Download Waugh et al., [5] studied the stability, compatibility, and

6. Brief resume of intended work:
6.1Need for study:
When drugs need to be injected, any one of several routes can be used to administer the drug.
The most common injectable routes of administration are intravenous (in the vein),
intramuscular (in the muscle), and subcutaneous (in the skin) [1]. Intravenous administration
of drugs has advantages over other routes of administration because it provides the fastest
route to the bloodstream. There are no barriers like skin or muscle to absorb the drug first,
which allow the most rapid onset of action. If a patient cannot take medication by mouth
because he is unconscious or vomiting, then intravenous administration is the best route [1].
There are two types of intravenous administration. The first is an intravenous injection in
which the prepared medication is drawn up into a syringe and administered immediately. The
amount of medication is usually a small volume pushed through an IV line that is already in
place on the patient.
The second type of administration is an IV infusion. Infusions are given to overcome
dehydration, to build up depleted blood volumes, and to serve as an aid for the administration
of medications. An infusion allows a larger volume to be given at a constant rate, depending
on the drug to be administered. Infusions can be administered continuously or intermittently.
Continuous infusions are used to administer larger volumes of solutions over several hours at
a slow, constant rate. Intermittent infusions are used to administer a relatively small volume
over a shorter time at specific intervals.
Large volume parenterals (LVP’s) is defined as “a single-dose injection that is intended for
intravenous use and is packaged in containers labelled as containing more than 100 mL”.
They are sterile, pyrogen-free, and essentially free of particulate matter and are isotonic
preparations [2].
Infusion therapy deals with the question: “How can I bring this substance/solution (optimally)
into the body?” This is done with the help of containers. Containers are defined as “that
which holds the article and is or may be in indirect contact with the articles” [2]. LVP’s are
packed in glass bottles or in large volume flexible containers [2]. Initially glass bottles were
the standard container. They have lots of disadvantages like:

The glass bottle is breakable.

It has a considerable weight.

It must be vented - this requires monitoring at the end of the infusion to prevent a
possible air embolism.

It cannot support a pressure infusion using a pressure cuff.

It has a piercing site which is not per se sterile and must therefore be disinfected.

It entails the risk of considerable particle contamination.
To overcome the above drawbacks today they are increasingly being superseded by plastic
containers or bags. Low weight, low costs and a range of application advantages have made
infusion bags popular particularly with standard solutions [2]. Infusion bags feature the
following advantages:

They are user-friendly, i.e. it is not possible for the infusion system and in particular
the drop chamber to run empty because the bag collapses and at the end of the
infusion there is an automatic stop of the fluid column thus making it a closed system
which in turn makes an air embolism impossible.

The infusion sets functions without venting.

It is easy to mix the contents when admixtures are made.

They are flexible (important for pressure infusions).

They are transparent (important for detecting possible precipitations).

They are easy to use for a pressure infusion
The infusion bags are made from any of the materials like poly vinyl chloride (PVC),
polyethylene (PE) poly propylene (PP), ethylene vinyl acetate (EVA), Polyamide (Nylon),
Polycarbonate (PC) and Polyolefin (mixtures of low density PE, high density PE, PP, and
EVA) [2].
Antibacterials are those agents which are used in the treatment of infections caused by
bacteria. The patients suffering from certain conditions like urinary tract infections have to be
administered with antibacterial parenteral preparations for over a period of time depending
upon the severity of the infection.
The major concerns with these preparations are the stability of the preparation in various
diluents and infusion bags [3, 4]. In addition to stability, leaching from various infusion bags
caused by this formulation should be measured which is another concern with the infusion
bags. Therefore, it necessitates stability and leaching studies for antibacterial parenterals
preparations.
Here the attempt will be made to formulate different classes of antibacterial LVP’s and these
will be packed in infusion bags. Once packed these have to be evaluated for pH, sterility,
stability [5, 6], compatibility [5-7], clarity, antibacterial activity, presence of particulate
matter, extraction study [8-10], toxicity, safety, etc.
6.2 Objective of study:
The objective of the proposed study would be:

To develop infusion bags of selected antibacterial agents.

Physico-chemical evaluation of the developed infusion bags in solutions like sodium
chloride (0.9%), dextrose (5%) or water for injection.

