GENERAL METHODS FORDESIGN AND EVALUATION OF OSMOTIC PUMPS
Introduction: Osmotic device are most promising strategy based systems for controlled drug delivery. Osmotic pump offers many advantages over other controlled drug delivery systems, i.e. improved patient compliance with reduced dosing frequency and more consistence and prolonged therapeutic effect with uniform blood concentration. Moreover they are slightly inexpensive and production scale up is easy.
OSMOSIS:• Osmosis refers to the process of movement of solvent from lower concentration of solute towards higher concentration of solute across a semipermeable membrane until there is an equal concentration of fluid on both sides of the membrane.• Osmotic pressure is a colligative property.• Difference between diffusion and osmosis:• In diffusion both the solute and solvent molecules migrate freely whereas if the solution is confined in a membrane permeable only to solvent molecules, it is known as osmosis.• Osmotic pressures of concentrated solutions of soluble solutes commonly used in controlled formulations are extermely high because high osmotic pressures are responsible for high water flow across semi- permeable membrane.• Eg: Sodium chloride – 356 atm. Fructose – 355atm.
Material used in formulation of Osmotic Pumps.1) Semi permeable Membrane: It is used to controlled the amount of water entering to dosage form. Cellulose acetate is a commonly employed semi permeable polymer for the preparation of osmotic pumps. Others are poly (vinyl methyl) ether copolymers, poly (orthoesters), poly acetals and selectively permeable poly (glycolic acid) and poly (lactic acid) derivatives can be used as semi permeable film forming materials .2) Hydrophilic and Hydrophobic Polymers: These polymers are used in the formulation development of osmotic systems for making drug containing matrix core.
The highly water soluble compounds can be co-entrapped in hydrophobic matrices and moderately water soluble compounds can be co-entrapped in hydrophilic matrices to obtain more controlled release. Swellable polymers are used for the pumps containing moderately water soluble drugs since they increase the hydrostatic pressure inside the pump due to their swelling nature where as non- swellable polymers are use in case of highly water soluble drugs. The selection is based on the solubility of the drug as well as the amount and rate of drug to be released from the pump.3) Wicking Agents: A wicking agent is defined as a material with the ability to draw water into the porous network of a delivery device. A wicking agent is of either swellable or non-swellable nature. Eg;collodial silicon dioxide,kaolin, titanium dioxide,sodium lauryl sulphate,low molecular weight polyvinyl pyrollidone,etc.
4) Osmogens: Osmogens are essential ingredient of the osmotic formulations. They maintain the osmotic presser in side the tablet of core and thus provide the controlled release. Eg: inorganic salts and carbohydrates.5) Surfactants : Surfactants are particularly useful when added to wall forming material. They produce an integral composite that is useful for making the wall of the device operative. Eg:polyoxyethelynated glyceryl recinoleate,glyceryl laurate,etc.6) Coating Solvents: Solvents suitable for making polymeric solution that is used for manufacturing the wall of the osmotic device include inert inorganic and organic solvents. The typical solvents include methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl acetate, cyclohexane, carbon tetrachloride, water etc. The mixtures of solvents such as acetone-methanol (80:20), acetone-ethanol (80:20), acetone-water (90:10), methylene chloride-methanol (79:21),etc.
7) Plasticizers: Plasticizers increase the workability, flexibility and permeability of the fluids. Generally from 0.001 to 50 parts of a plasticizer or a mixture of plasticizers are incorporated in to 100 parts of wall forming materials. Eg.dialkyl phthalates,alkyl adipates,citrates,benzoates,myristares,etc.8) Pore Forming Agents: These agents are particularly used in the pumps developed for poorly water-soluble drug and in the development of controlled porosity or multi-particulate osmotic pumps. These pore-forming agents cause the formation of micro porous membrane. E.g. sucrose, glucose, fructose, mannose, lactose, sorbitol, and mannitol . The microporous wall can be formed in situ by a pore formerby its leaching during operation of the system. The pores can be formed prior to operation by gas formation within coating polymer solutions which result inpores in the final form of the wall.
