NOVEL IMPLANT CRDDS:

by Dr. Shruti Bhat

Pulsating polymer Gel for Episodic Drug Delivery:

In the field of controlled release, constant rate of zero order delivery of drugs is often considered to be the gold standard. This philosophy reflects the notion that drug effect is directly related to the instantaneous concentration of drug in an appropriate biosphere. However, in recent decades evidence has accumulated that certain clones of drugs particularly hormones are best administered with a periodic pulsatile program. Such a program will mimic the normal endogenous pattern of hormone release from endocrine glands. In fact, hormone replacement therapy using zero order delivery has been shown to fail in some cases with the target endocrine fraction restored only when the normal pulsatile pattern of release is imitated by the delivery system.

Research workers then geared towards developing an implantable, autonomously pulsing drug delivery system which can be used for such hormones and whose pulse pattern is controlled by device design. No external energy source, such as electricity, magnetism or heat is required to activate the system. The system is based on a cross-linked poly (N-isopropyl acrylamide - co - methacrylic acid) hydrogel (HG) and the enzyme glucose oxidase (GO). GO is situated in a chamber and communicates with body fluids through the HG membrane. Glucose, at constant activity in the body permeates through the HG and causes the latter to collapse by neutralizing pendant carboxylic acid groups. By this means, glucose permeation is sharply reduced, and is subsequent proton production. Eventually the protons are released from the HG membrane and the latter re-swells, restoring glucose permeability. This process can be repeated indefinitely, provided the system maintains its integrity and the external glucose concentration remains constant. Drug release from the chamber will follow the pulsatile swelling of membrane.

Here, we conclude part II of our series.

In the next chapter, we shall begin with a new part, III and shall deal with new subjects of CRDDS, primarily, novel parenteral CRDDS, targeted approach of drug delivery etc.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Novel CRDDS with Prolonged gastric residence time:

by Dr. Shruti Bhat

Dosage forms with a prolonged gastric residence time (GRT) i.e. gastro-remaining or gastro retentive dosage forms (GRDF) have brought new and important therapeutic options.

For instance, they significantly extend the period of time over which drugs may be released and thus prolong dosing intervals and increase patient compliance beyond the compliance level of existing controlled release dosage forms. Also, GRDF’s greatly improve the pharmacotherapy of the stomach itself through local drug release, leading to high drug concentration at the gastric mucosa, which are sustained over long period of time. For example, the eradication of helicobacter pylori which today requires the administration of various medication several times a day according to a complicated regimen and which frequently fails as a result of insufficient patient compliance, could perhaps be achieved more reliably using GRDF to administer smaller drug doses fewer times. Finally GRDF will be used as carriers for drugs with so called “absorption windows”, these substances are taken up only from very specific sites of the gastro-intestinal mucosa, often in a proximal region of the small intestine.

Conventional controlled release dosage forms pass the absorption window while they still contain a large and rather undefined portions of the dose which is consequently lost for absorption. In contrast an appropriate GRDF would slowly release the complete dose over its defined GRT and thus make it continuously available to the appropriate tissue regions for absorption.

The controlled gastric retention of solid dosage forms may be achieved by the mechanism of mucoadhesion, floatation, sedimentation, expansion or by the simultaneous administration of pharmacological agents which delay gastric emptying.

1) Mucoadhesive Systems :

Muco adhesion tends to be not strong enough to impart dosage forms, the ability to resist the strong propulsive forces of the stomach wall. The continuous production of mucous by the gastric mucosa to replace the mucous which is lost through the peristaltic contraction and the dilution of the stomach content also seem to limit the potential of muco adhesion as a gastro-retentive force.

Flotation as a retention mechanism requires the presence of liquid on which the dosage form can float and it also presumes that the patient remains in an upright posture during the GRT; in a supine position the pylorus is located above the stomach body and allows the accelerated emptying of floating material.

Sedimentation on the other hand has been successfully employed by few research workers as a retention mechanism for pellets which are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cubic cm) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall.

Expansion has been shown to be a potentially reliable retention mechanism. Several devices features which extend, unfold or which are inflated by carbon dioxide generated in the device after administration. These dosage forms are excluded from the passage of the pyloric sphincter if they exceed a diameter of approximately 12-18 mm in their expanded state.

