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Probiotics and Antimicrobial Proteins
ISSN 1867-1306
Probiotics & Antimicro. Prot.
DOI 10.1007/s12602-013-9126-2
Probiotic Formulations: Application and
Status as Pharmaceuticals—A Review
V.Sreeja & Jashbhai B.Prajapati
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Probiotic Formulations: Application and Status
as Pharmaceuticals—A Review
V. Sreeja •Jashbhai B. Prajapati
Springer Science+Business Media New York 2013
Abstract The use of probiotics is a new way to control
and treat infections in this modern era. Application of
beneficial bacteria to protect against detrimental bacteria in
the gastrointestinal tract and thus reap a positive health
benefit is the basis of probiotic therapy. Probiotics have a
long global history of traditional use. They are normally
consumed through fermented foods and are currently sold
mostly as ingredients in foods or nutritional supplements.
They are also supplied as pharma products. Recent research
has highlighted the probiotic potential in the treatment or
prevention of disease conditions, maintenance of health,
improving immunity and in the reduction in the risk of
future diseases. But their position in the pharmaceutical
industry is still not very clear. Clinical practitioners use
probiotic pharma products mostly as supplements. Their
status as drugs is still unclear. This review is aimed to
analyze probiotics as pharmaceuticals, their current status
as dietary supplements and drugs, existing probiotic prep-
arations and future research needs.
Keywords Probiotics Pharmaceuticals Probiotic
therapy Probiotic preparations Regulations
Introduction
A gradual rise in immune-mediated gut-related health
problems, increased cost of medical care, emergence of
antibiotic resistant strains of pathogens, lack of safe
treatments and increasing inclination of mankind toward
natural means of health care have prompted the search for
alternative medical therapies. One alternative therapy that
is gaining momentum in the field of health care is probiotic
therapy [1–4]. It is based on the knowledge that the
intestinal microbiota provides protection against various
diseases through maintaining a healthy gastrointestinal
(GI) tract. Probiotics are composed of bacterial strains or
species which are common components of the normal
intestinal microbiota and possess a number of properties
that could be of benefit in maintaining a healthy GI tract
and thus good human health [3,5–7]. A number of in vivo
human clinical trials have proved the efficacy of probiotics
in the treatment and prevention of many forms of diarrheal
diseases such as rotavirus diarrhea [8], travelers’ diarrhea
[9], antibiotic-associated diarrhea (AAD) [10–12]; serious
intestinal conditions like necrotizing enterocolitis (NEC)
[4,13], inflammatory bowel disease (IBD) [13,14] and
bacterial vaginosis in women [15]. Probiotics also possess
the potential to treat clinical symptoms including cancer,
depressed immune function, inadequate lactase digestion,
infant allergies, failure-to-thrive, hyperlipidaemia, hepatic
diseases and Helicobacter pylori infections [16,17]. Due to
the above mentioned attributes, probiotics have found a
place in pharmaceutical formulations and are supplied as
pharma products [18]. Being a preventive as well as
curative therapy, the status of probiotics is still not clear in
the health industry. Adding to this fact is the lack of well-
defined regulations regarding probiotics. In the pharma
industry, probiotic formulations can be seen as either die-
tary supplements or drugs but the major limitation is the
lack of studies which are required for the development of
probiotics as modern therapeutic drugs. Pharmacology of
probiotic formulations is more complex than that of inert
drugs and require detailed pharmacokinetic studies [19].
V. Sreeja (&)J. B. Prajapati
Department of Dairy Microbiology, Sheth M C College of Dairy
Science, Anand Agricultural University,
Anand 388 110, Gujarat, India
e-mail: sreeja_p70@rediffmail.com
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DOI 10.1007/s12602-013-9126-2
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Probiotics
The evolution of the concept of probiotics is credited to the
Nobel Prize winning Russian scientist Elie Metchnikoff,
who believed that ‘the dependence of the intestinal
microbes on the food makes it possible to adopt measures
to modify the flora in our bodies and to replace the harmful
microbes with useful microbes’ [15]. Lilly and Stillwell
coined the term ‘Probiotics’ in 1965. The word probiotics
originates from Greek language, ‘Pro’ means ‘for’ and
‘Bios’ means ‘life,’ that is, ‘for life.’ The Food and Agri-
culture Organization of United Nations (FAO) and World
Health Organization (WHO) define probiotics used in food
as ‘Live microorganisms which when administered in
adequate amounts confer a health benefit on the host’ [20].