9) Flux Regulators:• Flux enhancing or flux decreasing agents are added to the wall forming material in regulating the fluid permeability of flux throuugh wall.• Eg:polyhydric alcohols, polybutylene,polypropylene,etc.
Types of Osmotic Pumps:1 Implantable osmotic pumps:3)Rose Nelson Pump The pump composed of three chambers: a drug chamber, a salt chamber holding solid salt, and a water chamber. A semi permeable membrane separates the salt from water chamber. The major problem associated with Rose Nelson pumps was that the osmotic action begin whenever water came in contact with the semi permeable membrane. This needed pumps to be stored empty and water to be loaded prior to use.
• Pulsatile delivery could be achieved by using Higuchi Leeper pump; The Pulsatile release of drug is achieved by drilling the orifice in elastic material that stretches under the osmotic pressure. Pulse release of drug is obtained after attaining a certain critical pressure, which causes the orifice to open. The pressure then reduces to cause orifice closing and the cycle repeats to provide drug delivery in a Pulsatile fashion.
3) Higuchi Theeuwes Osmotic Pump In this device, the rigid housing is consisted of a semi permeable membrane. The drug is loaded in the device only prior to its application, which extends advantage for storage of the device for longer duration. The release of the drug from the device is governed by the salt used in the salt chamber and the permeability characteristics of the outer membrane.
• It is composed of three concentric layers- the drug reservoir,the osmotic sleeve and the rate controlling semi–permeable membrane.• It contains an additional component called flow moderator is inserted into the body of the osmotic pump after filling.• When the system is placed in aqueous environment water enters the sleeve through semipermeable membranr,compresses the flexible drug reservoir and displaces the drug solution through the flow moderator.
2 Osmotically controlled oral drug delivery :(1)- Elementary osmotic pump (EOP) : Single layer tablet for delivery of drugs having moderate water (Alza Corp., USA) solubility. Can be utilized for zero-order delivery as well as pulsed release .
Elementary osmotic pump: Elementary osmotic pump: A novel elementary osmotic pump was developed for multidrug delivery treatments of type 2 diabetes. According to a study from Peoples Republic of China, "A simple elementary osmotic pump (EOP) system that could deliver metformin hydrochloride (MT) and glipizide (GZ) simultaneously for extended periods of time was developed in order to reduce the problems associated with multidrug therapy of type 2 noninsulin-dependent diabetes mellitus. In general, both highly and poorly water-soluble drugs are not good candidates for elementary osmotic delivery.
Push–pull osmotic pump Bilayer tablet, used to deliver drugs having low to high water (Alza Corp.) solubility. Products such as Ditropan XL (oxybutynin chloride), Procardia XL (nifedipine), and Glucotrol XL (glipizide) are based on this technology. An oral osmotic system which can deliver theophylline and salbutamol sulphate simultaneously for extended period of time was developed and characterized in a view to reduce the problems associated with the multidrug therapy of asthma. Simple controlled porosity osmotic pump contained both drugs (in freely soluble form) did not provide satisfactory extended release of theophylline. A modified two-layered, push–pull osmotic system was developed by using the basic designs of various oral osmotic pumps, such as controlled porosity osmotic pump (CPOP), elementary osmotic pump (EOP) and push–pull osmotic pump (PPOP).
OROS-CT (Alza Corp.) For targeted delivery to colon and can be used for local or systemic therapy. The effects of two oxprenolol oral osmotic (OROS) delivery systems on heart rate and blood pressure before and during recovery from exercise at a predetermined load were examined in twelve patients with hypertension previously responding to beta-blocker monotherapy. Haemodynamic responses were attenuated during the 24 h after single and repeated (15 days) once daily administrations of 10/170 and 16/260 oxprenolol OROS. At 24 h after repeated doses, compared to placebo there were significant reductions in resting blood pressure and in heart rate immediately following exercise. Attenuation of heart rate after exercise was dose related but differences between the systems with respect to resting heart rate and blood pressure were inconsistent. Antihypertensive responses after repeated doses were greater than those after single doses.
