INTRODUCTION:

For many decades’ treatment of an acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms, including tablets, capsules, pills, suppositories, creams, ointments, liquids, aerosols, and injectable as drug carriers. Even today these conventional drug delivery systems are the primary pharmaceutical products commonly seen in the prescription and over the counter drug market place. This type of drug delivery system is known to provide a prompt release of drug. Therefore, to achieve as well as to maintain the drug concentration with in therapeutically effective range needed for treatment, it is often necessary to take this type of drug delivery system several times day. This result in a significant fluctuation in drug levels. In order to overcome these problems-controlled drug delivery systems were employed.

Fig. 1: Hypothetical drug concentration profiles in the systemic circulation resulting from the consecutive administration of multiple doses of an immediate release drug delivery system compared to the ideal drug concentration profile required for treatment.

1. ADVANTAGES:

i. Patient Compliance: (patient acceptability):

Lack of compliance is generally observed with

1. Long term treatment of chronic disease.

2. Increase in number of doses.

3. Increase in side effects

The problem of lack of patient compliance can be resolved to some extent by administering controlled release drug delivery system.

ii. Reduced 'see- saw' fluctuation:

A well-designed controlled release drug delivery system can significantly reduce the frequency of drug dosing and also maintain a steadier drug concentration in blood circulation and target tissue cells.

iii. Reduced total dose:

Controlled release drug delivery systems have repeatedly been shown to use less amount of total drug to treat a diseased condition. By reducing the total amount of drug, decrease in systemic or local side effects are observed. This would also lead to greater economy.

iv. Improved efficiency in treatment:

A controlled release dosage forms leads to better management of the acute or chronic disease condition.

Other Advantages:

· Reduction in dosing frequency

· Reduced fluctuations in circulating drug levels

· Increased patient compliance and convenience

· Avoidance of night time dosing

· More uniform effect

· Reduction in GI irritation and dose related (local and systemic) side effects

4. Disadvantages:

i. Dose dumping:

Dose dumping is a phenomenon where by relatively large quantities of drug in a controlled release formulation is rapidly released.

ii. Less flexibility in accurate dose adjustment:

In conventional dosage forms, dose adjustments are much simpler e.g. tablet can be divided into two fractions. In case of controlled release dosage forms, this appears to be much more complicated. Controlled release property may get lost, if dosage form is fractured.

iii. Poor in Vitro – In Vivo Correlation:

In controlled release dosage form, the rate of drug release is deliberately reduced to achieve drug release possibly over a large region of gastrointestinal tract. Here the so called ‘Absorption window’ becomes important and may give rise to unsatisfactory drug absorption in vivo despite excellent in-vitro release characteristics.

iv. Patient variation:

The time period required for absorption of drug released from the dosage form may vary among individuals. Co-administration of other drugs, presence or absence of food and residence time in gastrointestinal tract is different among patients. This also gives rise to variation in clinical response among the patient.

Other disadvantages:

· High cost

· Unpredictable and often poor invitro in vivo correlation

· Dose dumping

· Reduced potential for dosage adjustment

· Increased potential for first pass clearance and also of poor systemic availability.

· Need additional patient education.

5. Rationale for Sustained/Controlled drug delivery:

The rationale for sustained/ controlled drug delivery is to alter the pharmacokinetic and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and/ or physiological parameters inherent to a selected route of administration. It is desirable that the duration of drug action become more a design properly of a rate-controlled dosage form, and less, or not at all, a property of drug molecule’s inherent kinetic properties.

As mentioned earlier, the primary objectives of sustained/controlled drug delivery are to ensure safety and to improve efficacy of drugs as well as patient compliance. This is achieved by better control of plasma drug levels and less frequent dosing. For conventional dosage forms, only the dose (D) and dosing interval () can vary and, for each drug, their exist a therapeutic window of plasma concentration, below which, therapeutic effect is insufficient and above which undesirable or toxic side effects or elicited.as an index of this window, the therapeutic index TI can be used.

Therapeutic index is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50). It is also defined as the ratio of maximum drug concentration (Cmax) in blood that can be tolerated to the minimum concentration (Cmin) needed to produce therapeutic response.

Theeuwes and bayne given the following relationship for the drugs whose disposition show pronounced linear, one compartment characteristics.it is given by

τ < t1/2 (In T I) /In 2

Where,

t1/2 = half-life.

Since the therapeutic index for most drugs is 2, it will be necessary to dose the patients at intervals shorter than the half-life. Such inconvenient regimens often result in reduced compliance and inadequate treatment.for drugs with multicompartmental characteristics a better estimate of the dosing interval may be obtained by replacing t1/2 with 0.693*(MRT), where MRT is the mean residence time.in such cases the drug should be given even more frequently than suggested by above equation.

