by Dr. Shruti Bhat

 

B.  Controlled Drug Release by Activation:

i)  Osmotic Pressure-Activated Drug delivery

A brief of osmotically active systems have already been discussed in Part I of this article.  Osmotically acting implantable device can be represented by Alzet Osmotic Pump.

Alzet Osmotic Pump  

In such a device, the drug reservoir is contained inside a collapsible, impermeable polyester bag, whose external surface is coated with a layer of osmotically active salt.  This reservoir compartment is then sealed inside a rigid housing walled with semi permeable polymer membrane.  At the implantation site, the water content in the tissue fluid will penetrate through the semi permeable membrane to dissolve the osmotically-active salt, creating an osmotic pressure in the narrow spacing between the flexible reservoir wall and the rigid semi permeable housing.  Under the osmotic pressure created, the reservoir compartment is reduced in volume and the drug solution is forced to release at a controlled rate through the flow moderator.  By varying the drug concentration in the solution, different amounts of drug can be released at constant rate, for a duration of 1-4 weeks.  Table 1 enlists few drugs delivered by miniature osmotic pumps.

ii)  Vapor Pressure-Activated Drug Delivery :


In this mode of controlled drug delivery, the drug reservoir, in a solution formulation, is controlled inside an infusate chamber, which is physically separated from the vapor chamber by a freely movable bellow.  The vapor chamber contains a vaporizable fluid, e.g. fluorocarbon, which vaporizes at body temperature and creates a vapor pressure.  Under the vapor pressure created, the bellows moves upward and forces the drug solution in the infusate chamber to release, through a series of flow regulator and delivery canal, into the blood circulation at a constant flow rate.  A typical example is the development of Infused, an implantable infusion pump, for the constant infusion of heparin for anticoagulation treatment, of insulin for antidiabetic medication and of morphine for patients suffering from the intensive pain of terminal cancer.

iii) Magnetism-Activated Drug Delivery


Macromolecular drugs, such as peptides, have been known to release only at a relatively low rate from a polymeric drug delivery device.  This low release rate has been improved by incorporating a magnetism triggering mechanism into the polymeric drug delivery device and a zero-order drug release profile has also been achieved by a hemisphere shaped geometry design.  By combining these two approaches, a subdermally implantable, magnetic-modulated hemispheric drug delivery device has been developed.  It is fabricated by positioning a donut-shaped magnet at the center of a biocompatible polymer matrix, which contains a homogeneous dispersion of macromolecular drugs at a rather high drug to polymer ratio to form a hemispheric magnetic pellet.  The hemispherical pellet is then coated with a pure polymer e.g. ethylene-vinyl acetate copolymer or silicone elastomers on all sides, except the cavity at the center of the flat surface, to permit the release of macromolecular drug only through the cavity.


iv) Ultrasound-Activated Drug Delivery

It was recently discovered that ultrasonic wave can also be utilized as an energy source to facilitate the release of drug at a higher rate from polymeric drug delivery device containing a bioerodible polymer matrix.  The potential application of ultrasonic wave for the modulation of drug release is still undergoing evaluation.

v)  Hydrolysis-Activated Drug Delivery

This type of implantable therapeutic system is fabricated by dispersing a loading dose of solid drug, in micronized form, homogeneously through a polymer matrix made from bioerodible or biodegradable polymer, which is then molded into a pellet - or bead-shaped implant.  The controlled release of the embedded drug particles is made possible by the combination of polymer erosion through hydrolysis and diffusion through polymer matrix.  The rate of drug release is determined by the rate of biodegradation, polymer composition and molecular weight, drug loading, and drug / polymer interactions.


For inquiries contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com

by Dr. Shruti Bhat

 

A.    Controlled Drug Release by Diffusion:

1.  Membrane Permeation-Controlled Drug Delivery :

In this mode of controlled drug delivery, the drug reservoir is encapsulated within a compartment totally enclosed by a rate-controlling polymeric membrane.  The drug reservoir can be either solid drug particles or a dispersion (or a solution) of solid drug particles in a liquid - or a micro porous (or a semi permeable) membrane.  The encapsulation of drug reservoir inside the polymeric membrane can be accomplished by molding, capsulation, micro encapsulation, or other techniques.  Different shapes and sizes of drug delivery devices can be fabricated.