However, reductions in resting and exercise heart rates were consistently less on chronic therapy. This may reflect enhanced expression of the partial agonist activity of oxprenolol due to altered receptor sensitivity after prolonged beta-blockade. The plasma oxprenolol profiles after both systems indicated slow absorption and substantial concentrations were apparent 24 h after drug administration. These observations suggest that both oxprenolol OROS systems display sustained drug release and on once daily dosing provide 24 h beta-blockade and control of blood pressure at rest and following exercise.
L-OROS (Alza Corp.) Designed to deliver lipophilicliquid formulations and is suitable for delivery ofinsoluble drugs.Various L-OROS systems available to providecontrolled delivery of liquid drug formulations include L-OROS hardcap, L-OROS softcap and a delayed liquidbolus delivery system. Each of these systems includesa liquid drug layer, an osmotic engine or push layerand a SPM coating.The expansion of the osmotic layer results in thedevelopment of hydrostatic pressure inside thesystem, thereby forcing the liquid formulation to bedelivered at the delivery orifice.
• It is an osmotic tablet where in the delivery orifices (holes) are formed in situ through leaching of water soluble pore forming agents incorporated in SPM (e.g., urea, nicotinamide, sorbitol, etc). Drug release rate from CPOP depends on various factors like coating thickness, solubility of drug in tablet core, level of leachable pore forming agents and the osmotic pressure difference across the membrane.
A controlled porosity osmotic pump (CPOP) delivery system for sodium ferulate was prepared with cellulose acetate (CA) as semipermeable membrane, polyethyleneglycol 400 (PEG 400) as channeling agent and dibutylphthalate (DBP) as plasticizer and release controller. Effects of coating levels, PEG and DBP content and amount of sodium chloride on in vitro release were studied. Coating formulations were optimized by a L (3) orthogonal array design (OAD) with three factors at three levels using statistical analysis. Controlled porosity osmotic pump tablets of sodium ferulate made with the optimal formulation were found to have good in vitro and in vivo release characteristics.
The sandwiched osmotic tablet core, which is composed of a middle push layer and two attached drug layers, has been prepared and systematically studied with the purpose of delivering water-insoluble nifedipine. The advantage of the sandwiched osmotic tablet system over the commercialized push-pull osmotic tablet system is its simplicity of preparation, as the surface identification was avoided. It was observed that polyethylene oxides (PEO) with molecular weight (MW) of 300,000 and 8,000,000 g/mole were suitable for the thickening agent of drug layer and the expandable hydrogel of push layer, respectively. The weight ratio of 190/190 for drug layer/push layer was also found to be suitable. It has been observed that PEO amount of the push layer and the KCl amount of the drug layer had profoundly positive influence on nifedipine release. A push layer/drug layer co-controlled osmotic delivery mechanism has been proposed and the optimal tablet formulation has been obtained. It was also found that PEO and nifedipine were miscible, which may support the application of PEO in nifedipine dosage forms. Meanwhile, the PEO/nifedipine binary phase diagram has been constructed. The sandwiched osmotic tablet system can deliver nifedipine in an approximate zero-order rate up to 24 hours. It may be potentially used for the delivery of water-insoluble drugs.
