A Review On Microspheres technology and its application By Gunja Chaturvedi (I.D no- 2008H146101) Submitted in partial fulfilment of the course PHA G632: Dosage Form Design Date of Submission 01/04/2009 Submitted to Dr. R. N Saha (Instructor In-charge) BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE, PILANI, RAJASTHAN – 333 031 April 2009 REVIEW ON MICROSPHERES Chaturvedi Gunja , Bhagav Prakash, Prof. R.N Saha Birla Institute of Technology and Science, Pilani, Rajasthan (India) 3 Faculty of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 4 Dean, Faculty Division-3, Birla Institute of Technology & Science, Pilani, Rajasthan (India) Abstract :- Nonideal pharmaceutical, pharmacokinetic, and therapeutic properties often combine to reduce the effectiveness of certain compounds. For the vectoring of such compounds to target areas, liposomes, nanoparticles, and microspheres have been suggested. Since organ distribution of the latter is dependent upon their size and shape, it is reasonable to attempt second-order targeting of microspheres on this basis. The range of techniques for the preparation of microspheres offers a variety of opportunities to control aspects of drug administration.This approach facilitates accurate delivery of small quantities of potent drugs ,reduce drug concentrations at sites other than the target organ or tissue and protection of labile compounds before and after administration and prior to appearance at the site of action. Keywords: microspheres, formulation parameters, biodegradable polymers,matrix and reservoir type microspheres, particle size, ,colonic drug delivery, ,nasal delivery. Contents:- Introduction Definition and description History Potential use of microspheres Microspheres manufacture by different methods Approaches related to formulation and process parameters in microsphere manufacturing Effect of process and formulation parameters on inernal morphology of microspheres loaded with hydrophobic drug Proteins encapsulated in microspheres and its stability Preparation of Biodegradable Microspheres and Matrix Devices Containing Naltrexone ● Approaches towards drug targeting using microspheres Nasal delivery Colonic drug delivery ● References Introduction drugs in vivo can be manipulated by The range of techniques for the coupling the drug to a carrier particle. The preparation of microspheres offers a clearance kinetics,tissue distribution, variety of opportunities to control aspects metabolism and cellular interaction of the of drug administration.This approach drug are strongly influenced by the facilitates the accurate delivery of small behaviour of the carrier. The exploitation quantity of the potent drugs ,reduced drug of these changes in pharmacodynamics concentration at the site other than the behaviour may lead to enhanced target site and the protection of the labile therapeutic effect. However ,an intelligent compound before and after the approach to therapeutics employing drug administration and prior to appearance at carriers technology requires a detailed the site of action.The behaviour of the understanding of the carrier interaction with critical cellular and organ systems THE POTENTIAL USE OF and of the limitations of the systems with MCROSPHERES IN respect to the formulation procedures and PHARMACEUTICAL INDUSTRY stability. A variety of agents have been Conversion of oils and other used as drug carrier, including liquids to solids for ease of immunoglobulins serum proteins handling ,liposomes, microspheres ,nanoparticles Taste and odour masking ,microcapsules and even cells such as Increasing the stability of the drug erythrocytes. The characteristics of against the environmental microspheres containing drug should be conditions correlated with the required therapeutic To delay the volatilisation action and are dictated by the materials Separation of incompatible and the methods employed in the materials manufacture of delivery systems.  Improvement of flow properties of powders DEFINITION AND GENERAL Safe handling of toxic substances DESCRIPTION Improve the solubility of water Microspheres can be defined as solid, insoluble substances by aiding in approximately spherical particles ranging dispersion of such material in in size from 1 to 1000 µm.They are made aqueous media of polymeric,waxy or other protective materials,that is biodegradable synthetic Production of sustained polymers and modified natural products release,controlled release and such as starches,gums ,proteins,fats and targeted medications waxes.The natural polymers include Reduce the dose dumping albumin and gelatine, the synthetic potential compared to large polymer include polylactic acid and implantable devices.  polyglycolic acid. The solvents used to dissolve the polymeric materials chosen according to the polymer and drug Microspheres manufacture solubilities and stabilities ,process safety The most important physicochemical and economic considerations. characteristics that may be controlled in Microspheres are small and have large microsphere manufacture are: surface-to-volume ratio. At the lower end - Partical size and of their size range they have colloidal distribution properties. The interfacial properties of - Polymer molecular weight microspheres are extremely important - Ratio of drug to polymer ,often indicating their activity.  - Total mass of drug and polymer Different methods of microspheres HISTORY The concept of packaging microscopic manufacturing are: quantities of materials within - Wax coating and hot microspheres dates back to the 1930s and melt the work of Bungenberg de Jong and - Spray coating and pan coworkers on entrapment of substances coating within coacervates. The first commercial - Coacervation application of encapsulation was by the - Spray drying National Cash Register Company for the - Solvent evaporation manufacture of carbonless copying paper. and precipitation The technology and applications have - Freeze drying advanced over the last several dacades.  - Chemical and thermal cross – linking Wax coating and hot melt: wax may be variables like pH,ionic used to coat the core particles, strength,macromolecule encapsulating the drug by dissolution or concentration,macromolecule ratio and dispersion in molten wax. The waxy macromolecular weight which results in a solution or suspension is dispersed by larger number of controllable parameters. high speed mixing into cold solution, such These can be manipulated to produce as cold liquid paraffin. The mixture is microspheres with specific properties. agitated for at least one hour. The external phase (liquid paraffin) is then decanted Spray drying: It is single step,closed- and the microspheres are suspended in a system process applicable to wide variety non- miscible solvent and allowed to air of materials,including heat-sensitive dry. Wax coated microspheres ,while materials. The drug and polymer coating inexpensive and often used,release drug materials are dissolved in suitable more rapidly than polymeric microspheres. solvent(aqueous or non-aqueous) or the Carnauba wax and beeswax can be used as drug may be present as a suspension in the the coating materials and these can be polymer solution. Alternatively, it may be mixed in order to achieve desired dissolved or suspended within an characteristics. emulsion or coacervate system. For example,biodegradable polylactide Spray coating and pan coating: spray microspheres can be prepared by coating and pan coating employ heat- dissolving the drug and the polymer in jacketed coating pans in which the solid methylene chloride. The microsphere size drug core particles are rotated and into is controlled by the rate of spraying,the which the coating material is sprayed. The feed rate of the polymer drug solution,the core particles are in size range of nozzle size ,the temperature in drying and micrometers upto few millimetres. The collecting chambers,and the size of the coating material is usually sprayed at two chambers. The quality of the spray angle from the side into the pan. The dried products are improved by the process is continued until an even coating addition of plasticizers that promote the is completed. Coating a large number of polymer coalescence and film formation particles may provide a safer and more and enhance the formation of smooth consistent release pattern than coated surfaced and spherical microspheres. tablets. In addition,several batches of microspheres cab be prepared with Solvent evaporation: For this method the different coating thickness and mixed to drug and the polymer must be soluble in achieve specific controlled release pattern. organic solvent,frequently methylene chloride. The solution containing polymer Coacervation : This process is a simple and drug may be dispersed in an aqueous separation of macromolecular solution phase to form droplets. Continuous mixing into two immiscible liquid phases,a dense and elevated temperatures may be coacervate phase,which is relatively employed to evaporate the more volatile concentrated in macromolecules and a organic solvents and leave the solid dilute equilibrium phase. In presence of polymer-drug particles suspended in an only one macromolecule this process is aqueous medium. The particles are finally referred to as simple coacervation. When filtered from the suspension. two or more macromolecules of opposite charge are present ,it is referred to as Precipitation : It is a variation on the complex coacervation. Former one is evaporation method. The emulsion induced by various parameters like change consists of polar droplets dispersed in a in temperature, addition of non-solvent or non-polar medium. Solvent may be microions , which results in dehydration of removed from the droplets by the use of a macromolecules because they promote cosolvent. The resulting increase in the polymer-polymer interactions over polymer concentration causes precipitation polymer- solvent interaction. And the forming a suspension of microspheres. latter is induced by large number of Freeze Drying: This technique involves the freezing of the emulsion and the relative freezing points of the continuous and dispersed phases are important. The continuous phase solvent is usually organic and is removed by sublimation at low temperature and pressure. Finally the dispersed phase solvent of the droplets is removed by sublimation,leaving