Representatives of this type of implantable therapeutic systems are Progestasert IUD and occusert system already discussed in Part I of the article.

 
2.  Matrix Diffusion-Controlled Drug Delivery :

In this mode of controlled drug delivery, the drug reservoir is formed by homogeneous dispersion of solid drug particles throughout a lipophilic or hydrophilic polymer.  The dispersion of solid drug particles in the polymer matrix can be accomplished by blending solid drugs with a viscous liquid polymer or a semisolid polymer at room temperature, followed by cross linking of polymer chains, or by mixing solid drugs with a melted polymer at an elevated temperature.  These drug-polymer dispersions are then extruded to form drug delivery devices of various shapes and sizes.  It can also be fabricated by dissolving the solid drug and / or the polymer in a common organic solvent followed by mixing and solvent evaporation in a mould at elevated temperature and / or under vacuum which defines the flux of drug release at a steady state from a matrix diffusion-controlled drug delivery device.  Representative of this type of implantable therapeutic system are:

a) Contraceptive Vaginal Ring

It is fabricated by dispersing a contraceptive steroid, e.g., medroxyprogesterone acetate, as micronized solid particles in a viscous mixture of silicone elastomer and catalyst and then extruding vaginal ring.  It is designed to be inserted into the vagina and positioned around the cervix for 21 days to achieve a constant plasma progestin level and cyclic intravaginal contraception.

b)  Syncro-Mate-B Implant

It is fabricated by dissolving norgestomet crystals in an alcoholic solution of ethylene glycomethacrylate (Hydron S) and then polymerizing the drug-polymer mixture by the addition of a cross linking agent, such as ethylene dimethacrylate, and an oxidizing catalyst to form a cylinder-shaped insoluble Hydron implant.  This tiny subdermal implant is engineered to be inserted into the subcutaneous tissue, using a specially designed implanter to release norgestomet at a rate of 504 mcg/cm2 /day1/2 for up to 16 days for estrus control and synchronization in livestock.

c)  Compusode Implant

It is fabricated by dispersing micronized estradiol crystals in a viscous mixture of silicone elastomer and catalyst and then coating the estradiol-polymer dispersion around a rigid silicone rod by extrusion technique to form a cylinder-shaped implant.  This subdermal implant is designed for subcutaneous ear implantation. It steers for 200 to 400 days and to release a controlled quantity of estradiol for growth promotion.

In the next chapter, we shall discuss further on this topic of different rate controlling parameters for implant delivery systems.


3.  Microreservoir Dissolution-Controlled Drug Delivery

In this mode of controlled drug delivery, the drug reservoir, which is a suspension of drug crystals in an aqueous solution of a water miscible polymer, forms a homogeneous dispersion of millions of discrete, unleachable, microscopic drug reservoir in a polymer matrix.  The micro dispersion is accomplished by high-energy dispersion technique.  Different shapes and sizes of drug delivery devices can then be fabricated from this micro reservoir-type drug delivery system by molding or extrusion technique.  Depending upon the physicochemical properties of drugs and the desired rate of drug release, the device can be further coated with a layer of biocompatible polymer to modify the mechanism and the rate of drug release.

Representatives of this type of drug delivery devices are: -

a)  Syncro-Mat-C Implant

It is a cylindrical implant with improvement in both release rate profile and cost saving over the Syncro-Mate-B implant discussed earlier.  It is fabricated by dispersing the drug reservoir, which is a suspension of norgestomet in an aqueous solution of PEG 400, to form millions of microscopic drug reservoirs in a viscous mixture of silicone elastomers by high-energy dispersion technique.  After the addition of catalyst, the resultant composition is delivered into a silicone medical-grade tubing, which serves as the mould as well as the coating membrane, by extrusion technique and is polymerized in situ.  The polymerized solid drug-polymer composition is then cut into cylinder-shaped drug delivery device with open ends.  This tiny subdermal implant is designed to be inserted, by a specially designed implanter, and to deliver norgestomet in the subcutaneous tissue in livestock’s earflap for up to 20 days for the control and synchronization of estrus and ovulation.

