“FORMULATION AND DEVELOPMENT
OFGENERIC INJECTABLE FORMUALATIONS”
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA.
BY
ANIL K S
DEPARTMENT OF PHARMACEUTICS
PES COLLEGE OF PHARMACY
BANGALORE
(2012-14)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE-II
1. NAME OF THE
CANDIDATE
AND ADDRESS
ANIL K S
1st M. Pharm (PHARMACEUTICS)
PES College of Pharmacy
Hanumanthanagar
Bangalore-560 050
Email. [email protected]
PERMANENT ADDRESS:
S/o K R SHANKAR
No 434,Kanagal post
Periyapatna (taluk)
MYSORE-571187
2. NAME OF THE
INSTITUTION
P.E.S. COLLEGE OF PHARMACY
50 FEET ROAD,
HANUMANTH NAGAR,
BANGALORE-560050.
3. COURSE OF STUDY
AND SUBJECT
MASTER OF PHARMACY IN
PHARMACEUTICS
4. DATE OF ADMISSION
OF COURSE
12th AUGUST 2012
5. TITLE OF TOPIC:
“FORMULATION AND
DEVELOPMENTOFGENERIC
INJECTABLEFORMUALATIONS”
PROFORMA FOR REGISTRATION OF SUBJECT FOR
DISSERTATION
6.
BRIEF RESUME OF THE INTENDED WORK:
6.1 NEED FOR THE STUDY
The parenteral route of administration is the most effective route
for the delivery of the active pharmaceutical substances with narrow
therapeutic index; drugs with poor oral bioavailability and drugs with high
first pass metabolism.
Advantages and Disadvantages of the Parenteral Route:
• The IV route is the fastest method for delivering systemic drugs.
• preferred administration in an emergency situation
• It can provide fluids, electrolytes, and nutrition.
• patients who cannot take food or have serious problems with the GI
tract
• It provides higher concentration of drug to bloodstream or tissues.
• advantageous in serious bacterial infection
• IV infusion provides a continuous amount of needed medication
• without fluctuation in blood levels of other routes
• infusion rate can be adjusted
• to provide more or less medication as the situation dictates
• Intramuscular (IM) and subcutaneous routes of administration are
convenient ways to deliver medications
• Compared with the oral route:
• onset of response of the medication is faster
Vitamins are used therapeutically, both to correct vitamins deficiency and
for its apparent pharmacological effects. The vitamin is available in
various forms for either oral or parenteral administration. Preparations
designed for sublingual or intranasal administration are also available, but
they are relatively expensive and there is not much research on their use.
There appears to be some confusion among practitioners of natural
medicine about whether oral or parenteral administration is preferable for
patients requiring vitamins therapy. For example, due to lack of intrinsic
factor and gastric hydrochloric acid, patients with pernicious anemia are
capable of absorbing an average of 1.2% of an orally administered dose of
cyanocobalamin. An oral dose of 100-250 mcg/day will maintain
adequate serum vitamin B12 levels in most patients with pernicious
anemia, although some patients may require as much as 1,000 mcg/day.
Therefore, patients with pernicious anemia who are being treated with oral
vitamin B12 are generally advised to take 1,000 mcg/day. For those with
newly diagnosed pernicious anemia, some doctors recommend an oral
dose of 2,000 mcg/day (or injections) during the first month, in order to
replenish body stores. On the other hand, patients who are likely to be
noncompliant with oral therapy should be seen regularly by a doctor and
treated with intramuscular injections.
When vitamin B12 is being used for its pharmacological effects, as in the
treatment of fatigue, Bell’s palsy, diabetic neuropathy, sub-deltoid
bursitis, or asthma, intramuscular injections appear to be preferable to oral
administration. It appears that supra-physiological serum concentrations
are usually needed for vitamin B12 to exert its pharmacological effects,
and that these serum concentrations can be achieved only with parenteral
administration.1
The objective of the present study is to prepare generic injectable of
vitamins. These drugs are both soluble or insoluble in water. For insoluble
drugs using any of the solubilization techniques, such as complexation,
cosolvency, hydrotropy, use of surfactants, or alteration of pH, an aqueous
based injection formulation will be prepared using optimization methods.