polymer- drug particles. Chemical and thermal cross- linking: microspheres made from natural polymers Fig 1. structure of ABT627 are prepared by a cross-linking process; polymer include gelatin, albumin ,starch and dextran. A water-oil emulsion is prepared ,where the water phase is a From the above studies it was found that solution of polymer that contains drug to for the encapsulation of the hydrophobic be incorporated. The oil phase is a suitable substances into PLGA matrix, CP/DP ratio vegetable oil or oil - organic solvent is a crucial factor. It was observed that the mixture containing an oil soluble drug loading increased significantly with emulsifier. Once the desired water-oil increasing CP/DP ratio accompanied by emulsion is formed ,the water soluble decreasing the burst effect. At the CP/DP polymer is solidified by thermal treatment ratio 20,the microspheres with a core shell or addition of a chemical cross-linking structure were observed and the internal agent such as glutaraldehyde to form a porosity of the microspheres decreased stable chemical cross link as in albumin. If with increasing the CP/DP ratio. chemical or heat cross linking is used , the Increasing the PLGA concentration amount of chemical and the period and ,increased particle size but decreased drug intensity of heating are critical in release rate was observed. Increasing the determining the release rates and swelling PVA concentration in continuous phase properties of the microspheres. ,,, from 0.1% to 0.5% increased the drug release rate. The maximum solubility of Approaches related to formulation and the drug in PLGA microspheres is process parameters in microsphere approximately 30% under which it was manufacturing dispersed in PLGA matrix in a molecular state. Its release rate was decreased with 1.Effect of process and formulation increasing the intial drug loading. parameters on inernal morphology of ABT627 was slowly released from the microspheres loaded with a hydrophobic PLGA microspheres over 30 days by a drug: ABT627 is a newly synthesized combination of pore diffusion and polymer drug for the treatment of prostate cancer. degradation. During the first 13 days,it It is a lipophilic drug ,and taking it as a was released mainly by diffusion model drug the effect of continuous phase/ supported by unchanged internal dispersed phase ratio(CP/DP ratio),PLGA morphology of the microspheres after 7 concentration ,continuous phase pH days of release. Internal morphology ,polyvinyl alcohol concentration and initial observation after incubating the drug loading on the physicochemical microspheres for 17 days indicated that characteristics of the developed ABT627/PLGA microspheres were mainly microspheres was studied and internal degraded by auto-catalyzation from morphology of the microspheres was inside,as revealed by core-shell structure analyzed by stereological method to of the microsphere at the release stage. ,, elucidate the distribution and the release mechanism of the drug from microspheres. 2.Reversible protein precipitation to production of various proteins has become ensure stability during encapsulation possible with the recent advances in within PLGA microspheres: although the biotechnology,their use for therapeutic purpose has been limited due to physical toxic PLGA solvent which could be used and chemical instability. Due to relatively to prepare PLGA microspheres. Moreover high enzymatic susceptibility and short ,it is a protic solvent containing hydrogen half life,much attention has been paid to attached to oxygen so that it is able to their delivery from systems controlling form hydrogen bonds or to donate a proton local release. Since a solid-state protein such as in stabilizing PEG. The presence exhibits restricted conformational of glucofurol induces a liquid –liquid flexibility,non-aqueous encapsulation phase separation resulting in a protein – approaches have emerged to ensure rich phase and a protein –poor phase. The protein stability upon encapsulation within addition of salt (sodium chloride) helped biodegradable polyester in collecting the maximum amount of microspheres.Various methods like spray- protein precipitates by reducing the drying or spray-freeze drying have been electrostatic repulsive interactions between reported for the preparation of small charged proteins and promoting attractive protein particles. Although these methods hydrophobic interactions. The reason can generate protein particles ,they present behind selecting sodium chloride was some drawbacks for microencapsulation related to its possible use in parenteral that they are technically complex and lead pharmaceutical formulations and to its to low protein recovery and also may intermediate location in the lyotrophic denature the proteins. The aim of this series and also it decreases theprotein study was to develop a non- denaturing solubility very little with minimal method to prepare protein particles. Freeze denaturant effects. The various process –drying has often been used to obtain parameters discussed above were modified protein particles without protein loss but it to optimize the precipitation efficiency of induce the formation of large