper-infused gummies with desirable texture and functional attributes.
15.  G. Govind Reddy et al. 2015 The cornerstone of gels is a soft, pliable, elastic matrix in which the active chemicals can be dissolved or disseminated to a chewable gummy formulation. Chewable gummy formulation ingredients include water, sugar, flavouring, gelling agent, and sweetener. When creating functional gummy candy, these factors should be taken into account in order to meet the needs and expectations of the consumer. The purpose of sweeteners and flavors is to promote consumer acceptance by hiding the taste of the active components. The chewable gummy preparation's gelling agent, which creates a matrix structure, is a crucial ingredient. The following are included in this review article: materials and procedures like gummy base preparation and molding technique, evaluation parameters like pH, texture analysis, weight uniformity, organoleptic observations, etc. It is approved by the patient and complies with the conditions.
16. Nur Cebi et al. 2019Nur Cebi et al. 2019 Gelatin is widely used in gummy candies because of its unique functional properties. Generally, porcine and bovine gelatins are used in the food industry. FTIR-ATR combined with chemometrics analysis such as hierarchical cluster analysis (HCA) (OPUS Version 7.2 software), principal component analysis (PCA) (OPUS Version 7.2 software) and partial least squares-discriminant analysis (PLS-DA) (Matlab R2017b) were used for classification and discrimination of gelatin gummy candies related to their gelatin source. The spectral region between 1734 and 1528?cm−1 was selected for chemometric analysis. The potential of FTIR spectroscopy for determination of bovine and porcine source in gummy candies was examined and validated by a real-time polymerase chain reaction (PCR) method. Twenty commercial samples were tested by developed ATR-FTIR methodology and RT-PCR technique, mutually confirming and supporting results were obtained. Gummy candies were classified and discriminated in relation to the bovine or porcine source of gelatin with 100% success without any sample preparation using FTIR-ATR technique.

 Mozhgan Roubaix et al. 2024 The research aimed to enhance the nutritional value of gummy candies by incorporating pistachio green hull extract (PGHE), stevia, and starch into the formulations. The gummy candies formulations were optimized using PGHE (1–5 %), stevia (0.013–0.040 %) and gelatin-to-starch ratio (9:1, 2:8, and 3:7) by response surface methodology (RSM), central composite design (CCD), with six canter points. The physicochemical and textural properties of the gummy candies were assessed. Three optimal formulations were determined, which were preferred by the majority of panelists. One of them was selected for testing total phenolic content (680.31 ± 0.6 mg GAE/100g gummy candy), antioxidant activity (IC50 = 277 μg/mL), FTIR analysis, morphology examination, and storage stability. This study resulted in the development of gummy candies that not only offer a reduced-sugar product (50 %; equal to 12 % of sucrose) with high antioxidant activity but also eliminate the need for artificial flavours and synthetic colorants in the formulation.

CHAPTER4: -MATERIALS AND METHODS

Materials

Isoniazid

Appearance - Colorless or white crystals or white crystalline powder

Melting point - 172.85?

log P -   -0.70

pKa - 1.82

Water solubility- 19.794 mol solubility

Ph- 5.6-6

Half Life - 1-4hrs

MOA  - Isoniazid is an antibiotic primarily used to treat tuberculosis (TB). Its mechanism of action involves inhibiting the synthesis of mycolic acids, which are essential components of the bacterial cell wall in Mycobacterium tuberculosis      Isoniazid is converted into its active form by the bacterial enzyme catalase-peroxidase (encoded by the katG gene). This active form then binds to the enzyme enoyl-acyl carrier protein reductase (InhA), which is involved in the synthesis of mycolic acids. By inhibiting InhA, isoniazid disrupts the production of mycolic acids, leading to the weakening and eventual destruction of the bacterial cell wall, making it lethal to the bacteria.[24] This action is bactericidal during the active multiplication phase of the bacteria and bacteriostatic during the dormant phase.

Sucrose:

Physical state- Crystalline powder

Color- White

Odor- Odorless

Solubility- It is soluble about 12% in 95% ethanol at room temperature[25]

Melting point- 186?

Description- Sucrose is a molecule comprised of two monosaccharides- glucose and fructose.

Structure of Sucrose                                Fig.17: Sucrose powder

Mechanism of action:

Sucrose, commonly known as table sugar, is a disaccharide composed of glucose and fructose. Its mechanism of action involves its digestion, absorption, and metabolism in the body.

