FORMULATION AND EVALUATION OF PROLIPOSOMES AS A CARRIER SYSTEM
FOR TRANSDERMAL DELIVERY OF ANTI-INFLAMMATORY DRUG
6. Brief Resume of Intended Work:
6.1: Need for the Study:
Anti-inflammatory refers to the property of a substance that reduces inflammation.
Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing
inflammation. Anti-inflammatory drugs act by inhibiting cyclooxygenases responsible for the
production of prostaglandins in arachidonic acid metabolism. Cyclooxygenase-1 (COX-1) is
responsible for the production of prostaglandins. Nonselective inhibition of COX-1 by systemic
NSAIDs has been implicated. Cyclooxygenase-2 (COX-2) expression, on the other hand, is an
inducible mediator of prostaglandin production, and increases dramatically during inflammation
and carcinogenesis, inhibition of COX-2 results in beneficial anti-inflammatory, pain, and
Proliposomes are defined as dry, free-flowing particles that immediately form a
liposomal dispersion on contact with water in the body1, 2. To achieve application transdermally,
viscosity of liposomes and to further improve their stability, liposomes can be converted to
proliposomes which then incorporated in a suitable transdermal gel using Carbopol 974P NF
resin. Since liposomes pose problems due to their physicochemical instability such as
aggregation, sedimentation, fusion, hydrolysis and/or the oxidation of phopholipids3,4,5. Freeze-
drying, freezing and thawing and the polymerization or chemical modifications of liposomes,
have been examined in reorder to overcome the stability problems associated with liposomes.
6.2: Review of literature:
Proliposomes were formulated containing salmon calcitonin by penetrating a methanol-
chloroformic solution of sCT and phosphotidylcholine into microporous sorbital
particles which is followed by vacuum evaporation of solvent by which free flowing of
liposomes were obtained. These on contact with water certain amount of sCT was
entrapped by liposomes. The permeability of sCT across Caco-2 cell mono layers was
increased by incorporating sCT into proliposomes. They had suggested that the
pharmacokinetics of sCT can be modified if it is adminsterd through proliposomes. The
development of various dosage forms of sCT,especially solid dosage forms feasible with
Proliposomes containing nicotine base (NB–proliposomes) or nicotine hydrogen tartarate
salt (NS–proliposomes) and a mixture of powdered nicotine hydrogen tartarate salt and
sorbitol (1:9 mixture, MP) were administered intranasally to rats at a nicotine dose of 1
mg/ kg and the results Prolonged delivery of nicotine was found to be achievable by the
intranasal administration of NB– proliposomes, NS–proliposomes and NS–sorbitol mixed
Proliposomal formulations were developed to enhance the oral bioavailability of
exemestane by improving solubility, dissolution and/or intestinal permeability.
Proliposomal powder formulations were prepared using different ratios of drug
(exemestane), distearoyl–phosphatidylcholine (DSPC), cholesterol and dimyristoyl–
phosphatidylglycerol (DMPG) by solvent evaporation method. It is evident from this that
Proliposomes provided enhanced exemestane dissolution due to incorporation into the
phospholipid bilayers and change in the physical state fromcrystalline to amorphous
which was confirmed from DSC studies8.
Formulated Free-flowing proliposomes which contained vinpocetine were prepared
successfully to increase the oral bioavailability of vinpocetine. In this study the
proliposomes were prepared by a novel method which was reported for the first time and
the formulation was optimized using the centre composite design (CCD)., The
preparation method of VP proliposome powders was more efficient and less toxic. The
optimized vinpocetine proliposomes did improve the oral bioavailability of vinpocetine in
New Zealand rabbits and offer a new approach to enhance the gastrointestinal absorption
of poorly water soluble drugs9.
The feasibility of proliposomes as a sustained transdermal dosage was examined.
Proliposomes containing varying amount of nicotine were prepared by a standard method
using sorbitol and lecithin. The porous structure of sorbitol in the proliposomes was
maintained, indicating that the majority of lecithin and nicotine is deposited within their
porous matrix of the sorbitol particles. As a consequence, the flow properties of the
proliposome particles were comparable to that of original sorbitol particles. It is evident
that sustained delivery of nicotine drug across the skin appears to be achievable through
topical application of nicotine-loaded proliposomes under occlusive conditions10.