Optimization methods will reduce the number of experiments, avoids trial
and error method, less time consuming and less expensive.
6.2 REVIEW OF LITERETURE
 Gracea N et al., carried out an evaluation of the efficacy
of injectablemicroencapsulated Vitamin B12 in
increasing
and
maintaining the serum and liver Vitamin B12concentrations of
lambs. Formulations of microencapsulated Vitamin B12 in lactideglycolide polymers wereinjected intramuscularly or subcutaneously
into the anterior neck region of groups of 10 lambs and their
efficacy
determined
from
changes
in
serum
and
liver Vitamin B12 concentrations. The 955 lactide-glycolide and the
100
lactide formulations containingmore
than
12.5%Vitamin B12 w/w significantly increased and maintained
serum Vitamin B12 concentrations for at least 210 days as well as
liver Vitamin B12 concentrations in treated lambs when compared
with
untreated
controls.
Injections of
microencapsulated Vitamin B12 in lactide-glycolide copolymers are
able to increase and maintain the Vitamin B12 status of lambs for at
least 210 days.2
 Jiben Roy et al., studied the Marketed Vitamin B-Complex
Injectable: Stability and Mutual Interaction. The Vitamin Bcomplex injectable in the Bangladesh drug market have been
studied for the stability and mutual interactions of the active
ingredients.
It
was
found
that
the
preparation
without
nicotinamidein the formulation has more stability than that of the
preparation having nicotinamide. The presence of nicotinamide in
a formulation containing four B-vitamins causes the degradation
of thiamine to a sub-standard level within one year of the 2year's
shelf-life.3
 Wang J et al., carried out Antitumor effects and pharmacokinetics
of aclacinomycin A carried by injectable emulsions composed of
vitamin E, cholesterol, and PEG-lipid. The aim of this study was
to prepare injectable emulsions of aclacinomycin A (E-ACM) and
evaluate
its
acute
toxicity,
antitumor
effects,
and
pharmacokinetics. In E-ACM, the surfactants were polyethylene
glycol-lipid and cholesterol, and the oil phase was a vitamin E
solution of ACM. The particle size distribution and the zeta
potential of E-ACM were measured by the laser light dynamic
scattering method. The ACM-loading efficiency was measured by
using Sephadex G50 column chromatography. The acute toxicity,
antitumor effects, and pharmacokinetics of E-ACM were studied
in C57BL/6 mice bearing mouse murine histiocytoma M5076
tumors. The average diameter, zeta potential, and ACM-loading
efficiency of E-ACM were 123.0 ± 1.2 nm, − 12.67 ± 1.35 mv, and
96.3 ± 0.3% (n = 3), respectively. When stored at 7°C in the dark
for 1 year, the average diameter and ACM-loading efficiency of EACM changed into 126.3 ± 2.3 nm and 97.4 ± 0.8%, respectively,
whereas 6.5 ± 0.2% ACM decomposition was observed (n = 3).
The plasma areas under the bio-distribution curves (AUC)0.03–48h of
E-ACM was significantly greater than that of free ACM (F-ACM).
