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Friday, May 15, 2009

CONTROLED DRUG DELIVERY SYSTEM

CONTROLED DRUG DELIVERY SYSTEM

Rajitha PanonummalHH, Vimal Mathew

National College of Pharmacy, Manassery, Calicut

Therapeutic efficacy and safety of drugs, administrated by conventional methods, can be improved by more precise spatial and temporal placement within the body, thereby reducing both the size and number of doses by using controlled drug delivery system. An ideal controlled drug delivery system is the one which delivers the drug at predetermined rate, locally or systemically for a specified period of time. An ideal targeted drug delivery system deliver the drug only to its site of action.


An ideal drug delivery system should,

deliver drug at a rate dictated by the needs of the body over the period of treatment

channel the active entity solely to the site of action

To make it in practice various controlled and targeted drug delivery system are introduced. Controlled delivery of drugs, proteins and other bioactive agents can be achieved by incorporating them either in dissolved or dispersed form in polymers.


In general controlled delivery attempts to

  1. Sustain drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with a sawtooth kinetic pattern.
  2. localize drug action by spatial placement of a controlled release system (rate controlled) adjacent to or in the diseased tissue or organ.
  3. target drug action by using carriers to deliver drugs to particular target cell type.


Objectives of controlled drug delivery systems

The chief objective of most products should be controlled delivery to reduce dosing frequency to an extend that once daily does is sufficient for therapeutic management though a uniform plasma concentration at a steady state. The major objectives include

  1. Predict drug release rated form and drug diffusion behaviour through polymers, thus avoiding excessive experimentation.
  2. Elucidate the physical mechanism of drug transport by simply comparing the release data mathematical models.
  3. Design new drug delivery system based on general release expressions.
  4. Optimise the release kinetics.


Factor influencing the design and performance of controlled drug delivery system

  1. Biopharmaceutic characteristic of the drug
    1. Molecular weight of the drug
    2. Aqueous solubility of the drug
    3. Apparent partition coefficient
    4. Drug Pka and ionization physiological PH
    5. Drug stability
    6. Mechanism and site of absorption
    7. Route of administration.
  2. Pharmacokinetic characteristic of the drug
    1. Absorption rate
    2. Elimination half life
    3. Rate of metabolism
    4. Dosage form index
  3. Pharmacodynamics characteristic of the drug
    1. Therapeutic range
    2. Therapeutic index
    3. Plasma–concentration–response relationship


Classification of controlled drug delivery system

  1. Oral controlled drug delivery system
    1. Continuous release system

      Dissolution controlled release system.
      Diffusion controlled release system
      Diffusion and dissolution controlled release system.
      ion exchange resin drug complexes
      slow dissolving salt and complexes
      PH independent formulations.
      Osmotic pressure controlled systems
      Hydrodynamic pressure controlled systems.

    2. Delayed transit and continuous release systems

      Altered density system.
      Mucoadhesive system.
      Size based systems.

    3. Delayed Release system

      Intestinal release system.
      Colonic release system

  2. Parenteral controlled release systems
    1. Injectable
    2. Implants
    3. Transdermal drug delivery systems
    4. Ophthalmic drug delivery systems
    5. Intravaginal and intrauterine drug delivery systems


Advantages of controlled drug deli every systems

  1. Improved patient convenience and compliance
  2. Reduction in fluctuation in steady state levels.
  3. Increased safety margin of high potency drugs.
  4. Reduction in dose.
  5. Reduction in health care cost.


Disadvantages of controlled drug deli every systems

  1. Decreased systemic availability
  2. Poor invitro-inviovo correlations
  3. Chances of dose dumping
  4. Dose withdrawal is not possible.
  5. Higher cost of formulation


OSMOTIC PRESSURE ACTIVATED DRUG DELIVERY SYSTEM INTRODUCTION

Osmotic devices are most promising strategy based system for controlled drug delivery. They are the most reliable controlled drug delivery system and could be employed as oral drug delivery system or implantable devices.

Osmotic drug delivery system utilize Osmosis as the major driving force for drug release. Adequate water solubility of the drug is a prerequisite for osmotic drug delivery system. Osmotic drug delivery devices are composed of an osmotically active drug core, which is surrounded by a rate controlling membrane. Osmotic drug delivery system differs form diffusion based systems in that the delivery of the active agents is driven by an osmotic gradient rather than the concentration of drug in the device


There are over 240 patented osmotic drug delivery systems. Present day osmotic devices are the modified version of Rose Nelson pump.


As described earlier, the system is fabricated by applying a semi permeable membrane around a core of an osmotically active drug or a core of an osmotically inactive drug in combination with an osmotically active salts. It contains at least one delivery orifice in coating semiperemble membrane for the delivery of drug. The orifice is drilled by laser or by a high speed mechanical drill. Insitu formation is also used for making orifices in the system. Hence a water soluble additive is added to the coating membrane blend. The coating membrane so formed when in contact with water leaches the water soluble additive resulting in formation of micro porous membrane.

