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Review Article Journal of Pharmaceutical Research
A Review On: Nutraceuticals Challenges in Formulation and Its Regulatory Aspects
Radheshyam
Assistant Professor, Department of Pharmacology, Shakti college *Corresponding author
of Pharmacy, Balrampur, U P, India Radheshyam, Assistant Professor, Department of Pharmacology, Shakti
college of Pharmacy, Balrampur, U P, India
Submitted: 30 June 2021; Accepted: 06 July 2021; Published: 16 July 2021
Citation: Radheshyam (2021) A Review On: Nutraceuticals Challenges in Formulation and Its Regulatory Aspects. J Pharmaceut Res
6: 88-94.
Abstract
Nutraceuticals have sparked great attention because of their perceived safety, The current article focuses on the need for
appropriate diets, health issues associated with failure to adhere to the known healthy eating models, development of new
nutraceuticals/functional foods/food supplements with novel health benefits, elucidation mechanisms of action of these
products, and to define and understand the analytical, challenges during the formulation of different dosage form, current
scenario in India, future and regulatory aspects of nutraceuticals. the Indian industry and regulatory scenario are rela-
tively nascent and have great potential to develop and compete with other international agencies. This is a rapidly growing
industry in India and several initiatives have been taken in this direction to make India one of the key future players in
the area of nutraceuticals. This article can help you stay up to date on the latest advancements in nutraceutical research.
Keywords: Nutraceuticals, Food Safety, Probiotics
Introduction 6. Economically challenged patients [2-6].
The word “nutrition” and “pharmaceutical”, was coined in 1989
by Stephen L. Defelice, founder and chairman of the Foundation With few exceptions, the U. S. Food and Drug Administration
of Innovation Medicine. Nutraceuticals are products derived from (FDA) has not approved nutraceuticals for health benefits or dis-
food sources that are purported to provide extra health benefits, in ease prevention; nonetheless, the manufacturers of nutraceuticals
addition to the basic nutritional value found in foods. Depending have been touting them as health-promoting agents.
on the jurisdiction, products may claim to prevent chronic diseas- Categories Based on Natural Source
es, improve health, delay the aging process, increase life expectan-
cy, or support the structure or function of the body [1]. • Carbohydrates & Fiber
• Fat & Essential fatty acids
The Following are the Causes Behind the Move Toward • Protein
Nutraceuticals: • Minerals like Macro minerals & Trace minerals
1. A growing percentage of customers are concerned about ris- • Vitamins
ing healthcare prices. • Water
2. People who are dissatisfied with pharmaceutical agents for
health promotion are turning to nutraceuticals to improve their Other nutrients like Antioxidants, Phytochemicals & Intestinal
health and avoid chronic disease. bacterial flora Recombinant nutraceuticals. Are simply natural
3. Health care providers know that our overly processed food with no changes to the food. Food contains several natural compo-
supply, which is derived from crops cultivated with chemical nents that deliver benefits beyond basic nutrition, such as lycopene
fertilizers, pesticides, herbicides, and frequently genetical- in tomatoes, omega-3 fatty acids in salmon or saponins in soy [7,
ly engineered seeds, lacks the nutrients required for optimal 8].
health. Dietary Supplements
4. People who believe in prevention rather than treatment.
5. People suffering from chronic ailments who have found no Dietary supplement is a product that provides concentrated nutri-
relief from allopathic therapy. ents taken from food sources in liquid or pill form. The term was
J Pharmaceut Res, 2021 www.opastonline.com Volume 6 |Issue 2 | 88
defined in the United States by the Dietary Supplement Health and • Has the ability to attach to human intestinal cells and prolif-
Education Act (DSHEA) of 1994: “A dietary augment is a prod- erate in the gut.
uct taken by mouth that contains a “dietary element” designed to • Can function as an antagonist against pathogenic or carcino-
supplement the diet.” Vitamins, minerals, herbs or other botani- genic microorganisms.
cals, amino acids, and components such as enzymes, organ tissues, • Clinically verified and confirmed health benefits [9].
glandular, and metabolites are examples of “dietary ingredients” in
these goods. Dietary supplements can also be extractsor concen- Nutraceutical Enzymes
trates, and may be found in many forms such as tablets, capsules, Enzymes are an essential part of life, without which our bodies
soft gels, gel caps, liquids, or powders. would cease to function. Those people who are suffering from
medical conditions such as hypoglycemia, blood sugar disorders,
Dietary supplements do not need to be authorized by the US Food digestive problems and obesity, eliminate the symptoms by en-
and Drug Administration (FDA) before being marketed, but firms zyme supplements to their diet. These enzymes are derived from
must register their production facilities with the FDA. microbial, plant and animal sources [12, 13].
