|Year : 2015 | Volume
| Issue : 1 | Page : 37-44
Development of a novel 3-month drug releasing risperidone microspheres
Bhanusree Yerragunta1, Satheesh Jogala1, Krishna Mohan Chinnala2, Jithan Aukunuru1
1 Department of Pharmaceutics, Mother Teresa College of Pharmacy, Osmania University, Hyderabad, India
2 Department of Pharmacology, St. John College of Pharmacy, Kakatiya University, Warangal, Telangana, India
|Date of Submission||01-Apr-2014|
|Date of Decision||17-May-2014|
|Date of Acceptance||06-Jul-2014|
|Date of Web Publication||21-Jan-2015|
Department of Pharmaceutics, Mother Teresa College of Pharmacy, Osmania University, Hyderabad
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: The purpose of this study was to develop an ideal microsphere formulation of risperidone that would prolong the drug release for 3 months in vivo and avoid the need for co-administration of oral tablets. Materials and Methods Polycaprolactones (PCL) were used as polymers to prepare microspheres. The research included screening and optimizing of suitable commercial polymers of variable molecular weights: PCL-14000, PCL-45000, PCL-80000 or the blends of these polymers to prepare microspheres with zero-order drug-releasing properties without the lag phase. In the present study, the sustained release risperidone microspheres were prepared by o/w emulsion solvent evaporation technique and the yield was determined. Microspheres were evaluated for their drug content and in vitro drug release. Microspheres prepared using a blend of PCL-45000 and PCL-80000 at a ratio of 1:1 resulted in the release of the drug in a time frame of 90 days, demonstrated zero-order drug release without lag time and burst release. This formulation was considered optimized formulation. Optimized formulation was characterized for solid state of the drug using differential scanning calorimetry, surface morphology using scanning electron microscopy and in vivo drug release in rats. Results: The surface of the optimized formulation was smooth, and the drug changed its physical form in the presence of blends of polymers and upon fabrication of microspheres. The optimized formulation also released the drug in vivo for a period of 90 days. Conclusions: From our study, it was concluded that these optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal Consta™ and, therefore, could further improve patient compliance.
Keywords: In vivo, microspheres, polycaprolactone blends, risperidone, risperdal consta
|How to cite this article:|
Yerragunta B, Jogala S, Chinnala KM, Aukunuru J. Development of a novel 3-month drug releasing risperidone microspheres. J Pharm Bioall Sci 2015;7:37-44
|How to cite this URL:|
Yerragunta B, Jogala S, Chinnala KM, Aukunuru J. Development of a novel 3-month drug releasing risperidone microspheres. J Pharm Bioall Sci [serial online] 2015 [cited 2020 Feb 29];7:37-44. Available from: http://www.jpbsonline.org/text.asp?2015/7/1/37/148777
In order to overcome the limitations of conventional drug delivery, newer drug delivery systems were developed and evaluated for a variety of drugs. In this regard, controlled release systems have currently occupied the mainstay of these systems.  Although controlled release systems are classified into various classes such as rate-programmed drug delivery systems, activation modulated drug delivery systems, mechanically activated drug delivery systems, feedback regulated drug delivery systems, only rate-programmed systems are so far successful in the market and their production is viable and practicable. These are available to be administered via a variety of routes. In rate-programmed systems, a simple controlled release delivery system is most successful. Of these systems, several parenteral controlled systems are currently available in the market. Some parenteral controlled release systems are designed to achieve therapeutically effective concentrations of drug in the systemic circulation over an extended period of time thus achieving better patient compliance and allowing a reduction of both the total dose of the drug administered and the incidence of adverse side-effects. Other parenteral controlled release microspheres are the reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration at the site of interest without untoward effects. Of these, biodegradable microspheric drug delivery system for controlled drug release has gained enormous attention due to its wide range of applications.  It has more advantages over various other dosage forms. Moreover, the microspheres are of micron size so they can easily fit into various capillary beds and various parenteral sites which are also of micron size. Although these microspheres can be prepared using a variety of polymers, biodegradable polymers such as polylactide-co-glycolide and polycaprolactone have gained enormous prominence because of their practical and market viable drug delivery applications.  Further, both the polymers are approved by United States Food and Drug Administration (FDA) for a variety of purposes. From the literature survey, it is found that polycaprolactones (PCL) has been in focus in the search for appropriate matrices for drug delivery microspheres, due to its ease of preparation, commercial availability at reasonable cost, versatility, biocompatibility and hydrolytic degradation into resorbable, harm-less products and also it is a promising candidate for controlled release applications. Further, it is compatible with numerous other polymers. Blends of PCL have a great potential for drug delivery applications.  In the present study, we chose the blend PCL with different molecular weights to prepare novel respiridone microspheres that can be injected at a specific site of the body to control the drug release into the systemic circulation. Injection site for this preparation is particularly subcutaneous, intramuscular or intraperitoneal.