The heart, lung, and kidney AUC0.03–48h of E-ACM were
significantly smaller than those of F-ACM whereas the liver and
spleen AUC0.03–48h of E-ACM were not significantly different from
those of F-ACM. The tumor AUC0.03–48h of E-ACM was
significantly greater than that of F-ACM. E-ACM had lower acute
toxicity and greater potential antitumor effects than F-ACM in
M5076 tumor-bearing C57BL/6 mice. E-ACM is a useful tumortargeting drug delivery system. © 2002 Wiley-Liss, Inc. and the
American Pharmaceutical Association J Pharm Sci 91:1128–1134,
2002. 4
 Cusack PM et al., studied the Effects of injectable vitamins A, D,
E and C on the health and growth rate of feedlot cattle destined for
the Australian domestic market. Systematic allocation of 2465
cattle at feedlot entry to: a commercial vitamin A, D and E
preparation at the label dose rate; commercial vitamin A, D and E
at twice the label dose rate; a formulation with no vitamin D, a
lower concentration of vitamin A and a higher concentration of
vitamin E; and the oil-based carrier alone at volumes
corresponding to the above treatments. Comparisons of growth
rate, disease and mortality were made between the groups at the
conclusion of the feeding period. In a separate experiment, 176
cattle were alternately administered injectable vitamin C at the
time of treatment for BRD, or were not injected with vitamin C,
and mortality was compared between the groups. The routine
injection of cattle with vitamins A, D and E at feedlot entry is
unlikely to result in improvements in health and growth rate where
cattle are provided with these vitamins in their diets at
concentrations
equal
to
the
National
Research
Council
recommendations. Mortality rate in cattle diagnosed with BRD
may be reduced by intramuscular injection of vitamin C at the
time of treatment with antibiotics.5
 Lindemann MD et al., carried out the A regional evaluation of
injections of high levels of vitamin A on reproductive performance
of sows. A regional study involving 443 litters from 182 sows was
conducted at 5 cooperating experiment stations to determine the
effects of an i.m. injection of vitamin A at weaning and breeding
on subsequent litter size of sows. A common vitamin-mineral
premix that supplied 11,000 IU of vitamin A/kg of diet (as-fed)
was used by all stations. The treatment × parity interactions were
stronger than the treatment × station effects, and when the litter
size response was separated into early parity sows (parity 1 and 2)
and late-parity sows (parity 3 to 6), the treatment × station
interactions were no longer present in either subgroup. The results
of this regional project demonstrated that injection of high doses
of vitamin A in young sows at weaning and breeding improves the
subsequent number of pigs born and weaned per litter, indicating
that vitamin A requirements for maximal performance may vary
with age. 6
1.
• M Nahar et al., carried out the formulation and evaluation of
saquinavirinjection. In the present investigation, it was proposed to
formulate the aqueous injection of saquinavir, which should
definitely be more effective, economical, safe and with the least
side effects as compared to its existing dosage forms, e.g., hard and
soft gelatin capsule. The solubilization of saquinavir (antiHIV
drug), practically insoluble in water, by means of physiologically
active hydrotropes and cosolvents has been investigated. The
results indicate that enhancement in solubility of saquinavir in the
presence of hydrotrope at low concentration is due to weak ionic
interaction. At higher concentrations (>0.4 M), complexation is
found to be the probable mechanism for solubility enhancement by
nicotinamidebut nature of complex formed is not clear; whereas for
ascorbic acid, self-association is the probable mechanism at these
concentrations. Using these two approaches, various formulations
of saquinavir were developed, and haemolysis study and dilution
study of these formulations were carried out. Formulation
containing nicotinamide as hydrotrope showed promising results. 7
• Chung CH et al., reviewed the utilization of injectable NSAID in
local Accident&Emergency (A&E) practice. NSAID utilization
data, in relation to type and specialty, were retrieved through the
hospital and central pharmacy computer systems of Hospital
Authority.A&E departments were the main users of injectable
NSAID. Their expenditure exceeded other forms of NSAID and
narcotic analgesics. It was concluded that the use of injectable
NSAID in local A&E practice may be excessive. 8
• Arora Sanjay et al., explained acute pain is an extremely common
presenting symptom to the emergency department (ED), making it
imperative that emergency physicians provide adequate, safe and
cost-effective analgesia. Non steroidal anti-inflammatory drugs
(NSAIDs) are often first-line treatments for moderate to severe
pain. Physicians can choose between intramuscular (IM) or
intravenous (IV) Ketorolac, the mechanism of action is identical
