Fundamentals for Controlled Release Systems

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viragshah's picture

Recently, Controlled Release (CR) systems have become a very useful tool in medical practice, offering a wide range of actual and perceived advantages to the patients. CR Systems are designed to maintain constant therapeutic plasma concentration of the drug within the therapeutic range of drug over prolonged periods. These delivery systems offer numerous advantages in comparison to conventional dosage forms, which include fewer doses per day or week and reduce in adverse effects The present presentation includes  Introduction.  Classification of Controlled Release System based on fabrication techniques.  Mechanism of controlled drug release using polymers.  Polymer used for controlled drug release.  Overview of application of mathematical models for controlled release products.  Evaluation of CR product  Conclusion Key words: Controlled Release (CR), Dissolution controlled, Diffusion controlled, Osmotically controlled, Mathematical models. Profile page link of the author: http://www.pharmainfo.net/viragshah Profile page link of the co-author: http://www.pharmainfo.net/shindemadhuri28

There are 42 Comments

Santosh kumar. JH's picture

Great work done!!
My question is you're saying that CR formulations will have an zero order release pattern and SR release formulations shows first order release pattern.

As per my knowledge I got to know that SR dosage forms consists of :
1. Loading dose to reach the desired plasma concentration; which releases the drug in first order fashion.
2. Maintainance dose to maintain the desired plasma concentration; the release of the drug follows zero order.

Am I right??
Please clarify me the difference between the two terminologies??

viragshah's picture

Hello, Santosh Thanks for your comments SR dosage form release the drug for an extended period of time while CR system are able to provide an actual therapeutic control, whether it is of temporal nature,spatial nature or both, means the system attempts to control drug concentration in the targeted tissue. So we can clear say that all sustained release system cannot be considered CR system. Now about the kinetics, SR dosage form maintain the therapeutic drug level for an extended period of time. This is achieved by zero-order release which consist of release of drug from dosage form which is independent of amount of drug in the dosage form (constant release rate).SR dosage form do not attain this type of release and try to mimic zero order and provide release in slow-first order fashion (i.e.concentration dependent). I think my explanation is satisfactory you will get it. If any query please free to ask me. For more details view the following reference: 1.Gilbert B., Christopher R. Modern Pharmaceutics.3rd ed. New York: Marcel Dekker, 2005. 501-528. Print. 2.Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. 335-371. Print. http://www.pharmainfo.net/viragshah

viragshah's picture

Hello Santosh

The difference between controlled-release and sustained-release is that controlled-release is a perfectly zero-order release; that is, the drug releases over time irrespective of concentration. Sustained-release implies slow release of the drug over a time period;

it may or may not be a controlled-release. The examples of slow first order release obtained by a sustained release pre parathion is generally achieved by the release of the drug from a dosage form. Also there are four models for drug based on the drug release patterns which should be studied to know the detail concept of kinetics of SR and CR.This is more elaborated in reference Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. for better understanding.

Reference: http://www.pharmainfo.net/reviews/controlled-released-system-review Thanks.

 

 

 

anil kumar appapurapu's picture

Abstract: "CR Systems are designed to maintain constant therapeutic plasma concentration of the drug within the therapeutic range of drug over prolonged periods"

is it also possible for the drugs of

1. less stable at biological PH

2. low therapeutic index

3. High protein distributed drugs

4. sensitive to degradation by enzymes

if possible pls give the explanation

anilkumar

viragshah's picture

Hello Anil Sir

1. In case of less stability of drug molecule at biological pH we can prefer local delivery of the drug at the targeted area. But if the systemic delivery is desired then their is need to change the drug chemistry or formulating prodrug or salt form of the drug which are stable at the biological pH. One example is illustrated in an research article of Morpholinoalkyl ester prodrugs of diclofenac to make it more stable at pH 7.4. References: Tammara VK, Narurkar MM, Crider AM, Khan MA, Morpholinoalkyl ester prodrugs of diclofenac: synthesis, in vitro and in vivo evaluation. J Pharm Sci. 1994 May;83(5):644-8.

