FORMULATION AND EVALUATION OF NANOPARTICLES FOR ANTI-HYPERTENSIVE DRUG
Synopsis for M.Pharm Dissertation submitted to the
Rajiv Gandhi University of health Sciences Karnataka, Bangalore
By
YENDETI. RAGHUVEER
M. PHARM., PART-I
Under The Guidance Of
Mrs.NINA VARGHESE
Professor and HOD
DEPARTMENT OF PHARMACEUTICS
INSTITUTION
EAST POINT COLLEGE OF PHARMACY
BANGALORE
KARNATAKA
2010-2011
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 /Name of the Candidate and Address
/ YENDETI RAGHUVEEREast Point College of Pharmacy No. 147,
Bidarahalli,
Virgonagar,
Bangalore 560 049
P: 2847 3777 F: 2847 39990
PERMANENT ADDRESS
YENDETI RAGHUVEER
S/O Y.SUBBA RAO,
DR NO:39-8-20(1),
GOPALNAGAR,
ONGOLE PRAKASAM (DT)
ANDRAPRADESH 523001
2 /
Name of the Institution
/ East Point College of Pharmacy No. 147,Bidarahalli,
Virgonagar,
Bangalore 560 049
P: 2847 3777 F: 2847 3999
3 /
Course of Study and Subject
/MASTER OF PHARMACY
(PHARMACEUTICS)
4 /Date of the Admission
/ 01/10/20105 / Title of the Topic :
FORMULATION AND EVALUATION OF
NANOPARTICLES FOR ANTI-
HYPERTENSIVE DRUG
6 / BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR STUDY
6.2 REVIEW OF LITERATURE
6.3 OBJECTIVE OF STUDY / ENCLOSURE-I
ENCLOSURE-II
ENCLOSURE-III
7 / MATERIALS AND METHODS
7.1 SOURCE OF DATA
7.2 METHOD OF COLLECTION OF DATA
7.3 DOES STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS? IF SO , DESCRIBE BRIEFLY / ENCLOSURE-IV
ENCLOSURE-V
ENCLOSURE-VI
8 / LIST OF REFERENCES / ENCLOSURE-VII
6
6.1
6.2
6.3
7
7.1 / ENCLOSURE-I
BRIEF RESUME OF THE INTENDED WORK
NEED FOR THE STUDY
The oral route is preferred for drug therapy of chronic conditions. However, numerous potent lipophilic drugs exhibit low oral bioavailability due to their poor aqueous solubility.
For this class of compounds, ‘low solubility/high permeability class’, dissolution in the environmental lumen is the rate-controlling step in the absorption process. Efforts are ongoing to enhance the oral bioavailability of lipophilic drugs in order to increase their clinical efficacy.
Various formulation strategies are reported in the literature, including the use of surfactants, solid dispersions, micronization, liposomes, with each formulation approach having its specific advantages and limitations. In recent years much attention has been focused on formulation on nanoparticle.
Nanoparticles have versatile potential for efficient exploitation of different drug delivery formulations and routes because of the properties provided by their small size. These possible benefits include controlled release, protection of the active pharmaceutical ingredient and drug targeting. Nanoparticles are expected to offer new solutions e.g. for gene therapy and delivery of peptide drugs. Generally, nanoparticles are applied as an injectable or oral solution, but their use as dried material in formulations such as tablets or inhalable powders is equally conceivable. Although the research on pharmaceutical nanoparticles has been extensive during recent years, breakthrough of products to the market has not yet occurred. Problems like poor drug encapsulation efficiency and difficulties in controlling and scaling up of the preparation process have inhibited progress.
Nanoparticles are sub-merged colloidal structures composed of synthetic/semi-synthetic polymer. Polymers used may be natural or synthetic. Drug may be added to previously prepared nanoparticles/during preparation. Drug is entrapped in the solution system. The physical chemistry of these liquid nano formulations is same as that of colloidal dispersion i.e. the surface changes, dispensability, density, hydrophobicity /hydrophilicity and other critical factors determine the, stability of the system.