In general, the dosing interval may be increased either by modifying the drug molecule to decrease the rate of elimination or by modifying the release rate of a dosage form. Both approaches seek to decrease fluctuations in plasma levels during multiple dosing, allowing the dosing interval to increase without either overdosing or underdosing.

6. Factors:

A. Factors Influencing the design and performance of Sustained/Controlled release Products:

The following are factors influencing the design and performance of sustained/controlled release products.

1. Drug properties:

The drug properties (Physicochemical) such as stability, solubility, partitioning characteristics, chargeand protein binding play a dominant role in the design and performance of controlled release products.

Route of drug delivery:

· Route of drug delivery plays important role in design of controlled release products.

· At times, in certain routes of administration the drug delivery system exerts negative influence on drug efficacy, hence other routes of administration should be considered.

In this way route of drug delivery play a role in design of controlled release products.

2. Target sites:

In order to minimize the unwanted side effects the drug is allowed to reach the targeted site directly. This can be achieved by the use of carriers.

3. Acute or chronic therapy:

Consideration of whether one expects to achieve cure or control of a condition and the expected length of drug therapy are important factors in designing controlled release systems.

4. The disease:

Disease state plays a significant role in the design of a suitable drug delivery system.

Eg: To design an ocular controlled release product for an external inflammation, the time course of changes in protein content in ocular fluids and in the integrity of the ocular barriers would have to take into consideration.

5. The patient:

Whether the patient is ambulatory or bedridden, young or old, obese or gaunt etc can influence the design of a controlled release product. An implant or intramuscular injection of a drug to abedridden patient with little muscle movement may perform in a manner significantly different from that of an ambulatory patient.

6. Physicochemical Properties of a Drug Influencing Drug Product Design and Performance²:

The following are the physicochemical properties of a drug influencing drug product design and performance

1. Polymer solubility (CP)

2. Solution solubility (CS)

3. Partition Coefficient (K)

4. Polymer Diffusivity (DP)

5. Solution Diffusivity (DS)

6. Drug loading dose (A)

7. Surface area.

8. Protein binding

1. Polymer solubility (cp):

Until unless the drug particle dissociates from crystal, dissolve into surrounding polymer, diffuse through it, the drug cannot be treated to be released from the controlled release devices. This suggests that the solubility of drug in a rate controlling polymer matrix or membrane plays a rate controlling role in its release from polymeric device. To release at an appropriate rate, the drug requires adequate solubility. Hence polymer solubility (CP) can be appropriately seen in all the release rate equations of all types of controlled drug delivery systems. The relationship between the drug release rate (Q/t) and the magnitude of polymer solubility (CP) will be linear. This relationship should be followed by membrane-permeation type as well as for microreservoir type of drug delivery devices.

The difference in solubilities among drugs is very striking.

Example 1: Solubility of steroids in silicone polymer can range from 1-2 g/ml to as high as 1152.8 g/ml. This dramatic difference is very much dependent on the differences in their chemical structure, variation in functional groups and their stereochemical configurations.

Example 2: Addition of –OH group reduces the solubility of Progesterone in lipophilic polymer. Esterification of –OH groups increases the solubility.

The presence of fillers (silicon earth) was reported to increase the polymer solubility of drugs as a result of Langmuir adsorption of drugs on to the filler particles.

2. Solution solubility (CS):

Various studies stated that the release of drugs from controlled release devices is truly influenced by its solution solubility (CS). In-vivo sink condition is effectively simulated in In-vitro studies. This can be done by

· Concentration in bulk (Cb) should be zero.

· By maintaining solution concentration (CS) very high than bulk concentration (Cb). i.e., CS>>Cb.

· By using cosolvent (Water miscible co-solvents)

Ex: Aqueous solubility of ethynodiolactate was increased 3.584fold by using PEG 400.

Aqueous solubility of drug varies significantly similar to that of polymer solubility, which is very much dependent upon the difference in their chemical structure, the type and physiochemical nature of the functional groups and stereochemical configuration.

Ex: Esterification of Testosterone reduces aqueous solubility.

The drug having very low aqueous Solubility like steroids and Metronidazole, the solubility of the drugs can be increased by various Pharmaceutical approaches like Micelle formation, complexation, cosolvency, without chemical modification of drug molecules.

Finally, due to the solution solubility, variations are seen in release pattern of the controlled drug delivery device (Invitro study).

Ex: Norgestomet and hydron implants.

3. Partition coefficient (k):

The Partition Coefficient (K) of a drug for its interfacial partitioning from the surface of a drug delivery system towards an elution medium is defined as

K = Cs/Cp

Any variation in either Cs or Cp values results in a change in the magnitude of K values. Invitro studies of Norgestomet from silicon capsules shows that, by changing the solubility of Norgestomet in elution, the magnitude of partition coefficient thus varies, leading to a variation in drug release rate. The effect of alkyl chain length on the magnitude of the partition coefficient is exponential as defined below.