2. The drug with low therapeutic index are having a narrow margin of safety and are dificult to formulate in controlled release system. The effective therapeutic index can be affected or modified by drug targeting, in which the therapeutic agent is concentrated in its area of effect. For example, in case of radiation therapy for cancerous tumors, directing the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. References http://en.wikipedia.org/wiki/Therapeutic_index Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. pg. 341.

3. Extensive binding to plasma proteins will be evidenced by a long half life of elimination for drugs and such drugs generally most require a sustained release dosage form.

References: http://www.pharmainfo.net/reviews/controlled-released-system-review

4. Sensitive to degradation by enzymes: The delivered the drug in controlled manner which is sensitive to degradation by enzymes following concept can be applied to such type of drug: a. Targetting the drug the site of action b. By passing first pass effect(if degradation occurs their) by using parenteral route (implants, depots etc.) c. Prodrug concept d. Modification the chemistry of such entity. Reference: Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. Thanks. Regards Virag Shah http://www.pharmainfo.net/viragshah

anil kumar appapurapu's picture

power point good work and here the questionnaire slide no. 10 is all drugs absorbed by mechanism except Carrier mediated transport process are eligible for CR formulation?

anilkumar

viragshah's picture

Hello Anil Sir your question is very broad one.

If we are considering only mechanism of drug absorption as a selecting criteria for drug in this system then my answer will be yes the drug absorb through other mechanisms except drug absorption occurring through absorption window and/or absorbed actively (e.g riboflavin) are good candidates and can be be formulated as CR system. But in case of formulating drug in CR mechanism of drug absorption is only one of the factor, apart from this there are many factors which should be considered such as molecular weight of the drug, aqueous solubility, apparent partition coefficient, pKa, ionization, stability and various pharmacokinetic parameters such as absorption rate, elimination half-life, rate of metabolism, dosage form index etc. pharmacodynamic factors such as therepeutic range, therepeutic index, plasma concentration-response relationship.

References: 1.Gilbert B., Christopher R. Modern Pharmaceutics.3rd ed. New York: Marcel Dekker, 2005. 501-528. Print. 2.Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. 335-371. Print.

Thanks. Regards Virag Shah http://www.pharmainfo.net/viragshah

viragshah's picture

Hello Arun

In case of most of the CR system the drug level is maintained for a longer or specific period time, so there is chances of drug tolerance. drugs which exhibit tolerance should not be delivered at a constant rate, since the drug effect decreases with time at constant drug level. Incase of drug tolerance pulsatile drug delivery type of controlled drug system should be preferred to prevent the drug tolerance by the patient In these type of system, there is rapid and transient release of a certain amount of drug molecules within a short period of time immediately after a predetermined off-release period. If you want a more detail about this the link of this pulsatile drug delivery system review:

http://www.niper.ac.in/crips_june_27_2007.pdf

 

 

viragshah's picture

Hello Arun The controlled release system when compared with conventional system is having an advantage of reduction in side effect and increase in tolerance of the drug. Drug plasma levels in this systems are maintained within a narrow window with no sharp peaks and with AUC of plasma concentration versus time curve comparable with total AUC from multiple dosing with immediate release dosage forms. This greatly reduces the possibility of side effects as the scale of side effects increase as we approach the Maximum Safe Concentration. But once the dose is administered then retrieval of drug is difficult in case of toxicity,poisoning or hypersensitivity reactions as compared to conventional system.