Osmotic delivery system tends to be unaffected by invivo variables and to exhibit excellent correlation between invivo and invitro release. The offer a precise delivery rate and are not dependent on the physical or chemical properties of the drug substances. The rate of release of drug can be made independent of such variable as PH and agitation rate. When properly designed system exhibit zero order release of the drug because the drug content in the system does not effect the osmotic gradient. The system can be designed to provide a variety of release profile for targeted or systemic delivery, such as increasing or decreasing rate of zero order. The system can also be engineered to control the site of action.


ADVANTAGES

  1. Desired zero order delivery rates is achieved with osmotic systems.
  2. Delivery rate osmotic greater as compared to diffusion based systems.
  3. Delayed or pulsed drug delivery is obtainable with osmotic system
  4. Rate of drug release is independent of gastric ph and hydrodynamic conditions
  5. Release rate is predictable
  6. High degree of invitro-invivo correlation is obtainable


DISADVANTAGES

  1. High cost.
  2. Chances of dose dumping.
  3. Reduced potential for dosage adjustments
  4. Increased potential for first pass clearance
  5. Poor systematic availability in general.


OSMOTIC SYSTEM THEORY



Osmotic system release a therapeutic agent at a predetermined, typically zero order delivery rater based on the principle of osmosis. Osmotic system imbibe water from the body through a semipermiable membrane in to an osmotic materials, which swell resulting in slow and even delivery of drug formulations.



Picture

The semi permeable membrane (A) is permeable to water compartment (C) but impermeable to the solute in compartment (B) when the pressure is equal between (B) and (C) i.e., Po = P, water will permeate through the semi permeable membrane from (C) to (B), reflecting the gradient in chemical potential of the solvent between the two compartments. As the P is increase in (B) the chemical potential of the solvent in (B) increases. When the P in (B) reaches the osmotic pressure p of the solution in (B), the chemical potential in the solvent in the two compartments becomes equalized and net transport of the solvent through the membrane ceases. The osmotic pressure in (B) is,


p = (mC – mB)/V


m = chemical potential of water

V = partial molar volume of water

When the chemical potential is written in terms of activity 'a' of the solvent in B

p = -RT(lna)/V

Grater the gradient in osmotic Pressure, the greater will be the rate of transport of solvent through the membrane.





From monequilibrium thermodynamics, the rate of water transport through the membrane can be written as dv/ dt = (A/h)Lp(sDp - Dp).


Dv / dt - Volume flow of solvent through the membrane

A - Cross sectional area for transport

h - Membrane thickness.

Lp - Hydraulic permeability of the membrane

s - Reflection coefficient

Dp - Osmotic pressure difference across the membrane.

DP - Hydrostatic pressure difference across the membrane


Hydrostatic pressure inside most osmotic drug delivering systems is generally less than 1. That is in comparison with the with the osmotic pressure of saturated solution of most pharmaceutical solutes, the hydrostatic pressure differential is negligible


DP >>DP

dv = (A/ h) k Dp. Where k = Lps, effective permeability of the

dt Membrane


The semi permeable membrane used in most osmotic drug delivery systems exhibit reflection coefficient quite close to 1, in which case k~Lp.


The rate of drug delivery (dm /dt ) from the generic osmotic pump is given by

dm /dt = (dv /dt) C C – concentration of drug

dm /dt = (A /h) k DpC ----------------- (1)


Depending on the system designs, A, h, k, Dp and C may vary with time


dm/dt = [A(t) / h(t)] k(t) Dp(t)(t) ---------------------(2)


For some applications (2) can be written in times of degree of hydrations of the system (H)

dm / dt = ( AH/h) kDpHC --------------------------(3)

Considering (1), (2) & (3) reveals that the a variety of delivery rate profiles (Increasing overtime, decreasing over time or zero order) are possible depending on the specific design of the osmotic system.


In osmotic drug delivery systems commonly used semi permeable membrane are cellulose esters, & polyurethane. The osmotic agent of choice is NaCl. Delivery orifice must be small enough to minimize diffusional fluxes and large enough to prevent pressure buildup.


Oral osmotic drug delivery system:

For most drug products, the oral route remains the predominant and most acceptable mode of administration. Certain molecules have low bioavailability because of solubility or permeability limitations. Development of an extended release dosage form also requires the dmg to have reasonable absorption throughout the length of GI tract. Osmotic tablet technology is the most complex and one that can deliver a zero order or time independent release of long from the dosage form.


Release kinetics: After administration of osmotic system, water is imbibed into the core osmotically through semi permeable membrane executing in development of hydrostatic pressure that pumps drug containing solution or suspension out of the core through one or more delivery parts. The delivery from the system is controlled by the solvent influent through semipermeable membrane.


The release kinetic is expanded as

dmt /dt = APw Dp Cd / H


dmt /dt - Quantity of drug released ever time.