Log Kn = log k0 - nCH2

Where Kn is the partition coefficient for the compound with an alkyl chain length of n CH2 groups. K0 is the Y intercept at zero carbon number, CH2 is the slope of the log Kn versus n plot. The attainment of negative slope results from the fact that as alkyl chain increases, polymer solubility (CP) of the drug is enhanced with an expense of their solution solubility (CS) leading to reduction in partition coefficient (Kn).

On the other hand, addition of hydrophilic functional groups, such as –OH groups to a drug molecule tends to improve the solubility at the expense of the polymer solubility in a lipophilic polymer.

Ex: Progesterone in silicone Polymer and elution solution. This results in increase in partition coefficient.

The linear relationship between membrane permeability Pm and the partition coefficient K is

Pm = DPK

Ex: Transdermal permeation of steroid

Variation in the cosolvency also have an effect on partition coefficient (K)–either increase or decrease, has also been reported.

4. Polymer diffusivity (dp):

The diffusion at small molecules in a polymer structure is an energy activated process, in which the diffusant molecule moves to a successive series of equilibrium positions when a sufficient amount of energy, called energy of activation for diffusion Ed, has been acquired by the diffusant and its surrounding polymer matrix. The energy activated diffusion process is frequently described by the following Arrhenius relationship.

DP = Do e –(Ed/RT)

Where,

Do is a temperature frequency factor,

Ed is the energy of activation of polymer for diffusion; distributed throughout many degrees of freedom in the system, R & T have their usual thermodynamic meaning.

The energy of activation for polymer diffusion Ed is thus the sum of the energy intramolecular bending Eb and the energy of intermolecular repulsion Er.

Ed = Eb + Er

The results of model calculation indicated that the magnitude of Eb is very high for short segment polymer chain, but decreases as polymer chain becomes longer. On theother hand, Er increases as polymer chain becomes longer, i.e., degree of freedom becomes larger.

5. Solution diffusivity (ds):

The diffusion of solute molecules in a solution medium may be considered as a result of random motion of molecules. The solution diffusion process can be discussed by void occupation model and the theory of free volume.

DS= Do e- (En/RT)

Where,

DS = solution diffusivity

D0 = pre-exponential factor

En = energy of activation for solution diffusion.

For a solute whose molar volume is greater than or equal to the molar volume of water molecules, the diffusivity of the solute molecules in the aqueous solution (at 250C) is inversely proportional to the cube root of molar volume. The molar volume of a solute molecule is an additive property of its constituent atoms and functional groups. When solution diffusivity of various chemical group was compared on the basis of molecular volume. The relative rates found that Alkane> Alcohols> Amides> Acids> Amino acids> Dicarboxylic acids.

The diffusivity of solute molecules in an aqueous solution usually decreases as its concentration increase. This reduction is frequently related to the increase in viscosity that usually accompanies the increase in solution concentration. The effect of viscosity (μ) is related to solution diffusivity (DS).

DS = w / μ

Where,

w is proportional constant.

6. Protein binding:

Drug protein binding can serve as a depot for drug producing a prolonged release profile, especially if a high degree of drug –binding occurs. Drugs bound to mucin may increase absorption, if the bound drug acts as a depot.

Drugs are plasma protein bound and their distribution into extravascular space is governed by equilibrium process of dissociation of drug from protein. The drug-protein complex acts as require SRDF. In general, charged compounds have a greater tendency to bind a protein.

Ex: 95% PPB drugs are Diazepam, Dicoumarol, Novobiocin.

A drug must diffuse through a variety of biological membranes in the body. The ability of a drug to diffuse through membranes is so called diffusivity which is a function of molecular weight.

Log D = - Sv log v + Kv = - SM log M + Km

7. Molecular size and diffusivity:

Where,

D=Diffusivity

V= Molecular volume

M= Molecular weight

Sv, SM, Kv, Km= Constant

The normal range of molecular weight is 150-400.High molecular weight drugs shows slow release.

8. Dose size:

For oral dosage form a dose size of 0.5 to 1.0 gm is considered maximal. Higher doses have to be given as liquids. Drugs with low therapeutic index need to be given additional core if dose size is high.

9. Surface area:

· Both the in-vivo and in-vitro rates of drug release dependant on the surface area of the drug delivery device.

· Greater the surface area greater will be the rate of drug release.

10. Drug loading dose:

· In preparation of the device varying loading doses of drugs are incorporated, as required for different length of treatment.

· Variation in the loading doses results only in the change in duration of action with constant drug release profile.

7. Biological Factors Influencing Design and Performance of Sustained/Controlled Release Products:

Absorption:

To maintain constant blood or tissue level of drug, it must be uniformly released from the sustained release system and then uniformly absorbed. Usually, the rate-limiting step in drug delivery from a sustained release product is release, from the dosage form rather than absorption. The rate, extent and uniformity of absorption is an important factor, as here Kr<<<Ka. The optimum absorption rate must be 0.17 to 0.23 hr -1. The area of absorption in the GIT is also important.