Various mechanisms ensure the full reversibility of the expansion. Prototypes have already achieved the desired expansion and release profiles with model drugs in pilot clinical trials in which ultrasound and magnetic resonance imaging were employed as methods to visualize the gastric residence of the dosage form.

There are few pharmacological approaches to achieve a moderately increased GRT of oral dosage forms. However, the concept of simultaneous administration of a drug to delay gastric emptying together with a therapeutic drug will most likely not receive the favor of clinicians and regulatory agencies because of the questionable benefit to risk ratio associated with these devices.

In the next chapter, we shall discuss novel implantable drug delivery systems.

For any clarification or advise on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Novel oral controlled release drug delivery systems-

by Dr. Shruti Bhat

Technology in the field of controlled delivery has gone forward at a rapidly accelerating pace and promises many new and exciting developments.

Research on novel oral controlled release delivery systems focuses on increasing gastric retention or gastro-intestinal absorption. Currently, retention time is quite variable and depends on the individual. Gastric platforms have been developed that adhere to the stomach wall, thereby increasing gastric residence time and allowing for prolonged duration of therapy.

Latest Advances in Oral Transmucosal Delivery:

The controlled delivery of macromolecular drugs represents one of the greatest challenges in drug delivery. Transmucosal delivery across the tissues of the oral cavity is an attractive means for non-invasively administering such drugs. Oral transmucosal (OTM) administration offers several advantages for controlled drug delivery viz. bypass hepatic first pass effect.

The oral mucosa can be generally divided into two categories:

Keratinized tissues (gingiva and palate) and

Non-keratinized epithelial tissues (sublingual & buccal).

The non-keratinized oral mucosa is highly permeable and blood flow to the oral mucosa is exceptionally high. In addition, an oral mucosal tissue is readily accessible and localization of dosage form with a defined surface area over extended periods should maximize absorption and provide higher degree of control and reproducibility relative to other mucosal delivery routes. These factors combined with the relatively rugged nature of the oral mucosa to physical and chemical injury make OTM an attractive mode for macromolecular drug administration.


One example of OTM based DDS is a bi-layered tablet, which consists of a biocompatible adhesive layer that adheres to the gingiva and an active layer containing drug and optionally a tissue permeation enhancer. The active layer contacts the inner surface of the upper lip opposite the gingival application site and delivers the drug as the entire tablet dissolves. The choice of formulation components of the adhesive and active layers of the OTM system is dependent on the desired release characteristics of the active compound, dissolution time can be varied based on the physico-chemical properties of the drug and the profile desired by the glucagon-like peptide (GLP-1) containing tablet for NIDDM therapy.

Potentially therapeutic plasma levels of GLP-1 were achieved after administration of a single OTM tablet in type 2 diabetic patients. The peptide had marked glucose lowering effect during the first two hours. The bioavailability of GLP-1 after oral transmucosal administration was estimated as 47% relative to subcutaneous administration.

In the next chapter, we shall discuss various technologies of novel oral CRDDS.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

QUALITY CONTROL AND REGULATORY REQUIREMENTS OF CRDDS -

by Dr. Shruti Bhat

Quality parameters such as assay, content uniformity, and dissolution rate test along with the already established destructive & non-destructive tests for physical parameters need to be carried out for the controlled release systems as well.

In order to gain FDA approval of New Drug Application for a new chemical entity initially marketed in Controlled Release Dosage forms (as with all other similar products), clinical studies in patients establishing the safety and efficacy of each particular dosage form are required. For drugs that have been previously approved as safe and effective in controlled release dosage forms, data are required to establish bioavailability / bioequivalence to an approved controlled release drug product.

Single dose bioavailability studies are acceptable for determining the fraction of the amount absorbed, lack of dose dumping, lack of food effects etc. Pharmacokinetic studies, performed under steady-state conditions are acceptable to demonstrate comparability to an approved immediate release drug product, occupancy time within a therapeutic window, percent fluctuation etc.