Due to their health attributes, probiotics generated con-
siderable interest in the area of functional foods and
pharmaceutical formulations [18]. An increasing amount of
research work suggests that probiotics can be used in the
treatment and prevention of infections and chronic
inflammatory disorders of the gastrointestinal tract. A
majority of the probiotic organisms are recognized by the
food and drug administration (FDA), USA as generally
regarded as safe (GRAS) [21]. Most probiotics consist of
lactic acid bacterial strains belonging to the Genera Lac-
tobacillus and Bifidobacterium. These bacteria are found in
large quantities in the human intestine. However, several
strains of Streptococci, Enterococci, Pediococci, Bacilli
and some yeast (Saccharomyces boulardii and Saccharo-
myces cerevisiae) are also regarded as probiotic strains
[18]. Some selected probiotic strains and their reported
effects in clinical studies are depicted in Table 1.
Probiotic Therapy
The existing clinical attitude always favored the use of
antibiotics for killing and eradication of disease causing
microorganisms. But, the biological relationship between
multicellular organisms and the microbial world is now
considered to be one of symbiosis rather than enmity [3].
Hence, the belief that, preservation of the normal flora,
rather than its deletion, can provide the greatest clinical
benefit, led to the emergence of probiotics for therapy.
Probiotic therapy is considered as a natural way of sup-
pressing the growth of pathogens in a non-invasive way, is
free from undesirable side effects and is preventive in
nature in comparison with antibiotic therapy. It can be an
alternative as well as complement to antibiotic therapy. In
probiotic therapy, oral administration of probiotics is
mainly through foods and/or pharmaceuticals. But food
applications are limited by the need for refrigerated storage
and decreased shelf life of foods. Also, people with
stomach disorders (digestion related) cannot consume large
quantities of probiotic foods. Pharmaceutical preparations
of probiotics can overcome these limitations.
Probiotics as Biological Drugs
Regardless of current marketing strategies of delivering
probiotics as ingredients in foods, nutritional supplements
and as pharma products, when it is intended to prevent or
treat a disease or abnormal condition, it becomes a ‘drug.’
According to an FDA working definition, probiotics are
classified as ‘live biotherapeutics’: ‘live microorganisms
with an intended therapeutic effect in humans, including
bacteria and yeast used in disease prevention or treatment,
intended local or regional action.’ It includes ‘probiotics
for clinical use’ [39]. The term live biotherapeutic product
(LBP) refers to products containing whole, live microor-
ganisms (i.e., bacteria, yeast) with an intended therapeutic
or preventive effect in humans, regardless of the route of
administration (oral, intra-vaginal, topical, etc.) [40,41].
Some of the expected characteristics of probiotic strains or
probiotic formulations as biological drugs are listed in
Table 2. Orally administered probiotics are usually mar-
keted as dietary supplements, conventional foods, medical
foods and drugs (biologics). Foods and dietary supplements
cannot carry the claims of being a biological drug product
for use in the treatment, prevention, cure, mitigation or
diagnosis of a specific human disease. However,
researchers often study probiotic products, which are
marketed as supplements and foods, for the purpose of
treating or preventing a disease. Because dietary supple-
ments and foods differ from therapeutic agents in how they
are being regulated by the US FDA, these study agents
are considered therapeutic agents or investigational new
drugs.
Regulations
The existing regulatory aspects or standards on probiotics
differ from country to country. Among the European
countries, probiotics are considered under foods/functional
foods/novel foods/natural remedy. Probiotic foods and
food supplements are covered by the Food Products
Directive and Regulation (regulation 178/2002/EC; direc-
tive 2000/13/EU). Some probiotic products which were
earlier marketed as herbal products and could not obtain a
drug registration as per the directive of Herbal Medicinal
Products Directive (2004/24/EC) are put under food sup-
plements category. It is necessary that all probiotic food
and supplement health claims are scientifically evaluated
by the European Food Safety Authority (EFSA) prior
Probiotics & Antimicro. Prot.
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to their use in the European Union (www.cmaj.ca).