b)  Dua-Release Vaginal Contraceptive Ring

It is fabricated by dispersing the drug reservoir, which is a suspension of a progestin and an estrogen in an aqueous solution of PEG 400, to form many microscopic drug reservoirs in a viscous mixture of silicone elastomers by high-energy mixing technique.  After addition of catalyst, the resultant composition is extruded into a mould, by extrusion technique, and is polymerized by heat to form a donut-shaped vaginal ring.  It is designed to permit the user to insert the ring themselves and to release both progestin and estrogen, at a specific rate ratio, in the vagina for 21 days to achieve a cyclic intravaginal contraception.

For inquiries contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com

by Dr. Shruti Bhat

Controlled Release Drug Delivery System - definition, types, factors impelling transition to rate control delivery systems, classification and design of CRDDS, per oral CRDDS, dental, ocular, and intravaginal / intrauterine controlled release systems have already been dealt with in Part I of the series.

The present series i.e. part II, encompasses Implantable, Injectable CRDDS, Analytical controls and Regulatory considerations of CRDDS and Novel CRDDS

 
1)  IMPLANT CONTROLLED RELEASE DELIVERY SYSTEM :

Lafarge pioneered in 1861, the concept of  implantable therapeutic systems for long-term, continuous drug administration with the development of a subcutaneously implantable drug pellet.  The technique was then rediscovered in 1936 by Deanesly and Parkes, who administered crystalline hormones in the form of solid steroid pellets to mimic the steady, continuous secretion of hormones from an active gland for hormone substitution therapy.

Approaches to development of implantable therapeutic systems:

Historically, the subcutaneous implantation of drug pellet is known to be the first medical approach aiming to achieve prolonged and continuous administration of drugs.  Over the years, a number of approaches have been developed to achieve controlled administration of biologically active agents via. Implantation of insertion in the tissues.  These approaches are outlined as follows:

A.  Controlled drug release by diffusion  

    1.  Membrane permeation-controlled drug delivery using:

            a.  Nonporous membranes

            b.  Micro porous membranes

            c.  Semi permeable membranes

    2.  Matrix diffusion-controlled drug delivery using:

            a.  Lipophilic polymers

            b.  Hydrophilic (swellable) polymers

            c.  Porous polymers

    3.  Micro reservoir dissolution-controlled drug delivery using:

            a.  Hydrophilic reservoir / Lipophilic matrix

            b.  Lipophilic reservoir / Hydrophilic matrix

B.  Controlled drug release by activation  

    1.  Osmotic pressure-activated drug delivery

    2.  Vapor pressure-activated drug delivery

    3.  Magnetism-activated drug delivery

    4.  Ultrasound-activated drug delivery

    5.  Hydrolysis-activated drug delivery

 
An ideal implantable therapeutic system should be with minimal tissue-implant interactions, nontoxic, non-carcinogenic, removable if required and should release the drug at a constant, programmed rate for a predetermined duration of medication.  The polymers used in the therapeutic system must not cause irritation at the implantation site, or promote infection or sterile abscess.  The most common polymers used are hydrogels, silicones and biodegradable materials.

In the next chapter, we shall take up different types of rate controlling methods for implant delivery systems.
 

For inquiries, contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com .

By Dr. Shruti Bhat

Sustained and controlled-release devices for drug delivery in the vaginal and uterine areas are most often for the delivery of contraceptive steroid hormones.  The advantages in administration by this route--prolonged release, minimal systemic side effects, and an increase in bioavailability-- allow for less total drug than with an oral dose.  First-pass metabolism that inactivates many steroids hormones can be avoided.

One such application is the medicated vaginal ring.  Therapeutic levels of medroxy progesterone have been achieved at a total dose that was one-sixth the required oral dose and ring expulsion, to name a few.  Microcapsules have also recently been useful for vaginal and cervical delivery.  Local progesterone release from this dosage form can alter cervical mucus to interfere with sperm migration.  Other steroids have also attained sustained delivery by an intracervical system.  The sustained release of progesterone from various polymers given vaginally have also been found useful in cervical opening and induction of labor. 