The specific types of in-vivo studies include:

1) Fasted single dose studies
2) Post prandial study
3) Multiple dose steady-state studies.


Regulatory Considerations for Specialized CRDDS:

Novel CRDDS evolved in recent years viz. Ocusert, Oros, Copper and Progesterone releasing IUD’s and transdermal systems are considered new drugs requiring full new drug applications (NDA) as a basis of drug approval. In addition to safety and efficacy considerations which includes an understanding of the drug input function, plasma blood level oscillation and the drug’s pharmacodynamics, there are biopharmaceutic and pharmacodynamic issues that need to be addressed by the manufacturer such as :

1) Reproductivity of the new drug delivery system by in-vivo or in vitro studies.

2) A defined bioavailability profile which rules out dose dumping.

3) Demonstration of reasonably good absorption relative to an appropriate standard and which considers important elements e.g. obviating of first pass gut or liver metabolism.

4) A well-defined pharmacokinetic profile to support drug labeling.

5) In vitro characterization (when possible)

In the next chapter, we shall touch upon novel oral controlled release drug delivery systems.

For expert opinion on on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Parenteral Controlled Release Drug Delivery Systems (CRDDS) - An overview.

by Dr. Shruti Bhat

The intravenous, subcutaneous, intramuscularly, intraperitoneal and intrathecal routes are examples of parenteral routes of drug administration. Up to the present, efforts in developing controlled release parenteral dosage forms seem to have concentrated on the subcutaneous and intramuscularly routes, resulting in products such as aqueous and oily suspensions and oily solutions.

There are a number of injectables depot formulations on the market for e.g.-

Penicillin & Procaine suspensions (Duracillin Squibb);

Medroxyprogesterone acetate suspension (Depo-Provera, Upjohn) ;

Fluphenazine enanthate and decanoate in oil solutions (Prolixin enanthate and Prolixin decanoate; Squibb) ;

ACTH - Zn tannate / gelatin preparation (H.P. Acthar, Armour);

Microcrystalline deoxycorticosone pivalate in oleaginous suspension (Percortan pivalate; Ciba);

Testosterone enanthate (Delasteryl; Squibb);

Testosterone enanthate / estradiol valerate in ethyl oleate BP repository vehicle (Ditate - DS, Savage);

Nandrolone decanoate injection (Decadurabolin, Organon) and

Insulin Zinc suspensions (Utralente, Lente and semi-lente, Novo).

The rate of drug absorption and hence duration of therapeutic activities will be determined by the nature of the vehicle, the physico-chemical characteristics of the drug or its derivatives and the interactions of drug with vehicle and tissue / fluids.

Biopharmaceutics of CR Parenteral Products :

When a CR drug formulation is administered parenterally into a tissue space, muscle or adipose tissue, a depot is formed. Before the drug can exert its therapeutic action, it must first be released from the formulation into the general circulation and then to the site of drug action.

Generally, the release rate of a drug is affected by the dissolution, partitioning or absorption step. However, in many cases, the rate-limiting step is dissolution of drug particles in the formulation and / or partitioning of drug molecules from the vehicle to the surrounding tissue fluid. Thus, factors that affect the dissolution step and / or the partitioning step will affect parenteral drug absorption.

Details on CRDDS of parenteral delivery systems, drug targetting shall be dealt with soon in the forth coming chapters.

In the next chapter, we shall discuss quality control and regulatory requirements of controlled release drug delivery systems.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Controlled release drug delivery systems using Activation technology-

by Dr. Shruti Bhat

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.

For inquiries on molecules that can be formulated using this technology or advise on formulation development please contact 1-514-743-6159

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 anti-coagulation treatment, of insulin for anti-diabetic 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 co-polymer 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.

This technology has great promises for drug- targeting viz. cancer therapy, osteoporosis, arthritis etc.


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.

In the next chapter, we shall touch upon parenteral controlled delivery systems.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Examples of Controlled Release Drug Delivery Systems-

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.


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, un-leachable, 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 physico-chemical properties of drugs and the desired rate of drug release, the device can be further coated with a layer of bio compatible 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.