Accordingly, nutrition and health claims on foods are
regulated under the EC Regulation No. 1924/2006. This
enables two different kinds of proprietary health claims to
be made; those for beneficial physiological effects on body
functions (according to article 13.5) and claims for
reduction in disease risk (according to article 14). In the
latter, the regulation actually refers to a reduction in a risk
factor and not to actual endpoints of disease. In this way,
the regulation is able to differentiate between health claims
appropriate for food and medical claims that can only be
used for drugs. At present, EFSA experts do not accept that
sufficient data are available to substantiate health claims on
the beneficial effects of any probiotic strains [42–44] and
suggested that future studies should be designed, executed
and evaluated by a multidisciplinary team, consisting of
microbiologists, nutritionists, statisticians, etc., focusing on
three aspects of research viz, study design, biomarkers and
Table 1 Some commercially used probiotic strains and their reported effects in clinical studies
Probiotic strains Reported clinical benefits Reference
Bifidobacterium BB-12 Alleviates symptoms of atopic eczema, immune modulating effect, improves
eradication of H. pylori, protective effects against acute diarrhea
[22–24]
L. acidophilus La-5 Balancing intestinal microflora, protection against traveler’s diarrhea, immune
enhancement, improves eradication of H. pylori, relieves constipation and
improves intestinal conditions
[25,26]
Lactobacillus casei 431 Enhance the immune response after vaccination, faster recovery from diarrheal
episodes in children
[29,30]
Streptococcus thermophilus TH-4 ?BB12 Impact on colic/irritability in infants, and reduces use of antibiotics, reduces risk of
rotavirus diarrhea in infants
[29,30]
L. acidophilus NCFB 1748 Lowering of fecal enzyme activity, decreasing fecal mutagenicity, prevention of
radiotherapy-related diarrhea, improvement of constipation
[11]
Lactobacillus F19 Improving gastrointestinal flora and immune health [31]
Lactobacillus fermentum strain
VRI 003 (PCC
)
Clinical efficacy within immune health, as an adjuvant to flu vaccine, in supporting
the immune response in athletes and in relation to atopic dermatitis
[32,33]
L. casei Shirota Prevention of intestinal disturbances, lowering fecal enzyme activities, positive
effects on reducing the recurrence of superficial bladder cancer.
[11]
Lactobacillus acidophilus NCFM ?
Bifidobacterium lactis Bi-07
Reduced abdominal bloating [34]
L. rhamnosus GG Reduces risk of upper respiratory tract infections in children, Treatment of diarrhea [35–37]
L. reuteri Shortening of rotavirus diarrhea. Colonizing the intestinal tract. [11]
Lactobacillus salivarius WB21 Improvement/maintenance of oral health in subjects at a high risk of periodontal
disease
[38]
S. boulardii Prevention of antibiotic-associated diarrhea. Treatment of C. dificile colitis [11]
Saccharomyces cerevisiae variant boulardii
CNCM I-1079
To treat the symptoms in acute cases of diarrhea, prevent and treat the symptoms of
traveler’s diarrhea and prevent and treat the symptoms of diarrhea occurring
during tube feeding
[79,80]
Lactobacillus Rosell-52, Bifidobacterium
Rosell-175, Lactobacillus Rosell-11
Prevention of pathogens and traveler’s diarrhea [79,80]
Table 2 Expected characteristics of probiotic strains or products as biological drugs
Selected strain should help in the healthy functioning of human body systems.
Strain used should be a fully characterized one using scientifically valid techniques to confirm the strain identity and its critical characteristics
Each strain should be pure and when used in combination of pure strains, the proportion should be known.
The strain should have ability to pass through digestive system in live condition and possibility of its intestinal implantation.
The culture should maintain its original properties while preparation of formulation and subsequent treatment to prepare in suitable dosage
form.
Should have undergone required in vitro and in vivo clinical studies to confirm its effect on the particular clinical condition.
Capable of delivering an accurate dosage form and content.
Potency of the formulation with respect to its ability to effect a given result.
Stability throughout its specified shelf life in a specified matrix.
Probiotics & Antimicro. Prot.
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clinical endpoints. Some of the important suggestions made
by the expert panel of EFSA are mentioned below.
•The preferred study design would include (a) large
(multicenter), randomized controlled trials with suffi-
cient statistical power, (b) a priori hypothesis with a
well-characterized probiotic strain to support the
hypothesis and (c) a limited number of endpoints to
show either a beneficial effect on body function or a
reduction in a risk factor and to indicate a working
mechanism of activity.
•There is an urgent need to define which biomarkers are
considered valuable for substantiation of a health claim,
and there is a need for researchers to develop and
validate new biomarkers that would be generally
accepted as appropriate and valid indicators of health
status. In this respect, the panel was of the opinion that
the increased availability of genome sequences together
with systems biology approaches will facilitate eluci-
dation of probiotic mechanisms of activity.