A - Surface area of the coating.

Pw - permeability of semi permeable membrane to water

Dp - Osmotic pressure between core and surrounding fluid.

Cd - Concentration of drug in solution pumped out of the device.

H - Thickness of the membrane.


The desired release kinetics is obtained by controlling 3 functions

  • Osmotic pressure difference across the semipermeable membrane
  • Permeability of semipermeable membrane to water
  • Coating thickness


Classification: Oral Osmotic drug delivery systems are principally classified as

1) Elementary osmotic pump (EOP)) Alza corp , USA)

EOP is the simplest form of osmotic pump. Controlled drug delivering from EOP is affected by water permeation characteristics of semipermeable membrane surrounding the core with or without osmogen and the osmotic properties of the core formulation. EOP is formed by compressing a drug with or without a suitable osmogen, then coated with a semipermeable membrane and a small hole is drilled through the membrane. When exposed to the aqueous environment, the core imbibes water osmotically at a controlled rate, which is determined by the water permeability of the semipermeable membrane and by the osmotic pressure of core formulation. The volume of saturated drug solution delivered is equal to the volume of solvent uptake. The rate of solute delivery by the system is constant as long as the excess of solid is present inside the device but the rate decline parabolically towards zero order, once the concentrative falls below saturation.


2) Push Pull Osmotic Pump (PPOP) (ALZACORP. USA)


It is a bilayered tablet coated with a semipermeable membrane. Drug osmogent is present in the upper compartment & lower compartment consist of polymeric osmotic agent. A delivery orifice is drilled on the drug side of the tablet. When the system comes in contact with the aqueous environment, polymeric osmotic layer swells and pushes the drug layer there by delivering the drug in the form of a fine dispersion via the orifice.


3) Controlled Porosity Osmotic Pump (CPOP)


CPOP contains water soluble addictives (Dimethyl sulfone, Nicotinomide) in the coating membrane, which after coming in contact with aqueous environment dissolves and results in formation of micro porous membrane. The resulting membrane is substantially permeable to bath water and dissolved solute. The drug release from this type of system is independent of PH and follow zero under kinetics.


4) Liquid Oral Osmotic System (L-OROS) (ALZA Corp, USA)

The device containing three lamina

  • Rate controlling membrane
  • Osmotic layer
  • Soft gelatin capsule

During operation, water permeates across the rate controlling membrane and causes expansion of the osmotic layer resulting in to development of hydrostatic pressure inside the system which forces the liquid formulation out of the delivery orifice.


5) Sandwiched Osmotic Tablets (SOTS) (Andrx Pharma)


SOTS consist of a middle push layer in the core, attached to two drug layer coated with a semipermeable membrane, having two delivery orifices, one on each side of the drug layer. When placed in the aqueous environment, the middle push layer composed of an osmotic polymer swells and the drug is released from the two delivery orifice on two opposite sides of the tablet.


6) Colon Targeted Oral Osmotic System (OROS-CJ) (Alza. Corp, USA)


It is a two component pharmaceutical system continuing

  • Hard gelatin capsule coated with a semipermeable polymer membrane.
  • Enteric coated PPOPs, vary from five to six in numbers, which are filled in to hard gelatin capsule.


After administration, when the system comes in contact with GI fluid, gelatin capsule dissolves while the enteric coating prevents the operation of PPOP in the stomach. The enteric waiting dissolves as the system enters the small intestine. Water is imbibed and the push compantinent swells causing the delivery of drug at a controlled rate governed by the nature of the semipermeable membrane.


7) Osmotic Matrix Tablet (OSMAT) (Shine labs, USA)


This type of system utilizes the swellings property of hydrophilic polymer, which swells and gells in aqueous medium forming a semipermeable membrane insitu. The release from this system is affected by inclusion of osmogent with a matrix delivery of drug from OSMAT is independent of agitation & is low coast technology.

Basic design of Oral Osmotic Tablet(OROS)











It works on the principle of osmotic pressure to release the drug at a constant zero order rates. A corresponding of drug and osmotically active substances such as Kcl or manitol is surrounded by a rigid semipermeable membrane coating such as cellulose ester or cellulose ether having an orifice of 0.4 mm diameter produced by laser beam for drug exit. When exposed to GI fluids, water flows through the semipermeable membrane in to the tablet due to osmotic pressure difference which dissolves the drug and pump it out through the orifice by the osmotic force. Such devices can be used to target specific areas of the GI. The OROS principal can be used to design multiunit dosage forms consisting of drug core particles coated with a water permeable membrane in which the delivery orifice is made by using a channeling agent such as PVP and the coated particles filled in a capsule. Rate controlling factors are orifice diameter, Membrane area, membrane thickness, membrane permeability, Osmotic properties of the core, Drug solubility etc.