1. Digestion:

When consumed, sucrose is broken down into its constituent monosaccharides (glucose and fructose) by the enzyme sucrase (also known as invertase), which is present in the small intestine. This enzymatic breakdown occurs primarily in the brush border of enterocytes (intestinal cells).

2. Absorption:

The glucose and fructose produced from sucrose digestion are absorbed through the walls of

the small intestine into the bloodstream.[26]

Glucose is absorbed via sodium-dependent glucose transporters (SGLTs) in the intestines, while fructose is absorbed via the facilitated glucose transporter (GLUT5).

3. Metabolism:

Once in the bloodstream, glucose triggers the release of insulin from the pancreas. Insulin facilitates the uptake of glucose by various tissues (especially muscle and fat cells) for energy or storage as glycogen in the liver and muscles.

Fructose is primarily metabolized in the liver, where it is converted into glucose, glycogen, or fat, depending on the body's energy needs.

Sorbitol:

Physical state- Crystalline powder

Color – White in color

Oduor - Odorless

Ph- 6-7

Melting point- 95?

Description- It is found naturally in fruits and vegetables. It helps protect against tooth decay.[27]

   Structure of Sorbitol                               Fig. 8: Sorbitol powder

Sodium Benzoate:

Physical state: - crystalline

Color: -white in color

Order: -odorless

Melting point: - 410°C

Description: - It is used as preservative in various products

Structure of Sodium Benzoate              Fig. 18: - Sodium Benzoate

Citric Acid

Physical state: - crystalline

Color: - white or colorless

Oduor: - odorless

Melting point: - 153?

Description – it is found in citrus fruits

        Structure of citric acid               Fig 19 :-  citric acid powder

Gelatin: -

Physical state- Transparent, brittle

Color- Colorless or Slightly yellow

Odor- Odorless

Melting point- 22? - 40?

Solubility- Dissolve in water at temperatures above 35- 40?

Ph- 4.5- 6.5

Description- That comes from animal parts like skin, bones and tendons.

Structure of gelatin                                      Fig 20:- Gelatin

MATERIALS

Different substances have been utilized in this formulation. As sweeteners, sucrose and sorbitol are utilized. Gelatin is a gelling agent, colourant, and flavouring agent that can be purchased from the local market. This preservation and flavouring ingredient, acquired from Merck Pharma, is known as citric acid. Albendazole from Sigma Aldrich is the main ingredient in antihelmintic formulations. Water that has been distilled in a laboratory is the vehicle. All of the ingredients purchased are of pharmaceutical grade and should be used as they were purchased.[28]

Preformulation Studies

The powder mixture was analyzed prior to the gummy synthesis. The quality of the powder that produces high-grade gummies was assessed using a variety of parameters, such as hygroscopicity, bulk density, tapped density, Carr’s index, Hausner’s ratio, and angle of repose

Hygroscopicity

The amount of water present in the material was determined using the quantitative reaction of water with iodine and Sulphur dioxide in the presence of a low molecular weight alcohol and an organic base.[29]

Bulk Characterization

To understanding the micrometric characteristics of powder blends; bulk density, tapped densities, Hausner’s ratio, and carr’s index were determined.

Bulk Density

A granule is a particle gas combination containing both inter-particle gaps and intra-particle voids, it may be calculated using the formula below

Bulk density = Mass  

                        Bulk Volume             

Tapped Density

The tapped density of a powder represents its random dense packing that can be calculated by:12

Tapped density =        Mass

                                 Tapped Volume

Hausner Ratio

This ratio can be applied to provide an index of the flow characteristics of a granule. Hausner ratio is being an indicator of the flowability of bulk solids.

It is calculated by:

Hausner ratio = Tapped density

                          bulk density

Carr’s Ratio

Carr’s ratio is applied assuming that the compressibility of a solid is related to its flowability, it is supposed to measure the bulk and tapped density of bulk materials and calculate a ratio to estimate the flow of material.[30] It is measured by following formula,

Carr's ratio = Bulk density  ´ × 100

                  Tapped density

Angle Of Repose

A funnel was used to accurately pour a powder mixture so that the maximum cone height (h) could be achieved. The funnel’s height should not exceed 1 cm above the cone height (h) and the Angle of repose was calculated by using the following formula.

q= tan- 1 h

              r

Where “h” is the height and “r” radius

Inclusion/Exclusion Criteria

Because Isoniazid is not recommended for children under the age of two, and there is a risk of choking, gummies are intended to be used for children over the age of two.