•Consensus is needed among the scientific and medical
communities with respect to new and useful clinical
intermediate endpoints to measure the extent, duration
or severity of disease. In the absence of unambiguous
biomarkers, these generally accepted clinical endpoints
will be of importance for the approval of future disease
risk reduction claims and in some cases for health
maintenance claims [42].
In Japan, a specific FOSHU label (Food for Specified
Health Use) allows health claim on a food package along
with a nationally known symbol. FOSHU is given only
after the scientific dossier which fully substantiates the
claim(s) made has been approved by the Japanese Ministry
of Health and Welfare [43]. In the USA, probiotics are
considered under dietary supplements and requires FDA
approval for use as biologicals. The US FDA is the key
federal regulatory agency whose authority has an impact on
both the clinical research and the development of probio-
tics as biological drugs. As products, probiotics may be
regulated by several FDA centers depending on which
regulatory category is being used. These centers include
Center for Food Safety and Applied Nutrition, which is
responsible for foods, dietary supplements, and ‘foods for
special dietary uses,’ Center for Veterinary Medicine,
which is responsible for animal feed products and animal
drugs, and Centre for Biologics Evaluation and Research
(CBER), which regulates human biologics [37]. Central
Drugs Standard Control Organization (CDSCO), Ministry
of Health & Family Welfare, Government of India provide
general information about drug regulatory requirements in
India. The Drugs and Cosmetics Act, 1940 regulates the
import, manufacture, distribution and sale of drugs in India.
As such, there are no guidelines that exist in India for use
of probiotics as drugs. But for probiotics in food, the Indian
Council of Medical Research (ICMR) along with the
Department of Biotechnology (DBT) formulated the
guidelines in 2011. These guidelines are for probiotics
being used as food or food ingredients. These are not meant
for probiotics delivered as pharmaceuticals or genetically
modified microorganisms (GMOs) [45]. As far as Food
Safety Standards Act [46] is concerned, a special third
category—‘Foods for Special Dietary Uses/Functional
Foods/Nutraceuticals/Health Supplements’—has been
mentioned. But does not differentiate functional food,
nutraceutical, dietary supplements and instead classified
all these products as food for special dietary application.
This allows for functional food and food supplements with
therapeutic claims to be marketed without declaration of
nutraceutical content, clinical trial results and health
studies.
Probiotics as Pharma
As far as existing pharmacological applications of probi-
otics are considered, a handful of well-defined strains are
being clinically tested and tried for management of gas-
trointestinal diseases (IBS, ulcerative colitis, ulcerative
colitis, abdominal bloating), infantile colic, improving
immunity, vaginal diseases, cold and flu. Most of the
commercial probiotic products consist of combinations of
probiotic strains and are available in the form of powder,
capsule, tablets, drops, chewing gum, lozenges, straws,
stick packs, bottle caps, etc. In addition to probiotic strains,
supplement formulations may also be added with vitamins
and prebiotics. Some probiotics meant for infants are sold
in oil suspensions making them easier to administer to
infants. Also, use of probiotics along with oral rehydration
salts is an option for the treatment of acute diarrhea. Here,
salts and the probiotic strain can be packed either in sep-
arate sachets or the salt solution can be put in a carton and
the bacteria in a straw. Some of these products have
obtained drug status also [44]. Nestle
´has launched first
FDA approved probiotic-supplemented infant formula,
‘Good Start Supreme’ with Natural Cultures, containing
BIFIDUS BL (B. lactis BB12) [47]. The probiotic package
forms available in the market today are designed to meet
the consumer demands of ease of handling, ease of addition
to food and targeted purpose for which it is designed. These
probiotic products can be taken either directly or along
with food, beverages, etc. Most dietary supplements are
sold in the form of capsules. These are available in dif-
ferent sizes and varieties. Stick packs and straws allow easy
dispense of probiotics into food, beverage or directly into
mouth. Probiotic lozenges and chewing gums are products
marketed for oral health to prevent halitosis and gingival
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disease. It could be revealed from literature that VSL
pharmaceuticals, Danisco-Dupont, Chr. Hansen, Biogaia,
Yakult Honsha, Institut Rosell-Lallemand, Bio-K plus
International and Probi are some of the major players in the
current probiotic market. Detailed list of companies
in probiotic pharam market can be obtained from http://
www.isapp.net/indust_comm.asp#2012.