particles. To four model proteins : lysozyme,α- obtain fine particles and preserve protein chromotrypsin ,peroxidase and β- integrity,proteins have been freeze- dried galactosidase. As monitored by enzymatic with PEG which induces a two –phase activity measurement of rehydrated separation. This approach has been used particles ,conditions to obtain more than for protein microencapsulation by 95% of the reversible precipitates were solid/oil/water (s/o/w) and s/o/o defined for each protein. The study of the techniques. However ,the remaining rehydrated particles by absorbance amount of PEG in the freeze-dried protein spectroscopy, fluorescence spectroscopy products leads to an important initial burst and circular dichroism showed an absence (20% in 1 hr) upon release from PLGA of structural- perturbation after microspheres, and so an adaptation of the precipitation. The protein particles were process was necessary. So in order to then microencapsulated within PLGA obtain protein particles without these microspheres using s/o/w technique. The disadvantages,from an aqueous solution average encapsulation yield was around protein precipitation was induced via 80% and no loss of protein activity isoelectric precipitation, reduction of occurred after the encapsulaton step. dielectric constant by addition of water- Additionally , a lysozyme in vitro release miscible organic solvents ,the reduction of study showed that all of the released the protein charge by changing the pH and lysozyme was biologically active. So this the addition of the polymers or salts. In method of protein precipitation is this study, an organic solvent ,Glycofurol appropriate for the encapsulation in ,was employed by preference to induce the PLGA microspheres of various proteins formation of fine protein particles. It was without inactivation. ,, chosen as a precipitant because it is non- 3. Preparation of Biodegradable antagonists. In this study ,poly(L-lactide) Microspheres and Matrix Devices (PLA) microspheres containing naltrexone Containing Naltrexone: Naltrexone is an prepared by sol-vent evaporation opiate antagonist used mainly as an technique were compressed at adjunct to prevent relapse in detoxified temperatures above the Tg of the polymer. opioid-dependent patients. It is currently The effect of different process parameters, given orally as tablets or capsules in a such as drug/polymer ratio and stirring daily dose of 50 mg. Naltrexone is orally rate during preparation of micro-spheres, active with a relatively short half-life and on the morphology, size distribution, and subject to extensive hepatic first-pass in vitro drug release of microspheres was metabolism.Naltrexone provides no studied. euphoric effects, and there are no observ- able pharmacological consequences when a patient discontinues the drug. For naltrexone treatment to be effective, a sufficient level of the drug concentration must be maintained. The minimum effective concentra-tion of naltrexone for the treatment of opiate addiction is estimated to be in the range of 0.5 to 1.0 ng/mL. Detoxified patients are advised to continue the naltrexone therapy for 4 to 8 months. This treatment typically requires the patient to self-administer dosages of the drug several times a week. The main drawback in naltrexone treatment protocol Fig.2.Effect of particle size on drug release is patient compliance. A possible means of from microspheres with 20% drug loading improving patient compliance and concomitant rehabilitation is the use of controlled drug delivery systems of opioid Fig.4. Effect of drug loading on drug release from microspheres with the same size range By increasing the stirring speed from 400 Fig.3. Effect of particle size on drug to 1200 rpm, the mean diameter of release from microspheres with 40% drug microspheres decreased from 251 μm to loading 104 μm. The drug release rate from smaller microspheres was faster than from larger microspheres. However, drug release from microspheres with low drug content (20% wt/wt) was not affected by the particle size of microspheres. Increasing the drug content of nasal delivery has limitations which have microspheres from 20% to 50% wt/wt led restricted its use to the delivery of a few to signifi-cantly faster drug release from drug molecules. The permeability of nasal microspheres. It was also shown that drug mucosa is normally low for the polar release from matrix devices pre-pared by molecules: for small polar drugs the compression of naltrexone microspheres is bioavailability is generally in the region of much slower than that of microspheres. No 10% and for the peptides such as burst re-lease was observed with matrix calcitonin and insulin normally not above devices. Applying higher compression 1%. Another factor of importance for the force, when compressing micro-spheres to low membrane transport is the general produce tablets, resulted in lower drug re- rapid clearance of the administered lease from matrix devices. The results formulation from the nasal cavity due to suggest that by regulating different mucociliary clearance mechanism. It has variables, desired release profiles of been shown that for both liquid and naltrexone can be