FORMULATION PARAMETERS

1) Drug solubility: Drugs with high and low water solubility do not form a good candidate for osmotic delivery. Solubility modulators can be used to modify the solubility of drug particles. eg: Diltiazem hydrochloride, which is highly water soluble, is predominantly released by first order kinetic rather than zero order kinetics . So NaCl is used as solubility modulator so that 75% of drug is released by zero order kinetics other substance like cyclodextrins, effervescent mixtures etc are also used as solubility modulators.

2) Osmotic Pressure: Drugs selected as candidate for osmotic system, should posses Osmotic as the release rate of drug from osmotic system is directly proportional to the osmotic pressure of the core formulation. If the dmg does not posses sufficient osmotic p, a osmogent like NaCl, Glucose, Sucrose, Glycine etc. is to be added in the core formulation to control the release of dmg from the osmotic system.

3) Delivery Orifice: Delivery orifice is created in the osmotic system either by mechanical drilling or laser drilling in the semipermeable membrane of the system. In case of CPOP the instu pore formation take place depending on the concentration of the pore forming agent in the polymeric solution. The size of the delivery orifice has to be optimized as a small delivery orifice is too small, the hydrostatic p may not be released causing deformation of the system or unpredictable dmg release profile, while if delivery orifice is too large, solute diffuse in may take place.


4) Polymers used: The polymers used should be semipermeable in nature. The polymers commonly used for this purpose are cellulose ester such as cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose propionate and cellulose acetate butyrate. Swellable polymers are used in osmotic system for poorly soluble drugs. Eg: vinyl pyrrolidone,polyethylene oxide.


5) Advantages:

1) Desired zero order delivery rates is achievable with osmotic system.

2) Delivery rate with osmotic is greater as compared to system based on diffusion of comparatable size.

3) Delayed or pulsed drug delivery is obtainable with osmotic system.

4) Constant rate of drug release independent of gastric PH & hydrodynamic condition is obtainable

5) Release rate from osmotic system is highly predictable

6) Osmotic system can be formulated for drugs having extremes of water solubility.

7) Osmotic system can be designed to deliver liquid formulation as well.

8) High degree of invitro-invivo correlation is obtainable.

OROS system for verapmit: A controlled release osmotic device containing verapmit intended for dosing at bed time for releasing verapmil to coincide with an early morning rise of BP associated with hyper tension and angina is prepared by the following steps

a) Formulation and preparation of active drug layer:

Verapmit hydrochloride 600g

Poly ethylene oxide 305g

NaCl 40g

Poly vinyl pyrolidone 50g

Magnesium stearate 5g


All ingredients except magnesium stearate were granulated with anlydrous ethanol. The dried granules were lubricated with magnesium stearate. This procedure provides granules for active drug layer.

b) Formulation of preparation of Osmotic layer.

Poly ethylene oxide 735g

NaCl 200g

Methocel E5 50g

Ferric oxide 10g

Magnesium stearate 5g


All ingredients except magnesium stearate were granulated with anlydrous ethanol. The dried granules were lubricated with magnesium stearate. This procedure provides granules for osmotic layer


c) Preparation of bilayer core: A bilayer core tablet comprising an active drug layer and an osmotic layer was prepared in a tablet press. A subcoat may be applied on the bilayer core tablet using enteric coating materials.


d) Formulation & preparation of semipermeable wall:

Cellulose acetate 55%

Hydroxy propyl cellulose 40%

Poly ethylene glycol 5%

All ingredients in the formulation are dissolved in 80% acetone & 20% of methanol. The bilayer tablets were coated in water. Two orifices were drilled on the side of the device containing the active dmg.






IMPLANTABLE OSMOTIC DMG DELIVERY SYSTEMS:


DUROS IMPLANTS : DUROSE technology is a miniature drug dispersing system that operators like a miniature syringe and release minute quantities of concentrated drug formulation in a continues consistent flow over months or years. The system is implanted under skin.


System design: It consists of an outer cylindrical titanium alloy reservoir. This reservoir has high impact strength and protects the drug molecules from enzymes, body moisture and cellular components that might deactivate the drug prior to delivery. At one end of the reservoir is positioned the membrane, constructed from a specially designed polyurethane polymer. Positioned next to the membrane is the osmotic engine. The engine contains primarily NaCl, which is combined with other pharmaceutical excipients in tablet from. Next to the engine is the piston. The piston is made from elestomeric materials and serves to separate the osmotic engine from the drug formulation in the drug reservoir compartment. At the distal end of the range from simple. Straight channels to more complicated design configurations.


The drug formulation is contained in the drug reservoir compartment. The drug formulation may be either a solution or suspension DUROS drug solution may both aqueous or nonacqueous in nature. DUROS drug formulation must exhibit at body temperature for extended period of time. Usually 3 months to 1 year it is possible to develop stable formulation of protein and peptides. Because the DUROS system dispenses such small amount of formulation per day, organic solvent such as benzyl alcohol or DMSO can be delivered with out concern for adverse patient effects. All materials in the DUROS system were chosen for their biocompatibility and suitability for implant use.