In the next chapter, we shall continue our discussion on implantable delivery systems.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com

My other blog that might be of interest- www.QA-Expert.com

CONTROLLED RELEASE DRUG DELIVERY SYSTEMS PART II: IMPLANT SYSTEMS

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 expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- http://www.qa-expert.com/

Vaginal and Uterine Controlled Drug Delivery Systems :

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 un-medicated 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 un-medicated, 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. These would comprise of part II of the series. Tomorrow, we shall take up implant DDS.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog of interest- http://www.qa-expert.com/

Design of Transdermal Delivery Systems-

by Dr. Shruti Bhat

Transdermal drug delivery systems fall into two broad categories:

1) Monolithic systems and

2) Reservoir systems

Monolithic Transdermal Therapeutic System:

A typical monolithic system therapeutic transdermal 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 equilibrium, 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.

Tomorrow, we discuss further on other types CRDDS- the vaginal & uterine systems.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Transdermal drug delivery systems-

by Dr.Shruti Bhat

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 transdermal 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 transdermal 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.

In the next chapter, we discuss design of transdermals CRDDS.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Business strategies employed by Japanese pharmaceutical manufacturers-

by Dr. Shruti Bhat


Over reliance on mature drugs-

Most of the leading Japanese pharmaceutical companies have mature product portfolios, with a heavy reliance on products over 10 years old.

An over-reliance on older drugs leaves companies in any market exposed to a greater risk of declining sales as a result of competition from both new products and generics. However, in Japan it also has a major effect on the impact of reimbursement price cuts. The Japanese government imposes biennial reductions in the level at which hospitals and pharmacies are reimbursed in order to restrain the rapid rise in the country’s health care bill.

The average impact of the 2002 reductions was 6.3%, however the reduction for each drug varies according to a number of factors, and “long-listed” products are subject to additional price reductions. An example of a drug that suffered a large impact in 2002 is Sumitomo’s Sumiferon, which was subject to a 25% reimbursement price cut. Therefore, not only does a reliance on older products provide less potential for future growth, but it also increases the risk of declining sales. The next price cuts are expected in 2004.

Increased spending-

In the past, Japanese pharmaceutical companies have had a lower average R&D spend in comparison to their Western counterparts, partly due to their heavy reliance on in-licensing and the lack of reward for innovation in the country’s drug pricing system. The average ratio of R&D as a proportion of total sales was 12.8% for the leading Japanese companies in 2002, compared to an average for 34 of the leading Western companies at 17.2%.

Japanese companies have begun to recognize the need to boost their portfolios through in-house R&D, and R&D expenditure rose by an average of 9.2% between 2001 and 2002, compared to an average increase in ethical sales of only 4.4%.

Strategic changes-

While most of the Japanese pharmaceutical companies are increasing their R&D expenditure, many are also reorganizing their entire R&D. Daiichi is a key example of a company that has changed the structure of its R&D operations, announcing in August 2003 that it is shifting control of its global drug development operations to the US.

Daiichi aims to achieve this by setting up a new company in the US, headed by a non-Japanese president, with responsibility for therapeutic strategy and clinical trial design on the macro level, as well as authority over which drug candidates have the greatest commercial potential.

A key reason for this geographic shift is the higher cost associated with completing clinical trials in Japan, where the cost of late stage trials have been reported as two to four times higher than those in the US or Europe. This trend is also motivated by the recognition that getting drugs onto the larger US market earlier can reap considerable rewards. Japan's other leading drug makers may now follow suit.

For inquires and clarification, please email me at drshrutibhat@gmail.com or call 1-514-743-6159.

Leading Pharmaceutical Companies in Japan-

by Dr. Shruti Bhat

In 2001, in an unprecedented move, Roche succeeded in negotiating the acquisition of Chugai and more recently, in 2003 Merck & Co. acquired 100 percent ownership of Banyu Pharmaceuticals. There is still a long way to go, however; Japan’s political system is not geared towards rapid reforms. There is little immediate prospect of a Mutual Recognition Agreement between Japan and the worlds other major regulators, and backsliding on the part of Japanese regulators is feared by many.