The nano particles may be sphere, capsules, and crystals of nano size i.e. less than (10-1000microns) 10-9 cm.
Nanotechnology was the apt choice since it has wide range of methodologies in eveloping drug delivery systems. Of various methods available Solvent evaporation method was selected. Poloximer are anionic co block polymers widely engaged in the production of nano particles.
Many antihypertensive drugs have their primary action on systemic vascular resistance. Some of these drugs produce vasodilation by interfering with sympathetic adrenergic vascular tone (sympatholytics) or by blocking the formation of angiotensin II or its vascular receptors. Other drugs are direct arterial dilators, and some are mixed arterial and venous dilators. Although less commonly used because of a high incidence of side effects, there are drugs that act on regions in the brain that control sympathetic autonomic outflow. By reducing sympathetic efferent activity, centrally acting drugs decrease arterial pressure by decreasing systemic vascular resistance and cardiac output.
The main objective of the work is to successfully formulate sustained release drug delivery system so as to reduce the dosing frequency and toxic effects on patient population thereby increases patient compliance
ENCLOSURE-II
Review of the literature
Wei Lia, et al prepared revaprazan hydrochloride nanosuspension Revaprazan hydrochloride (RH) is a new reversible proton pump inhibitor. However, due to poor water solubility, oral bioavailability of the drug was relatively low. To investigate the particle size reduction effect of RH on dissolution and absorption, three suspensions that containing different sized particles were prepared by high pressure homogenization and in vitro/in vivo evaluations were carried out. DSC and powder X-ray diffraction were used to study crystalline state of freeze dried powder of RH suspensions and the results showed that particles of RH microsuspension and nanosuspension remained in the same crystalline state as coarse suspension, but had lower lattice energy. In the in vitro dissolution test, both microsuspension and nanosuspension showed increased dissolution rate. In the in vivo evaluation,compared to coarse suspension, RH nanosuspension exhibited significant increase in AUC0–t , Cmax and decrease in Tmax, MRT. Nevertheless, RH microsuspension did not display any significant differences in these pharmacokinetic parameters compared to the coarse suspension. The findings revealed that particle size reduction can influence RH absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of RH in rats.
Yong-Xing Zhaoa et al prepared a nanosuspension of Hydroxycamptothecin using . Poloxamer 188 as polymer. It is a promising anticancer agent that possesses the ability to inhibit the growth of a wide range of human tumors. Owing to its poor solubility and instability, the pharmaceutical development and clinical utilization of hydroxycamptothecin have been limited. In the present study, a novel precipitation-combined high-pressure homogenization (PCH) technique was used to prepare hydroxycamptothecin nanosuspensions. Based on the homogenization pressure and number of cycles, the process with 10 cycles at 18,000 psi of homogenization pressure was found to be the most efficient method to achieve consistent particle size reduction. It was used to prepare nanosuspensions for characterization and evaluation of the formulation performance. Lyophilization of hydroxycamptothecin nanosuspensions, the shape and crystal form of the drug, and antiproliferative activity were also studied. The mean particle size (z-ave) of the reconstituted freeze-dried powder was small and uniform. The freeze-dried powder might be a good choice for intravenously administrating poorly soluble hydroxycamptothecin, which proved to have higher cytotoxicity against the cancer cells than hydroxycamptothecin injections (p < 0.001). Overall, these studies have demonstrated that the PCH technique can be used successfully to prepare hydroxycamptothecin nanosuspensions.