The orifice was designed with a small inner diameter and a suitable length so that the diffusional contribution to the rate of release of drug is minimized at low delivery rate


System configuration: The release rate and duration of a DUROS implant depend on the drug concentration, the overall system and reservoir size and the membrane and osmotic engine design. Altering the membrane permeability can change the release rate and system duration. Eg the 4mm diameter by 45mm length DUROS implant has been developed to achieve 1,2.3.5 and 12 months duration system to accommodate less potent molecule and their higher therapeutic doses, implants with larger drug reservoir volumes can be designed eg. A larger implant lasting 12 months could deliver 1.4 micl/ day of a 100mg/ ml drug formulation similarly a drug formulation at 400mg/ml could deliver 560micg/ day
( 20mg/implant).

Implantation: The preferred site of implantation is subcutaneous placement in the inside of the upper arm. When implanted a large, constant osmotic gradient is established between the tissue water and the osmotic engine. For system administration in the DUROS system is implanted subcutaneously in an outpatient setting with local anesthesia removal at the end of the delivery period is accomplished by an outpatient procedure. Implant is also adaptable to other site of administrations like i.v, intrathecal and other forms of targeted drug delivery systems.


Working: The DUROS implant functions according to the osmotic principal. In operation, water is drown through the membrane in response to a osmotic gradient between the osmotic engine and moisture in the surrounding interstitial fluid. The rate of water influx is governed by the permeation characteristic of the semipermeable membrane. As water flows into the DUROS implant the osmotic engine expands as it imibibes water and excerts a p on the piston. The rescuping movement of the pistone delivers dmg formulation from the orifice at a rate corresponding to the rate of water permeation.


Release kinetics: The rate of dmg delivery from the Duros system is described as


Dm/ dt = KDPAC

h

dm / dt - dmg delivery status

K - Effective hydrolic permeability

DP - Osmotic p difference across the membrane

A - Membrane surface area

H - membrane thickness

C - Dmg concentration in the reservoir


For constant delivery rate applications steady delivery results because:


  • It is constant because the membrane has been shown not foul or change permeability during delivery
  • DP is constant because the osmotic engine is formulated with excess NaCl.
  • A 7 h are constant by design
  • C is constant for a stable dmg formulation.


'K' can be varied by controlling the properties od f the polyurethane co-polymer in the rate controlling membrane. In this maner, system dimations can be varied from 1 months to 1 year. At a fixed k, dmg delivery rates can be varied by adjusting c, the dmg concentration in this manner a variety of dosage strength of fixed dimation can be produced.


The equation for delivery from osmotic system can be written in a more detailed form, to demonstrate the effect of backup a delivery arte as follows


Dm/dt = K(Dp-p)A

h

p - Pressure inside the DUROS system.

Backpressure inside the DUROS system are generally at most several himdred psi. hence the impact of backpressure on the water imbibitan rate is negligible. This property gives the DUROS technology the capability to deliver visicus suspensions formulations.


APPLICATIONS OF DUROS TECHNOLOGY

1) Chromogesi TM (sufentanil) pain therapy system


To address the needs of chronic pain sufferers, Duros technology has been applied to the delivery of the opoid dmg sufentanil. The rescuing chronogesic TM pain therapy system is designed to deliver the dmg at physician specified doses for 3 months, and is targeted to patients with opioid responsive chronic pain that results from a variety of causes. The system has approximately the size of a wooden match stick. The dmg formulation consist of a solution of sufentamil free base in benzyl alcohol. Varying the concentration results in four system strength, with delivery rate ranging from 3.3mg/d to 13.3mg/d(nominal). Studies have demonstrated acceptable formulation stability at 400c (Greater than 3 months) and at 250c (12 months study ongoing). The chronogesic system isimplanted in the inside of the upper arm using a specially designed sterile implanter. CHRONOGESIC also. Demonstrated improvement in select side effects when compared to prestudy medications figure presents the invitro release performance four different dosage strengths of the chronogentest tubes containing phosphate buffered saline them stated at 370c. at specified time internal, the system were placed in to new test tubes containing fresh phosphate buffered saline prewamed at 370c. the amount of dmg released in to the saline was quantified using a reverse phase HPLC method. After an initial start up period, the chonogeric system released sufentanil at steady zero order duration.


2) Targeted dmg delivery with catheterized osmotic pump.

Catheters of different designs can be attached to the exit port of an osmotic pump for targeted dmg delivery. A number of organs and tissues have been evaluated as target sites in various animal models using Alzet osmotic pumps. Catheter should be flexible, compatable with target6ed tissues / organs and monreactive with and now absorptive towards dmg solution. The most commonly used materials for catheters include silicone elastomers and polylefin polymers such as low density p dyethylene. Pharmacological agents for targeted delivery include various small molecular weight dmgs as well as peptides and proteins. The most common. catheter material for site specific dmg delivery using Alzet with a catheter has been a low density polyethylene tubing(PE60)


3) Site specific dmg delivery using Duros with a precision minature catheter.