A more common contraceptive device is the intrauterine device (IUD).  The first intrauterine devices used were of the unmedicated type.  These have received increased attention since the use of polythylene plastics and silicone rubbers.  These materials had the ability to resume their shape following distortion.  Because they are unmedicated, these IUDs cannot be classified as sustained release products.  It is believed their mechanism of action is due to local endometrial responses, both cellular and cytosecretory.  Initial investigations of these devices led to the conclusions that the larger the device, the more effective it was in preventing pregnancy.  Large devices, however, increased the possibility of uterine cramps, bleeding, and expulsion of the device. 

Efforts to improve IUD’s have led to the use of medicated devices.  Two types of agents are generally used, contraceptive metals and steroid hormones.  The metal device is exemplified by the CU-7, a polypropylene plastic device in the shape of number 7.  Copper is released by a combination of ionization and chelation from a copper wire wrapped around the vertical limb.  This system is effective for up to 40 months.  

The hormone-releasing devices have a closer resemblance to standard methods of sustained release because they involve the release of a steroid compound by diffusion.  

In the coming chapters, we shall discuss on controlled release injections, implant delivery systems, quality control of CRDDS, Regulatory considerations and Novel CRDDS.............
 
For inquiries contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

By Dr. Shruti Bhat

Transdermal drug delivery systems fall into two broad categories:

1)  Monolithic systems and
2) Reservoir systems

Monolithic Transderm Therapeutic System:

A typical monolithic system therapeutic transderm system (TTS) has 3 layers, an impermeable backing, and an adhesive matrix that contains the drug.  In this system, the matrix material controls the drug-diffusion rate from the device.   Initially the drug contained in the device is uniformly distributed throughout the polymer matrix, when the system is placed on the skin, the drug contained in the surface layers permeates into the skin first at a relatively rapid rate.  As the surface layers of the polymer matrix become depleted of drug, the drug-release rate falls as the drug is removed from the interior of the device and must diffuse progressively further to reach the device surface.

Reservoir Transdermal Therapeutic System :-

This type of a device also has a backing and adhesive layer, but the drug is now contained in a reservoir, from which its diffusion is controlled by a separate rate-controlling membrane layer.  The drug is usually contained within the reservoir as a suspension in a liquid or gel carrier phase.  On storage, a portion of the drug contained in the reservoir migrates into the membrane and adhesive layers.  When the device is placed on the skin, this drug is released rapidly, giving an initial burst effect.  Thereafter, drug release is controlled by the rule of drug diffusion through the membrane and adhesive layers to the skin.  This release will be maintained at a constant value so long as the solution inside the device reservoir is saturated. i.e. excess undissolved drug is present.  Drug diffusing from the reservoir solution is then immediately replenished by dissolution of some of the excess drug.  When the last excess drug dissolves, the drug concentration drops below the saturation value and the drug-release rate falls.  With this type of device, the release rate can be altered by changing the membrane thickness and permeability. 

A final type of system, having drug-release kinesis intermediate between a monolithic and reservoir system, is obtained when a membrane is over coated onto a monolithic polymer matrix containing dispersed drug. The drug release is initially controlled by the membrane, but as the drug contained in the polymer matrix adjacent to the membrane is depleted the release rate falls because the drug must now diffuse through an increasingly thick layer of matrix.

Currently available marketed controlled TTS can be classified into 4 types as follows:

1) Membrane permeation-controlled system in which the drug permeation is controlled by a polymeric membrane. Transderm-Scop (scopolamine;Ciba-Geigy)

2) Adhesive dispersion-type system is similar to the foregoing but lacks the polymer membrane, instead the drug is dispersed into an adhesive polymer.Deponit (nitroglycerin; Wyeth)

3)  Matrix diffusion-controlled system in which the drug is homogeneously dispersed in a    hydrophilic polymer, diffusion from the matrix controls release rate.Nitrodur (nitroglycerin; Key)