A drug with slow absorption is a poor candidate for such dosage forms since continuous release will result in a pool of unabsorbed drug e.g. iron.

Distribution:

The distribution of drugs into tissues can be an important factor in the overall drug elimination kinetics since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibration with blood and extracellular fluid.

The Vd and the ratio of drug in tissue to that of plasma at steady state are important parameters to be considered in determining the release rate.

Metabolism:

Metabolism to other active form can also be considered as sustained effect. Enzyme inhibition or induction by drug results in fluctuating blood level with chronic use. Hepatic first pass metabolism also has the same effect. The extent of metabolism should be identical and predictable when the drug is administered by different routes.

If a drug, upon chronic administration, is capable of either inducing or inhibiting enzyme synthesis, it will be poor candidate. If there is a variable blood level of drug through either intestinal metabolism or through a first-pass effect, this also will make preparation of sustained release product difficult.

Elimination half-life:

The biological half-life and hence duration of action of a drug obviously play a major role in the process of considering a drug for sustained release. Factors influencing the biological half-life of a drug include its elimination, metabolism, and distribution patterns.

Most drugs have half-life of elimination in the range of 1-20 hr. Smaller the t ½, larger the amount of drug to be incorporated in the sustained release dosage form. For drugs with t ½ less than 2 hours, a very large dose may be required to maintain the high release rate. Drug with the half-life in the range of 2 to 4 hours make good candidate for such a system. e.g. Propranolol. Drugs with long half-life need not be presented in such a formulation e.g. Amlodipine. A candidate drug must have t ½ can be correlated with its pharmacologic response.

Side effects:

The incident of side effects can be minimized by controlling the concentration at which the drug exists in plasma at any given time; hence sustained release formulation appears to offer a solution to this problem.

Dosage form index (DI):

It is defined as the ratio of Css.max to Css.min. Since the goal of controlled release formulation is to improve therapy by reducing the dosage form index while maintaining the plasma drug levels within the therapeutic window, ideally its value should be as close to 1 as possible.

Margin of safety:

The most widely used measure of the margin of safety of a drug is its therapeutic index.

Ti = TD50 /Ed50

Where,

TD50 = Median toxic dose

ED50 = Median effective dose

The larger the value of Ti, the safer the drug. The release rate of a drug with very small value of Ti usually is poor candidates for formulation into sustained release products

7. Pharmacokinetic Basis:

· The compartmental analysis approach was initially proposed to describe the multi-exponential line course and plasma concentrations of drug is the body following drug administration.

· Physiological models were subsequently derived relating drug transfer on the basis of organ x tissue blood flows x extraction ratios of the active moieties.

Conventional dosage forms are rapidly absorbed, with the pealex and valley (or) Saw –tooth kinetic blood concentration profile (Ascending x descending).

· Dose response data define a quantitative term, frequently used in pharmacokinetic analysis of controlled drug delivery is known as the Therapeutic Index DDTI

Controlled drug deliveries following aims were identified to study the pharmacokinetic behaviour.

· The maintenance of Therapeutic concentrate with minimal fluctuations x *** over an extended period of time throughout a during interval.

· To keep the drug concentrations with in a therapeutic range, at a steady state.

· To keep the release rate (limitations to which) to such an extent that the final product should have a bio availability at least 80% relative to that of conventional delivery device.

· To minimize the role of formulation factors in the development of a dosing regimen, nor example increasing the elimination T½ of the drug.

· Better compliance and lower o of toxicity.

Compartmental Pharmacokinetic models used in sustained/controlled Drug Delivery:

In classical cases, the rate of drug absorption generally exceeds the rate of elimination. Under such conditions, a distribution phase can be run following a conventional drug delivery administration.

· However, a sustained ion-controlled release delivery system is a drug with a relatively short elimination half-life (T½ x 4 hrs) exhibits a situation in which the rate of absorption is so slow that it eventually creates on indefinable distribution phase.

1. Models of Drug input and Elimination: (Welling 1983):

These are based upon either Zero-order (or) 1st order rate constants for absorption and elimination.

Table 1: Model of Drug input and Elimination

Drug Input Stage 1	Drug Input Stage 2	Elimination	Rate limiting step	Model Selected
Zero Order	-	First order	Rate of Drug Release	Iv Infusion
Slow 1^st order	-	First order	Rate of Drug Elimination	Conventional Formula
Rapid first order	Zero Order	First order	Rate of drug Absorption	Sustaenous release
Rapid first order	Slow 1^st order	First order	Rate of drug Absorption	Sustained

These models are based on following assumptions.

· The elimination of drug follows first order process.

· The rate of drug distribution is governed by the rate of drug absorption and drug elimination.