To delivery dmg to a specific target site, a proprietary miniaturized catheter is attached to the Duros system to direct the follow of dmg directly to the target organ or tissues. The precision, miniature size and performance characteristic of the Duros system will allow for continues site specific delivery to a variety of precise locations with in the body . two examples are described as follows:

a) Duros interathecal ipioid delivery system: interathecal delivery of opioids dmgs likemerphine, hydromerpine is indicated for a number of chronic pain conditions chronic back & legpain, chronic cancer pain, painful neuropathy etc. there dmg is directly delivered in to the intrathecal space surrounding the spinal and using DUROS system, significantly smaller doses of the dmg are required to elicit pain relief. The system is surgically implanted subcutareously near the target site of dmg administration. The catheter is attached to the DUROS system & turneled under the skin to the site where opioid is to be delivered. The direction of dmg delivery is approximately 3 month. The proprietary catheter has an hold up of about 20ml.

b) Duros intratumoural delivery of antineoplastic agents:

antineaplastic agents are delivered in to the brain system for local or site specific of actrons. This delivery increase the concentration dmg at the tumour target, increase the concentration of exposure of tumor to the dmg, decrease the systemic exposure and toxicilies. Extreme caution must be taken and method used is the insertion of a catheter in to the pons of the brain stem for intratumoural chemotherapy.


4) DUROS leuprolide:

it is implanted subustaneously in the inner aspect of the upper arm for providing palliative treatment of adrrameed prostate cancer. After an year it is removed and replaced with new system.


5) Salmon calcitonin:

Salmon calcitonin formulation at 50mg/ml in neat DMSO has been delivered from a DUROS implant(150ml – reservoir) at approximately 0.4ml/day. The system is used for the treatment of osteoporosis and pagets disease.


6) a -interferons:

a-INF have antiviral & antiproliferabile activities and is used for the treatment of Thepatitisc assuming a 150mldmg reservoir and a 3 month duration the formulation concentradiou required for a patent dose is 5-10mg/ml. however a-INF is not stable as a solution, so suspension form is suitable. Nasacqus suspensions provides an alternative for dmgs with stability limitations. Eg: lyophillised a -INF was suspended at 5mg/ml in perffurodecalin and stored at 370c for 1 year. Lyophillised material is too large to be efficiently pumped from a DUROS implant, so spray dried particles are used in release rate studies


7) Factor IX:

it is a serive protease in the clotting cascade used in treatment of tharmophibia B. implantable dosage of factor IX would be suitable for pediatric cases, resulting in maximum of 500iv/day 12mg/day).A catheter would be needed since it is administrated by I V.




ALZET OSMOTIC PUMPS


System designs: it is a miniature implantable researclo dmg delivery system for lasonatory animals. The pumps are designed to deliver homogenous solutions or suspension continuosly at a controlled rate for extended periods. The pumps are capsule shaped and range from 1.5 to 5.1 in length and 0.6 – 1.4 in diameter.


Alzet osmotic pumps are composed of three concentric layers; the dmg reservoir, the osmotic sleeve and the rate controlling semipermeable membrane. The dmg reservoir is a cylindrical cavity molded from a synthetic hydrocarbon elastomer with an orifice for dmg delivery. The reservoir walls are impermeable to water and thus prevent migration of chemical muities between the dmg reservoir and the osmotic sleeve. An osmotic sleeve containing NaCl surrounds the dmg reservoir. The outermost layer is composed of a rigid semipermeable membrane made of cellulose ester blend. At the orifice end, a flow moderator with a 21 –gage stainless steel tube is inserted in to the body of the osmotic pump after filling. The follow moderator minimizes passive diffusion and corrective losses and reduces the effect of air bubbles trapped in the dmg solution. A catheter can be attached to the low moderator.


System configuration : Alzet pumps deliver at fixed rates between 0.25 and 10ml/h for 1 day to 4 weeks invivo and invitro delivery rates from alzet pumps are in this 5% of each other.

Implantation: ALzet pumps are commonly implant subcutaneously or intraperitonally. However pump have also been used for intracerebral, i.v and in the arterial delivery as well as targeted delivery to the spinal card, spleum and liner. Local delivery may be appropriate for potent proteins, immunotherapy and antisense and gene therapy, when systemic administration may toxic to tissues and cells.

Formulation parameters: Optimal formulation for Alzet pumps must be compatible with the dmg. The pump reservoir and the site administration Alzet pump reservoir are compatible with buffers, acidic and basic aqueous solutions, 2% tuleen and cosolvent mixture containing DMSO, ethanol, glycerol, propylene glycol or polyethylene glycol, 300 but they are not compatible with most natural oils. The solution formulation should be at room T so that pumps can be filled without generating trapped air bubbles. Viscous dmg solution and homogenous suspensions can be administered care should be taken to ensure dmg stability, sterility and isotovicity so tht degradation, microbial contamination and inflammation do not owners.