The introduction of a reference pricing system was abandoned in 1999, although many suspect it may re-emerge in the near future. In addition to increased multinational activity, the creation of Astellas Pharma Inc through the merger between Yamanouchi Pharmaceutical and Fujisawa, and the proposed merger between two of Japan’s leading drug companies, Sankyo and Daiichi, promises to boost the domestic production sector and perhaps herald a new era for the industry, where the nation’s leading manufacturers are increasingly being forced to forge agreements with each other to enable them to compete with rivals from overseas.

The best future prospects in the Japanese medical sector are related to the care of the elderly. The number of people aged 65 and over will exceed 25 percent of the population over the next 20 years. April 2000 saw the introduction of Japan’s major new insurance system for care of the elderly. The initial annual cost of this scheme is estimated at $40 billion or around 15 percent of total health care expenditure.

Global pharmaceutical companies have already begun to take advantage of the changing regulatory and economic conditions in Japan. The pharmaceutical companies have been taking note of such situation. They are queuing up to avail the favorable conditions .

The following five years will see further mergers and acquisitions as already demonstrated by the leading companies within Japan.

The Leading Pharmaceutical Companies Within Japan
1. Takeda
2. Astellas
3. Daiichi Sankyo
4. Pfizer
5. Roche (Chugai)
6. Eisai
7. Dainippon Sumitomo
8. Novartis
9. Taisho
10. Mitsubishi Pharma

In the wake of the current industrial and economic situation it is being assumed that more Japanese pharmaceutical companies would either emerge with outstation companies or be owned by them. The market is therefore an attractive target for western companies’ expansion plans. The building of strong in-house R&D capabilities will be central to Japanese Pharma companies’ strategies for survival. However, improving R&D capabilities will not be achieved by increasing spending alone; strategic and organizational change is also needed.

Of all the Japanese pharmaceutical companies only Takeda is counted amongst the best twenty pharmaceutical companies in the world. Despite the various problems that continue to affect them the research and development facilities of the Japanese pharmaceutical companies are significant.

Japanese pharmaceutical companies: Survival through improved R&D

A strong R&D base needed- The advantages to building a strong R&D base are considerable for Japanese companies. At a basic level, this should provide more reliable opportunities to drive future sales growth; reducing the reliance on licensing drugs from Western companies.
More importantly, it could provide the strategic opportunities necessary to ensure Japanese companies’ survival in the face of increasing competition, even enabling them to secure a position among the global pharmaceutical leaders in international markets.

The size of the Japanese pharmaceutical market makes it an attractive target for Western companies’ expansion plans, but the low level of market growth is contributing to an increasingly difficult operating environment for domestic players. The continued pace of regulatory reform, aimed largely at reducing the government’s health care bill is increasing the need for Japanese companies to change their operating strategy.

For inquires and clarification, please email me at drshrutibhat@gmail.com or call 1-514-743-6159.

Japanese Pharmaceutical Industry- An Introduction.

by Dr. Shruti Bhat


Japanese Pharmaceutical Market-

The Japanese market is the second largest pharmaceutical market globally, after the US, with estimated sales of $60 billion constitutes approximately 11% of the world market. However, it is a market that frustrates the major pharmaceutical companies as it is growing at a significantly lower rate of growth than the average of the world pharmaceutical markets. This has also often affected the Japanese Pharmaceutical Companies in a negative way .

Historically this lower growth rate has been attributed to the struggling Japanese economy, but more recently the biennial NHI drug price reductions have been the determining factor of the Japanese pharmaceutical market.

The Japanese indigenous pharmaceutical companies are the prime forces in the Japanese market. These Japanese pharmaceutical companies however have been held back by their own inability to capture the western pharmaceutical market and the shortcomings in their own economy. The experts feel that in order for the Japanese pharmaceutical companies to do well in the near future the national government should be taking steps to make sure that the prices of health care products come down. In all probability the Japanese pharmaceutical companies are unlikely to witness a major turnaround before 2011. Presently the companies as well as the overall market are going through an extremely critical phase. The pharmaceutical companies have been gearing up to face the challenges posed by the ultra competitive international medicine market.

Pivotal period of change:

The Japanese pharmaceutical market is entering a pivotal period of change. Although it is unlikely to see high growth before 2011, industry experts expects significant company activity as Japanese pharmaceutical companies strive towards international competitiveness.