In this study, the goal was to develop a novel microsphere formulation for risperidone, an atypical antipsychotic. The atypical antipsychotics are now considered to be the first-line treatments for schizophrenia, while risperidone proved to be superior atypical antipsychotic with more significant serotonin antagonism compared to dopamine antagonism.  Schizophrenia is a mental disorder with acute and chronic symptoms. When an acute psychotic episode has been resolved, drug is given chronically as prophylaxis to prevent relapse. In this regard, risperidone demonstrated to be a superior agent in both acute phases as well as a prophylactic agent.  In clinics, both oral formulations and parenteral depots for risperidone are currently available. Parenteral sustained release dosage forms in the form of microspheres demonstrated to be superior to oral formulations in terms of patient compliance. The already approved risperidone microsphere is an intramuscular preparation marketed by Johnson and Johnson Corp. USA in the name of Risperdal Consta™. This preparation once injected can result in therapeutic levels only after 2-3 weeks. During this lag phase, oral supplementation is given. The therapeutic action then lasts for next 2-3 weeks. This is mainly because the formulation is prepared using high molecular weight poly (lactic-co-glycolic acid) (PLGA) (75:25), which has a very slow degradation in the body. Further, a zero-order drug release is also not achieved during 4-6 weeks. To address this problem research groups have developed similar formulations with other PLGAs. ,, Although the results from their studies led to formulations which avoided oral supplementation and demonstrated zero-order drug release, the in vivo drug release was sustained for only up to 45 days. However, a 3 month drug-releasing microsphere formulation can be prepared using PCLs. PCL is another biodegradable polymer approved by FDA. It is a hydrophobic polymer with degradation rates slower than commonly used PLGA and forms more porous sustained release parenteral depots. Thus, more prolonged drug release with no lag time and zero-order drug release can be obtained with this polymer. In view of the need for the study, it was considered worthwhile to formulate risperidone loaded microspheres and carryout their in vitro/in vivo characterization with following objectives: (1) To prepare and characterize a novel parenteral depot microsphere formulation for respiridone using different molecular weights of PCL includes 14000, 45000, 80000 and its blends. (2) To achieve a complete release of the drug from the microspheres in a period of 3 months without the lag phase and initial burst release. (3) To compare in vitro/in vivo release profiles of optimized formulation with marketed formulation Risperidal Consta™.
| Materials and Methods|| |
Drug and chemicals used in the study were of analytical grade and procured either gift samples or purchased. Risperidone and PLGA (75:25) were gift samples from Relisys Medical Devices Pvt. Ltd., Hyderabad, India. PCL (M.Wts 14000, 45000 and 80000) were purchased from Sigma-Aldrich Ltd., Germany. Dichloromethane, polyvinyl alcohol, were purchased from standard deviation Fine Chemicals Ltd. The ultraviolet (UV)-visible spectrophotometer from fisher scientific and high-performance liquid chromatograph (HPLC) from waters corporation was used in the analysis of the samples. Differential scanning calorimetry (DSC) used to characterize the solid state of the drug in the formulation was from Shimadzu. A JSM-5200 scanning electron microscope (SEM) was used to study the surface morphology of the microspheres. All the other equipment used electronic balance, shaking water bath, high-speed centrifuge were all from standard sources.
Preparation of microspheres
Risperidone microspheres were prepared by solvent evaporation method. The composition used to prepare microspheres is shown in [Table 1]. A 50 mg of drug was dissolved in 5ml of organic solvent and then 100 mg of polymer was added to this solution, stirred well. A 4% w/v of polyvinyl alcohol was used as an aqueous phase. Microspheres were prepared by slowly injecting the organic phase into the aqueous solution, while stirring on a magnetic stirrer. This results in o/w emulsion. The magnetic stirrer was maintained at the required speed for 3-4 h to evaporate the organic solvent. Finally, the particles formed were filtered and then kept in desiccator overnight for the absorption of moisture. In this way, the microspheres were obtained.