The aim of this study was to develop a liposomal drug carrier system, able to provide
sustained and controlled release of appropriate drug for local vaginal therapy. To
optimize the preparation of liposomes with regards to size and entrapment efficiency,
liposomes containing calcein were prepared by five different methods. And is is evident
that Proliposome and polyol dilution methods would be the right choice of preparation
methods for preparing liposomes due to their high trapping efficiency of model
substance. Both methods are simple, reproducible and suitable for mass production of
liposomes, stable in conditions chosen to mimic the human vaginal environment (buffer
pH 4.5). Incorporation of those liposomes in Carbopol gels further improved their
stability and confirmed the applicability of liposome gels as a novel vaginal delivery
Formulation of free flowing proliposomes containing propranolol hydrochloride (PH)
were evaluated for their potential as a nasal drug delivery system of propranolol to
sustain the plasma concentration of the drug. In vitro release of PH was significantly
retarded by incorporating PH in the proliposomes, when compared with PH-loaded
sorbitol, The results indicate that the proliposome system can be a potential candidate for
the sustained delivery system of propranolol through nasal mucosa12.
Cormolyn Beads for oral drug delivery was formulated. Phospholipid
(distearylphosphatidylcholine) cholesterol surfactant (Tween80/sodiumcholate) systems
were spray-coated on beads containing cromolyn sodium and the dosage forms were
characterized for vesicle formation and encapsulation efficiency. Spontaneous formation
of vesicles upon dilution of beads was observed. Enhancement in cromolyn transport was
higher with phospholipids-surfactant proliposomal formulations compared to surfactant-
free lipid formulations or pure surfactant solutions, most significant enhancement being
with formulations with low surfactant Concentration. Results suggested that
phospholipids-surfactant proliposomal beads offer a good potential for improved oral
delivery of cromolyn13.
Liposomal solutions of ibuprofen·Na (20 mg:ml) were prepared by high-pressure
homogenization from egg phosphatidylcholine. The liposomal gel consisted of poloxamer
407 and the liposomal solution. No signs in the 1H-NMR spectroscopy of line
broadenings or chemical shifts were observed. The liposomal formulations were
reproducible and stable. The liposomal poloxamer gel represents a new formulation
approach to increase the local epidural availability of ibuprofen. It appeared to be a
promising injectable controlled-release drug delivery system14.
Miconazole Nitrate loaded topical liposomes as miconozole nitrate is a widely used
antifungal agent, but its use in topical formulations is not efficacious because deep seated
fungal infections are difficult to treat with conventional formulations. So, entrapped drug
in liposomes that can facilitate localized delivery of the drug and improved availability
by means of a controlled release pattern which can advances the treatment of deep fungal
infections. The prepared products were characterized for liposome specific properties
such as microscopic appearance, size and degree of entrapment15.
6.3 Aim and objective of the study:
Formulation and evaluation of Proliposome loaded with anti-inflammatory for Transdermal
delivery. Proliposomal delivery has been recognized as an alternative to improve the
bioavailability of drugs for topical transdermal delivery. Proliposomes are solid dry powder
systems having good stability as compared to liposomes with a potential drug delivery via the
transdermal route for both steroidal and non-steroidal anti-inflammatory drugs.
Materials & Methods:
1. Preparation of Proliposomes:
Proliposomal formulations were prepared by using rota evaporator same as conventional
liposomes but here the soluble carriers used to convert dry powder. The dry powder further
converted to gel for delivering through transdermal route by using a suitable gelling agent.
In order to optimize and evaluate various proliposome formulations, different experiments
conducted based on concentration of lecithin, drug and solid carrier.