Working: when the pumps is laced in an aqueous enviorment, water is transported across the semipermeable membrane in to osmotic sleeve. As the osmotic sleeve imbibes water it swells, generating pressure to collapse the flexible dmg reservoir. Therefore the delivery rate of an Alzet pump is determined by the rate at which water crosse the semipermeable membrane and enters the osmotic sleeve. The rate of water influx in to the osmotic sleeve is inturn dependent on the permeability and dimensions of the semipermeable emembrane, this rate is also affected by the T and osmotic P difference across the membrane. The difference in the osmotic P between the osmotic sleeve and the surrounding interstitial fluid( or implantation) consist the osmotic gradient. The osmotic cleaning agent (NaCl) maintains a constant osmotic gradiet for the dination of dmg delivery. In turns, the osmotic gradient drives the water through the membrane, swelling the osmotic sleeve, collapsing the reservoir and delivery dmg from the reservoir at a controlled rate.


Applications: Alzet pumps have been used to deliver a range of small and large molecules in a wide variety of animal species. Pumps have been used to deliver human growth hormones, bombastic panatly rid hormones etc. followings are some application of Alzet pumps

  1. Antisene oligonucleotides: treatment of malignancies with antisense oligonucleotides can dounregulated gene expression and retard tumor growth. Administration of Oligonucleotides via an osmotic pump provides zero order release, thus counteracting the rapid degradation and clearance of these molecules inbiological system. Pump were filled with 5mm acquous solution of oligonucleotides with a perfusion rate of 0.5 mg/h, flow was directed to the tumor size for 2 weeks. The mean tumor mass was 50% smaller in the anti sense treats animals than in the animal treated with sense oligonucleotides. Anti sense therapy has also been targeted in tumor regression a reduction in tumor size
  2. Nerve growth factors: nerve growth factors(NGF) is iritical for the normal development and maintenance of te peripheral sympathetic and peripheral ganglia. Continuous administration of NGF to the CNS significantly reduced retrograde neuronal death of septal sholinegic nervous after injury. NGF(250mg/ml 2.5s) was dissolved in saline and continuously infused in to the lateral vertical of rates for 2 weeks at 0.5 ml/h(Alzet model 2002) with the aid of an infusion cermula. After pump explanation at the end of the study, the remaining NGF was arrayed and was found to have retained activity. Following a 2 weeks infusion of NGF, identification of Cholinergic nervous revealed at 350% increase in the survival of axotomised septal cgolinergic nervous.
  3. Inert leulines: inetrleulin 6 is a multifunctional cytoine that acts as a signal for lymphocyte activation and most deference mechanism for the immune system, it was administrated subcutaneously to rats for 1 mint (Alzetmodels 2L2 and 2mL4) after an adjuvant njection was given to induce an arthnitis. Conscious infusion of it 6 significantly (P,0.05) reduces adjivant arthritis.
  4. Octreotide: Expression of somatostatin receptors on human tumors, including neuroendocrise, lung and breast malignancies has been documented. Alzet pumps were implanted subaitaneously in mice and delivered 0.5 ml/h octreatide. An analog of somatostatin for 2 week. Growth of human breast tumor was significantly inhibited in mice with pumps unpared with that in mice given octreotide injections or in no treated controls. Continuous infurim of 10mg/kg/h octreotide yielded plasma levels of 5.7 mg/ml, with a mean tumor volume 37% of that of the control animals at 1 months


Osmotic dmg delivery system for poorly soluble dmgs:


Osmotic dmg delivery system utilize osmosis as the major driving force for dmg release adequate water solubility of the dmg is a pre requisite for osmotic dmg delivery system. This was major factor limiting the use of such systems for poorly soluble dmgs. However various approaches have been designed to modify the basic system to combat this limitations. These mainly include increase in water flur through the use of high peemableility polyurethane membrane, Zer-os tablet technology, osmagent coated with elastic semipermeable membrane, microporus coats, permseeetive and asymmetric membrane coating etc.


POORLY SOLUBLE DMGS AND OSMOTIC DMG


Delivery:

OROS- Push -pull:

The Oros push pull system was developed at ALZA to overcome the challenge of delivering poorly soluble dmgs using Osmotic dmg delivery. The push pull system comprises a bilayer or trilayer tablet are consisting of are push layer and one or more dmg layer. The dmg layer contains the poorly soluble dmg. The osmotic agents and suspending agents. The push layer contains among other things, osmotic agents are water soluble polymers. A semipermeable membrane surrounds the tablet core and an orifice drilled in it on the dmg layer side. Upon ingestion of the push pull system, water is drown in to the dmg layer, where the dmg is suspended in the fluid. The push layer expands when water is drawn in due to the presence of water soluble polymers. The expanding push layer deliver the dmg surpension through the exit orifice at a controlled rate in the GI tract. The dmg is then required to be dissolved in the GI fluid before absorbed into the system circulation.