How is the change expected to happen in the Japanese pharmaceutical industry ?

Japan has tightened its drug approval processes. According to research firm Research and Markets, Japan is doing its level best to improve its drug approval processes and the regulatory laws.

Despite its prolonged economic troubles in recent years, Japan remains the world’s second largest pharmaceutical market, after the US. It also remains one of the less penetrable. A strong and highly advanced domestic manufacturing industry, an opaque regulatory system and extensive cultural differences have made the Japanese market a difficult and long-term prospect.

There have however been recent signs that Japan is attempting to improve the drug approval process and move more into line with Western countries regarding regulatory laws. Significant cuts in government reimbursement levels in recent years have affected the market for pharmaceuticals, already depressed by the country’s faltering economy, while recent court judgements have weakened the country’s intellectual property laws.

In April 2000, the Japanese government promised measures to streamline the regulatory process and to make that process more transparent to outsiders, a promise reaffirmed at the subsequent G8 summit. Much of this has been at the behest of the US and Japan’s leading supplier of pharmaceuticals. The newly-created PMDA agency has been introduced in 2004, in an attempt to improve drug approval times and bring them more into line with their US and European counterparts. The market is therefore increasingly open to overseas products, and many domestic companies are being forced into measures such as mergers and expansion of R&D facilities in a bid to ensure survival in the marketplace.

In the next chapter we shall touch upon how was this change in the Japanese pharma market scenario used by the pharmaceutical industry.

For inquires and clarification, please email me at drshrutibhat@gmail.com or call 1-514-743-6159.

Dental and Ocular Controlled Release Drug Delivery systems - a Preview

by Dr. Shruti Bhat

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.

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.

Tomorrow, we discuss further on yet another type of CR systems - the transdermals CRDDS.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog of interest- www.QA-Expert.com

Per Oral Controlled Drug Delivery Systems

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. 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.


iv) OSMOTICALLY Controlled SYSTEM:

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.

Tomorrow, we discuss further on the other types of CR DDS.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

Classification of Controlled Release Drug Delivery Systems- in continuation of series, CR systems Part I

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 till date as controlled release formulations.

My experience with development of around 50 controlled / modified released products being sold in markets world over, has been great...........Do share with me your experiences as well.

For expert opinion on formulation development, please contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com .

My other blog that might be of interest- www.QA-Expert.com

CONTROLLED RELEASE DRUG DELIVERY SYSTEMS : PART I

by Dr. Shruti Bhat

The deployment of drugs within the body is becoming more precise with the advent of rate-controlled dosage forms. Building on an expanding knowledge of pharmacokinetic and the concentration effect relation of drugs, this development represents a logical extension of pharmaceutical technology.

Conventional drug therapy typically involves the periodic dosing of a therapeutic agent that has been formulated in a manner to ensure its stability, activity and bioavailability. For most drugs, conventional methods of formulation are quite effective. However, some drugs are unstable and toxic and have a narrow therapeutic range, exhibit extreme dissolution problems, require localization to a particular site in the body, or require strict compliance or long-term use. In such cases, a method of administration of the drug is desirable to maintain fixed plasma drug levels and can be achieved by the use of specialized drug delivery system.

The continuing quest for precision is apparent from an examination of the evolution of pharmaceutical technology from imprecisely bioassay medicinals of modern pharmaceutical products of defined chemical composition and precisely specified content. Recently, there has been a sharpening focus on the kinetic properties of dosage forms, reflected on the concepts of bioavailability and bioequivalence. The move beyond content specified pharmaceuticals to those explicitly specified by the rate at which they liberate their active ingredients in vivo is now gathering momentum. The kinetic specification of rate is not an alternate to the static, specification of content, but a complement to it.

Factors Impelling Transition to Rate - Specified PRODUCTS:

Many kinds of factors; namely - technological, scientific, medical and commercial are cause for this change.