Dose and Delivery of Probiotics
With regard to doses, the use of multiple probiotic strains
and the many doses, dosing patterns, strain variations,
variation in the consumer and the health endpoint being
tested result in making generalizations difficult. It is gen-
erally considered that doses between 10
6
and 10
9
colony
forming units (cfu) daily are required, and most clinical
trials use doses within these ranges [10]. But literature
review indicated that in the clinical trials, the range of
doses reported is quite broad and varied from anything
between 4 billion cfu/day in some cases to 200–800 billion
cfu/day in other cases. Commercial probiotic preparations
also showed wide variation between the actual probiotic
content in them and the labeled claim of contents. Hence,
to compensate for this, probiotic product manufacturers
usually add very high amount of overages, which not only
increase the cost of production but also result in variable
dose of the probiotic [48].
Oral delivery has been considered as best way to deliver
live cells to humans for therapy. The colon, a part of the
gastrointestinal (GI) tract, is the oral targeted site [49,50].
Vaginal or rectal is the other delivery routes of probiotics.
Vaginal administration is found to be a good way to obtain
lactobacilli recolonisation and has been tested in the pre-
vention or treatment of bacterial vaginosis or recurrent
urinary tract infections in women. The use of rectal therapy
has some advantages as a more varied selection of micro-
organisms that do not have to be resistant to pH can be used
and can be deposited at the site of action in the case of gut
disorders. But there are very limited studies on this and
there is a risk of spreading fecal pathogens also [51].
Excipients
Most of the commercially available probiotic preparations
contain different excipients along with the active ingredient
(probiotics). These are used in virtually all drug products
and are essential for product performance. Product per-
formance depends extensively upon the physical and
chemical properties of these excipients. The functional
purposes of excipients are many, viz, to act as a diluent,
lubricant, colorant, binder, coating agent, sweetening
agent, anti-caking agent, suppository base, etc. [52]. Most
commonly used excipients for probiotic preparations like
bulk powder, tablet and capsules include microcrystalline
cellulose (as binder/diluent), rice maltodextrin (as binder/
diluent), silicon dioxide (gliding/anti-caking agent), mag-
nesium stearate (as lubricant), hydroxy propyl methyl
cellulose (as suspending/viscosity agent), etc. [52,53].
Clinically Proven Probiotic Preparations
Some of the well-known probiotics/probiotic preparations,
which are present in the market and are supported by
human clinical trials (randomized, double-blind, placebo-
controlled) for their efficacy in the management of certain
clinical conditions, are briefly presented below.
VSL#3
VSL#3 is a probiotic cocktail containing bifidobacteria
(B. longum, B. infantis, B. breve), lactobacilli (L. acidophilus,
L. casei, L. bulgaricus, L. plantarum) and Streptococcus
salivarius subspecies thermophilus. It has been clinically
proven in the dietary management of ulcerative colitis (UC)
[54], ileal pouch and irritable bowel syndrome [55–57]. It is
recognized by the American College of Gastroenterology
Practice Parameter Committee as a tool for the dietary
management of an ileal pouch and is available in powder
form and capsules. It uses eight different strains of beneficial
bacteria and is a trade mark of European probiotic maker
VSL Pharmaceuticals, Inc. Each VSL#3-DS packet contains
900 billion cfu, and each packet of VSL#3 contains 450
billion cfu.
Probio-Tec Strains
Offered by Chr. Hansen, Bifidobacterium BB-12, L. aci-
dophilus NCFB 1748, Lactobacillus F19, L. acidophilus
LA-5, L. casei 431, L. rhamnosus GG, Streptococcus
thermophilus TH-4, L. fermentum PCC have been clinically
studied for their health benefits and have demonstrated
clinical efficacy in immune health [27,28,32,58–60],
gastrointestinal health and relief of occasional diarrhea, in
combating antibiotic side effects [61,62], urogenital dis-
order, skin disorders [22,63], constipation [26], antibiotic-
associated diarrhea in children [64], infantile diarrhea [24],
colic/irritability in infants [29]. Lactobacillus rhamnosus
GR-1 and L. reuteri RC-14 are found to play an important
role in establishing the vaginal flora [65,66] as well as in
the treatment of bacterial vaginosis [67,68] and vulvo-
vaginal candidiasis [69]. Probio-Tec
probiotic cultures
are either used alone or in combination with other Chr.
Hansen strains. The products are available in different
dosage forms like, powder, capsules, chewable tablets,
stick packs. Chr. Hansen produces its products in
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accordance with pharma cGMP standards and ISO
9001:2002 and 22000:2005 certifications.