Francesco et al prepared nano suspension using Pluronic F68 (Poloxamer 188) to optimise dissolution properties of lipophilic, poorly soluble drugs, thus improving their oral bioavailability. The non-steroidal anti-inflammatory drug diclofenac acid (DCF), which is known to exist in different crystal forms, was chosen as a model drug. To this purpose, the influence of homogenization technique was studied by preparing several nanosuspensions with two different crystalline forms of the drug (DCF1 and DCF2). Particle size and size distribution, morphology,microstructure, and thermal behaviour of the different formulations were studied by photon correlation spectroscopy (PCS), scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). Solubility studies of the bulk drug crystalline forms and dissolution experiments of nanosuspensions in comparison with different controls (bulk drug, physical mixtures, coarse suspensions) were carried out in differentmedia: distilled water, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Besideswell known factors capable of affecting drug nanoparticle dissolution, results showed that drug dissolution rate in nanosuspensions is strongly affected by the drug solubility, which depends on the crystal form, and preparation procedure (high pressure homogenization process). Results demonstrated that this process partially transformed DCF2 in DCF1while it did not have any effect on the DCF1 crystals.
B.Van Eerdenbrugh et al prepared a nano suspension of loviride using. Poloxamer 188 as polymer to improve the dissolution and absorption properties of, a poorly soluble antiviral agent, sucrose co-freeze–dried nanopowders were prepared, characterized and evaluated. Tween 80/poloxamer 188-stabilized nanosuspensions were produced on a laboratory scale using media milling. The milling process was monitored by dynamic light scattering (DLS) and resulted in particles with a mean size of 264±14 nm and a distribution width of 59±6 nm after 4 h of milling. Co-freeze–drying of the nanosuspensions with sucrose had an inhibiting effect on nanoparticle agglomeration and yielded solid “nanopowders” that were resuspendable and homogeneous with respect to loviride content. X-ray powder diffraction (XRPD) confirmed the presence of small loviride crystallites and indicated that sucrose and poloxamer 188 were crystalline. Differential scanning calorimetry (DSC) showed melting peaks of poloxamer 188, sucrose and loviride. Time-resolved XRPD indicated that sucrose crystallization was complete within 24 h of storage. Scanning electron microscopy (SEM) suggested the formation of sheet-like matrix structures. The dissolution rate of loviride from the nanopowders was excellent. A Caco-2 experiment on the nanopowder showed a significantly higher cumulative amount transported after 120min (1.59±0.02g) compared to the physical mixture (0.93±0.01g) and the untreated loviride (0.74±0.03g).
Ganderc, et al prepared a nano suspension of micanazole a poorly water soluble drug. New drug substances from early development are often poorly water-soluble, which causes poor bioavailability upon peroral administration and hampers drug administration through other routes such as the parenteral or ocular routes. One approach to improve drug solubility and administration flexibility is by wet milling to nanosize. Particle size reduction increases the surface energy which requires adequate stabilization by excipients. In
this study, the practically water-insoluble miconazole was nanoground, and a variety of surface active and polymeric excipients were tested for their stabilizing effects. For efficient milling, two preformulation criteria had to be fulfilled: a relatively low contact angle (<70◦) and high dispersibility of the native drug particles in the milling medium. Hydroxypropylcellulose (HPC-LF) in combination with sodium dodecyl sulfate (SDS) stabilized best the miconazole nanosuspensions. A design of experiments was used to achieve drug particle mean sizes of 140–170 nm by varying the concentrations of miconazole (5 and 20%, w/w), SDS (0.05 and 0.2%, w/w), and HPC-LF (1.25 and 5%, w/w).Further experiments revealed that minimal 0.0125% SDS and 3.125% HPC-LF were required for miconazole nanogrinding and nanosuspension stabilisation. Storage of the nanosuspensions at 5 ◦C for up to 6 months caused only minor changes, whereas storage at 25 ◦C resulted in particle agglomeration and single crystal growth. Altogether the study showed that excellent wetting of drug particles as well as their electrostatic and steric stabilization by excipients is necessary to produce stable nanosuspensions by nanogrinding.
