This document describes the design, fabrication, and evaluation of a novel sustained release drug delivery system using rosuvastatin pharmacosomes. Rosuvastatin was complexed with lecithin phospholipids to form pharmacosomes via a hand shaking method. The pharmacosomes showed improved solubility, drug loading efficiency, and sustained release properties compared to pure rosuvastatin. In vivo studies in rats demonstrated the pharmacosomes more effectively lowered cholesterol and triglyceride levels over longer periods compared to standard rosuvastatin treatment. Thus, the rosuvastatin pharmacosomes represent a promising sustained release drug delivery system with benefits like enhanced bioavailability and reduced dosing.
1. “DESIGN, FABRICATION AND EVALUATION OF
PHARMACOSOME OF ROSUVASTATIN- A NOVEL
SUSTAINED RELEASE DRUG DELIVERY
SYSTEM”
Under Guidance of
PROF. DR. TAPAS KUMAR PAL
Presented by
ABHISHEKH PODDER
M.PHARM 4th SEMESTER
REG NO.-12277231002
ROLL NO.-27720312001
PHARMACEUTICS
NSHM KNOWLEDGE CAMPUS- KOLKATA ,
GROUP OF INSTITUTIONS
2. INTRODUCTION
• Pharmacosomes are lipid based vesicular drug delivery
system that are elaborated as the amphiphilic colloidal
dispersions of drugs having a covalent bonding with
phospholipids.
• Depending upon the chemical structure of the drug-
phospholipid complex, they may exist as ultrafine vesicular,
micellar or hexagonal aggregates.
3. MERITS OF PHARMACOSOME
• Enhancement in bioavailability of poorly water soluble as well
as poorly lipophilic drugs.
• Entrapment efficiency is not only high but also predetermined.
• Pharmacosome can mobilise biomembranes enabling a better
transfer of active ingredient.
• Pharmacosome shows better stability profile due to chemical
bonding in between phospholipid and drug.
4. VESICULAR
SYSTEM
ISSUES ENCOUNTERED ADVANTAGE OF
PHARMACOSOME
LIPOSOME 1.Expensive
2.Degradation by oxidation
3.Lack of purity of natural
phospholipids
4.Chances of leaching of drug
1.Cheaper
2.Oxidation resistant
3.Pure natural
phospholipid not needed
4.Covalent linkage
prevents drug leakage.
NIOSOME 1.Time consuming prepn.
2. Comparatively less efficient
3. Instability
1.Less time consuming
prepn.
2.More efficient
3.More stable
TRANSFEROSOME 1.Expensive,
2.Chemical instability
1.Cheap
2.Chemically stable
PHARMACOSOMES DIFFERS FROM LIPOSOME, NIOSOME
AND TRANSFEROSOME
5. CRITERION OF DRUG FOR DEVELOPMENT OF
PHARMACOSOME
A drug possessing a free carboxyl group or an active hydrogen
atom (-NH2, -OH, -COOH) can be esterified with or without a
spacer chain to the PHOSPHOLIPID molecule
Molecular structure of Phosphatidylcholine – a Phospholipid
6. MATERIALS OF PHARMACOSOME
• Drug – Rosuvastatin Calcium ( BCS class II drug)
Appearence: White amorphous powder
Melting point: 122C
Solubility: Sparingly soluble in water and methanol and slightly soluble
in ethanol.
(Bioavailability 20%)
• Phospholipid- Lecithin Soya (30 %)
• Appearance: Yellowish to brown powder
7. OBJECTIVES OF PRESENT STUDY
• To identify, asses purity & strength of Rosuvastatin calcium
• To prepare Pharmacosome of Rosuvastatin .
• To evaluate the Physicochemical charecter of Pharmacosomes.
• To evaluate increase of solubility and drug release profile.
• To evaluate increase of sustained profile of drug release and
drug diffusion.
• To assess improvement in patient compliance by dose
reduction.
• To make more efficacious & economic anti-hyperlipidemic
therapy.
• Stability study of optimized formulation.