L-OROS: to overcome the dmg solubility issue AIZA developed the L-OROS system where a liquid softgel product containing dmg in a dissolved state is initially manufactured and then coated with a banier membrane, then an osmotic push layer and then a semi permeable membrane drilled with an exit orifice.


Ensotrol: Shire Laboratories uses an integrated approach to dmg delivery focusing an identification of barriers to oral drug delivery screening of enhancers to overcome the identified barriers and incorporation of the identified enhancers in to controlled release technology to create an optimized dosage form. The Ensotrol osmotic delivery system for poorly soluble dmgs consist of a single layer tablet core surrounded by a semipermeable membrane. The membrane is drilled with an exit orifice, the tablet core include the dmg, osmotic agent, wicking agent and solubility enhancers to help to dissolve the dmg. When the Ensotrol tablet is swallowed water enters the core through the membrane. The presence of the solubility enhancers in the core helps to dissolve the exit orifice to the GI human where it can be absorbed in to the systemic circulation.


To test the Ensotrol technology, a phase clinical study was conducted in a group of 18 subject's comparing 60mg infediphine in an Ensotrol formulation with procardia XL containing 60mg nifediphine in an OROS push pull system, the mean plasma profile from the two products and shown in figure 10.



SOME MARKETED OSMOTIC DOSAGE FORMS


PRODUCT NAME

ACTIVE DRUG

DESIGN

DOSE

Acutrim

Phenyl propanolamine

Elementary pump

75mg

Alpress LP

Prezosin

Push – pull

2.5,5 mg

Cardira XL

DOXAZIN

Push – pull

4,8 mg

Covena HS

Verapamil

Push – pull with time delay

180, 240mg

Ditropan XL

Oxybutyninchloride

Push – pill

5, 10 mg

Dynacirc CR

Isradipine

Push – pull

5, 10mg

Efidac 24

Pseudo ephedrine

Elementary pump

60mg IR,180mg CR

Efidac 24

Chlorpheneramive maleate

Elementary pump

4mg IR, 12mg CR

Volm ax

Albut rol

Elementary pump

4,8 mg

Procardia X2

Nofedipine

Push pll

30, 60,090mg


Evaluation of osmotic dmg delivery system:


Invitro evaluation : The invitro release of dmgs from oral osmotic system has been evaluated by conventional USP paddle and basket type apparatus Vs patent, described standard dissolution apparatus and commercial applied analytical standard dissolution apparatus.


The dissolution medium is generally distilled water as well as gastric fluid (for first 2-4 hours) and intestinal fluid (for subsequent hours) have benn used.


The standard specification, which are followed for the oral controlled dmg delivery can be for oral osmotic pumps


Invivo evaluavtion


This evaluation has been usually camed out in dogs, moneys can also be used. But in most cases dogs are preferred.


Osmotic were evaluated for following parameters namely


  • Physical appearance
  • Dimensions
  • Hardness
  • Friability
  • Invitro dmg release
  • Type of polymer used
  • Concentration of polymer
  • Concentration of osmo agent
  • PH modulating agent on release rate.


Grarimetric erosion studies were also performed in some selected formulations. Influence of dissolution medium, osmotic P, and agitation on dmg release was also investigated


Future trands:


Drug delivery in general will continue to see significant growth in the pharmaceutical industry corporation of dmg delivery concepts such as bioanailabilty enhasment and controlled release in to the development of new chemical entilies(NCE) is the logical steps.


Conclusion:

Osmotic dmg delivery system as a dosage form for controlled delivery of dmg has gained popularity over time because of the potential advantages like zero order delivery rate, no affect of gastric PH & hydrodynamic conditions on release rate etc. osmotic dmg delivery system provides a means for modulating solubility and osmotic pressure of dmgs on the care by varying the formulation factors


Alzet pump and Duros implant offer a relatively smooth pharmacokinetic profile as compared with traditional bolus dosing methods. The Alzet pump and Duros implant can deliver dmg at controlled rates within the therapeutic range for long periods. The Alzet pump and Duros implant were designed for the delivery of pharmaceutically active compounds in lab aratomy animals and in human application respectively. Both systems have benn shown to exhibit excellent invivol invitro delivery rate correlation, enabling accurate prediction of delivery rates prior able to protect biomolicules prior to the delivery


Conclusion:


Osmotic combining both osmotic and erosion characteristic judiciously improved control of release kinetics of porly soluble mgs. Osmat thins represents asimle, easy to fabticate, versatile, osmotically driven controlled dmg delivery system based an low cost technology. Osmotic technology produce a slightly higher cost of goods than matrix tablets or multiparticular in capsule dosage from.

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Oral Drug Delivery Market