4) Microreservoir dissolution-controlled system in which microscopic spheres of drug    reservoir are dispersed in a polymer matrix.Nitrodisc (nitroglycerin; Searle)

Most marketed systems are of the polymeric membrane-controlled type, representative of these is Transderm-Scop.  This product is designed to deliver scopolamine over a period of days, without the side effects commonly encountered when the drug is administered orally.  The system consists of a reservoir containing the drug dispersed in a separate phase within a highly permeable matrix.  This is laminated between the rate-controlling micro porous membrane and an external backing that is impermeable to drug and moisture.  The pores of the rate-controlling membrane are filled with a fluid that is highly permeable to scopolamine.  This allows delivery of the drug to be controlled by diffusion through the device and skin.  Control is achieved because, at equibrium, the membrane is rate limiting for drug permeation.  To initiate an immediate effect, a priming dose is contained in a gel on the membrane side of the device.

Another drug that is popular for controlled transdermal release is nitroglycerin.  Conventionally, this drug is administered sublingually, although the duration of action by this route is quite short.  This is acceptable for acute anginal attacks, but not for prophylactic treatment.  Oral administration has the disadvantage that large fractions of the dose are lost to first-pass metabolism in the liver.  Topical ointments have long been used for prophylactic treatment of angina, but their duration is only 4-8 hr and, in addition, are not aesthetically acceptable.  The trandermal nitroglycerin devices employ a variety of systems to provide 24 hr delivery. 


For any inquiries contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

By Dr. Shruti Bhat

IV) TRANSDERMAL SYSTEMS:

The transdermal route of drug administration offers several advantages over other methods of delivery.  For some cases, oral delivery may be contraindicated, or the drug may be poorly absorbed.  This would also include situations for which the drug undergoes a substantial first pass effect and systematic therapy is desired.

The skin, although presenting a barrier to most drug absorption, provides a very large surface area for diffusion.  Below the barrier of the stratum corneum is an extensive network of capillaries.  Since the venous return from these capillary beds does not flow directly to the liver, compounds are not exposed to these enzymes during absorption.  A most notable example of such a drug is nitroglycerin, which has been administered both sublingually and trandermally to avoid first-pass metabolism.  Other drugs that have seen success in controlled trandermal delivery are testosterone, fentanyl, bupranolol and clonidine.

Transdermal controlled-release systems can be used to deliver drugs with short biological half-lives and can maintain plasma levels of very potent drugs within a narrow therapeutic range for prolonged periods.  Should problems occur with the system, or a change in the status of the patient require modification of therapy, the system is readily accessible and easily removed. 

One of the primary disadvantages of this method of delivery is that drugs requiring high blood levels to achieve an effect are difficult to load into a trandermal system owing to the large amount of material required.  These systems would naturally be contraindicated if the drug or vehicle caused irritation to the skin.  Also, various factors affecting the skin, such as age, physical condition, and device location, can change the reliability of the system’s ability to deliver medication in a controlled manner.  In other words, both the drug and the nature of the skin can affect the system design. 

SKIN DEPOT EFFECT -  Difference between transdermal dds Vs. other delivery routes :- 

When a transdermal patch is applied to the skin, the steady-state systemic dosage may not be reached for some time because of absorption of the drug in the skin.  If skin absorption is large, the time required to saturate the skin with drug may be long compared to the time the device is on the skin.  It is not possible then to simply equate the rate of drug delivery with the rate of appearance of drug in the systemic circulation even for device rate controlling systems.


For the majority of drugs, a plot of drug release from the device and drug absorption rate at the site of action has the general shape shown in this figure.  Initially, there is a difference between the drug release from the device curve and drug systemic absorption curve, because some drug is immobilized in the skin.  Ultimately, the skin absorption sites are saturated and the steady state is reached, when the rate of drug released equals the rate of appearance in the blood.  When the rate device is removed, drug release from the device abruptly halts.  Release of drug absorbed in the skin, however, will continue for some time. In many cases, this depot effect may be sufficiently marked that the skin-loading time is comparable with the time the device is on the skin, so that the drug delivery does not reach steady state before the device is exhausted or removed.  However, if therapy involves repeated applications of trandermal patches, this may not matter since the depot effect due to one device will be compensated for by the release of drug from an earlier device.  Nevertheless, the depot effect is a major factor to be taken into account in device design.  