HOWARU
Danisco’s range of highly documented, health-enhancing
cultures include single strain options like HOWARU
Dophilus, Bifido and Rhamnosus and proprietary blends
such as HOWARU Protect (for cold and flu), HOWARU
Restore (for gut microbiota restoration) and HOWARU
Balance(for improving digestion and immunity). Their
clinically important strains are Bifidobacterium lactis
HN019, B. lactis Bi-07 L. acidophilus NCFM and
L. rhamnosus HN001. The product support documentation
includes Halal and Kosher Certification, ISO 9001,
HACCP. The strains have been researched for their effects
in a number of clinical situations like IBS, bloating and GI
disorders [70–72].
BioGaia
BioGaia’s clinically proven probiotics include L. reuteri
Protectis delivered in a probiotic straw, chewable tablets
and drops for improved gut and immune health in adults
and infants [73–76] and L. reuteri Prodentis (active agent
in BioGaia lozenges and gum) for oral health.
BLIS K12
A product from BLIS Technologies Ltd, BLIS K12
TM
contains S. salivarius K-12 and is used for oral health [77].
ProbioKid
This children-specific synbiotic is formulated by Institute
Rosell-Lallemand, Canada, and is proved to posses the
ability to reduce the risks of common infections in children
during the winter period [78]. The three probiotic strains
in the formulation are Lactobacillus Rosell-52,
Bifidobacterium Rosell-71 and Bifidobacterium Rosell-33.
It also contains prebiotic FOS (Fructooligosaccharides) and
is available in sachet form.
Lalflor and Protecflor
Lalflor is a pharmaceutical grade S. boulardii yeast strain
used either as a ready to market formula or as a room stable
active pharmaceutical ingredient for the formulation of
registered drugs or innovative formula, such as probiotic
bacteria and yeast associations for a synergistic effect. The
strain S. cerevisiae variant boulardii CNCM I-1079 is
produced by Institut Rosell-Lallemand. Offered in capsule
form, it is recommended to treat the symptoms in acute
cases of diarrhea, prevent and treat the symptoms of trav-
eler’s diarrhea and prevent and treat the symptoms of
diarrhea occurring during tube feeding. Protecflor
com-
bines probiotic yeast S. cerevisiae variant boulardii CNCM
I-1079 with three specific probiotic bacteria strains—
Lactobacillus Rosell-11, Lactobacillus Rosell-52 and
Bifidobacterium Rosell-175. The strain is registered at the
Pasteur Institute, France [79,80].
Immunobiotix
A proprietary blend of probiotic organisms produced by
Nutraceutix is administered by BIO-tract
delivery tech-
nology that delivers live organisms past harsh stomach acids
to the intestinal tract and are found to enhance immunity.
Nutraceutix supplies nearly twenty naturally occurring pro-
biotic strains and incorporates patented LiveBac
process-
ing and BIO-tract
and new Viablend
TM
delivery
technologies into custom probiotic products [81,82].
Lactobacillus sporogenes
This probiotic preparation has a long history of use and
contains Bacillus coagulans. It is available in the form of
bulk powder, capsules, enteric coated pellets and tablets. A
number of Indian pharmaceutical companies manufacture
this probiotic preparation under different trade names like
Sporlac, Lactospore, Sanvita, Lacbon, etc. Apart from
dietary supplement, bacillus probiotics are used as a ther-
apeutic product for the treatment of gastrointestinal and
urinary tract infections. Formulations include L. sporoge-
nes alone or combined with lactobacilli or bifidobacteria,
vitamins, minerals, hormones and prebiotics [48,83–85].
Probiotic Pearls
There are several probiotic supplements designed in pearl
form to provide extra protection to the probiotic cells. These
include acidophilus pearls by Enzymatic therapy, smarter
probiotics by Integrative therapeutics, primadophilus pro-
bifia pearls by Naturesway, biobeads probiotic acidophilus
by Natrol, flora five probiotic pearls by Global health trax.
All are said to have a triple layer encapsulation for the safe
delivery of probiotics to intestinal tract and is a blend of
L. acidophilus and B. longum. The strains are not revealed as
the particular strains used in the products are proprietary.
Each pearl contain 1 billion cfu. It is said to support digestion
and a healthy intestinal system when taken daily [86,87].
Linex Forte
A registered medicinal product in the Slovenian market,
Linex forte is said to be effective in treating diarrhea,
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flatulence and distention. It contains probiotic strains
belonging to lactobacillus and Bifidobacterium [88].