In vitro evaluation of microspheres
prepared risperidone microspheres were characterized for particle size, drug entrapment efficiency, in vitro drug release, thermal behavior and surface morphology. The mean particle size was determined by using an optical microscope. In this method, 200 particles were considered. Percentage practical yield is calculated to know about percentage yield or efficiency of any method. Thus it helps in the selection of the appropriate method of production. Practical yield was calculated as the weight of risperidone microspheres recovered from each batch in relation to the sum of starting material. The percentage yield of prepared risperidone microspheres was determined by using the formula: Percentage yield = (practical yield/theoretical yield) ×100. Efficiency of drug entrapment for each batch was calculated in terms of percentage drug entrapment (PDE) as per the following formula: PDE = (practical drug content/theoretical drug content) ×100. To determine the drug content, 10 mg of each batch of microspheres were dissolved in 10 ml of dichloromethane and 1 ml of methanol to prevent immediate evaporation of dichloromethane in a volumetric flask, shaken well, and immediately 0.5 ml of aliquot was taken from the above solution and made the volume up to 10 ml with methanol stirred well, filtered and then analyzed for the drug content in UV spectroscopy at 278 nm. This assay was developed in our laboratory and was validated by spiking the known amount of the drug into placebo particles and the same extraction process used for drug-loaded particles was followed.
To conduct release studies, each batch of risperidone microspheres and risperdal consta microspheres equivalent to 10 mg were taken in microtubes and suspended in 1 ml 7.4 pH buffer solution. These microtubes were placed in horizontal water bath shaker. The whole assembly was maintained at 37°C using a thermostatic water bath shaker. At the end of specific time periods, these micro tubes were taken and placed in a centrifuge maintained at a speed of 5000 rpm for 10 min. After centrifugation of samples, 1 ml of the supernatant solution was withdrawn, filtered, and it was further diluted to 5 ml with buffer. Meanwhile the volume withdrawn was replenished with an equal volume of fresh buffer solution, the microsphere suspension resuspended, and the release study was continued. The amount of risperidone released was analyzed by UV spectrophotometer at the λmax value of 278 nm using distilled water as the blank. Dissolution profiles of the formulations were compared by plotting percentage cumulative drug release versus time. In this way, drug release was analyzed for a period of 90 days. In vitro drug release profile of optimized formulation was compared with that of Risperidal Consta™. Lag phase for drug release was then evaluated. Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, the first order, Higuchi, Hixon-Crowell erosion and Ritger-Peppas release model.
Thermal properties of the powder samples were investigated with a DSC. Approximately 2 mg of sample was analyzed in an open aluminum pan and heated at scanning rate of 5°C/min between 0°C and 240°C. Aluminum was used as a standard reference material. The thermograms of risperidone, physical mixture of blend of PCL-45000 and PCL-80000, physical mixture of drug with the blend of polymers PCL-45000 and PCL-80000, optimized formulation (drug loaded with PCL-45000 and PCL-80000) microspheres and placebo microspheres were obtained. In order to examine the particle surface morphology and shape SEM was used. Dry risperidone microspheres were spread over a slab. The sample was shadowed in a cathodic evaporator with a gold layer 20 nm thick. Photographs were taken using a JSM-5200 SEM (Tokyo, Japan) operated at 20 kV. Pictures of risperidone microspheres were taken by random scanning of slab.
In vivo studies
Institutional Animal Ethical Committee of St. John College of Pharmacy approved (025/IAEC/St.JCOP/2013) all protocols and the study was conducted after following the CPCSEA guidelines. A total of 18 rats were used in the studies. These rats were divided into three groups one given with an intravenous dose of risperidone, the second group was administered one time with F-5 microspheres and the third groups administered with risperdal consta. Microspheres were injected via the subcutaneous route. All the administrations are containing 50 mg of drug. The microspheres were sterilized under UV light for 24 h prior to administration. Over a period of 90 days, blood was collected and analyzed for plasma risperidone level using a solid phase extraction protocol followed by HPLC. A previously published method was used for this purpose.  Briefly, the plasma was processed and then the drug was assayed in the serum using a HPLC method with UV detection at 280 nm. 5 ml samples of blood were collected at each time point. Blood was centrifuged for 30 min to obtained serum that was refrigerated in the freezer till analysis was performed. Plasma risperidone concentrations were determined. The standard of risperidone was prepared in normal rat plasma following the same method as used for the samples. HPLC was performed using a Waters XTerra RP 18.5 μm, 4.6 × 150 mm column. Mobile phase was composed of 55 volume % water with 35volume % acetonitrile and 10 volume% 100 mM ammonium bicarbonate, pH 10. The flow rate was set at 1.0 ml/min, and peaks were detected at a wavelength of 280 nm for risperidone with a run time of 30 min for each sample.