irrespective of the route the medication is given(reversible
inhibition
of
prostaglandin
synthesis
at
the
level
of
cyclooxygenase). Despite the similar pharmacodynamics, many
physicians believe that parenteral ketorolac is more efficacious,
despite a greater cost and a more invasive route of administration. 9
• Brandon Bookstaver P et al., reviewed the current data on the use of
the first approved intravenous Ibuprofen product for the
management of post-operative pain and fever. Several randomized
controlled studies have demonstrated the opioid-sparing and
analgesic effects of 400 and 800 mg doses of intravenous Ibuprofen
in a series of post-operative patient populations. Two recent studies
have also noted the improvement in fever curves in critically ill and
burn patients. The review addresses the clinical utility of a
parenteral NSAID in a hospitalized patient for post operative pain
management and fever reduction. 10
• Rajesh Kumar Maheswari et al,.formulated& evaluated injection of
Aceclofenac. Aceclofenac is practically insoluble in water. The
effect of hydrotopes such as urea and sodium citrate and blends
(urea + sodium citrate) on the solubility of Aceclofenac was
investigated. The enhancement in the solubility of aceclofenac was
more than 5 and 25 folds in 30% sodium citrate solution and 30%
urea solution, respectively, as compared to its solubility in distilled
water. The enhancement in the solubility of Aceclofenac in a mixed
hydrotropic solution containing >20% urea and 10% sodium citrate
solution was more than 250 folds, This proved a synergistic
enhancement in solubility of a poorly water- soluble drug due to
mixed hydrotropy. 11
• A.M Mcgee et al., reported about the skin nercosis following an
intramuscular injection of NSAIDS to the anteriolaterial area of the
thigh in two patients. Both of two patients required further multiple
operations and one developed life threatening septicaemia. Skin
nercosis although rare, recognized adverse reaction to intra
muscular NSAID injection. 12
• Bhatt Krunal et al,.Formulated and evaluated a safe and stable
injectable formulation of Diclofenac sodium using 2-hydroxy
propyl beta cyclodextrin. The Solubility and stability of Diclofenac
sodium was improved& enhanced by making inclusion complex
with 2-hydroxy propyl beta cyclodextrin. Among the various
antioxidants studied, it was observed that N-acetyl-L-cysteine and
Disodium EDTA in combination, shown good stability profile as
compared to other antioxidants. 13
• N K Jain et al,.FormulatedPiraxicam injection, which is an
analgesic, antipyretic and anti inflammatory agent. It is practically
it is insoluble in water. The aqueous solubility of piraxicam was
increased using hydrotopes and co solvents and formulated in
aqueous injections & evaluated in-vitro and in vivo evaluation. 14
• K.S Rathor et al., enhanced the solubility of Nimesulide and
formulated into an injection, Nimesulide is insoluble in water. The
very poor aqueous solubility and wettability of the drug give rise to
difficulties in the pharmaceutical formulation of parenteral
solutions and may lead to a variable bioavailability. The present
work
investigates
the
solubility
enhancement
and
hence
bioavailability of the drug. Solubility of drug can be increased by
variety
of
contemporary
methods
such
as
hydrotropic
solubilization, solid dispersions. Hence in the present investigation
to enhance the solubility of Nimesulide using hydrotopes such as
sodium benzoate, sodium-o-hydroxy benzoate, and sodium-phydroxy benzoate. Hydrotropy used to increase in solubility in
water of various substances due to the presence of large amount of
additives. The feasibility of preparing injection was examined, and
suitable batches with good solubility profile were selected and
parenteral dosage form was formulated. 15
6.3 OBJECTIVES OF THE STUDY:
The present study is aimed to prepare generic injectable formulation
of vitamins. The drug formulation and developmentsteps are as
follows :
 Evaluation of compatibility between drug and excipients
 Preparation of a stable formulation at room temperature.
 Studying the container compatibility study of the prepared
formulation.
 Evaluation of the developed formulation for Physico-chemical
properties.
 Stability studies of selected formulations as per ICH Guidelines.
 Documentation of resultant data.
6.4. Source of Data
A. Journals & articles :
• Advanced drug delivery reviews.
• International Journal of Pharmaceutical Sciences.
• International Journal of Pharmaceutical and Biological
Archives.
• International Journal of Pharmaceutics.
• Journal of Clinical therapeutics.
B. Web sites:
www.sciencedirect.com
www.pubmed.com
www.google.com
6.5. Does the study require any investigation or intervention to be
conducted on patients
or other humans or animals? If so, please
mention briefly.
-NO-
6.6. Has ethical clearance been obtained from your institution?
- NOT APPLICABLE-
LIST OF REFERENCES
1. Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best
kept secret? JAMA 1991;265:94-95.