Stability study of the preparations in infusion bags as per ICH guidelines.
6.3 Review of literature:
Jeanette et al., [3] has studied the physico-chemical stability of nelarabine infusion solutions
in EVA infusion bags. Results showed that the stability tests revealed that nelarabine infusion
solutions are physico-chemically stable for a minimum of four weeks. Nelarabine
concentrations remained at a level of > 95% of the initial concentration independent of the
storage conditions. Exposure to daylight did not influence the stability of the nelarabine
infusion solutions. No colour change or precipitation occurred. The pH of the infusion
solutions varied between 5.7 and 6.5.
Zhang et al., [4] studied the stability of piperacillin and ticarcillin in autodose infusion system
bags. Piperacillin sodium and ticarcillin disodium exhibited physical and chemical stability
consistent with previous studies on these drugs. The developed infusion bags were not found
to adversely affect the physical and chemical stability of these penicillin antibiotics.
Waugh et al., [5] studied the stability, compatibility, and plasticizer extraction of taxol (NSC125973) injection diluted in infusion solutions and stored in various containers. Results
showed that the taxol preparation was stable and compatible but showed leaching only in
PVC infusion bags.
Thiesen et al., [6] studied the Physico-chemical stability of docetaxel premix solution and
docetaxel infusion solutions in PVC bags and polyolefine containers. The stability tests
revealed that reconstituted docetaxel solutions are physico-chemically stable. Diluted
infusion solutions with either vehicle-solution, proved physico-chemically stable for a
minimum of four weeks, when prepared in polyolefine containers and stored at room
temperature. Diluted docetaxel infusion solutions in PVC bags should be stored only for short
periods and the solutions must be carefully inspected before infusion. In addition, non-PVC
containers should be preferred to minimize patient’s exposure to DEHP.
Moulay et al., [7] studied the stability, compatibility and plasticizer extraction of miconazole
injection added to infusion solutions and stored in PVC containers. Miconazole was visually
and chemically stable for up to 24 h. The storage of miconazole solutions in PVC bags seems
to be limited by the leaching of DEHP rather than by degradation. To minimize patient
exposure to DEHP, miconazole solutions should be infused immediately after their
preparation in PVC bags.
7. Materials and methodology:
7.1 Source of data:
Preliminary data required for the experimental study would be obtained from scientific
journals, scientific books.
7.2 Method of collection of data:
Data on drug and excipients will be collected from the drug information center, standard
books, catalogs etc.
i. Materials:
In the proposed work, different antibacterial parenteral formulations are prepared using
antibacterials which are admixed with sodium chloride (0.9% w/v), dextrose (5% w/v), sterile
water for injection, bacteriostatic water for injection etc. And other required ingredients will
be procured commercially.
ii. Methods:
An intravenous admixture consists of several sterile products added into an IV fluid for
administration. They are carried out in a class 100 area. The ingredients will be mixed using
aseptic technique; this may be accomplished by mixing them inside a laminar flow hood.
Each sterile product must be added into the IV fluid with a fresh disposable syringe.
iii. Evaluation:
The prepared formulations in infusion bags will be evaluated for pH, leaching, stability,
compatibility sterility, test for leakage, test for clarity, extraction study, test for particulate
matter, and test for microbial growth, toxicity and safety.
7.3 Does this study require any investigation or intervention to be conducted on patients
or other animals? If so, please describe briefly.
No
7.4 Has ethical clearance been obtained from your institution in case of 2.4?
Not applicable.
8. References:
1. James CB, Alan LF. Parenteral products. In: Gilbert SB editor. Modern
pharmaceutics. 2nd ed. New York: Marcel Dekker, Inc; 1990. P. 491-536.
2. Gregory AS. Characteristics and requirements of large volume parenterals (LVP’s).
USP workshop on thresholds and best practices for parenteral and ophthalmic drug
products; 2011 Feb 22-23; Bethesda MD USA.
3. Jeanette K, Irene K. Physico-chemical stability of nelarabine infusion solutions in
EVA infusion bags. EJHP Sci 2011;17:7-12.
4. Zhang Y, Trissel LA. Stability of piperacillin and ticarcillin in autodose infusion
system bags. Ann Pharmacother 2001;35:1360-3.
5. Waugh WN, Trissel LA, Stella VJ. Stability, compatibility, and plasticizer extraction
of taxol (NSC-125973) injection diluted in infusion solutions and stored in various
containers. Am J Hosp Pharm 1991;48:1520-4
6. Thiesen J, Kramer I. Physico-chemical stability of docetaxel premix solution and
docetaxel infusion solutions in PVC bags and polyolefine containers. Pharm World
Sci 1999;21:137-41.
7. Moulay EL, Dine T, Michel L, Claude B, Marie LM, Francis G et al. Stability,
compatibility and plasticizer extraction of miconazole injection added to infusion
solutions and stored in PVC containers. J Pharm Biomed Anal 1995;13:1363-72.
8. Anna T, Gerd W, Rainer B, Frank W. Investigation into the sorption of nitroglycerin
and diazepam into PVC tubes and alternative tube materials during application. Int J
Pharm 2009;369:30-7.
9. Weir SJ, Myers VA, Bengtson KD, Ueda CT. Sorption of amiodarone to polyvinyl
chloride infusion bags and administration sets. Am J Hosp Pharm 1985;42:2679-83.
10. Petros AP, Andrew K, Kaori I, Shiho Y. Stability of doripenem in vitro in
representative infusion solutions and infusion bags. J Clinthera 2008;30:2075-87.
11. Lawrence AT, Quanyun A. Stability of cefepime hydrochloride in autodose infusion
system bags. Ann Pharmacother 2003;37:804-7.
12. Allwood MC, Martin H. The extraction of diethylhexylphthalate (DEHP) from
polyvinyl chloride components of intravenous infusion containers and administration
sets by paclitaxel injection. Int J Pharm 116;127:65-71.