C.Jacobs et al has formulated a mucoadhesive Nanosuspension of bupravaquone Bupravaquone is a new naphthoquinone antibiotic against Cryptosporidium par6um and other parasites. It has attracted interest for the treatment of C. par6um infections, because of the lack of a drug in the treatment of mostly AIDS patients. The bioavailability of bupravaquone is limited when given orally. To overcome the problem of the high elimination rate caused by diarrhoea, typical for C. par6um infections, bupravaquone was formulated as a mucoadhesive nanosuspension, i.e. combining the properties of mucoadhesive drug delivery systems, in this case hydro gels, with nanosuspensions. In this study different polymers:hydro gels were employed to create a prolonged retention time for the drug in the infected gastrointestinal tract (GIT). The second step to improve the bioavailability of bupravaquone was the formulation as nanosuspension. Therefore various concentrations of bupravaquone with different surfactants were tested. The production of these nanosuspensions was carried out by high pressure homogenisation. In addition to the classical stepwise production, about a new one step production method is described.
R. Shegokar, Ph.D et al formulated Nanosuspension of Nevirapine which is a poorly water-soluble antiretroviral drug. Intravenous nevirapine nanosuspensions (NS) (457 ± 10 nm) were prepared by high-pressure homogenization. NS were surface modified by stabilizer adsorption, e.g., serum albumin, polysaccharide and polyethylene glycol (PEG) 1000. The NS were characterized for mean particle size, particle size distribution and polydispersity index. The targeting potential of the nonmodified and three
surface-modified NS to the mononuclear phagocytic system (MPS) cells that serve as potent viral reservoirs was assessed by in vitro protein adsorption studies using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). The adsorption patterns were qualitatively identical, but showed quantitative differences. The relatively adsorbed high amounts Q4 of immunoglobulins indicate uptake by liver and spleen, observed quantitative differences (e.g., the amount of dysopsonin albumin and apolipoproteins) can modulate the organ distribution. Controlled in vitro optimization of the protein adsorption by surface modification of the nanocrystals can reduce the number of animals required for in vivo studies and accelerate development of targeted nanoparticles.
Afrouz Yousefi et al Prepared a Pegylated Nano-Liposomal Formulation Containing Docetaxel . An improved pegylated liposomal formulation of docetaxel has been developed with the purpose of improving the docetaxel solubility without any need to use tween80 that is responsible for hypersensitivities following administration. Liposomes all had spherical shape with size of 130–160 nm. The most important finding of this study is that pegylated liposomes were prepared with significant increase in docetaxel encapsulation efficiency and stability of the formulation in comparison with last reports on docetaxel liposomes. In vitro release studies revealed that such a formulation could be stable in the blood circulation and meet the requirements for an effective drug delivery system.
Madaswamy S. et al formulated PLGA nanoparticle formulations of risperidone and develop extended-release poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles of risperidone and thermal-responsive in situ gel containing risperidone nanoparticles for parenteral (subcutaneous) delivery and to reduce the dosedependent extrapyramidal side effects of risperidone. PLGA nanoparticles of risperidone were designed by nanoprecipitation method using polymeric stabilizer (Poloxamer 407). The prepared nanoparticles were characterized for particle size by photon correlation spectroscopy and atomic force microscopy. Poloxamer 407–based in situ gel containing PLGA nanoparticles of risperidone was prepared by modified cold method to control the initial rapid release from the nanoparticles. The in vivo efficacy (antipsychotic effect) of prepared formulations (nanoparticles and in situ gel containing nanoparticles) was studied by administering them subcutaneously to mice. Extrapyramidal side effects of the formulations were also studied. The particle size of the prepared nanoparticles ranged between 85 and 219 nm. About 89% to 95% drug encapsulation efficiency was achieved when risperidone was loaded at 1.7% to 8.3% by weight of the polymer. During in vivo studies prepared risperidone formulations showed an antipsychotic effect that was significantly prolonged over that of risperidone solution for up to 72 hours with fewer extrapyramidal side effects. The prolonged effect of risperidone was obtained from the risperidone formulations administered subcutaneously, and this may improve the treatment of psychotic disorders by dose reduction.