achieved using a PLA powder formulations that are not micropar-ticulate system or matrix mucoadhesive ,the half life of clearance devices. ,, are in order of 15 -20 mins. So in this study chitosan derivative MPC is used to Approaches towards drug targeting produce microspheres for nasal delivery of using microspheres metoclopramide. The mechanism of action of chitosan in improving the transport of 1.Spray –dried microspheres based on polar drugs across the epithelial methylpyrrolidinone chitosan as new membrane is believed to be combination carrier for nasal administration of of bioadhesion and transient opening of metoclopramide : In recent years,chitosan tight junctions in the cell membrane to derivatives have been studied to improve enable the passage of the polar drugs. A polymer solubility at different pH values non –derivatized chitosan has been used as and to promote the permeability of anionic comparison and metoclopramide drugs thereby avoiding the precipitation of hydrochloride has been chosen as model the drug –polymer complexes.5 – drug. The metoclopramide loaded MPC methylpyrrolidinone chitosan (MPC) is a microspheres were made by spray –drying chitosan derivative in which the amino technique. They showed similar properties group of the glucosamine units of the of microparticles made by chitosan polysaccharide backbone are partially chosen as reference with respect to size substituted by methylpyrrolidinone(MP) in and in vitro release behaviour. And the position 5. It belongs to the class of the gel microspheres based on MPC are –forming reabsorbable biopolymeric characterized by better substituted chitosans possessing mucoadhesiveness,less swelling capability documented biological significance. This and more prolonged ex –vivo permeation chitosan derivative combines the profile than the particles containing biocompatibility of chitosan and the chitosan,moreover they are able to provide hydrophilic characteristics of the a gel (when they come in contact with pyrroilidinone moiety ,being particularly aqueous solutions) which shows different susceptible to the hydrolytic action of properties dependent upon the medium lysozyme. used. These properties make microspheres Nasal delivery has generated interest as an based on derivatized chitosan suitable for alternative route for the administration of nasal administration,infact the drugs and biomolecules that are mucoadhesiveness might prolong the susceptible to enzymatic or acidic residential time of the formulation inside degradation and first –pass hepatic the nasal cavity while a moderate swelling metabolism. Possible pathways for a drug could avoid potential mucosal damages or to permeate across the nasal mucosa are inconveniences to the possible users. ,, passive transport ation ,carrier mediated ,transcytosis and transport through 2.Development of enteric –coated calcium intercellular tight junctions. However ,the pectinate microspheres intended for colonic drug delivery: Among the various suitable pectin type is very essential strategies proposed to target orally considering that increase in Ca amounts administered drugs to the colon ,those gave rise to a decrease in rate of drug based on drug release triggered by colon release. From the release test performed microflora are generally considered the under pH gradient and in presence of most effective regarding target selectivity. pectinolytic enzymes in simulated colonic And for this purpose the natural medium it was revealed that the Ca – biodegradable polymers such as pectins pectinate MS did not undergo any are employed due to their ability to act as selective colonic –microflora triggered specific substrate for colonic microflora drug release mechanism and the observed and also combined with their high slowing down effect of free Ca ions in the safety,non –toxicity and biocompatibility enzymatic degradation rate of the pectin characteristics. Most of the colon targeted matrix can only partially concur to explain drug delivery system developed so far are the almost complete lack of activity shown single –unit systems. On contrary ,multi – by pectinolytic enzymes. Inspite of this particulate systems can offer several unexpected result,the CF020 MS ,realized advantages over single –unit formulations with low Ca chloride concentration (2.5% like quick spread out on their arrival to the w/v) and coated with an appropriate colon,with a sharp increase in the surface thickness pf a pH –dependent polymeric area exposed to bacterial breakdown that film (100%w/v), demonstrated to be produces rapid drug release and thereby suitable to adequately modulate drug improves the drug absorption. In this study release through a mixed approach of pH enteric –coated calcium pectinate and transit –time control,completely microspheres are formulated as a colon – avoiding drug release during the first 2 h targeted delivery system and in gastric ambient,limiting to less than Theophylline is used as a model drug since 10% release in the following 2 h and it is well absorbed in the large intestine in reaching 100% release in the colonic humans and both its anti –asthma activity simulated medium within less than 24 and pharmacokinetic