Method of gummies preparation

The method of gummy preparation includes the preparation of two solutions, i.e., a solution of water and sugar and a water and gelatin solution. As in Table 1, the ratio of water to sorbitol was kept at 2:1, and the ratio of water to sugar was kept at 1:1. Add 12.60 g sugar and 4.06 g sorbitol to 10 mL of water in a beaker. This solution was heated on medium-high while being stirred with a glass stirrer. Adjust the temperature to a point where the temperature of the solution doesn’t rise above 130°C. Keep heating until viscous sugar syrup is formed. Avoid overheating to prevent the caramelization of sugars. Once a thick, consistent syrup is obtained, turn off the flame. Lower its temperature to 60°C. In a solution of sugar and sorbitol, add 4.06 g of citric acid to the solution. In another beaker, 3.22 g of gelatin was admixed with 5 mL of water and heated for a few minutes on low heat. The ratio of gelatin to water was kept at nearly 1:2. Then pour the gelatin solution into the warm sugar solution and mix thoroughly, and then heat the mixture for a few seconds to 70°C. Add 2.8 g of albendazole to the above mixture and stir to form a uniform solution. Now add 5.04 mL of flavorant and 0.035 g of sodium benzoate, one by one, to the solution and mix it thoroughly. Lubricate the silicone mould with glycerin to avoid sticking. Pour the warm mixture into the mould and tap them on the shelf to even up the level of fillings. Remove and wipe any excess solution from the mould. Place the mould in a safe place at room temperature for 60 min. Seven formulations (F1–F9) were synthesized by varying the concentrations of sucrose, sorbitol, and gelatin as shown in Table 1.[31]

Characterization (Post Formulation Studies) Organoleptic Evaluation

By using our senses, it is utilized to assess the flavour of the dosage forms. 20 healthy volunteers with an appropriate sense of taste were recruited, and after being asked to chew the gummies, they were questioned about their evaluation according to the organoleptic evaluation scale as described in Table

Weight Variation/Uniformity Of Mass

Each of the 20 gummies were weighed individually, the average weight was calculated and the individual gummies weights were compared to it. If no more than two gummies fall outside the allowed % range as shown in Table 4. and no gummies deviates by more than twice the allowed range, the gummies pass the test. The following formulas are used:

            Weight Variation =  Iw - Aw×  ´ 100

                                               Aw

Hardness Test

A hardness tester crushed the gummies (one at a time) while keeping the force applied in the same direction. Higher hardness values may be taken into consideration if justified contact to simulated saliva. According to the FDA guidance gummies, hardness must lie within a range of 1-5 kg/cm2.

Friability

A sample of 10 gummies at random and placing them in the plastic chamber of the Rosch Friabilator, the friability of gummies was examined. For 4 min, the friabilator drum was circulated at 25 rpm. The formula given below was used to compute the percentage drop in gummies weight. Friability should be under 1%.

Friability = Initial weight - Final weight ×  100 Initial weight

Moisture Content

Drying finely ground samples (10 g) in an air oven at 105°C overnight to create a constant weight was carried out.

% Moisture Content =   Weight of water in material ×100

Weight of dry matter of material

PH Determination

A micro pH meter with a glass combination electrode was used to monitor the pH. The materials were divided into thin slices, added to boiling water (1:3, w: w), and mixed continuously until completely dissolved. The pH was measured after the heated solution was tempered at 25°C. Each measurement was taken thrice times. The acceptable pH range of chewable gummies

IN VITRO Disintegration Test

The USP disintegration apparatus is made up of six glass tubes that are 3 inches long, open at the top, and positioned at the bottom end of the basket rack assembly against the 10-mesh screen. Plastic discs with perforations can also be utilized in the tests. These are put on top of the gummies and have a negative impact on them. Use the tool for a predetermined period of time. If all particles pass through the 10-mesh screen at the designated time while the gummies are unplugged, the gummies complies with the test. Any remaining material must have a soft bulk and no visible solid core. Gummies was found to disintegrate within 15 min.