effects of continual risperidone treatment in the rats administered F5 microspheres was also assessed using locomotor testing. Such a methodology was previously used for risperidone implants.  The locomotor activity can be easily measured using an actophotometer which operates on photoelectric cells which are connected in the circuit with a counter. When the beam of light falling on the photocell is cut off by the animal, a count was recorded. The test was conducted every 10 days on the same set of animals which are used for assessing drug levels using HPLC. The equipment was turned on and each rat was placed in the activity cage for 10 min. The locomotor activity of the rats was then determined and compared with that of control rats which did not receive any treatment. Six rats were used for this purpose. These rats were nurtured, in the same way, as done for the formulation treated group. The protocol for animal studies was approved by Institutional Animal Ethical Committee approval from St. John College of Pharmacy, and the experiments were conducted following the guidelines of CPCSEA.
studies were performed according to previously reported method. The formulation was stored in amber colored glass bottles at 4°C ± 1°C, room temperature 25°C ± 1°C, and in hot air oven at 40°C ± 1°C for a period of 6 months.  The samples were analyzed every 10 days by HPLC as indicated in the pharmacokinetic studies. The amount of the drug that remained in the implant was considered to be the stable portion for every time point of analysis.
experiments were done 6 times and the data were expressed as mean ± standard deviation, and Tukey's post-hoc test was done to analyze the significance of the difference between different groups using the statistical analysis software package SPSS (Version 16.0, IBM, USA).
| Results|| |
Eight microsphere formulations were prepared with the biodegradable polymers PCL-14000, PCL-45000 PCL-80000 and its blends and also with PLGA (75:25) [Table 1]. The average particle size and entrapment efficiency of each batch are shown in [Table 2]. The particle size varied from 4 to 8 μm. The percentage entrapment efficiency was found to be from 13.7% to 24.9%. A maximum of 24.9% drug entrapment efficiency was obtained in the risperidone microspheres of formulation F1 in which the amount of drug incorporated was 50 mg and the PCL-14000 amount was 100 mg. It was noticed that the formulation F5 which was the preferred formulation has shown the lowest drug entrapment efficiency. This can be attributed to high solubility of the polymer in an organic solvent or due to low solidification of the polymer during the process of preparation.
|Table 2: Particle size and entrapment efficiencies of all the microspheres |
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In vitro drug release from risperidone, microspheres was performed in horizontal water bath shaker. The calibration curve of the drug was constructed to determine the concentration of the drug from the absorbance values. From this, the cumulative % drug release was determined. The plots of cumulative percentage drug release v/s time for all the formulations were drawn and represented graphically as shown in [Figure 1] and [Figure 2]. The in vitro performance of risperidone microspheres showed prolonged and sustained release of risperidone. The polycaprolactone based formulations F5 showed complete release (100%) of the entrapped drug and F3 showed a minimum of 75% cumulative drug release in 90 days. The drug release from PLGA based microspheres for risperidone was slower when compared to that of polycaprolactone based microspheres. The PLGA based formulations risperdal consta and F8 released the drug completely for over a period of 60 and 50 days, respectively. From the [Figure 1], it is clear that formulation F5 showed complete drug release and achieved 3 month depot with zero-order release profile and without the lag phase and initial burst release. This was the formulation prepared using a blend of PCL-45000 with PCL-80000 at a ratio 1:1 Therefore, this formulation was considered as the optimized formulation. The drug release was further compared with marketed risperdal consta. There was a significant lag time with risperdal consta while with F5 formulation there was no lag time. While risperdal consta released the drug for 60 days, the optimized F5 formulation released the drug for 90 days. The comparison of the release profiles is shown in [Figure 2]. The release profiles of risperidone from the microspheres of the formulation F5 were processed into graphs for comparison of different orders of drug release and to understand the mechanism of drug release. The data were processed for regression analysis using MS-Excel statistical functions. According to in vitro dissolution kinetics, optimized the formulation (F5) show the R 2 = 0.9876 for zero-order release and for the first-order release R 2 = 0.956, whereas Y-axis represents % drug remaining. Hence the release of risperidone from optimized formulation was considered to be zero-order. The Higuchi model equation showed R 2 = 0.9696, Hixon-crowel cube root law showed R 2 = 0.9943 and also when the data was fitted into Korsmeyer-Peppa's equation it showed R 2 = 0.985 with slope (n) value of 0.845. Thus, diffusion of the drug was the main mechanism for drug release for the optimized formulation. According to Korsemeyer-Peppas it follows anomalous (nonfickian) diffusion mechanism. This optimized formulation F5 was then characterized for solid state of the drug by DSC, surface morphology by SEM, in vivo drug release and stability studies.