properties make it an hours., interesting candidate for such kind of Conclusion:- modified –release preparations. The Drugs can be targeted to specific sites in influence of pectine type ,calcium ion the body using microspheres. Degree of concentration and cross –linking time on targeting can be achieved by localization both drug entrapment efficiency and dug of the drug to a specific area in the release pattern was investigated. And the body(for example in lungs),to a particular effect of varying the level of the pH – group of cells(for example, kupffer cells) dependent coating polymer (Eudragit and even to the intracellular S100) was also evaluated. The Ca structures(such as lyzosomes or cell pectinate microsphere(MS) prepared with nucleus). The rate of drug release from the CF020 i.e low –methoxylated amidated microspheres dictates their therapeutic pectins were better than those obtained action. Release is governed by the with AU701 i.e low –methoxylated pectins molecular structure of the drug and the ,for both their greater stability during polymer,the resistance of the polymer to storage and more regular and degradation ,and the surface area homogeneous morphological properties. alongwith the porosity of the The shape of the former MS was poorly microspheres. The internal structure of the influenced by the variations in Ca microspheres can vary as a function of the concentrations maintaining a microencapsulation process employed. homogeneous spherical form also at lower Controlled drug release from microspheres Ca concentration.while the latter required occurs by diffusion of the drug through a at least 20% w/v of Ca ion concentration polymeric excipient, diffusion of the for obtaining MS of satisfactory and well entrapped drug through the pores in the reproducible morphological properties. polymeric microspheres. Microspheres This finding lead to an important with high drug content release the active conclusion that the choice of the most ingredient more rapidly than with a low load. Physicochemical properties of the drug and excipient such as permeability of one in the other, identity of the polymer, degree of crystallinity ,inclusion of plasticizers and fillers and thickness of the polymer influences the drug release rate. Reference: 1. Diane J.Burgress,Dept of pharmaceutical sciences,University of Connecticut,Storrs ,Connecticut ,U.SA. Anthony J.Hickey ,Dept of Pharmaceutics,The University of North Carolina at Chapel Hill,Chapel Hill,North Carolina,U.S.A ( Encyclopedia ofPharmaceutical Technology,2328 -2337) 2. Fujimoto,S;Miyazaki,M.;Endolh,F ;Takahashi,O;Shrestha,RD; Okui,K; Mori- moto,Y;Terao,K Cancer 1985,55,522 -526 3. Gupta,PK ;Hung ,CT ;Perrier,DG ,Int .J.Pharm.1986 ,33,137 -146 . 4. Gupta,PK ;Hung ,CT ;Perrier,DG ,Int .J.Pharm.1986 ,33,147 -153 . 5. Shirui Mao,Yi Shi,Luk Li,Jing Xu ,Andreas Schaper,Thomas Kissel,Dept of Pharmaceutics and Biopharmacy,Philipps- University of Marburg,Marburg ,Germany(EJBP 68,(2008),214-223) 6. R.Jalil,J.R.Nixon ,Biodegradable poly(lactic acid)and poly(lactide-co-glycolide) microcapsules,297 -325 . 7. R.A .Jain ,The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide)(PLGA) devices,Biomaterials 21(2000) 2475- 2490. 8. Alexandra Giteau ,Marie-Claire Venier-Julienne, Stephane Marchal,Jean-Luc Courthaudon ,Michele Sergent ,Claudia Montero-Menei,Jean-Michel Verdier,Jean – Pierre Benoit.( EJBP 70(2008) 127- 136) 9. V.Luginbuehl,L.Meinel,H.P.Merkle ,B Gander, Localized delivery of growth factors for bone repair ,Eur.J.Pharm.Biopharm.58(2) (2004) 197 -208. 10. V.R Sinha ,A.Trehan ,Biodegradable microspheres for protein delivery,J. controlled release 90 (3) (2003) 261 -280. 11. Elisabetta Gavini,Giovanna Rassu,Corrado Muzzarelli,Massimo Cossu,Paolo Giunchedi.Dept of Drug Sciences,University of Sassari,Sassari,Italy,Institute of Biochemistry ,University of Ancona,Ancona.Italy.(EJBP 68(2008) 245- 252) 12. J.H. Hamman,M.Stander ,HE Junginger,A.F Kotze ,Enhancement of paracellular drug transport across mucosal epithelia by N-trimethyl chitosan chloride ,S.T.P Pharm Sci. 10(2000) 35-38. 13. M.Thanou,M.T. Nihot ,M .Jansen,J.Coos Verhoef ,H.E Junginger,Mono- N- carboxymethyl chitosan (MCC) ,a polyampholytic chitosan derivative enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo,J.Pharm Sci. 90 (2001) 38- 46. 14. Francesca Maestrelli,Marzia Cirri,Giovanna Corti,Natascia Mennini,Paola Mura.Dept of Pharmaceutical sciences,University of Florence.Italy(EJBP 69(2008) 508-518) 15. M.Ashford ,J.T.Fell,targeting drugs to the colon: delivery systems for oral administration,J.Drug Target.2 (1994) 241- 257. 16. Preparation of Biodegradable Microspheres and Matrix Devices Containing Naltrexone. Rassoul Dinarvand,Shadi M.Moghadam,Leyla Mohammadyari-Fard ,Fatemeh Atyabi Dept of Pharmaceutics ,Faculty of Pharmacy,Tehran University of Medical Sciences ,Tehran ,Iran(AAPS PharmSciTech 2003; 4 (3) Article 34 (http://www.pharmscitech.org)) 17. Way WL, Fields HL, Way EL. Opioid analgesics and antago-nists. In: Katzung BG, ed. Basic and 18. Clinical Pharmacology. 7th ed. Norwalk, CN: Appleton and Lange; 1998:512-513.
Pages to are hidden for
"REVIEW ON MICROSPHERES"Please download to view full document