For any inquiries contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com

By Dr. Shruti Bhat

II) DENTAL SYSTEMS:

Controlled and sustained drug delivery has recently begun to make an impression in the area of treatment of dental diseases.  Many researchers demonstrated that CRDDS of antimicrobial agents such as chlorhexidine, ofloxacin and metronidazole could effectively treat and prevent peridontitis. The incidence of dental carries and formation of plaque can also be reduced by CRDDS of fluoride.  Delivery systems used are film forming solutions, polymer inserts, implants and patches.  Since dental diseases are usually chronic, sustained release of therapeutic agents in the oral cavity would obviously be desirable.

III)   OCULAR  SYSTEMS :

The eye is unique in its therapeutic challenges.  An efficient mechanism, that of tears and tear drainage, which quickly eliminates drug solution, makes topical delivery to the eye somewhat different from most other areas of the body.  Usually less than 10% of a topically applied dose is absorbed into the eye, leaving the rest of the dose to potentially absorb into the blood stream resulting in unwanted side effects.  The goal of most controlled delivery systems is to maintain the drug in the precorneal area and allow its diffusion across the cornea.  Suspensions and ointments, although able to provide some sustaining effect, do not offer the amount of control desired.  Polymeric matrices can often significantly reduce drainage but other newer methods of controlled drug delivery can also be used.

The application of ocular therapy generally includes drugs for glaucoma, artificial tears, and anticancer drugs for intraocular malignancies.  The sustained release of artificial tears has been achieved by hydroxypropylcellulose polymer insert.  However, the best-known application of diffusional therapy in the eye, Ocusert-Pilo. The device is a relatively simple structure with two rate-controlling membranes surrounding the drug reservoir containing pilocarpine.  Thus, a thin, flexible lamellar ellipse is created and serves as a model reservoir device.  The unit is placed in the eye and resides in the lower cul-de-sac, just below the cornea.  Since, the device itself remains in the eye, the drug is released into the tear film.

The advantage of such a device is that it can control intraocular pressure for up to a week.  Further, control is achieved with less drug and hence fewer side effects, since the release of drug is close to zero order.  The system is more convenient, since application is weekly as opposed to the four times a day dosing for pilocarpine solutions.  This greatly improves patient compliance and assures round-the-clock medication, which is of great importance for glaucoma treatment.  The main disadvantage of the system is that it is often difficult to retain in the eye, and can cause some discomfort.

Another method of delivery of drug to the anterior segment of the eye, which has proved successful, is that of prodrug administration.  Since the corneal surface presents an effective lipoidal barrier, especially to hydrophilic compounds, it seems reasonable that a prodrug that is more lipophilic than the parent drug will be more successful in penetrating this barrier.  Many drugs have been derivatized for prodrug ocular delivery e.g. timolol, nadolol, pilocarpine, prostaglandin F 2 a , terbulatine, aciclovir, vidarabine and idoxuridine. 

New sustained release technologies are gaining importance in ocular delivery as in other routes.  Liposomes as drug carriers have achieved enhanced ocular delivery of certain drugs; antibiotics and peptides.  Biodegradable matrix drug delivery of pilocarpine can be achieved with a polymeric dispersion.  Implantation of polymers containing endotoxin for neovascularization, gancyclovir, 5-flurouracil and injections of doxorubicin have also resulted in sustained delivery.  However, topical ocular delivery is preferred considerably over implants and injection.

For inquiries contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com 

By Dr. Shruti Bhat

In these systems, osmotic pressure provides the driving force to generate controlled release of drug.  These systems generally appear in 2 different forms.  The first contains the drug as a solid core together with electrolyte, which is dissolved by the incoming water.  The electrolyte provides the high osmotic pressure difference.  The second system contains the drug in solution in an impermeable membrane within the device.  The electrolyte surrounds the bag.  Both systems have single or multiple holes bored through the membrane to allow drug release.