1) Availability or viability of technology:

The 1970’s saw great technological advances in the rate-controlled administration of drugs. One of the first examples was the conversion of the large and cumbersome infusion pumps used in physiology laboratories into the compact, convenient and reliable infusion pumps now widely used for drug administration in acute intensive care. In another series of innovative methods of membrane controlled molecular movement were developed and entirely new rate-controlled pharmaceutical dosage forms such as long duration ophthalmics, hormonal IUD’s, transdermal drug delivery system, osmotically controlled tablets and bioerodible injections were created. The very existence of this technology is a force for transition. It has begun to unleash the imagination of researchers in pharmacology and medicine, stimulating them to explore the action (s) of drugs. When drug concentrations in blood and tissues are controlled, the aim is either maintaining constant concentration or controlling release to follow pre-designed therapeutic drug level patterns.

2) Rate Control in Intensive Care :

Rate - controlled continuous drug delivery is now the rule rather than the exception in acute intensive care e.g. after major surgery, coronary occlusion and serious trauma. Rate control involves both safe and effective use of potent agents whose concentrations in the blood must be maintained within a narrow range. Molecules such as nitroprusside, dopamine, heparin, dobutamine, lidocaine, norepinehrine and nitroglycerin are examples of such agents. Rate control also makes it practical to utilize drugs that have very short half-lives and in general to design dosage forms that provide duration of function that are multiples of the pharmacokinetic half life of the drugs administered.

3) Rate -control as physiological principle :

The body’s own control systems for regulating hormonal secretions are now recognized as operating on the basis of continuous rate control. Hormones manifest such selectivity of action only when their rate of secretion is controlled. Giving the same hormones by conventional dosing (e.g. insulin injections) is a poor imitation of nature. In acute diabetic ketoacidosis, rate-controlled IV infusion of insulin has replaced the practice of giving insulin by injections, because rate controlled infusion is a safer and more effective method of treatment. Improving the management of day-to-day insulin requirements has evoked great interest giving rise to various efforts to provide continuous insulin administration, which necessarily implies rate control. The actions of many drugs are related to their concentration in the blood. Controlling those concentrations can therefore be a method of improving the selectivity of a drug’s beneficial actions, provided that the beneficial actions are elicited by lower concentrations than those needed to elicit unpleasant or adverse effects. Consequently, it is now generally recognized that a drug’s full potential remains unknown until it has been studied with extended-duration, rate-controlled delivery. It is also generally recognized that the relationship between concentration and effect is much more easily discerned if drug concentration is maintained at a steady level rather than allowed to vary, as occurs with conventional dosing methods. Few examples of agents whose selectivity of therapeutic action or physiologic action is related to the rate of administration, include Hydrochlorothiazide, Insulin, Morphine, nitroprusside, pilocarpine etc.

4) Competition from generic drugs :

Drug patents have defined life cycle and the products based upon them become subject to competition from generic-drug houses. Nevertheless, developing a new superior patent protected product based on an un-patented drug is sometimes possible by incorporating an un-patented drug into a patent protected, rate-controlled dosage form. The essential element in the strategy of innovation is proof that the resulting product is superior to the drug in conventional form.

5) Discovery of New Therapeutic ACTIONS:

Sometimes an older pharmaceutical product is discovered to have an entirely new use. Examples are minocycline (prevention of traveler’s diarrhea & treatment of chlamydial infections), metronidazole (prevention and treatment of anaerobic infections) and sulfinpyrazone (prevention of myocardial reinfarction) etc. By establishing that a dosage form can be produced that is bioequivalent to that of the innovating firm, manufacturer can make all therapeutic claims associated with the innovator’s product. Dosing so, however, becomes far more difficult if clinical trials to establish new therapeutic claims are preceded by dosage form innovation that results in a patent-protected, rate-controlled product superior to the drug in conventional form.

6) Economic consideration :

The research and development costs of bringing a new drug to market can run as high as US $ 15-70 million. Any approach that could reduce these costs or the risks associated with drug development would be welcome. The screening of potential new drugs focus most often on maximum oral activity. Toxic side effects that are usually dose related are then titrated against therapeutic efficacy until an analog is found that has a sufficient therapeutic index. During this screening procedure many potent drugs with low side effects are eliminated because they are not orally active or lack sufficiently long half-life to be parenterally useful. It is here that rate control delivery presents its advantage.