Idoform and Bifiform
These are probiotic brands from Ferrosan in the European
markets. Idoform Travel is used as an effective means to
ensure a healthy and well-balanced intestinal flora and
avoid symptoms of traveler’s diarrhea for travelers. The
product contains five well-documented probiotics strains
(BB-12, LA-5, LBY-27, LGG and STY-31). It is delivered
in the form of chewable tablets to be taken once daily.
Idoform A-biotic is marketed in Finland and Idoform
Classic Plus in Norway. Biliform is found to be effective
for the treatment of Helicobacter pylori infections [89,90].
Some common commercial probiotic supplements
marketed in US include Align (Proctor & Gamble),
BifidoBiotics (Allergy Research Group), Culturelle
(Amerifit Nutrition, Inc), Florastor (Biocodex), Nature’s
Biotics (Life Science Products), Primal Defense Kids
(Garden of Life), Probiotica (McNeil Consumer Healthcare),
ABC Dophilus powder for infants and children (Solgar),
Flora.Q (Bradley Pharmaceutical, Inc) [47].
Indian Scenario
The Indian probiotic market is growing at 40 percent per
annum [91]. This expanding probiotic market has attracted
pharmacos like Alkem Laboratories, Dr Reddy’s Laboratories
(DRL), Glenmark, Ranbaxy Laboratories, Cipla, Aristo,
Lupin and Tablets India to take interest in probiotics. The
Indian functional food market already has probiotic products
launched by Yakult, Amul, Nestle and Mother Dairy. At
present, there exist over 40 probiotic drug brands in India of
which a majority are in the area of gastroenterology. Big
pharmacos like DRL, Glenmark, CD Pharma and Alkem have
already launched drugs with probiotics. Many major Indian
pharmacos are also in the process of developing and in-
licensing probiotic drugs. After launching Inersan with
Ranbaxy, VSL is planning to launch its lead drug VSL-3 used
to treat irritable bowel syndrome in India. There are also other
probiotic drugs like Enterogermina (from Sanofi-Aventis),
ViBact (USV), Darolac (Aristo), Pre-Pro (Fourrts), Bifilac
(Tablet India), Sporlac (Uni-Sankyo), Prowel and Sporotic
(Alkem) and Econorm and Becelac (DRL) available in the
Indian market. Some probiotic preparations existing in the
Indian pharma industry is mentioned in Table 3.
Limitations So Far
The scientific and medical validation of probiotic products has
been extremely slow and time consuming. Lack of adequate
information, by which the consumer and health professional
can judge the efficacy and safety of retailed probiotics limit
their efficient use in therapy. Also compared to synthetic
drugs, probiotic products are more complex and require con-
sistent sourcing. Their formulation and packaging require
utmost care to ensure viability and stability of cells [40].Large
scale trials of efficacy that are used in the pharmaceutical
industry is lacking in case of probiotic products. Without these
trials and subsequent approval by fastidious regulatory
agencies such as the FDA, probiotics cannot find a well-
deserving place in the self-care health market. It is important
that the specific strains and dosing patterns are clearly reported
and that there is adequate quality control to ensure the possi-
bility of ultimate recommendations of a specific agent for a
specific purpose [92,93]. In the Indian market, some
unscrupulous probiotic products are also seen without any
information about the strain of probiotic bacteria and any
evidence of clinically proven health benefit. Some probiotics
are also sold in mixed formulation with antibiotics.
A Word of Caution
Probiotics may show some adverse effects under specific
conditions, and few cases related to such adverse effects of
probiotic use in humans have been reported. The risks involved
in the probiotic treatment are reviewed by Boyle et al. [93].
Various study results showed an increased risk of sepsis in
immunocompromised, immunodeficient people and prema-
turely borne babies. Hence, caution should be observed in the
use of probiotics in these groups. In 2008, a multicenter,
double-blind, randomized controlled trial designed to evaluate
whether probiotics could reduce the incidence of infectious
complications in 300 patients with severe acute pancreatitis
resulted in the death of twenty-four patients treated with pro-
biotics in the Netherlands. In the probiotics g roup, nine patients
developed bowel ischemia (eight of whom died), whereas none
developed this complication in the placebo-group. Use of
probiotics on gravely ill patients, probiotics administration
through feeding tubes into the intestines or patients in the acute
phase of the disease when the bacteria was administered were
taken as the cause of death. But the important point is that the
death rate was high among probiotics administered patients
[94]. Hence, it is advisable to prescribe probiotics looking to
the conditions of the patient. However, there are no significant
reports elucidating adverse effects on healthy persons con-
suming probiotics for general health.