A multiparticulate delayed release system based on coated pellets containing an osmotic active ingredient is presented. The coating consists of a semipermeable membrane of cellulose acetate. After application water penetrates into the core and forms a saturated solution of the soluble components. The osmotic pressure gradient induces a water influx resulting in a rapid expansion of the membrane leading to the formation of pores. The osmotic ingredient and the drug are released through these pores according to a zero order kinetic. In comparison with the sodium chloride free formulation the inclusion of the osmotically active ingredient results in a completely different dissolution behavior. Lag time and dissolution rate are dependent on the coating level and the osmotic properties of the dissolution medium. However, the dissolution rate is sufficient even with high coating levels to obtain delayed release properties. The model proposed is supported by data from determination of pellet swelling behaviour, sodium chloride release, single pellet dissolution and release in media of different pH and osmolality.
Advantages and application: Delivery of the Drug can be designed to follow zero order kinetics. The Drug release from OCODDS is independent to gastric pH and Hydrodynamic condition. The delivery rate of the Drug from the system is highly predictable and can be pre programmed.
Disadvantages: Subject to dose dumping if membrane breaks [e.g. someone chews it] Slightly more expensive to formulate and complicated. Possible hole plugging
In Vitro Evaluation:1. In vitro Dissolution: The in vitro release of drug from oral osmotic system has been evaluated by the conventional USP paddle and basket type apparatus. US patent described the use of commercial vankel standard dissolution apparatus. The dissolution media is generally distilled water as well as stimulated gastric fluid (for first 2-4 hr) and stimulated intestinal fluids (for subsequent hours) have been used. The standard specification, which are followed for the oral controlled drug delivery systems are equivalently applied for oral osmotic pump.
2 Scanning Electron MicroscopyCoating membranes of formulation obtained beforeand after complete dissolution of core contents can beexamined for their porous morphology by scanningelectron microscope.3Effect of pHTo study the effect of pH and to assure a reliableperformance of the developed formulationsindependent of pH, in vitro release studies can beconducted in media of different pH.4 Effect of Agitational IntensityIn order to study the effect of agitational intensity ofthe release media, release studies were performed indissolution apparatus at various rotational speeds.
5 Effect of Osmotic PressureTo confirm the major mechanism of drug release,release studies of the optimized formulation can beconducted in media of different osmotic pressure. Toincrease the osmotic pressure of the release media(pre-equilibrated to 37°C ± 1°C), mannitol (osmoticallyeffective solute) can be added.6 Kinetics of Drug Release the data obtained can be fitted in different models atdifferent time intervals and by using satistics we canknow kinetics of drug release.
Weigh the empty pump together with its flow moderatorFilling the pump is accomplished with a small syringe Draw the solution into thesyringe and attach the filling tube.With the flow moderator removed, hold the pump in an upright position and insertthe filling tube through the opening at the top of the pump until it can go nofurther. This places the tip of the tube near the bottom of the pump reservoir.Push the plunger of the syringe slowly, holding the pump in anupright position. When the solution appears at the outlet, stop filling and carefullyremove the tube.Wipe off the excess solution and insert the flow moderator, overflow should bewiped off.Weigh the filled pump.
References: (1) Handbook of Pharmaceutical Controlled Release Technology by Donald L. Wise (2) Ansel’ Pharmaceutical dosage form and Drug delivery system by Ansel (3) Biopharmaceutics and Pharmacokinetics A Treatise by D.M. Brahmankar. (4) Essentials of Medical Pharmacology by K.D. Tripathy. (5) Jain.N.K.;Advances in controlled and novel drug delivery;2006;CBS Publishers;1;pg18-39. (6) Vyas S.P.;Khar.K.Roop;Controlled drug delivery,Concepts and Advances;2002;Vallabh Prakashan;Delhi;1;pg477-501. (7) Kanagale P, Lohray BB, Misra A, Davadra P, Kini R. Formulation and Optimization of Porous Osmotic Pump–based Controlled Release System of Oxybutynin. AAPS PharmSciTech. 2007; 8(3): Article 53.
(8) Journal of Controlled Release 35 (1995) 1-21 ; 57 (1999) 65- 73 ; 9 (2004) 75-89. (9) European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 11-18 .(10) International Journal of Pharmaceutics 311 (2006) 147-156.