IN VITRO Dissolution Testing

Gummies are tested for dissolution to determine rate at which it produces a solution. British and US Pharmacopoeia dissolution apparatus (paddle/basket apparatus) are made of a cylindrical vessel. Using a water bath or heating apparatus, the test vessel’s internal temperature can be maintained at 37 ± 0.5°C while maintaining a consistent bath fluid level. Withdraw a sample not less than 1 cm from the vessel wall, from the area centered between the dissolving medium’s surface and the top of the spinning basket, within a certain time frame or at each interval provided. Most formulations in dissolution tests released 85% of the drug after 15 min.20Kinetics of drug release: Various statistical methods have been used to determine the release kinetics of formulations. The models were the Kosmeyers Peppas model, the first-order model and the zero-order model.

Fourier Transform Infrared (FT-IR) Spectroscopy

Evaluation of drug-excipient compatibility in the mixtures and formulations was tested using a Cary-630 FTIR spectrometer (Agilent Technologies, Santa Clara, CA, USA). Sampling was conducted using MIRacle Attenuated Total Reflection (Pike Technologies MIRacle ATR, Madison, WI, USA) equipped with a single-bounce, diamond-coated Zinc selenide (Zones) internal reflection element. The IR Spectra of the samples were collected between the wavenumber range 650–4000 cm−1

Chapter 5

RESULTS AND DISSCUSION

UV-VIS Spectrophotometer Analysis:

UV-Vis spectrophotometer was used for the analysis and quantification of drug Concentration ranging from 5μg to 25μg/mL for INH and 2μg to detected at 266nm. Figure show the R2 value and calibration curve.

Table: -2 Calibration Curve for Isoniazid

Evaluation Parameters

Table :-3 Organoleptic Evaluation Scale.

Table:-4 USP Limits for Weight Variation Test for Coated Gummies.

A granule is a particle gas combination containing both inter-particle gaps and intra-particle voids, it may be calculated using the formula below.

Bulk Density

A granule is a particle gas combination containing both inter-particle gaps and intra-particle voids, it may be calculated using the formula below.

Bulk density = Mass

                     Bulk Volume

Tapped Density

The tapped density of a powder represents its random dense packing that can be calculated by:12

Tapped density =        Mass  

                            Tapped Volume

Hausner Ratio

This ratio can be applied to provide an index of the flow characteristics of a granule. Hausner ratio is being an indicator of the flowability of bulk solids.

It is calculated by:

Hausner ratio =  Tapped density

                            Bulk density

Carr’s Ratio

Carr’s ratio is applied assuming that the compressibility of a solid is related to its flowability, it is supposed to measure the bulk and tapped density of bulk materials and calculate a ratio to estimate the flow of material.12 It is measured by following formula,

Carr's ratio =  Bulk density  100                                                                        Tapped density

Angle Of Repose

A funnel was used to accurately pour a powder mixture so that the maximum cone height (h) could be achieved. The funnel’s height should not exceed 1 cm above the cone height (h) and the Angle of repose was calculated by using the following formula.

q= tan- 1 h

               r

Where “h” is the height and “r” radius

Inclusion/Exclusion Criteria

Because albenzaole is not recommended for children under the age of two, and there is a risk of choking, gummies are intended to be used for children over the age of two

FTIR spectroscopy was utilized to assess the compatibility between the active pharmaceutical ingredients (APIs), INH, and PDX, and various excipients used in the final formulation (F7). The characteristic transmittance bands for each component were examined for shifts or disappearances that might indicate molecular-level interactions[48] Pure Isoniazid exhibits characteristic bands at 3303 and 3107 cm−1 (N-H stretching), 3010 cm−1 (C-H stretching), 1663 cm−1 (C=O stretching), and 1633 cm−1 (C=C stretching)[49] Pyridoxine showed characteristic bands at 1017, 1274 and 1541 cm−1 originated from stretching vibrations of the pyridine ring[50], Gelatin revealed its strong amide A band due to N-H stretching above 3000 cm−1 and amide I band near 1650 cm−1 resulting from C=O stretching. The amide II band, due to N-H bending coupled with C-N stretching, is observed around 1550 cm−1[51] FTIR spectrum of carrageenan showed characteristic bands at 3382, 1637, 1374, 1223 and 1125 cm−1[52] Whereas the characterization of xylitol has shown characteristic bands at 3354,3284 cm−1 (O-H stretching), 1418 cm−1(C-H stretching)[53] The physical mixture and the final formulation (F7) showed the same characteristic bands at 3107, 1663,1633, 1541,1374, 1223 and 1125 cm−1. In the case of the final formulation (F7), the results indicated that isoniazid did not significantly interact with the excipients under the conditions applied in the formulation process, affirming the suitability for this formulation and the stability of the APIs within the matrix.

