eISSN: 2320-1428
Int.J.Inv.Pharm.Sci.,3(1)2015;953-957 www.ijips.net
INTERNATIONAL JOURNAL OF INVENTIONS IN PHARMACEUTICAL SCIENCES ITRACONAZOLE LOADED MICROSPONGES- A NOVEL CARRIER SYSTEM RAMADEVI BHIMAVARAPU*, KARUNA PRIYA CHITRA, P.KARUNKIRAN, G.RAVITEJA, Y.MEHARAGAVENDRA, S.SUNDARAMMA, D.CHAITANYA Sri Siddhartha Pharmacy College, Ammavarithota, Nuzvid, Krishna dt, Andra Pradesh-521201. Accepted On: 20th Feb 2015
For correspondence:
[email protected]
ABSTRACT: The Microsponge Delivery System (MDS) is a unique technology for the controlled release of topical agents and consists of macro porous beads, typically 10-25 microns in diameter, loaded with active agent. Microsponges proved as effective drug delivery for topical application. Itraconazole is a triazole antifungal agent used to treat both superficial and systemic fungal infections. The purpose of the present study was to prepare Itraconazole loaded microsponges using Quasi-emulsion solvent diffusion technique. The formulations IMS1, IMS2 were made by taking ratio of polymer to drug as 1:6 and 1:12 respectively, which involves an external phase consisting of 100 ml distilled water and 1g polyvinyl alcohol. The internal phase consisted of Itraconazole (0.6, 1.2g), dichloromethane 5ml, Eudragit RS100 0.5g and Polyethylene glycol 1%w/v, which was added to facilitate the plasticity to polymer. The internal phase was added to the external phase at room temperature. After emulsification, the mixture was continuously stirred for 8hours at 500rpm and filtered to separate the microsponges and then dried. The formulations were evaluated for percent loading efficiency, drug entrapment efficiency, morphology, and surface topography by SEM, in-vitro releases and release kinetics and pore diameter of Microsponge were measured. Fourier transform infrared spectroscopy revealed that there was no interaction between drug and excipients. In this study we found that controlled release of Itraconazole successively achieved by Microsponge delivery system.
Keywords: Microsponge, Itraconazole, Quasi- emulsion solvent diffusion technique. INTRODUCTION:
pass its hepatic metabolism and to study the effect of different
In recent years, there has been considerable emphasis given to
polymers on drug release pattern.
develop novel Microsponge based drug delivery systems, in order
MATERIALS AND METHODS:
to modify and control the release behavior of the drugs. By
Itraconazole gift sample obtained from Manus aktteva biopharma
incorporation into a carrier system, it is possible to alter the
LLP, Ahmedabad, Hyderabad; PEG, Eudragit RS100, PVA and
therapeutic index and duration of the activity of drugs.
Dichloromethane procured from pravah laboratories, Hyderabad.
Microsponge consists of a myriad of interconnecting voids within a
PREFORMULATION STUDIES:
non-collapsible structure, with a large porous surface
[1]
. The size
Solubility Studies [3]:
of the Microsponge can be vary, usually from 5 - 300 μm in
Weighed accurately about 10gm of pure drug and dissolved each in
diameter, depending upon the degree of smoothness or after feel
5ml of the solvent system i.e. water, methyl chloride,
required for the end formula. Microsponge can absorb or entrap
tetrahydrofuran, alcohol in a well-closed airtight containers.
emollients, essential oils, sunscreens, fragrances, and anti-
Successive amount of the drug added into the containers containing
infective, antifungal, and anti-inflammatory agents. The topical
solvent until the solution became saturated solution. Then the
agent formulation with the MDS can be prepared in many different
containers were placed in a thermostat shaker for 24hrs a
forms, such as a gel, cream, or lotion. Once the formulation is
percentage solubility in each container was noted.
topically applied to the desired area of the skin, the active
Determination of Bulk Density [4]:
ingredients diffuse out of the spheres into the vehicle and then onto
Approximately 100gm of powder drug weighed accurately and
the skin. While the rate of release of the active ingredient from the
transferred to a measuring cylinder and its bulk volume measured
formulation can be predetermined, the release initiated or
out. The same procedure repeated as triplicate and the average bulk
accelerated by many release triggers, including pressure and
density calculated out. The bulk density calculated by using the
temperature changes. The Microsponge cannot pass through to the
formula.