Dietary supplements, with a few well-defined exclusions, may Prebiotics
only be marketed to maintain the structure or function of the body Prebiotics are a relatively recent addition to our lexicon and are
and may not claim to cure a disease or condition, and must include chemicals that we do not digest when we ingest them. Instead, they
a label that states: “These statements have not been evaluated by serve as a source of nutrients for the beneficial probiotic bacteria.
the Food and Drug Administration.” This product is not meant to This promotes the growth of probiotic bacteria in a favorable envi-
be used to diagnose, treat, cure, or prevent illness.” It accomplishes ronment, lowering the likelihood that dangerous germs may begin
this by utilizing the efficiency of such nutraceuticals in detoxifying to proliferate in our digestive system. Inulin is a prebiotic that is
the body, avoiding vitamin and mineral shortages, and restoring commonly found in processed meals. It is, in essence, a form of
good digestion and dietary habits [9, 10]. fiber derived from the roots of plants such as chicory, Jerusalem
They are Grouped on the Basis Of artichoke, and even dandelions [14].
Chemical Constituents Non-Traditional Nutraceuticals
A) Nutrients Are artificial foods prepared with the help of biotechnology. Food
B) Herbals samples contain bioactive components which are engineered to
C) Phytochemicals produce products for human- wellness. They are arranged into.
Fortified nutraceuticals.
Phytochemicals are plant nutrients that have specific biological Recombinant nutraceuticals.
functions in maintaining human health. They work in the follow-
ing ways. Fortified Nutraceuticals
1. Biochemical reaction substrate. They are enhanced by vitamins and minerals, normally up to 100
2. Enzymatic reaction cofactors percent of the nutritional dietary reference intake. It consists of
3. Enzymatic reaction inhibitors fortified foods derived through agricultural breeding, as well as
4. Absorbents that attach to and remove unwanted constituents additional nutrients and/or additives containing folic acid. Some
in the gut. examples include cholecalciferol-fortified milk, which is used to
5. Improve critical nutrient absorption and/or stability. treat vitamin D insufficiency [15].
6. Beneficial bacteria’s growth factor of choice.
7. Beneficial bacterium fermenting substrate Recombinant Nutraceuticals
8. Inhibitors of harmful gut bacteria that are selective. Biotechnology is used to make energy-saving foods such as bread,
9. Chemical scavengers that are reactive or poisonous. wine, fermented starch, yogurt, cheese, vinegar, and others. Bio-
10. Agonizing or antagonistic ligands for cell surface or intracel- technology enables the manufacture of probiotics and extraction
lular receptors [11]. by enzyme/fermentation technologies of bioactive constituents as
Microorganisms that are Probiotic well as genetic engineering.
They push away pathogens like yeasts, other bacteria, and viruses Commercial Nutraceuticals
that may otherwise cause sickness and form a mutually beneficial It’s more expensive and dangerous than ever before to find the
relationship with the human gastrointestinal system. They have an new chemical. Many pharmaceutical firms are currently striving
antimicrobial effect by altering the microflora, preventing patho- to produce nutraceuticals because of the enormous and increasing
gen adhesion to the intestinal epithelium, competing for nutrients market, without a doubt. Most of the treatment fields, for exam-
required for pathogen survival, producing an antitoxin effect, and ple anti-arthritis, cold and cough, sleep problems, digestion and
reversing some of the effects of infection on the intestinal epitheli- prevention of certain malignancies, osteoporosis, blood pressure,
um, such as secretory changes and neutrophil migration. cholesterol management, pain-mongering, depression and diabe-
• Probiotics should be derived from humans. tes, include nutraceuticals. Recognition of the health advantages
• Commonly found gram-positive organism. of omega 3 rich marine food intake is one of the most promising
• Has the ability to survive after passing through acid and bile. advances in research into the prevention of human nutrition and
J Pharmaceut Res, 2021 www.opastonline.com Volume 6 |Issue 2 | 89
illness in the past 3 decades [16]. Polyunsaturated (PUFA)
Dietary supplements, Eicosapentaenoic acid -EPA (20:5n-3)
Functional food, Docosahexaenoic acid - DHA (22:6n-3)
Medicinal food, Saturated fats- animal based products
Pharmaceuticals. MFA&PUF – plant origin
Medicinal Food Trans fatty acids are products of partial hydrogenation of PU
fats and are typically solids at room temperature.