|Figure 1: Comparison of drug release profiles from various risperidone microspheres|
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|Figure 2: Comparison of drug release profile of the optimized formulation with poly (lactic-co-glycolic acid) based formulations F8 and marketed risperdal consta|
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Differential scanning calorimetry studies were performed to understand the nature of the encapsulated drug in the matrix. The physical state of risperidone in the polymer matrix would also influence its release characteristics. To probe this effect, DSC analysis was performed on (a) pure risperidone drug, (b) PCL-45000 and PCL-80000 blend (c) physical mixture of drug with PCL blend (d) placebo microspheres (e) risperidone loaded microspheres (optimized formulation). The DSC thermograms are shown in [Figure 3]. In our present research work, both in the physical mixture and formulations, we have set the temperature range from 0 to 240ΊC. Risperidone melting point was considered as standard temp to compare with the physical mixture and formulations. Melting endotherm of pure risperidone was found to be 172.1°C. There was no peak detected in the temperature ranges of 100-220°C for blank microspheres, physical mixtures and for the optimized formulation (risperidone loaded PCL-45000-PCL-80000 microspheres). The absence of drug peak may be due to conversion of risperidone from crystalline state to amorphous. The absence of detectable crystalline domains in the optimized formulation clearly indicates that risperidone existed in amorphous or disordered-crystalline form of a molecular dispersion in the polymer blend matrix. DSC curves of the placebo blend microspheres and physical mixture of PCL-45000 with PCL-80000 are almost identical, indicating no influence of any fabrication process or residual solvent in the microspheres on their thermal properties. Hence, the displacement of the endothermic peak of risperidone loaded microspheres could be mainly due to the molecular dispersion of risperidone in the microspheres. Surface morphology of the microspheres was examined by SEM [Figure 4]. The microspheres of optimized formulation were examined. Microspheres were smooth and spherical in nature without agglomerations. Particles were obtained with nonporous nature.
|Figure 3: Differential scanning calorimetry thermograms of the microspheres, polymer blend, placebo microspheres and physical mixtures|
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|Figure 4: Scanning electron microscope pictures of risperidone microspheres|
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In the in vivo studies, plasma concentration at various time points was assessed upon administration of F5 formulation. In vivo, onset was rapid, and plasma concentration was in the range of 15-110 ng/ml for a substantial portion of release interval. Optimized microspheres released the drug for 3 months in vivo [Figure 5]. Risperdal Consta also demonstrated similar results. However, in this case, corroborating in vitro release, sustained in vivo release was also noted for 50 days and the formulation demonstrated significant lag time. Higher plasma levels, when compared to optimized formulation, were achieved with Risperdal Consta. In the pharmacodynamic assessment, the animals were observed for first 1-week to evaluate the signs of high initial drug release. There were no signs of distress during this time. There was no locomotor impairment, no difficulties in grooming, no loss of weight, ate and drank appropriately upon administration of microspheres. This suggested that there was no high initial drug release. In the assessment of locomotor activity, compared to control the group, there was a significant decrease in the locomotor activity of the rats administered microspheres during all the 3 months suggesting the presence of the drug in the plasma during this period, time, term [Figure 6].
|Figure 5: Plasma profile of the drug after administration of F5 microspheres and risperdal consta in the rats|
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|Figure 6: Locomotor activity in rats after 1-time administration of F5 microspheres|
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The stability studies were performed for 6 months, and the formulations were found to be stable at all temperature conditions. The results are verified with one-way ANOVA method, the stability test data was found significant for F5 at 5% level of significance (P < 0.05).
| Discussion|| |
Modifications to a drug or developing a dosage form for a drug to control the time course and specificity of the drug in the body has been attempted over several years. Controlled release constitutes any dosage form that provides medication over an extended time. Controlled release microspheres offer several improvements over existing technologies. The need of making any drug microspheres is to produce a drug delivery system, which is safe and capable of producing consistent blood levels of drug in the body for the required period of time. It also improves keeping and handling properties of the drug.