stratus corneum because of their size, so they remain on the skin surface, slowly releasing the active ingredients over a period. The rationale is that the slow rate of release acts to reduce the irritancy
Bulk Density =
Mass of the powder Bulk volume of the powder
associated with the topical agents, as the slow and gradual release
Determination of Tapped Density [4]:
pattern prevents excessive build-up of the active agents in the
Approximately 100gm of powder drug weighed and transferred to
epidermis and dermis
[2]
. Therefore, these particles reside on the
a measuring cylinder, and tapped manually until a constant volume
surface of the skin and in its fine lines thereby delivering the active
obtained. The same procedure repeated as triplicate and the
over prolonged time. Itraconazole is a broad-spectrum antifungal
average tapped density calculated out. The tapped density
agent undergoes first pass metabolism when taken orally.
calculated by using the formula.
Microsponge drug delivery system succeeds to have controlled
Determination of Angle of Repose [4]:
release of topical agents when applied to skin. The aim of the study
50gm of powder drug allowed falling through a funnel from certain
was to formulate and evaluate Itraconazole loaded Microsponge
height of 5cm, to form a conical heap of powder on a horizontal
and to enhance the bioavailability of Itraconazole in order to bi-
surface. The particle will slip and roll over each other when the
Page | 953
heap is formed. The slanting side of the heap forms an angle with the horizontal surface, known as Angle of repose. Angle of repose
Fourier Transform infrared (FTIR) analysis [8] :
calculated by using the formula
FT-IR spectra of Itraconazole, Eudragit RS 100, physical
-1
θ= tan h/r
mixture(s) of Itraconazole and Eudragit RS-100, and microsponge
h = height of the heap
formulations having drug: polymer ratios of 6:1, 12:1, (IMS1 –
Tapped density= Mass of the powder/ Tapped volume
IMS2) were incorporated in potassium bromide discs and evaluated
Whereas,
with a PERKIN-ELMER FT-IR spectrometer. Determination of Excipient Compatibility: 100mg
each
of
powder
drug,
PEG,
Kinetics of release [9] : Eudragit,
PVA,
dichloromethane were weighed .Admix drug and PEG (1:1), drug and Eudragit (1:1), drug and PVA (1:1), drug and dichloromethane (1:1) in airtight screw cap amber colored vials. Individual drug, PEG, Eudragit, PVA, dichloromethane placed in airtight screw cap amber colored vials, kept at room temperature as well as in hot air oven at 400C for one week and FTIR analysis carried out with saturated potassium bromide using pellet-making method.
release profile differences among microsponges, the drug-released amount versus time used. The release data analyzed with various mathematical models. Release evaluations [10]: Drug release from Microsponge systems of different polymer compositions studied by plotting cumulative % drug release against time.
FORMULATION STUDIES:
Dissolution tests [10]:
Method of preparation [5]:
In-vitro dissolution studies carried out using USP XX1V
All micro sponges prepared by a quasi-emulsion solvent diffusion method using an external phase of containing 200 ml distilled water and 40 mg polyvinyl alcohol (PVA) MW72000. The internal phase consisted of Itraconazole, ethyl alcohol, polymer and triethylcitrate (TEC), added at an amount of 20% of the polymer in order to facilitate the plasticity. At first, the internal phase was prepared at 60°C and added to the external phase at room temperature. After emulsification, the mixture continuously stirred for 2 hours. Then the mixture filtered to separate the microsponges. The product washed and dried at 40°C for 24 hours. Table.1. Formulation table Formulation code Drug: polymer(PVA) IMS1 1:6 IMS2 1:12
dissolution assembly (basket type, Electrolab TDT-08L) in 900 ml of 0.1N HCl at a stirring rate of 50 rpm and temperature of 37±0.50C. Drug release monitored for 6h. Samples (5 ml) withdrawn at regular time intervals and sink conditions maintained by replacing an equal amount of fresh dissolution medium. The samples were analyzed spectrophotometrically (ELICO) at a wavelength of 420 nm. Dissolution tests performed in triplicate. The dissolution data subjected to various release models, namely, Zero order, first order, Higuchi and Korsmeyar-Peppas. RESULTS AND DISCUSSION: Results of the measurement of solubility of pure Itraconazole are summarized in table no 2 and it indicates that the pure drug Itraconazole was freely soluble in methylene chloride, sparingly soluble in tetra hydro furan, very sparingly soluble in alcohol and partially soluble in water.