· All the kinetic processes except for drug absorption are linear.

a. Zero order absorption followed by I- order elimination.

b. Show I- order absorption followed by I- order elimination.

c. Rapid I-order absorption of part of the dose, then release and absorption of the remainder over an extended period of time by a O- order kinetic process followed by a I- order elimination.

d. Rapid F- order absorption of part of the dose, then release and absorption of the remainder over an extended period of time by a slower I- order kinetic process followed by I- order elimination.

Drugs after oral administration follow multicompartment pharmacokinetic models and this is a function of the affinity of the administered drug (or) delivery system for various tissues. Slow absorption of drugs from controlled release formulations impleads distribution phase, which remains observed by absorption process. It leads to a drug profile that can be more satisfactory defined by kinetic model based on one compartment modelling assumptions. In order to define the pharmacokinetic modelling of sustained release products following assumptions are made (Welling 1986).

· Drug absorption, metabolism and excretion are I-order rate processes.

· Drug absorptions elimination are irreversible.

· Drug that is released after oral administration is completely absorbed in the unionized form.

· Drug release from the modified release product is rate limiting in the absorption process.

These assumptions followsKalonkr significantly smaller than Ka the absorption step has been deleted from the original one compartment model in designing the model for modified release products.

a. Zero order absorption:

Drug profile from this type of delivery system is influenced by the rate at which drug is released from the dosage form and also the elimination rate.

· The time course of accumulation following a single dose administration is independent of release rate constant more over, the drug levels are directly proportional to controlled release rate constants.

· A drug with a short elimination half –life will approach steady state (sustained release) at a time faster than a drug with a longer elimination half-life.

Case Study:

Drug with elimination half-life – 1.5, 2 and 2.5 hrs

{Kq = 0.46, 0.34 and 0.27 respectively} approaches steady state at 8 hrs.

· Whereas drugs with longer elimination, half-life of 7.5 hr (Kq = 0.09th) could not achieve it in the same time period.

This indicates that for longer elimination half-life drugs it is not always possible to achieve a plateau (or) steady state with a single dose of a Zero-order release formulation.

· This model presents a situation where the orally administered drug is absorbed by an apparent O-order process/on process. In this case, the release of the drug out of the drug product is the rate limiting step.

b. First-order absorption:

· The amount and concentration of drug after single dose administration from a sustained release product following a I-order release kinetics.

c. Rapid 1-order – Zero order – I – order elimination:

Basic principle of this type relies on the fact that a controlled release component should be prescribed by an immediate release component, which will establish the desired blood level in the body.

· The amount of drug after single dose administration from a sustained release product equipped with a fast release component which then follows a Zero-order release loinetly.

· To achieve therapeutic level promptly and sustain the level for a given period of time, the total dose, thus required with delivery system can be presented.

Ex: Dose = Di+Dm.

Several methods have been adopted to calculate the proportions of Di and Dm that are required to achieve therapeutic blood levels.

· The most recent method is based on the assumption that the fast release component should provide the quantity of drug that would yield the desired therapeutic response at steady state.

Limitations:

The limitations of these models which operate following various rates of absorption and elimination is the difficulty of selection for fitting and analyzing experimental rate after administration of sustained delivery systems.

· Model dependent equation cannot analyzed the PK parameters of a sustained release product.

· In the case of oral administration the leonetic order of absorption possess may be a time ion size independent phenomena before it absorbs, reverse through the GIT to reach the site of absorption.

d. First- order, slow first-order and first– order elimination:

· The amount of drug after single dose administration from a sustained release product equipped with a fast release (I – order) followed by a first order.

Where Ko is the rate constant governing absorption and Kr <<Ka

Similar to previous model, satisfactory approximately of a control drug level can be obtained by suitable combinations of Di and Dm that release its drug by first order process.

Dose = Di + (Ke cd/Ka) vd

· Oscillations may occur with in a narrow and therapeutically acceptable range.

2. Loo – Riegelman and Wagner – Nelson Model:

It is well established that the plasma content ration course after IV administration can be expressed in terms of an apparent biexponential equation and that of oral administration by an apparent multiexponential equation of the processes like absorption is not required in the former case.

· The process of slow release from a sustained (or) controlled release delivery system may obscure the distribution phase, thus vanishing the exponential term which usually defines the distribution phase.

· The Loo-Reigelman model assesses drug absorption in general and specifically absorption from sustained release delivery systems.

The model states that the amount of drug absorbed at any given time equals the sum of the amount of drug present in the Central and peripheral compartment and of the amount eliminated by the all routes.

Thus the model does not predict any particular kinetic order of absorption and obviously it can be O-order, I-order (or) a combination or both.

The only assumption with this model is that the drug pharmacokinetics can be described by at least or two compartment model.

However, this is not a limiting presumption as this is the preferred category after IV administration of the majority of the drugs.

· This method can be applied to any multicompartment model.

· The implementation of this model requires the administration of the drug through the intravenous route as a reference. The model can be used for the following features.