A food formulated to be consumed or administered internally by a
physician for a specific dietary treatment of a disease or condition, MFA & PUFA do not promote formation of the fatty deposits that
for which distinguished nutritional requirements are established by can clog the arteries.
medical assessment, even with no components that promote dis-
ease or contents. Physicians have been recommended for different Saturated Fatty Acids Palmitic, lauric, myristic acids are major
health problems leading to impairment of conventional intake, di- cholesterol-elevating fatty acids in our diets.
gestion, absorption or metabolism of foods like phenyl ketonuria,
coeliac disease and lactose intolerance [17]. Eskimos –diet is rich in cholesterol and fat therefore they are free
Functional Foods from heart diseases Fish rich linolenic acid, found in fish + soy-
abean oils
Functional foods are “all foodstuffs or food ingredients, which can Linoleic acid –corn, soy bean oils.
offer health benefits other than those included within, according to Linolenic acid- Omega 3fatty acids
their commonly recognized definition. Functional food is intended Linolenic acid (18:3n-3) 18C, 3 double bonds, the 1st being at C-3
to enable customers, rather than by ingesting foods produced in from the methyl end.
the form of fluid or pill, to eat enhanced food near to their natural CH3CHCH=CHCHCH=CHCHCH=CH(CH)7 COOH
condition. Functional foods, called nutrition, have been either sup- 2 2 2 2
plemented or strengthened. This method restores the nutritional Precursor of
content of a meal to similar levels prior to processing. Additional - Eicosapentaenoic acid -epa (20:5n-3)
nutrients such as vitamin D in milk are sometimes supplemented - Docosahexaenoic acid - dha (22:6n-3) [20].
[18].
Challenges in Formulation of Nutraceutical Dosage
Functional foods are defined by Health Canada as “ordinary foods Form
that have components or substances added to provide a specific Analytical Challenges
medicinal or physiological advantage other than a merely nutri- 1. the nutraceuticals are a cluster of a chemical entity, and it is
tional impact.” In Japan, three standards must all functional foods comparatively difficult to identify and quantify all the ingre-
meet: food. dients in the products.
2. defining and identifying the impurities and ensuring that these
1. Present in its natural form instead of a capsule, pill or powder. impurities are not harmful to the consumer.
2. Eaten as frequently as day in the diet; and. 3. Having Structural Analysis of each entity in formulation is
3. In order to prevent or manage diseases, it must regulate a bio- difficult.
logical process [19].
Dietary Fibers are of Two Types Formulation Challenges
• Tablet Dosage form.
1. Water insoluble fibers. Botanicals are complex with multiple chemical components,
2. Water soluble fibers. can contain up to 50 active. ingredients; 70- 90% of the for-
Daily recommended intake is 30-40 gms. mula can be actives.
Sources There are no of active ingredients and excipients
Whole grain cereals, wheat products, Oats, dried beans, legumes. Nature of nutraceutical Ingredients bring challenges related to
particle size, flow, compressibility, moisture sensitivity, ingre-
Antioxidants are of 3 Categories dient interaction, content uniformity and quality control (QC)
testing as Botanicals and extracts can vary based on region the
1. True antioxidants. crop was grown, season grown in and other factors.
2. Reducing agents. Quantity of each ingredient to enable sufficient delivery of the
3. Antioxidant synergists beneficial ingredients, dose size of the active constituent is
Deficiency causes diseases like Cancers, rheumatoid arthritis, alz- large hence very less space for excipients in final formulation.
heimers disease, cardiovascular diseases. Nutraceutical formulations normally have more actives pres-
Lipids ent in higher weights than pharmaceutical formulas. The limits
of dose size typically result in restricted room for excipients.
Fats are highly concentrated sources of energy for body. A typical nutraceutical formulation has 70–90% actives with
Saturated fatty acids the balance as excipients, whereas traditional pharmaceutical
Monosaturated (MFA) formulations have 70–90% excipients and 10–30% actives.