EVALUATION: Morphology and surface topography of Microsponge
To determine the drug release mechanism and to compare the
[6]
:
Table.2. Solubility of Itraconazole
The morphology of Microsponge was examined using a scanning
Solvent system (ml)
Solubility
electron microscope (GEOL 5400, USA) operating at 20 kV. Dried
Water
Practically insoluble
microspheres were coated with gold–palladium alloy for 45s under
Methylene chloride
Soluble
Tetrahydrofuran Alcohol
Sparingly soluble Very slightly soluble
an argon atmosphere before observation. SEM photograph was recorded at magnification of X 500. Determination of loading efficiency and production yield [7]: The loading efficiency (percentage) of the micro sponges
Results of the measurement of flow properties of the prepared IMS
calculated according to the following equation:
1&2 were summarized in table 3 indicate that IMS (1:12) has good flow property when compared to IMS (1:6).
The production yield of the micro particles can be determined by calculating accurately the initial weight of the raw materials and the last weight of the microsponge obtained.
Page | 954
Table.3. Derived Properties of pure drug Trail Trail 1
Angle of repose (θ) 16.8533± 0.0236
Trail 2
16.7500 ± 0.0219
Trail 3
17.9647 ± 0.0234
0.510 ± 0.003
11.843 ± 0.002
Hauser’s ratio 1.134 ± 0.0286
0.4733 ± 0.002
0.538 ± 0.002
12.026 ± 0.035
1.136 ± 0.0205
0.4635 ± 0.002
0.524 ± 0.002
11.9274 ± 0.002
1.130 ± 0.0249
Bulk density (gm/cc) 0.4496 ± 0.002
Tapped density(gm/cc)
Compressibility index (%)
reported in the literature of polymer. All the characteristic peaks of Analysis of the FT-IR spectra (see Fig.3, 4) of the drug
Itraconazole were observed in the spectra of all the micro sponges
(Itraconazole), physical mixture of drug and Polymer and
IMS (1&2), thus indicating that no chemical interaction or changes
formulations IMS (1&2) indicate a characteristic C=O stretching
took place during the preparation of the formulations and that the
band at 2562.53 cm-1 for the drug, and an ester C=O stretching
drug
−1
peak around 2464.17 cm
was
stable
in
all
the
formulations.
for Drug- polymer, as has also been
Fig.1 FTIR Spectral Data of ITZ
(Itraconazole) Drug
Fig.3. FTIR Spectral Data of IMS1 (1:6)
Fig.2 FTIR Spectral Data of Drug + Polymer (Physical Mixture)
Fig.4. FTIR Spectral Data of IMS2 (1:12)
The morphology of Microsponge was examined using a scanning
an argon atmosphere before observation. SEM photograph was
electron microscope (GEOL 5400, USA) operating at 20 kV. Dried
recorded at magnification of X 500 as shown in fig.5 and fig.6.