· To measure the rate of extent of absorption.

· To determine the pharmacokinetic order of the absorption process.

8. Pharmacodynamics³:

Pk not only in the facilitating predictions of the time course of drug concentration in the body, but also in the developing a better understanding of the time course of drug action on the body.

· P kinetics describe what the body does to the drug. P. dynamics can relate drug effects on the body.

· P. D. can be defined as a Quantitive assessment of the time course of drug effects on the body after administration by any route.

· The measured response to a drug may be all (or) none (or) it may be graded.

There are 2 fundamental ways that Pharmacodynamic principles can be applied to the drug development process.

a. The pharmacokinetics of a drug will be known and a pharmacokinetic model can be established for the drug in humans (or) in some animal species. This pharmacokinetic model can then be worked to

b. Available pharmacodynamic data resulting in a unified concept relating the kinetics of the drug to the time course of the drug effect.

c. Where the pharmacokinetic characteristics of the drug cannot be adequately defined (or) where drug effect is apparently unrelated to concentration, alternative approaches can be utilized.

d. Implicit to many pharmacodnyanmic models is that measured drug (or) active metabolite concentrations in a sampled bio phase age in equilibrium with concentrations at the receptor (or) the site of drug action.

Concentration data obtained at Steady state may be particularly useful in defining a Pharmacodynamic model since single dose data alone may not be adequate to describe the effect of drug (or) active metabolite accumulation on the drugs pharmacological action upon multiple dosing.

· These models not only help to explain empirical data, but also provide a rationale for elucidating fundamental mechanisms thereby facilitating a prediction (or) drug activity in different subject (or) under altered physiological/disease state conditions.

Useful pharmacodynamci models are based on concentration Vs time data that are obtained at an “effect” site these models are based on the assumption that the actual blood sampling site is in equilibrium with drug at its effect site.

Pharmacodynamic model:

Oldest model–fixed–effect model, where drug concentration can be related to a pharmacological effect which is either observed (or) not observed.

Limitation on this model however is that at a given drug concentration, the effect may (or) may not be obtained in a given individual.

· The most fundamental model directly linking drug concentration and effect is the linear model, which can be described mathematically.

E = P.C.

E contified effect

CDrug concentration

P Linear parameter best linking E and C.

Depending on the drug and the effect being evicted a base line effect may be measured in the absence of drug i.e., when C = O at t = O) and in thus core the relationship can be rewritten.

Ex: E = P.C. + E0. E0  effect at time t = 0, C = 0.

The parameter P will then be estimated from a plot of E = E0 and C., Estimating E0 may not be a trivial matter necessarily and a variety of problems and methods for their solution have been Logarithmic model.

E = P. Logc+E0.

of a dosage form is given chronically, and concentrations at steady state are measured, this equation can be rewritten as

Ess= P. Log Css + E0ss.

Maximum drug affect Emax model, however incorporating concepts from enzymology and equilibrium theory and allows for a prediction of Cmax.

Emax  Theoretical maxima attainable effect attributable to the long and E50 is the concentration of drug elicting 50of this maximal effect.

9. Synthetic and Biocompatible Polymers used in Controlled release dosage forms:

Polymers are the macromolecules having large chains containing variety of functional groups can be blended with other low and high molecular weight materials.

· Polymers control the drug release rate from the formulations

· These polymers shows increased effectiveness in novel drug delivery

· Advances in polymer science show the more development in novel drug delivery. This new technologies which has been developed improved the

1. Drug modification by chemical mucous

2. Carrier based drug delivery

3. Drug entrapment in polymer matrices

· Newer technologies improve the efficacy of drug therapy their by improves human health

· Newer technological development in polymer based encapsulation and control drug release systems offer possibilities for optimizing the administration of drugs. These improvements contribute to make medical treatment more efficient and to minimize side effects and other types of inconviences for patients.

Polymers used as:

· Taste masking agent

· Film coating agent

· Control release agent

· To enhance stability

· To enhance bio availability

By use of monolithic delivery devices in which drug is dispersed in polymer matrix, the rate of drug release from matrices depends on initial concentration and relaxation of polymer chains. In case of biomedical area polymers are expected to perform long term studies.