 

In systems with solid drug dispersed with electrolyte, the size or membrane of bored hole (s) are the rate limiting factors for release of drug; since any variations in boring of the hole,  accomplished with a laser device, can have a substantial effect on release characteristics.  Most of the orally administered osmotic systems, are of this variety e.g. OROS (Acutrim) by Alza Corp. Inc.  A variation on this theme is an osmotic system of similar design without a hole.  The building osmotic pressure causes the tablet to burst, causing the entire drug to be rapidly released.  This design is useful for drugs that are difficult to formulate in tablet or capsule form.

 

The osmotic systems are advantageous in that they can deliver large volumes.  Most important, the release of drug is in theory independent of the drug’s properties.  This allows one dosage form design to be extended to almost any drug.  Disadvantages are that the systems are relatively expensive and are inappropriate for drugs unstable in solution.

 

V) ION-exchange SYSTEMS:

 

Ion-exchange systems generally use resins composed of water-insoluble cross-linked polymers.  These polymers contain self-forming functional groups in repeating positions on the polymer chain.  The drug is bound to the resin and released by exchanging with appropriately charged ions in contact with the ion-exchange groups.

 

The rate of drug diffusing out of the resin is controlled by the area of diffusion, diffusional path length and rigidity of the resin, which is a function of the amount of cross-linking agent used to prepare the resin.  This system is advantageous for drugs that are highly susceptible to degradation by enzymatic processes, since it offers a protective mechanism by temporarily altering the substrate.  This approach to sustained release, however, has the limitations that the release rate is proportionate to the concentration of the ions present in the area of administration.  Although the ionic concentration of the GI tract remains more or less constant, the release rate of drug can be affected by variability in diet, water intake and individual intestinal content. 

 

An improvement in this system is to coat the ion-exchange resin with a hydrophobic rate-limiting polymer, such as ethyl cellulose or wax.  These systems rely on polymer coat to govern the rate of drug availability.

 

vi) PRODRUG APPROACH:

 

The applications of the classical pro-drug approach in the design of oral sustained drug delivery forms has been limited due to various toxicological considerations.  However, theophylline, a fairly water soluble compound with good bioavailability having short biological half life and narrow therapeutic range (10 - 20 um /ml in plasma) when given orally but makes plasma concentration monitoring essential.  In an effort to overcome these shortcomings, several sustained release products of theophylline have been designed. 

 

For any inquiries contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com

By Dr. Shruti Bhat

Historically, the oral route to administration has been used the most for both conventional and controlled release delivery systems.  The earliest work in area of oral sustained release drug delivery system (dds) can be traced to the 1938 patent of Israel Lipowski.  This work involved coated pellets for prolonged release of drugs and was presumably the forerunner to the development of the coated particle approach to sustained dds that was introduced later by Blythe in the early 1950’s- ‘Spansule’ by Smith Kline French.

The Oral CRDDS may be formulated by employing the following mentioned kinetic phenomena:

i) Dissolution control (Reservoir / matrix)

ii) Diffusion control (Reservoir / matrix)

iii) Bioerodible and combination diffusion and dissolution systems

iv) Osmotically controlled systems

v)  Ion-exchange systems

vi) Pro-drug approach


I) DISSOLUTION Control SYSTEM:

Dissolution - controlled systems can be made to be sustaining in several different ways.  By alternating layers of drug with rate-controlling coats; a pulsed delivery can be achieved.  An alternative method is to administer the drug as a group of beads that have coatings of different thickness.  This is the principle of the ‘spansule’ capsule marketed by Smith Kline Beecham.

 ii) DIFFUSION Control SYSTEM:  

Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert membrane barrier.  Usually, this barrier is an insoluble polymer.  In general, two types of subclasses of diffusional systems are recognized; reservoir devices and matrix devices.

Reservoir Devices as the name implies are characterized by a core of drug, the reservoir, surrounded by a polymer membrane.  The nature of the membrane determines the rate of release of drug from the system.

Reservoir diffusional systems have several advantages over conventional dosage forms.  They can offer zero-order release of drug, the kinetics of which can be controlled by changing the characteristics of the polymer to meet the particular drug and therapy conditions.  The inherent disadvantage is that, unless the polymer is soluble, the system must somehow be removed from the body after the drug has been released.