microspheres were coated with gold–palladium alloy for 45s under
Page | 955
Fig.4. SEM Pictures of IMS1
Fig.5. SEM Pictures of IMS2 Formulations
Results of loading efficiency and production yield of pure
predominant mechanism of drug release. The Itraconazole loaded
Itraconazole loaded microsponges (IMS) are summarized in table 5
Microsponge evaluated for drug release using 0.1N HCl as the
indicates that production yield and loading efficiency for IMS2 is
dissolution media. The percentage drug release was 52.6 & 98.63
75.33 & 97.4 and IMS1 is 74.25 & 98.32 respectively which shows
for IMS1 & IMS2, respectively up to 6 hours as shown in table 6
that production yield for IMS2 is more and loading efficiency for
by using USP dissolution apparatus type-I (Basket). IMS1 (1:6)
IMS1 is more. The data obtained for in-vitro release fitted into
was found to be best formulation in terms of in-vitro drug release
equations for the zero order and first order, Higuchi, Korsmeyer,
with 52.63% release after 6 hrs. So IMS1 (1:6) showed better
and Hixson release models; the interpretation of the data based on
release than other formulation IMS2 (1:12). This study concluded
the value of the resulting regression co-efficient. The in-vitro drug
that a Microsponge with Eudragit RS-100 co-polymer in the ratio
release showed the highest regression value for the Higuchi model
of 1:6 was more efficient to give extended drug release.
(0.965 for 1:6 and 0.970 for 1:12), indicating diffraction to be the
Table.4. Loading Efficiency and Production Yield of Itraconazole Loaded Microsponges
Formulation code
% production yield
Theoretical drug content (%)
Actual drug content (%)
Loading efficiency
IMS 1 IMS 2
74.25 75.33
76.5 92.3
75.1 90.02
98.32 97.24
Table.5. Percentage drug release of prepared formulations
Time (min) 0 5 10 15 30 45 60 90 120 180 240 300 360
Cumulative percentage drug release IMS 1
IMS 2
0 3.34 6.94 10.62 12.97 15.88 18.99 20.86 22.61 25.72 36.74 46.65 52.63
0 6.34 11.14 16.62 21.97 25.88 31.99 37.86 49.61 56.72 74.74 85.65 98.63
Table.6. Release kinetic data of prepared microsponges
Kinetic order Zero order First order Higuchi Korsmeyer Hixson
Page | 956
IMS 1
IMS 2
0.946 0.85 0.965 0.90 0.89
0.963 0.839 0.970 0.86 0.90
incorporating multiple triggering mechanisms for the release of actives. J Micro encapsul. 1996; 13:575-588.
CONCLUSION: This study concluded that a Microsponge with Eudragit RS-100
[3]
Michael E Aulton. Pharmaceutics the science of dosage form design. Edn 2, 2002; pp-23.
[4]
ICH guideline Q4b annex 13. Note for evaluation and recommendation of pharmacopoeia texts for use in the ICH regions on bulk density and tapped density of powders. EMA/CHMP/ICH/405290/2010.
co-polymer in the ratio of 1:6 was more efficient to give extended drug release. Microsponge Delivery System (MDS) has become highly competitive and rapidly evolving technology and more and more research is carrying out for cost-effective therapy. MDS holds a promising future in various pharmaceutical applications in
[5]
the coming years as they have unique properties like enhanced product
performance,
elegancy,
extended
release,
reduced
Sarat Chandra Prasad, Ajay. M, Nagendra Babu. B, Prathyusha.P, Audinarayana.N Microsponge Drug Delivery System: A Review. Int J Pharm Research. 2011; 4: 5.
irritation, improved thermal, physical, and chemical stability so flexible to develop novel product forms. MDS, which is originally,
[6]
developed for topical delivery of drugs like anti-acne, antiinflammatory,
anti-fungal,
anti-dandruffs,
antipruritics,
[7]
rubefacients etc. Microsponge delivery systems that can precisely control the release rates or target drugs to a specific body site have an enormous impact on the health care system. Study concluded
JonesDS, Pearce KJ. Investigation of the effects of some process variables on, microencapsulation of propranolol HCl by solvent evaporation method. Int J Pharm. 1995; 118: 99-205.
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Nacht S, Kantz M. The Microsponge: A novel topical programmable delivery system. Top Drug DelivSyst.1992; 42:299-325.
[10]
Saxena S, Nacht S. Polymeric porous delivery systems:
[11]
Polytrap and Microsponge. In: Delivery System Handbook for Personal Care and Cosmetic Products: Technology, Applications and Formulations. New York: William Andrew Publishing; 2005. pp. 333-51.
in the ratio of 1:6 were more efficient to give extended drug
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