J Pharmaceut Res, 2021 www.opastonline.com Volume 6 |Issue 2 | 90
The fewer excipients and variety of actives in the same for- • Tailoring products to domestic tastes and preferences. These
mulation make it difficult to achieve certain desired outcomes, might include vegetarianism, Halal or Hindu dietary practic-
such as disintegration time, hardness and friability. es, traditional remedies, flavor and formulation preferences
Careful design of the tablet shape and form needs to be con- reflecting social and cultural diversity, or reluctance to see
sidered when choosing suitable tooling- Adding to the chal- functional benefits in staple foods.
lenge, many nutraceutical tablets tend to be produced using • Choice of Study Population is difficult. (Based on age, disease
neutral colours such as browns and greys with mottled, tex- condition etc) [24].
tured or granular appearances, which can make any emboss-
ing difficult to read. Regulatory Challenges
The addition of natural ingredients in nutraceuticals, which 1. Need to furnish adequate information with scientific evidence
have a tendency to be unrefined, abrasive, corrosive and hard, to prove that the product is safe, reproducible, and therapeuti-
results in the components used to process them being subject- cally efficient and whether it offers such effects for a definite
ed to damage [21]. period of time, say two or three years.
2. The need is to create a mechanism to prove that the product
Liquid Dosage Form quality is reproducible, and this mechanism needs to be in
Most of nutraceuticals are phytoconstituents, fatty acids, flavo- place with solid, scientific support experimentally that can be
noids volatile oils etc, Problems faced by these ingredients are. proved using a reliable technique [25].
1. Solubility of these ingredients. example: carotenoids. 3. Certification requirements often apply to excipients as well as
2. Stability of these ingredients. example: Coenzyme Q10, Ome- active ingredients.
ga 3 fatty acids. The oral delivery of probiotics is hampered by GMO Free
the low instability of the bacteria in the GIT and consequent Halal
loss of viability under the effect of high acidity and bile salt Kosher
concentrations [22]. WADA Compliance (World Anti-Doping Agency) country
3. Bioavailability and permeability of these ingredients. Exam- and product specific
ple: Curcumin. Even the bioavailability of the lipophilic anti- 4. Registration category/classification
oxidant coenzyme Q10 was challenged by its. • According to claims and ingredients, the formula may fit into
low aqueous solubility and slow dissolution rate in GI fluids different categories by country.
furnished by its highly lipophilic character (log P=21). • Registration complexity varies by category and country; dos-
permeability is limited by its large molecular weight (863), sier requirements vary greatly.
P-glycoprotein efflux and active transport by a number of • Testing requirements for finished products, as well as ingredi-
transporters (including peptide transporters (PEPT1), cation/ ents and excipients, are not uniform.
camitine transporters (OCT1, OCTN1, OCTN2 and OCT3)
and organic anion transporters (AE2 and MCTl) [23]. Concepts of Nutraceuticals
4. Interactions: Active constituent and excipient interaction. Ac- In the pharmaceutical development process, it is a requirement to
tive constituent and Active constituent interaction. have clinical test results from animal tests andstudies, for verifica-
tion of the effects. On the other hand, in the case of nutrition, there
Processing Challenges was no verification methodfor foods in preventing diseases in the
Large variation in heat, light and moisture sensitivity of ingredi- past. In recent years however, as food composition has been scien-
ents within one formula. Example in Probiotic encapsulation tech- tificallyproven to cause lifestyle-related diseases, and has become
nology Conditions that maintain cell viability like, a social issue.
– biomaterial selection-natural and synthetic polymers are used;
factors to be addressed are: Regulatory Aspects of Nutraceuticals
(i) physicochemical properties (chemical composition, morphol- The regulatory framework of nutraceuticals in India needs atten-
ogy, mechanical strength, stability in GI fluids) tion from the relevant authorities. Globally, the regulatory author-
(ii) toxicity assay; ities are aware of changing needs of consumers and proactively
(iii) manufacturing and sterilization processes. protect consumers by amending existing laws to accommodate
changes but in India old laws such as Prevention of Food Adul-
– solvent type and teration Act, 1954, which regulates packaged foods, still exist for
– toxicity and manufacturers. In addition, they need to abide by many other cum-
– choice of proper technology are of paramount concern. bersome laws such as:
– A subsequent challenge is to ascertain that the gastro-protected • Standards of Weights and Measures Act, 1976, and the Stan-
encapsulated probiotics are released in simulated intestinal fluid dards of Weights and Measures
(SIF) in vitro, a step that must be preceded by development of a • (Packaged Commodities) Rules, 1977 (SWMA)
standard protocol that simulates conditions prevailing in the GIT. • Infant Milk Substitutes, Feeding bottles and infant foods (reg-
ulation of production, Supply and Distribution) Act, 1992
Pschological challenges: nutraceuticals manufacturers must first with Rules, 1993 (IMS)
separate the products and treat nutraceuticals differently from • Edible Oils Packaging (Regulations) Order,1998
functional foods. • Fruit Products Order 1955 (FPO)
J Pharmaceut Res, 2021 www.opastonline.com Volume 6 |Issue 2 | 91
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