Bioactive proteins such as interferons, growth hormones, monoclonal antibodies and human insulin represent a new driving force behind accelerated research into controlled release technology. These drugs often have low bioavailabilities, low stability, pose substantial formulation problems and often must be delivered continuously within narrow therapeutic range. For e.g. human growth hormone, an unstable polypeptide should ideally be parenterally delivered to hormone deficient children continuously at a rate of 0.5 - 2mg./ day.

Also, the realization that these new drug delivery systems can add therapeutic value to proprietary drugs and economic value to off patent drugs, the pharmaceutical companies are now engaged in improving their product pipeline through development of improved drug delivery system.

Tomorrow, we shall discuss on terminology and classification of controlled release drug delivery systems.

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

My other blog that might be of interest- www.QA-Expert.com

Newer challenges- peptide, protein and oiligonucleotide / bio-tech based drug delivery systems

By Dr. Shruti Bhat.

In continuation with our discussion on new strides in formulation technologies, let us now briefly touch upon the peptide based pharmaceutical products.

Several routes viz. ocular, nasal, buccal, respiratory, stomach, colon, rectal and vaginal have already been explored for peptide based drugs such as angiotensins, badykinin, calcitonin, t-PA, urokinase, neuropeptide Y, enkephalin, interferon, insulin, oxytocin, gonadotrophins, etc. Presently, there are over 250 products formulated using biotechnology based peptide actives pending the USFDS marketing approval.

Alongside development of new delivery presentations as well as bio tech based actives such as peptides, a new biochemical pathway based on carbohydrates uptake and metabolism using cell surface “landscape” engineering technique is currently being investigated. This route promises a novel approach to tissue engineering and presents variety of applications in bringing about modifications of tumor cells that could increase their uptake of drugs. The groups of sialic acid derivatives- “landscape cell” that is chemically unique to the cell surface is being used as a “ chemical handle” for attaching molecular probes or various bio molecules. These cells revolutionize the ability to interface biological tissues since they selectively bind to synthetic/ natural drug moieties and deliver drugs on site. The hypothesis based on the fact that breast, colorectal and lung cancer cells produce unusually large amounts of receptor chemicals CD 44 and RHAMM- involved in initiating a cascade of events that lead to proliferation of both defense and cancer cells. This finding is particularly exciting since one of the technical barriers to effective use of gene therapy approach is targeting the antisepses (molecule) to the site of pathology. Hyaluronic acid, a disaccharide has been studied as a carrier for several drugs viz. diclofenac, cyclosprorine, paclitaxel, DNA as well as RNA (gene medications). Animal studies have shown that hyaluronan bound cyclosporine is more effective than cyclosporine alone in promoting cell death in colorectal tumors.

In studies in vitro, hyaluronan-anti sense RNA combination has proved 10-0 times more effective than antisense RNA alone in inhibiting cell proliferation of rat hepatoma cells. Similar was the observation with diclofenac sodium complexed with hyaluronan; the complex showing increased anti-inflammatory activity than diclofenac alone.

On a different front, researchers have unraveled the mechanism of protein carbohydrate interactions among cells involved in the inflammation process. It has been found that 3 proteins (so far identified) viz. L-selectin (on leukocyte), E-selectin and P-selectin (on endothelial cell wall) participate in the inflammatory response, each interacting with specific glycoprotein ligands. Knowing that the affinity and specificity of protein- carbohydrate interactions often depend on the formation of multiple receptor-ligand complexes, the researchers decided to use open ring polymerization technique to synthesize biologically active ligands containing multiple sulfated sugars (sulfated neoglycopolymers) that might target specific selections. The multi-valent saccharide derivatives may lead to completely new strategies for the modulation of cell –cell recognition.

In conclusion, it can be stated that pharmaceutical science and technology have progressed since 80’s on both the fronts – (i) new moieties/ pathways as well as (ii) novel presentation forms. Continued success to both !!

In the next chapter, I shall take up challenges in formulation of ''Controlled release drug delivery systems''.

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

My other blog that might be of interest- www.QA-Expert.com