8. PREPARATION OF PHARMACOSOME OF ROSUVASTATIN
(1:1MOLAR RATIO) BY HAND SHAKING METHOD
ACIDIFICATION OF ROSUVASTATIN CALCIUM:
Rosuvastatin in chloroform
Extraction
Rosuvastatin
Calcium
Rosuvastatin
acidification by
1(N) HCL
Shake-flask method
Measured residual drug as
Rosuvastatin calcium, remaining
in aqueous solution – 0.22%.
9. FLOW SHEET DIAGRAM OF ROSUVASTATIN(RSV)-PC COMPLEX
IN LABORATORY:
Rosuvastatin dissolved in
Chloroform (1 mole)
Phosphatidylcholine
dissolved in
Dichloromethane (1
mole)
Mixed well in a 250 ml round bottom flask and reflux for 3hrs at 45c
Transferred into a beaker for solvent
evaporation
Thin film is deposited on the walls of beaker
Vaccum drying in a vaccum dryer for 24hrs at 45c and 15
lb pressure
Collect the dried residues and placed in vaccum desiccator overnight
10. RESULTS
Calibration curve of Rosuvastatin
calcium in water
Calibration curve of Rosuvastatin
calcium in pH6.8 Phosphate buffer
y = 0.0378x
R² = 0.9992
0.000
0.100
0.200
0.300
0.400
0.500
0.600
0.700
0 5 10 15 20
concentration(µg/ml)
Absorbance
y = 0.032x
R² = 0.999
0
0.1
0.2
0.3
0.4
0.5
0.6
0 5 10 15 20
11. EVALUATION OF ROSUVASTATIN(RSV)-PC COMPLEX :
36 mg Rosuvastatin-Pc complex equivalent to10 mg Rosuvastatin
calcium accurately weighed
Added into a conical flask with 100ml of pH 6.8 phosphate buffer
Conical flask stirred continuously for 24 hr on a shaker incubator
Drug content
50 ml RSV-PC complex solution
Suitable dilutions were made
and measured at 242 nm uv
spectrophotometrically
40ml RSV-PC complex
solution with 40ml octanol
Solubility study
Aqueous layer and octanol
layer measured at 242 nm uv
spectrophotometrically
Shake-flask method
Diluted with 50ml pH 6.8 buffer
Membrane filtration
12. Code Drug content (%)* Drug loading(%)*
F1 91.1±0.64 25.3± 0.19
F2 94.4± 0.61 26.2± 0.13
F3 92.7± 0.62 25.8± 0.15
F4 90.4± 0.82 25.1±0.14
F5 91.9± 0.49 25.5± 0.14
F6 92.2± 0.63 25.6±0.11
*mean± S.D, n=3 ,(F1- F6)= Pharmacosome of Rosuvastatin
Drug content study:
13. Comparative Solubility study between Pharmacosome of
Rosuvastatin and pure drug Rosuvastatin Calcium
Code
Solubility in aquous
layer(µg/ml)*
Solubility in octanol
layer(µg/ml)* Log P
F1 91.12± 1.24 42.01±0.62 -0.33
F2 92.37± 1.94 41.70±1.13 -0.34
F3 90.79±0.78 44.36±0.71 -0.31
F4 83.06±1.33 46.56±1.68 -0.25
F5 86.42±1.58 45.25±0.87 -0.28
F6 87.89±1.77 44.66±1.12 -0.30
D1 11.0± 0.35 192.62± 1.59 1.24
*mean± S.D, n=3 ,(F1- F6)= Pharmacosome of Rosuvastatin, D1= Pure drug
Rosuvastatin Calcium
18. X Ray Diffraction(XRD)
A
B
C
A) XRD of Pure Rosuvastatin Calcium , B) XRD of lecithin soya (30%),
C) XRD of Pharmacosome of Rosuvastatin
19. Comparative % Cumulative dissolution release of Pharmacosome
formulations at different time with Pure Rosuvastatin Calcium
0
20
40
60
80
100
120
0 200 400 600 800 1000 1200 1400 1600
F1
F2
F3
F4
F5
F6
pure Rsv ca
Time in minutes
%Cumulativerelease
20. 0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 200 400 600 800 1000 1200 1400 1600
F1 F2 F3 F4 F5 F6 pure Rsv Ca
Time in minutes
%cumulativediffusion
Comparative % Cumulative diffusion study of Pharmacosome formulations
at different time with Pure Rosuvastatin Calcium
(Modified Franz diffusion cell using egg membrane)
21. Group Model
Gr. 1 Administered vehicle(0.1% Na CMC suspension,orally) and
served as Normal control
Gr. 2 Administered Triton X 100 and served as Positive
control(200mg/kg b.w, i.p)
Gr. 3 Administered daily dose of Rosuvastatin calcium(10mg/kg b.w
i.p)+ Tritron X 100 (200mg/kg b.w, orally)
Gr.4 Administered once single dose of Pharmacosome of
Rosuvastatin (36mg/kg b.w, orally) + Tritron X 100 (200mg/kg
b.w, i.p)
Comparison of in vivo efficiency of pharmacosome with standard drug
Rosuvastatin calcium as lipid lowering agent to reduce blood cholesterol
level
Statistical Analysis: All values are expressed as Mean± SEM for six animals
in each group using one way analysis of variance (ANOVA) followed by
Dunnett's Multiple Comparison Test .