Organoleptic Evaluation

By using our senses, it is utilized to assess the flavour of the dosage forms. 20 healthy volunteers with an appropriate sense of taste were recruited, and after being asked to chew the gummies, they were questioned about their evaluation according to the organoleptic evaluation scale as described in Table

Weight Variation/Uniformity of Mass

Each of the 20 gummies were weighed individually, the average weight was calculated and the individual gummies weights were compared to it. If no more than two gummies fall outside the allowed % range as shown in Table 4. and no gummies deviates by more than twice the allowed range, the gummies pass the test. The following formulas are used

Weight Variation =  Iw - Aw × 10

                                      Aw

Hardness Test

A hardness tester crushed the gummies (one at a time) while keeping the force applied in the same direction. Higher hardness values may be taken into consideration if justified contact to simulated saliva. According to the FDA guidance gummies, hardness must lie within a range of 1-5 kg/cm2.

Friability

A sample of 10 gummies at random and placing them in the plastic chamber of the Rosch Friabilator, the friability of gummies was examined. For 4 min, the friabilator drum was circulated at 25 rpm. The formula given below was used to compute the percentage drop in gummies weight. Friability should be under 1%.

Friability =  Initial weight - Final weight ×100

initial weight

Moisture Content

Drying finely ground samples (10 g) in an air oven at 105°C overnight to create a constant weight was carried out.

% Moisture Content =   Weight of water in material ×100

Weight of dry matter of material

PH Determination

A micro pH meter with a glass combination electrode was used to monitor the pH. The materials were divided into thin slices, added to boiling water (1:3, w: w), and mixed continuously until completely dissolved. The pH was measured after the heated solution was tempered at 25°C. Each measurement was taken thrice times. The acceptable pH range of chewable gummies is

IN VITRO Disintegration Test

The USP disintegration apparatus is made up of six glass tubes that are 3 inches long, open at the top, and positioned at the bottom end of the basket rack assembly against the 10-mesh screen. Plastic discs with perforations can also be utilized in the tests. These are put on top of the gummies and have a negative impact on them. Use the tool for a predetermined period of time. If all particles pass through the 10-mesh screen at the designated time while the gummies are unplugged, the gummies complies with the test. Any remaining material must have a soft bulk

The percentage of drug release was observed for a period of 30 minutes, as demonstrated in Table 7. In the kinetic investigation, the drug release percentage versus time graph plot was used to determine the order of release for all formulations. Most of the formulations tested in dissolution tests released 85% of the drug after 25 min. At time 0, there is no drug release. The initial release of the drug was relatively slow. All the formulations except F7 have released 50% of the drug within 15 min. For F7, more than 50% of the drug was released earlier, within 10 min. At the end of 30 min, F1–F7 have released the maximum amount of the drug. The formulation F7 showed the highest drug release within 30 min; that’s why it is considered to be the best formulation. The pattern of drug release is shown in Figure.22

During formulation kinetic data modelling, we concluded that the F1-F7 formulations were following first order because their R2 value is near 1. So, it was shown that the release of drugs is dependent on concentration, which explained the first-order behaviour of the formulation and immediate release kinetics. The n value in Korsmeyer and Peppa’s release kinetics model describes the formulation’s specified drug release through Fick’s law of diffusion. In this case, a transport mechanism that is Fickian corresponds to an n value less than 0.45. The release kinetics of seven different formulations are described in the Table 8.

Release Kinetics of Olanzapine Nanoparticles

The release mechanism of drug from gummies, were obtained by plotting the in vitro drug release data to various release models (Zero order, First order, Higuchi, Hixson Crowell and Korsemeyer Peppas) (Gandhi et al 2014 and Li et al 2014).

Fig. 29. Zero order release of olanzapine nanoparticles

Fig. 30. First order release of olanzapine nanoparticles

Fig. 31 Korsemeyer Peppas model of olanzapine nanoparticles