Risperidone is a benzisoxazole derivative belongs to BCS class II (low solubility and high permiability). , Scientists developed risperidone after understanding lysergic acid diethylamide drug model of schizophrenia. As per the results of these experiments, scientists not only focused on dopaminergic receptor blockade, but also, the serotoninergic (5-hydroxytryptamine) antagonism was investigated to treat schizophrenia. The success has been illustrated with risperidone. Risperidone belongs to second-generation antipsychotic. Risperidone has a higher risk of hyperprolactinemia comparable to first-generation antipsychotics, but fares better than many second-generation antipsychotics with regards to metabolic side-effects. Risperidone was first approved by the FDA for the management of acute schizophrenia in 1993 and was approved for the long-term maintenance treatment of schizophrenia in 2002. It is currently available in oral and depot formulations in the market. Depot formulations have found more significant advantages over oral dosage forms.  These advantages include: (1) Less frequent administration, e.g. the patient can receive an intramuscular injection every 3 or 4 weeks instead of oral tablets or capsules several times daily; (2) Fewer side effects and reduced medical work-load; (3) Improved patient compliance and more predictable absorption. These long-acting depot dosages of risperidone offer the full therapeutic potential of maintenance medication. It was marketed under the name Risperdal Consta™. These microspheres upon injection into intramuscular sites, initially releases about 3.5% of the drug, then there will be a lag time of approximately 3 weeks, followed by a 2 week release of therapeutic concentrations. As per this release profile, an extra dosing of oral risperidone or other antipsychotic agents is needed for the first 2 or 3 weeks with the initial dose of Risperdal Consta™ to ensure adequate therapeutic plasma concentration and also the risperidone release from Risperdal Consta™ during the 4 th -5 th week is also nonuniform. A rapid increase closely followed by a rapid reduction in the release rate is seen, and in this case the ratio of Cmax/Cmin is more than 10, which may lead to potential adverse effect. The high Mw (>100,000) and the monomer ratio of 75:25 (lactic acid:glycolic acid) PLGA used in the Risperdal Consta™ lead to a very slow biodegradation of the microspheres (more than 6 months) and poor tolerance of the patients. To overcome the weaknesses mentioned above, several groups developed novel parenteral sustained release implants and microspheres for risperidone. Su et al., has developed a PLGA based risperidone microspheres without a lag period and tested it successfully in a rat model.  Further, the microspheres released the drug according to a zero-order release profile. D'Souza et al., have developed novel risperidone microspheres and successfully avoided co-administration of oral tablets.  Further, this study demonstrated that microsphere dosage form for risperidone can be formulated with an optimum particle size and drug loading to provide initial bolus followed by maintenance levels, thereby eliminating combination therapy and improving the patience compliance. The microsphere formulations developed in the study by D'Souza et al., prolonged the release of the drug by only 45 days. On the other hand, all the implants that are reported so far are based on PLGAs and are able to release the drug for 1 or 2 months. Rabin et al., demonstrated in vitro and vivo proof of concept for risperidone implants using biodegradable PLGA copolymers.  However, the implant released the drug for only a short duration. However, implants and microspheres with different and more prolonged drug-releasing behaviour can be prepared using other biodegradable polymers such as PCL. For several drugs, the drug releasing behavior was found to be variable in PLGA and polycaprolactone.  Either quick or prolonged drug release can be achieved in the polycaprolactone based delivery systems when compared to PLGA based delivery systems. For paclitaxel, quicker release was achieved with polycaprolactone films compared to PLGA films. On the other hands, ketorolac tromethamine from polycaprolactone based microspheres had more prolonged release compared to the microspheres prepared using PLGA. Navitha et al., recently developed and investigated a 3 month PCL based drug-releasing implant for risperidone.  In this study, a 12 week steadily sustained release risperidone PCL microsphere without the lag period was designed and investigated. This study used a blend of a series of commercial PCLs of different molecular weights, which results in a variable release and faster degradation aimed to achieve an optimized 3 month depot formulation possessing both of the sustained zero-order release behavior without initial burst release and lag phase.