Matrix Device as the name implies, consists of drug dispersed homogeneously through out a polymer matrix.  Diffusion of the drug is based on: -

 a) Initial concentration of drug in the matrix. 

b) Porosity of matrix

c) Tortuosity of matrix

d) Polymer system forming the matrix and

e) Solubility of the drug.

Matrix system offers several advantages.  They are in general, easy to make and can be made to release high-molecular weight compounds.  The primary disadvantage of this system is that the remaining matrix “ghost” must be removed after the drug has been released. 

iii) BIOERODIBLE and Combination Diffusion and dissolution SYSTEMS:

Therapeutic system strictly will never be dependent on ‘dissolution’ only or ‘diffusion’ only Fig. 1 shows a schematic drawing illustrating three mechanisms for controlled release from a biodegradable / erodible matrix.  The complexity of the system arise from the fact that, as the polymer dissolves, the diffusional path length for the drug may change.  This usually results in moving-boundary diffusion system.  Zero order release can occur only if surface erosion occurs and surface area does not change with time.  The inherent advantage of such a system is that the bioerodible property of the matrix does not result in a ‘ghost matrix’.

Albumin, Celluloses, Gelatin, Chitosan, Methacrylic polymers, Carbopols etc. are few of the polymers employed in dissolution / diffusion CRDDS.

Tomorrow, we discuss further on the other types of oral CR DDS. For any inquiries on formulation development, please contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com .

By Dr. Shruti Bhat

TERMINOLOGY:

In the past, many terms viz. time-release, pulse-release, prolonged-release, sustained release, controlled release etc. have been used to refer to therapeutic systems.  However, “sustained” and “controlled” release represent separate delivery processes. “Sustained release” systems describe a drug delivery system with delayed and / or prolonged release of drug.  It also implies delayed therapeutic action and sustained duration of therapeutic effect.

“Controlled release” implies a predictability and reproducibility in the drug release kinetics.  In other words, sustained release dosage forms provide medication over an extended time period whereas controlled release systems attempt to control drug concentrations on the target tissue.  Site-specific systems and targeted delivery systems are the descriptive terms used to denote this type of delivery control.

CLASSIFICATION OF CONTROLLED RELEASE SYSTEMS:

Broadly, controlled release systems can be classified into two categories:

1) Based on Route of Administration:

·         Peroral dosage forms

·         Dental Systems

·         Ocular systems

·         Vaginal and Uterine systems

·         Injections and implants

 2) Based on Formulation Aspect:

·         Polymer based CR technology (dissolution/diffusion controlled)

·         Osmotic pumps

·         Mechanical pumps

·         Biodegradable carrier based CR system

·         Ion-exchange system

·         Prodrug approach

·         Micro emulsion / Multiple emulsions

·         Design of Controlled - Release Drug Delivery SYSTEM:

The design of controlled - released drug delivery system (CRDDS) accounts three important criteria viz. drug, delivery and destination. CRDDS can be designed using open or closed loop systems.

OPEN LOOP SYSTEM:

These systems comprise a drug platform; a reservoir, where the drug is stored; an energy source and in more sophisticated systems, a therapeutic program which meters the amount of agent passing through the rate-controlling mechanism.  Once the agent gets into the biological environment, a pharmacokinetic process occurs before distinguishable therapeutic and side actions manifest themselves. 

CLOSED LOOP SYSTEM:

In more complex closed loop systems, the pharmacokinetic process-taking place systemically is feed back to the drug delivery system.  This mechanism instructs the delivery system to alter its therapeutic program appropriately.  These systems are more complicated than open-loop systems because they require a very sensitive sensor in the biological environment that is capable of sending a negative feed back signal to the delivery system.

To date, most research in controlled release has involved an open-loop system. The design of the loop in turn is based on the pathway of drug distribution / disposition in the body.

Numerous molecules have been developed as controlled release formulations. I have developed close to 50 controlled / modified released products and the products are doing extremely well in the markets globally.

For any inquiries on formulation development, please contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com .