Water Soluble Synthetic Polymers:

Poly acrylic acid:

It is used as

· Cosmetic agent

· Immobilization of cationic drugs

Poly ethylene oxide:

It is used as

· Coagulant

· Flocculating agent

· Swelling agent

Poly Vinyl Pyrrolidone:

· It is used to make betadine with less toxicity than iodine

· It is used in tablet granulation

Poly vinyl alcohol:

· It acts as tablet binder

· Used in tablet coating

Cellulose Based Polymers:

Ethyl cellulose:

· It is insoluble but dispersible in water

· Acts as a aqueous coating system for sustained release preparations

Carboxy methyl cellulose:

· Acts as super disintegrant

· Acts as emulsion stabiliser

Hydroxy ethyl cellulose and hydroxy propyl cellulose:

· Soluble in water and alcohol

· Used in tablet coating

Hydroxy propyl methyl cellulose:

· Acts as binder for tablet matrix

· Used in tablet coating

Cellulose acetate phthalate (CAP):

It is used in enteric coating technology

Hydrocolloids:

· Acts as thickening agent

· Suspending agent in case of pastes, creams and gels

· Stabilizing agent for oil in water emulsions

· Acts as binder

· Acts as disintegrating agent

Chitosan:

· Used in control drug delivery

· Muco adhesive dosage forms

· Rapid release dosage forms

Starch Based Polymers

Starch acts as

· Binder

· Diluents

· Glidant

· Disintegrant

Sodium starch glycolate:

It acts as super disintegrating agent

Plastics and Rubbers:

Poly urethane:

It is used in transdermal patches

Silicones:

· Used in therapeutic devices

· Used in implant

Natural Origin Polymers used as Pharmaceutical Excipients:

Polysaccharides:

This polysaccharides is a class of biopolymers constituted by either one or two alternating monosaccharides which differ in their monosaccharide unit in the length of the chain, types of linking units and in the degree of branching.

Alginate:

It is derived from marine polysaccharides. It consist of β.D. mannuronic acid and α.L.guluronic acid

Haluronic acid:

Used as lubricant, shock absorbers

Bovine serum albumin (BSA):

These are biodegradable, non toxic and suitable for controlled drug delivery systems. These are prepared under mild conditions by coacervation method and desolvation process.in this cross linking was done by gluteraldehyde.

Collagen:

It is a major protein component.27 types of collagen has been identified. Type 1 collagen is used as a polymer because of high strength and more bio compatability.

10. Oral Controlled Delivery dosage forms:

Two basic types of controlled-delivery dosage forms have been designed in which diffusion is the rate-limiting step to generate temporal input profiles for drug delivery: matrix- and reservoir-type systems.

A matrix type system consists of a rate-controlling ingredient such as a polymer with drug uniformly dissolved or dispersed in it, and typically, a half-order drug release corresponds to desorption from the preloaded matrix.

A reservoir-type system separates a drug compartment from a polymer membrane that presents a diffusional barrier to yield drug flux of either zero order (with infinite dose) or first order (by dose depletion).

Diffusion Theory:

Diffusion can be defined as a process by which molecules transfer spontaneously from one region to another in such a way as to equalize chemical potential or thermodynamic activity. Although diffusion is a result of random molecular motion, with a wide spectrum of physicochemical properties occurring in various conditions and situations, the diffusion process can be abstracted to a simple system involving molecules of interest, a diffusional barrier, and a concentration gradient. The migrating molecules are termed diffusants (also called permeants or penetrants). The membrane or matrix in which the diffusant migrates is called the diffusional barrier. The external phase is called the medium. The concentration gradient or profile of the diffusant within the diffusional barrier is the driving force for diffusion. The mathematics of diffusion are discussed briefly in this section, with emphasis on both diffusion across a barrier membrane and diffusional release from a preloaded matrix the basic equations were put forth by Fick in 1855 as an analogy to the heat-conduction equation developed by Fourier in 1822. The theory of diffusion in isotropic substances therefore is based on the hypothesis that the flux J or rate of diffusion (amount Qt in time t) through a unit area of a barrier section is proportional to the concentration gradient within and normal to the section; that is,

J= dQt/dt= -D. dC/dt

This is Fick’s first law, with the proportionality constant D termed diffusivity or diffusion coefficient. The negative sign arises because the direction of molecular movement is opposite to the increase in the concentration.

11. Oral Diffusion-Controlled Systems⁴:

Matrix systems:

A matrix system consists of active and inactive ingredients that are homogeneously mixed in the dosage form. It is by far the most commonly used oral CR technology, and the popularity of matrix systems can be attributed to several factors. Matrix system is capable of accommodating both low and high drug load and active ingredients with a wide range of physical and chemical properties.

Fig. 2: Matrix DDS

The drug molecules elute out of the matrix only by dissolution followed by diffusion through the polymer structure in to the surrounding environment. It has been suggested that firstly the drug particles present in the layer closer to the surface of the device elute and after complete depletion of this layer the drug particles present in next layer starts depleting.