The optimizing study of preparation of microspheres was performed using an o/w emulsion solvent evaporation method, which was suitable for the encapsulation of a lipophilic drug such as risperidone. Variable encapsulation efficiencies were noted with various formulations prepared. It is interesting to note that microspheres of formulation F1 which are prepared using PCL-14000 demonstrated highest entrapment efficiency when compared to those prepared with PCLs of higher molecular weights. It is generally believed that increasing entrapment efficiency of the drugs would be obtained along with a high molecular weight or high intrinsic viscosity biopolymers used in microsphere preparation. Thus, the entrapment efficiency should be higher for PCL-80000 when compared to PCL-14000. However, we obtained contrary results. This can be explained taking into consideration various other factors. There is a common idea that fast polymer precipitation on the surface of the dispersed phase prevents drug loss into the continuous phase. This leads to higher encapsulation efficiencies. On the other hand, slow precipitation of the polymer at the time of fabrication of the microparticles may lead to reduced entrapment efficiency. This mainly depended on the solvent used in the preparation of microspheres. Selection of a suitable solvent for the preparation of microspheres can affect the entrapment efficiency. The solvent if precipitates the polymer quickly at the time of fabrication can lead to enhanced entrapment efficiency. Solubility of polymers in organic solvents can affect properties such as entrapment efficiency, matrix porosity and solvent residue. The solubility of different PCL used in this study in dichloromethane, the solvent used in this study may be different. As a reason, an anomalous result in entrapment efficiency, on the contrary, to the molecular weight dependency were obtained. Further, linear relationship between entrapment efficiency and polymer molecular weight were not obtained. Thus, apart from solubility of the polymer in the solvent used, other factors might also influence and can explain the phenomenon noticed with entrapment efficiency in this study. Among all the eight formulations prepared, based on the in vitro characterization, formulation F5 was found to be the most promising formulation because of 100% risperidone release without any lag phase and initial burst release from the microsphere. F5 is a novel blend microspheres prepared from PCL-45000 and PCL-80000. The reduction in burst release can be explained based on the diffusion of the drug into the release medium. Drug release from biodegradable polymer-based microspheres during the initial drug release stage depends on diffusional escape of the drug through channels existing in the polymer matrix. As the degradation time of biodegradable polymers vary from weeks to months, drug release during the first few days depends on how successfully the diffusion is controlled. In several situations, the burst release is due to poor control over the diffusion-based release in this stage. The degree of the initial burst from the microparticles depends on the ability of the polymer matrix to encapsulate the drug, thereby resulting in immediate diffusion. As we have not noticed any burst release with all the formulations, we could attribute this to the ideal methodology of preparation of the microspheres. In addition to this, the hydrophobicity and the affinity of the drug to the polymer could be the other reasons. The drug is hydrophobic and also could have more affinity for the biodegradable polymers and thus burst release was not observed. This is true with all the polymers used in the study. Lag time was also not observed with all the formulations of this study compared to the marketed risperda consta. This may be due to more hydrophobic nature of the polymer and more drug-polymer affinity in risperdal constant. Further, the main mechanism of drug release from these formulations could be diffusion, and this could be attributed to reduced lag times. To corroborate this fact, we have determined the drug release mechanism from various formulations prepared in this study. The drug release mechanisms also confirmed that the mechanism of drug release is diffusion. Thus, there could be reduced lag times with the formulation of this study. The drug changed its physical form upon fabrication into microspheres. SEM indicated smooth and spherical morphologies. The optimized formulation released the drug in vivo over a period of 3 months. The drug levels were found to be in the therapeutic window for all the 3 months suggesting the superior performance of the formulation in vivo as well. This has been confirmed both by drug levels and pharmacodynamic end points. Pharmacodynamics of the drug was measured using locomotor testing. The formulation demonstrated antipsychotic activity during all the 90 days. Compared to control, the locomotor activity with the formulation was reduced during all the 90 day. There was a slight bump in the locomotor activity during one of the earlier time points. This could be because of the need for the drug to stabilize and show consistent antipsychotic activity. Thus, risperidone loaded microspheres were fabricated, and complete drug release was successfully achieved with the optimized formulation over a period of 90 days.
| Acknowledgment|| |
The authors would like to acknowledge Osmania University for analytical services and Management of Mother Teresa College of Pharmacy for providing necessary facilities helpful in conducting the work.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]
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