3.1. Entrapment efficiency determination
3.2. Morphology study by SEM and TEM
3.3. Particle size determination of reconstituted liposomes
3.4. Assessment of physical stability for proliposomes
3.5. Leakage study of drug
3.6. In vitro release studies using diffusion cells
3.7. Ex vivo permeation studies using rat skin
7.1 Source of the data:
The data required for the work is collected from topic related text books, journals and articles
available in the Library of Krupanidhi college of Pharmacy and science direct, journals available
at Jgate – Helinet of the Rajiv Gandhi University of Health sciences Website and through various
other internet sources.
7.2 Method of collection of data:
The data will be collected from the prepared formulation, then subjecting the formulation to
different evaluation parameters like physical and chemical characterization which includes
determination of size and shape of vesicles, in-vitro drug release studies, stability studies on the
selected optimized formulation and other tests as necessary during the evaluation part of the
7.3 Does the study require any investigations or interventions to be Conducted on patients
or other humans or animals? If so, please Describe in brief.
Yes, study requires investigation on excised animal skin tissue. The objective is to
perform ex vivo permeation study of transdermal gel containing anti-inflammatory drug loaded
in proliposomes using excised rat skin.
7.4 Has ethical clearance been obtained from your institute in case 7.3
Ethical committee approval letter is enclosed.
8. List of references:
1. NI Payne, P Timmis, CA Ambrose, MD Warel, F Ridgway Proliposomes: a novel
solution to an old problem. J Pharm Sci 1986; 75(4):325–29.
2. NI Payne,I Browning,CA Hynes. Characterization of liposomes. J Pharm Sci 1986;
3. A Larrabee. Time-independent changes in the distribution of distearoyl
phosphatidylcholine vesicles Biochemistry 1979; 18(15):3321–26.
4. SE Schullery, CF Schmidt, P Felgner, TW Tillack, TE Thompson. Fusion of
dipalmitoylphosphatidylcholine vesicles, Biochemistry 1980; 19(17):3919–23.
5. M Wong, FH Anthony, TW Tillack, TE Thosmpson. Controlled Fusion of
dipalmitoylphsphatidyl-choline vesicles at 4ºC, Biochemistry 1982; 21(17):4126–32.
6. Keon Hyoung song, Suk Jae Chung, Chang Koo Shim. Preparation and evaluation of
proliposomes containing Salmon calcitonin. J Control Release 2002; 84:27-37.
7. Byung Hwa Jung, Bong Chul Chung. Prolonged delivery of nicotine in rats via nasal
administration of proliposomes. J Control Release 1999 Oct. p.73–79.
8. Praveen S. Hiremath, Kumaresh S. Soppimath, Guru V. Betageri. Proliposomes of
exemestane for improved oral delivery: Formulation and in vitro evaluation using
PAMPA, Caco-2 and rat intestine. Int J Pharm 2009; 380:96–104.
9. Hongtao Xu, Ling He, Shufang Nie, Jin Guan, Xiaoning Zhang, Xinggang Yang et al.
Optimized preparation of Vinpocetine proliposomes by a novel method and in vivo
evaluation of its pharmacokinetics in New Zealand rabbits. J Control Release 2009 Nov
10. Bo Young Hwang, Byung Hwa Jung, Suk Jae Chung, Min Hwa Lee, Chang Koo Shim.
In vitro skin permeation of nicotine from proliposomes. J Control Release 1997; 49:177–
11. Zeljka Pavelic, Natasa Skalko-Basnet, Rolf Schubert. Liposomal gels for vaginal drug
delivery. Int J Pharm 2001; 219:139–49.
12. Byung Nak Ahn, Shin Keun Kim and Chang Koo Shim. Proliposomes as an intranasal
dosage form for the sustained delivery of propranolol. J Control Release 1995 June;
13. Deepali D Deshmukh, William R Ravis, Guru V Betageri. Improved delivery of
cromolyn from oral proliposomes beads. Int J Pharm 2008; 358:128-36.
14. Anne Paavola, Ilkka Kilpelainen, Jouko Ylirussi, Per Rosenberg. Controlled release
injectable liposomal gel of ibuprofen for epidural analgesia. Int J Pharm 2000; 199:85-93.
15. Agarwal R and Katare OP. preparation and in vitro evaluation of Miconazole nitrate
loaded topical liposomes. J Pharm Tech 2002. p. 48-60.