References: 1.Das N., Das S., Controlled release of oral dosage form, Formulation, Fill & Finish, 2003, 10-16. 2. Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. pg. 337. 

pooja.chowdary's picture

Hi, Can u exemplify on the drugs which are poor candidates because of their ability to induce metabolism? Is the induction process initiated by the drug in such cases? can u give an example in that concern? Regards,
pooja
viragshah's picture

Hello, Pooja The drug which is extensively undergoes metabolism are good candidates for this systems as long as the rate of metabolism is not too rapid. Drug substances with identical and predictable metabolism process when administered by different routes are preferred. In case of drug candidate which is capable of either induction or inhibition of metabolism are poor candidates. The reason for this is the poor predication and maintains of steady-state blood levels of this type of drugs, which may lead to toxicity or low pharmacological effect. The induction process is not always initiated by drug as such but induce by the aid of other drugs or enzymes in the body. Some drug are there which have the ability to induce their own metabolism, such drugs are called as auto-inducer or self-inducer. Examples of auto-inductor class are carbamazepine, meprobamate, cyclophosphamide, rifampicin etc. Detail of carbamazepine which is an auto-inducer making it difficult to formulate in such type of system is as follows: Carbamazepine is a first-line anticonvulsant drug with established efficacy for the treatment of generalised tonic-clonic and partial seizures. Its long elimination half-life of 30 h reduces with chronic administration to around 10 h. This is a consequence of autoinduction of metabolism, which is also responsible for substantial intra- and interindividual variation in circulating concentrations within a dosage interval References: 1. Brahmankar D., Jaiswal S. Biopharmaceutics and Pharmacokinetics- A treatise. 1st ed. Delhi:Vallabh Prakashan, 1995. pg 148 & 341. 2. Macphee GJA, Butler E, Brodie MJ. Intradose and circadian variation in circulating carbamazepine and its epoxide in epileptic patients: a consequence of autoinduction of metabolism. Epilepsia 1987; 28: 286-294. Thanks. Regards, Virag Shah http://www.pharmainfo.net/viragshah

viragshah's picture

Hello, Safi Herbicides are the type of pesticides used to kill unwanted plants. Mathematical modeling of CR systems helps to provide an idea of mass transport of drug involved in controlling the drug release. In addition, if an adequate mathematical theory is identified for a particular pharmaceutical system which can be used to for studying the device design parameters on the resulting drug kinetics. As per your question mathematical modelling cannot be applied to herbicides as such. For obtaining the mathematical model you should firstly know the type of formulation (type of dosage form) in which this herbicides are prepared. If you have any example of such herbicides with the type of dosage form used so can help you. For deals for basic of mathematical models reference is as follows: P. Costa, J. M. S. Lobo, Modeling and comparison of dissolution profiles, Eur. J. Pharma. Sci. 2001;13:123-133 Thanks Regards, Virag Shah http://www.pharmainfo.net/viragshah

viragshah's picture

Hello, Sandeep Thanks for your comment.

The main role of the various polymers in CR system is to control the release of the medication from the dosage form.

A diverse range of mechanisms have been developed to achieve both temporal and distribution controlled release of drugs using polymers. For example, a drug that is to be released over an extended period in a patient's stomach where the pH is acidic and environmental conditions fluctuate widely will require a controlled release system very different from that of a drug that is to be delivered in a pulsatile manner within the blood system. The major mechanisms of controlled release and polymeric characteristics that are required to carry out these mechanisms are:

1. Temporal controlled: Most drug molecules need to be dissolved in the aqueous environment of the patient and freely diffuse within that media before they can act on their target receptors.

Polymeric devices that achieve temporal controlled release protect drug molecules from this aqueous living environment for preprogrammed periods of time. This protection can involve delaying the dissolution of drug molecules, inhibiting the diffusion of the drug out of the device, or controlling the flow of drug solutions. 2. Distribution controlled: This type of controlled is achieved by using impanting the drug delivery at the site.For the majority of diseases that require distribution controlled release of drug, a targeting mechanism must be employed that allows the delivery system to find the desired target. Polymers are used in two types of delivery systems for these applications, colloidal carriers and polymer-drug conjugates. In colloidal formulations, the polymer encapsulates drug within micro- or nanoparticles. In polymer-drug conjugates, the drug is covalently coupled to the polymer. In these forms of distribution controlled release, the polymer acts as a carrier but is not responsible for targeting the delivery device.