22. Comparative effect of pharmacosome of Rosuvastatin and standard
drug Rosuvastatin Calcium in Triglycerides(TG) levels
0
20
40
60
80
100
120
140
160
180
200
normal control positive control Rosuvastatin calcium+
tritron
Rosuvastatin
pharmacosome+ tritron
Triglycerideslevel(mg/dl)
Group
24 hr (TG)
48 hr (TG)
* *
*# *# *# *#
P value: P<0.0001***, P < 0.01* when compared with normal control,
P value: P<0.0001###, P < 0.01# when compared with positive control
23. Comparative effect of pharmacosome of Rosuvastatin and standard
drug Rosuvastatin Calcium in Total Cholesterol (TC)levels
0
20
40
60
80
100
120
140
160
normal control positive control Rosuvastatin calcium+
tritron
Rosuvastatin
pharmacosome+ tritron
TotalCholesterol(mg/dl)
Group
24 hr( TC)
48 hr (TC)
*
*
*#
*#
*#
*#
P value: P<0.0001***, P < 0.01* when compared with normal control,
P value: P<0.0001###, P < 0.01# when compared with positive control
24. Comparative effect of pharmacosome of Rosuvastatin and standard
drug Rosuvastatin Calcium in HDL- Cholesterol levels
0
5
10
15
20
25
30
35
40
45
normal control positive control Rosuvastatin calcium+
tritron
Rosuvastatin
pharmacosome+ tritron
HDLCholesterol(mg/dl)
Group
24 hr (HDL) 48 hr (HDL)
* #
*#
*#
*#
*
*
P value: P<0.0001***, P < 0.01* when compared with normal control,
P value: P<0.0001###, P < 0.01# when compared with positive control
25. 0
2
4
6
8
10
12
normal control positive control Rosuvastatin calcium+
tritron
Rosuvastatin
pharmacosome+ tritron
AI
Group
24 hr (AI)
48 hr (AI)
Comparative effect of pharmacosome of Rosuvastatin and
standard drug Rosuvastatin Calcium in Atherogenic Index (
TC/HDL-C):
26. Histopathology study of liver
A
B
C D
A) Normal control , B) Positive control, C) Standard drug treated,
D) Pharmacosome treated
27. Stability study of optimized formulation at ICH condition
(40C and 75%RH)
Code Drug Content (%) Drug loading (%)
F3(Initial) 92.7± 0.62 25.80± 0.15
F3 (After 2
month) 91.11±0.47 25.29±0.10
28. CONCLUSION
• This Pharmacosome of Rosuvastatin may be of potential use for
improving bioavailability.
• Pharmacosome seem to be potential candidate as an oral
sustained drug delivery system in this era of novel and sustained
drug delivery systems.
• Pharmacosome of Rosuvastatin are expected to improve the
patient compliance, form better dosage regimen, dose
reduction and provide optimum maintenance therapy to
Hyperlipedimic patients.