Future Research Needs
The entry of probiotics in the clinical or pharmaceutical
field is evident from an increase in the availability of
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variety of ‘over the counter’ (OTC) probiotic products.
Many of these may not have undergone the procedures
required for modern therapeutic drugs. Proper pharmaco-
kinetic approaches used in the development of a clinical
drug can be followed for development of probiotics as
modern therapeutic drugs. Along with this, some other
important areas which require research to elevate probio-
tics as pharmaceutical drug are mentioned here.
•As the probiotic therapy is based on intestinal flora, a
deeper understanding of gut microbiota is required with
respect to interrelationships of various species existing
there, changes in the gut microbial composition at
different age groups particularly in infants and elderly
and impact of nutritional status on the gut microbiota.
•Regulatory authorities as well as the probiotic manufac-
turers should have a deep understanding of the probiotic
science. Regulatory bodies should come up with well-
defined procedures for conducting studies related to
probiotic formulations so that probiotic manufacturers
are sure about fulfillment of legal requirements. Regu-
lations have a huge impact on the development and
marketing of probiotic products. Strict regulations can
wipe out faulty products from the market and genuine
products can gain more acceptances by consumers.
•Elevation of probiotics as an alternative therapy
requires active involvement of medical practitioners
along with probiotic manufacturers. Physicians are still
skeptical about use of probiotics as drugs.
•Most of the probiotic products available in the market
contain morethan one strain. Hence,how a probiotic strain
acts when used alone or in combination with other strains
need to be evaluated. Also, their individual role, interac-
tions, mechanisms of action, appropriate administrative
regimens should be understood especially when the
formulation is to be used for treatment of a disease
condition.
•Efficacy of probiotic formulation may change when
used along with other drugs for a particular disease.
Such cross-effects need to be studied in detail. A recent
systematic review and meta-analysis on probiotics for
the prevention and treatment of antibiotic-associated
diarrhea [12] suggested that use of probiotics as adjunct
therapy reduced the risk of AAD.
•Probiotic organisms as carriers of vaccines or other
beneficial substances to the host should be studied in
depth.
Conclusion
When the medical field is searching for alternative therapies
owing to the emergence of new and multidrug resistant
pathogens, use of probiotics in different diseases or health
conditions is attractive. However, elevation of probiotics as
routine therapy still requires many questions to be answered.
Studies in humans have to prove the efficacy of different
species, the conditions for their use, the optimal adminis-
tration route and the formulation. Suitability of the right
probiotics from a microbiological and clinical perspective is
important and for this the strict co-operation of microbiolo-
gists and physicians is needed. Also, the active ingredients
that are responsible for the clinical effects of probiotics, the
target sites of probiotics in the body, dose–response effects,
ability of probiotics to translocate and whether this is a
positive or negative trait, need to be established. The safety
aspect of commercial probiotics needs to be well established
and should be studied in more detail, especially in immu-
nocompromised hosts, infants and elderly. Also, the regu-
latory aspects need to be finalized.
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Table 3 Some probiotic preparations in Indian pharma industry
Name Manufacturer Constituent per unit Dose Package unit
Sporlac Uni-Sankyo Ltd. Lactobacillus sporogenes 60 million spores 1 Tablet 15 tablets
Darolac Aristopharmaceuticals Pvt. Ltd. L. sporogenes 2500 million spores 1 capsule 10 capsules
Lactogenes DT Medispan Ltd. L. sporogenes 10 million spores 1 Tablet 10 tablets
Alacforte Allience remedies L. sporogenes 120 million spores 1 Tablet 10 tablets
Sporlac sachet Uni- Sankyo Ltd L. sporogenes 150 million spores 1.8 gm 1.8 gm
Darolac sachet Aristopharmaceuticals Pvt. Ltd. L. sporogenes 1250 million spores 1 sachet 1 sachet
Babylac sachet Bactolac formulations Pvt. ltd L. sporogenes 1500 million spores 5 gm 30 gm
Lac (60 ml) Raphael Pharmaceuticals Pvt. Ltd. Lactic acid bacillus 40 million spores 5 ml 60 ml
Myconip vaginal pessary Uni-Sankyo Ltd. Lactic acid bacillus 150 million spores 1 Pessary 10 pessary
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