2. Gracea
N.D,
D.H.
L.
Evaluation
of
the
efficacy
of
injectablemicroencapsulated Vitamin B12 in increasing and
maintaining the serum and liver Vitamin B12concentrations of
lambs. N Z Vet J. 1999;47(1):3-7.
3. Jiben Roy, Miazddin Mahmud, Sobhan A, Aktheruzzaman M, Alfarooqueand M, Ali. E. Marketed Vitamin B-Complex Injectables:
Stability and Mutual Interaction. Drug Development and Industrial
Pharmacy. 1994;20(13):2157-63.
4. Wang J, Maitani Y, K. T. Antitumor effects and pharmacokinetics
of aclacinomycin A carried by injectable emulsions composed of
vitamin
E,
cholesterol,
and
PEG-lipid.
J
Pharm
Sci.
2002;91(4):1128-34.
5. Cusack PM, McMeniman NP, IJ. L. Effects of injectable vitamins
A, D, E and C on the health and growth rate of feedlot cattle
destined for the Australian domestic market. Aust Vet J.
2008;86(3):81-7.
6. Lindemann MD, Brendemuhl JH, Chiba LI, Darroch CS, Dove CR,
Estienne MJ, et al. A regional evaluation of injections of high levels
of vitamin A on reproductive performance of sows. J Anim Sci.
2008;86(2):333-8.
7. M Nahar, NK Jain. Formulation and evaluation of saquinavir
injection.
8. CH Chung. The use of injectable Non steroidal Anti-inflammatory
drugs in local accident & emergency practice. Hong Kong Journal
of Emergency Medicine. Apr2002; 9(2): 65-71.
9. Sanjay arora, JanathanWanger
G . Myth: Parenteral Ketorolac
provides more effective analgesia then oral ibuprofen. Medical
Mythology. 2007; 9(1):30-32.
10.Brandon Bookstaver P, April Miller D, Celeste Rudisill N, leann
Norris B. Intravenous ibuprofen: the first injectable product for the
treatment of pain and fever. Journal of pain research. 2010 may ;(
3) :67-79.
11.Rajesh Kumar Maheswari, ArpnaIndurkhya. Formulation and
Evaluation of Aceclofenac Injection Made by Mixed Hydrotropic
Solubilization. Technique. Iranian Journal of Pharmaceutical
Research. 2010; 9 (3): 233-242.
12.McGee AM, Davison PM .Skin necrosis following injection of Non
Steroidal anti Inflammatory drug. British journal of anesthesia.
2002; 88(1):139-140.
13.Krunal Bhatt, Piyalpatel RT. Formulation and evaluation of
Diclofenac sodium injection using 2-Hydroxy Propyl Beta Cyclo
Dextrin. International journal of pharmacy and pharmaceutical
scince.2011 may; 3: 250-252.
14.Singhaiajainadjain KS. Evaluation of Piroxicam Injection. Indian
journel of Pharma science. 1997; 59(6): 306-311.
15.Rathor KS, Gupta JDYS. Solubility Enhancement and formulation
of Nimesulide Injection using Hydrotopes. The Pharma review.
December 2006.
16.Leon lachmen, Herbert Lieberman A. The Theory and practice of
industrial pharmacy. In liquids. Special Indian edition. Nodia :
CBS Publisher ; 2010.p.457-466.
9.
SIGNATURE OF THE
CANDIDATE
10. REMARKS OF THE GUIDE
( Mr.ANIL K S )
Forwarded and recommended for the
approval
11. NAME & DESIGNATION OF:
GUIDE
Mr. R.Srinivasan
Asst. Professor
Dept. of Pharmaceutics,
PES College of Pharmacy,
Bangalore 560 050
SIGNATURE
CO-GUIDE
Mr. JUSTIN BABU,
Group Leader, strides arcolabs ltd.,
Bangalore.
SIGNATURE
HEAD OF THE DEPARTMENT Dr. SATISH C.S
SIGNATURE
12. Remarks of the Chairman and Prof. Dr. S. Mohan,
Principal& Director,
Principal:
P.E.S. College of Pharmacy,
Bangalore-560050.
SIGNATURE