References: 1. K. E. Uhrich, M. Scott, R. S. Langer, K. M. Shakesheff, Polymeric Systems for Controlled Drug Release, Chem. Rev. 1999;99:3181-3198. 2. G. Acharya, K. Park, Mechanisms of controlled drug release from drug-eluting stents, Adv Drug Del Rev. 2006;58:387- 401 

Arun Kumar Palle's picture

Can you give me the examples of polymers used, with their properties for consideration? Can you explain me about the calculation parameter?

viragshah's picture

Hello Arun Some of the most commonly and important examples of polymers are as follows: 1. Poly(ester) This are widely used biodegradable class of polymer,ex. of this are poly ethylene glycol (PEG), poly(lactic acid), poly(glycolic acid). PEG: Biocompatiability is one of the most noted advantage of this material, emerging uses for inclusion of PEG in a CR arises from its protein resistivity. Poly(lactic acid), poly(glycolic acid) & Poly(lactic acid co-glycolic acid (PLGA)): PLGA is considered as gold standard for degradable polymers. This type of polymer undergoes bulk degradation 2.Poly(ortho esters): This class of polymers inhibited drug release by diffusion mechanisms and allowed drug release only after the hydrolysis of polymer chains at the surface of the device. 3. Poly(anhydrides): best formed into drug-loaded devices by compression-molding or microencapsulation because of their high melting temperatures. 4.Poly(amides): Used for delivering drug which are having low molecular weight Your 2nd point is about the calculation parameter which help for selecting polymers are 1. Surface layer formation and mechanisms of dissolution: 2. Effect of molecular weight and polydispersity: 3. Effect of polymer structure, compostion and conformation: For more explanation you can read following references 1. K. E. Uhrich, M. Scott, R. S. Langer, K. M. Shakesheff, Polymeric Systems for Controlled Drug Release, Chem. Rev. 1999;99:3181-3198. 2. R. Langer, Polymer-Controlled Drug Delivery Systems, Acc. Chem. Res. 1993;26:537-542 If you dont find this articles then please let me know so will mail you softcopy. Thanks Regards, Virag Shah http://www.pharmainfo.net/viragshah
viragshah's picture

Hello Pooja Your question is interesting I will give explanation for your answer through an example which will be better for understanding. Tagetting of Brain is very difficult task as Blood Brain Barrier restricts the passage of substance into the brain. Work has been done on delivery of dalargin the enkephalin analog with two different peptide vectors, SynB1 and SynB3, to improve its brain delivery and its pharmacological effect by Rousselle C.et. al. The output of this work is that vector conjugation have increase the perfusion of darlagin in the brain. The link for this articles is as follows please read it for more details: http://jpet.aspetjournals.org/content/306/1/371.full.pdf Thanks Regards, Virag Shah http://www.pharmainfo.net/viragshah
Harsh bansal's picture

hello viragshah i would to like know that what is the difference between sustain and control release ??

harsh bansal

viragshah's picture

Hello Harsh Bansal SR Systems are the type of system which provide medication simply for an extended period time. Whereas, CR system are the type of system which provides some actual therapeutic control, which may be of temporal nature, spatial nature or both. So, the system attempts to control the therapeutic concentration in the target tissue. Hence it can be concluded that all SR dosage form cannot be considered as CR systems. Reference: For more details view the following reference: Gilbert B., Christopher R. Modern Pharmaceutics.3rd ed. New York: Marcel Dekker, 2005. 501-528. Print. Thanks. Regards, Virag Shah http://www.pharmainfo.net/viragshah
Harsh bansal's picture

hello virag its last day today... its very nice to meet u through this competition your presentation is nice all the best for your future thank you

harsh bansal

abhishekrathi's picture

Dear Author, All the best. Its been a very nice experience. It was a really awesome and knowledgeable. Thanks & Regards
Abhishek Rathi
Srinivas Dharam's picture

Hi very nice presentation, and informative. i have one doubt. is it true that only drugs which are having good aqeous solubility are good for CR.?
2) in one of your slide you mentioned that only drugs having low molecular weight are suitable.. so could please tell me what should be the range?

thank you in advance