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Abstract(Please copy/paste the abstract send to the congress) : |
Fabrication and Evaluation of Novel Risperidone Implants as a Long Term Antipsychotic Therapy
Farid A. Dorkoosh1 , Asieh Abdollahi2, Ebrahim Saadat H1
1Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 1439956131, Tehran, Iran; 2Department of Pharmaceutics, Faculty of Pharmacy, Azad University, Tehran, Iran
Dorkoosh@tums.ac.ir
ABSTRACT SUMMARY
A series of novel prolonged release risperidone implants were fabricated for treatment of psychotic disorders. Poly (DL-lactide-co-glycolide) (PLGA) polymer with either cholesterol (chol) or polyethylene glycol 400 (PEG) were selected as hydrophobic and hydrophilic excipients respectively. Implants were fabricated by injection molding method with cylindrical stainless steel molding device. Each implant with dimension of 10 mm in length and 2 mm in diameter evaluated for its physicochemical properties such as mechanical strength, water uptake and matrix erosion and physical state of risperidone in implant by differential scanning calorimetry (DSC) and X-ray diffraction analysis (XRD). The surface morphology of implants was assessed by scanning electron microscopy (SEM). Also drug loading and in vitro release analysis was performed for each formulation. Data showed higher mechanical strength for formulations with chol. Matrix erosion was calculated 0.8% and 1.6% for implants with chol and PEG as an excipient respectively. Also XRD analysis showed crystalline state of risperidone in implant matrix in all formulations. In vitro drug release studies showed 50 days slow and continuous release of about 95% of risperidone without significant initial burst for optimized respridone implants with chol as an excipient. Based on present study the prolonged released formulation of risperidone implant was obtained by using cholesterol as hydrophobic excipient in PLGA matrix.
INTRODUCTION
Among different drug delivery systems, implant is the most attractive system which is used both for hydrophobic and hydrophilic drugs with acceptable clinical outcomes. Basically implants composed of polymer(s), drug(s) and with or without excipients. Implant drug delivery has several advantages including, decreasing the frequency of administration with incorporating the total amount of needed drug in the defined period of time, excluding of missed dose especially in geriatrics, by passing first pass metabolism and also reduction of hospitalization and medical care1. There are lots of research in different field of therapies by implant drug delivery like contraception2, ophthalmology3, bone disease and fractions, dental implants and diabetes but it is less concentration on psychotic disorder and specially schizophrenia which is a chronic medical condition that needs long term of medical therapy.
Risperidone, a dopamine antagonist, is the most prescribed drug in the treatment guide line of schizophrenia. The chronic administration of this drug during the therapy makes it an attractive candidate for controlled release system. In this research different formulations of risperidone implants with PLGA and hydrophobic and hydrophilic excipients were fabricated and physicochemical characteristic and also in vitro release profile were studied.
EXPERIMENTAL METHODS Risperidone implants were fabricated via injection molding method with cylindrical shaped stainless steel (AISI 316L) molding device. Different formulation with various amounts of PLGA and 100 mg risperidone either with PEG (F1 and F3) or Chol (F2 and F4) as an excipient were fabricated. For each formulation PLGA and risperidone were dissolved in 5 ml dichloromethane with either Chol or PEG. The resultant solution was heated to 50 ° C to evaporate dichloromethane and formed viscous paste. The paste was injected into the die of molding device. After 30 min the cylindrical rod with the length of 40 mm and 2 mm in diameter casted and cut into four equal implants of 10 mm. Each implant was evaluated for physicochemical properties including water uptake and matrix erosion, mechanical strength, physical state of risperidone in implant matrix by differential scanning calorimerty (DSC) and X-ray diffraction (XRD) method. The surface morphology of implants was assessed by scanning electron microscopy. Also each implant analyzed for risperidone content via RP-HPLC (Agilent Technologies®). The mobile phase was methanol with flow rate of 1 mL/min through C18 column (150 × 4.6 mm, ODS 35 μm) and peak detection wave length of 275 nm. For release profile evaluation of risperidone, different formulations were placed at 500 mL PBS (pH=7.4, T= 37° C) on a shaker bath (40 rpm). At the defined period of time 1 mL aliquot of each formulation was withdrawn for
analysis by RP-HPLC as mentioned above. After each
sample removal a 1 mL of fresh buffer was replaced
for maintaining of sink condition.
Fig 1. a) SEM image of risperidone implant (F2) right after
fabrication and b) after 30 days of release study
Table 1. Different formulation of Risperidone implants
Formulation Risperidone
(mg)
PLGA
(mg)
Chol
(mg)
PEG
(mg)
F1 25 25 - 15
F2 25 25 15 -
F3 25 50 - 15
F4 25 50 15 -
RESULT AND DISCUSSION
Cylindrical risperidone implants were fabricated
with drug content of 25mg ± 1.2 mg. Water uptakes
and matrix erosion for implants with chol (F2 and F4)
was 28.5% and 0.8% and for implant with PEG (F1
and F3) was 71% and 1.6% respectively, which
indicates less erosion of implants with chol as an
excipient in matrix forming material. Mechanical
strength analysis showed higher forces needed to 10
mm displacement of implant with chol versus PEG
(1.84 N relative to 0.16 N). DSC and XRD analysis
demonstrate crystalline state of risperidone implants
in both matrices either with chol or PEG. SEM
images represented smooth surface area for both
implants right after fabrication and hollows in matrix
after 10 days of release experiment. In vitro release
analysis showed 30 and 46 days slow and continuous
release for PEG and chol implants respectively
without significant burst effect. Release rate for both
formulations followed zero order kinetics.
Time(Day)
0 5 10 15 20 25 30 35
Cumulative Release(%)
0
20
40
60
80
100
120
Fig 2. Release profile of risperidone implants (F1: ○ and F2: ●)
Time (Day)
0 10 20 30 40 50 60
Cumulative Release (%)
0
20
40
60
80
100
120
Fig 3. Release profile of risperidone implants (F3● and F4 :○)
CONCLUSIONS
Based on present study it can be concluded that
PLGA risperidone implant with chol as an excipient,
showed acceptable mechanical strength along with
prolonged release profile without significant burst
effect. Due to biocompatibility and safety of chol, it
can be used in implant formulations in order to
improve not only the mechanical properties but also
sustain profile release of drugs.
REFERENCES
1. Halliday, A; Moulton, S. Adv. Drug Del. Reviews
2012, 64 (10), 953-964.
2. Croxatt, H. Contraception 2002, 65 (1), 15-19.
3. Sami, D.; Young S.; Petersen, R. Survey of
Ophthalmology 2007, 52, (3), 224-265.
ACKNOWLDEGEMENTS
We would like to acknowledge Iranian National
Science Foundation for the grant No 89004212. |