With the passage of time and continuous drug release, the delivery rate normally decreases in these types of systems since the bioactive agent has to traverse a long distance progressively and thereby requires a longer diffusion time for ultimate delivery of drug

Mechanism:

In the matrix or monolithic system, drug is distributed through a polymer that serves as the diffusion barrier. The polymer matrix can either be nonporous/homogeneous or porous/granular. In the former, the matrix can be considered to consist of one phase through which the drug diffuses. In the latter, diffusion is restricted to pores in an otherwise impermeable material. The drug can be dissolved in the matrix or be dispersed in solid form. Whereas diffusion is the major rate-controlling mechanism matrix swelling and erosion can have significant impacts on the release rate for other matrix materials

*To further this discussion, we divide matrix systems into two categories, hydrophobic and hydrophilic systems, based on rate-controlling materials

Hydrophobic matrix systems:

This is the only system where use of a polymer is not essential to provide controlled drug release, although insoluble polymers have been used. As the term suggests, the primary rate-controlling components of a hydrophobic matrix are water insoluble in nature. These ingredients include waxes, glycerides, fatty acids, and polymeric materials such as ethylcellulose and methacrylate copolymers. To modulate drug release, it may be necessary to incorporate soluble ingredients such as lactose into the formulation.

Hydrophilic Matrix Systems:

The primary rate-controlling ingredients of a hydrophilic matrix are polymers that would swell on contact with the aqueous solution and form a gel layer on the surface of the system. Hydroxypropyl methylcellulose (HPMC) is the most commonly used hydrophilic polymer. Other polymers include high-molecular-weight polyethylene oxide (Polyox™), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), xantham gum, sodium alginate, and polyacrylic acid (Carbopol™). polymer dissolution (erosion) and diffusion of drug molecules across the gel layer have been identified as the rate-controlling mechanisms.

Advantages:

1. Very easy to fabricate in a wide range of sizes and shapes.

2. Suitable for both non-degradable and degradable systems.

3. No danger of ’dose dumping’ in case of rupture.

Disadvantages:

1. Achievement of ‘zero order’ release is difficult.

2. Not all drugs can be blended with a given polymeric matrix.

3. Water soluble drugs have a tendency to ‘burst’ from the system.

Reservoir systems:

A typical reservoir system consists of a core (the reservoir) and a coating membrane (the diffusion barrier). The core contains the active ingredients and excipients, whereas the membrane is made primarily of rate-controlling polymer(s). The governing release mechanism is diffusion from the reservoir across the membrane to the bulk solution, It is a membrane controlled reservoir system in which the therapeutic agent is contained in a core surrounded by a thin polymer membrane and the active agent is released to the surrounding environment by diffusion process through the rate-limiting membrane. For the reservoir type of systems, the drug delivery rate remains fairly constant. These systems consist of a reservoir of either solid drug dilute solution or highly concentrated drug solution within a polymer matrix, which in turn is surrounded by a film or membrane of a rate controlling material.

The drug molecules in the outer most layer of particles firstly have to dissociate from the crystal lattice before dissolving into and subsequently diffusing through the polymer structure and eventually leading to partitioning into the elution medium.

The rug release limiting structure is the polymer layer surrounding the reservoir. Since the polymer coating is essentially uniform the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery systems.

Mechanism:

Reservoir systems are similar in design to osmotic pumping systems, where the dissolved drug and constituent materials induce an osmotic pressure within the core. This pressure results in outward convection of dissolved drug, through holes in the coating Although diffusion is generally considered to be the dominating release mechanism in reservoir systems, osmotic pumping can also influence the release rate.

The most commonly used materials for constructing the membrane are ethylcellulose (Surelease™ or Aquacoat™) and acrylic copolymers (Eudragit™ RL30D, RS 30D, and NE 30D). Water-soluble polymers such as HPMC and polyethylene glycol (PEG) are employed as pore formers. Typically, special coating equipment such as the Wuster coater is required to apply the coating material uniformly

Fig. 3: Reservoir DDS

Advantages:

1. Acheivement of ‘zero order’ release is easy.

2. Very easy to fabricate in a wide range of sizes and shapes.

3. Drug inactivation by contact with the polymeric matrix can be avoided.

Disadvantages:

1. Rupture can result in dangerous ‘dose dumping’

2. Degradable reservoir systems may be difficult to design.

Ion-Exchange Resin or Ion-Exchange Polymer:

· Ion exchange resins are polymers that are capable of exchanging particular ions with in the polymer with ions in a solution that is passed through them.

This ability is also seen in various natural systems such as soils and living cells. The synthetic resins are used primarily for purifying water, but also for various other applications including separating out some elements.

· Ion exchange materials are insoluble substances containing loosely held ions which are able to be exchanged with other ions in solutions which come in contact with them.

· These exchanges take place without any physical alteration to the ion exchange material. Ionexchangers are insoluble acids or bases which have salts which are also insoluble, and this

· Enables them to exchange either positively charged ions (cation exchangers) or negatively charged ions (anion exchangers).

· Many natural substances such as proteins, cellulose, living cells and soil particles exhibit ion exchange properties which play an important role in the way the function in nature.

· Synthetic ion exchange materials based on coal and phenolic resins were first introduced for industrial use during the 1930.s. A few years later resins consisting of polystyrene with sulphonate groups to form cation exchangers or amine groups to form anion exchangers were developed. These two kinds of resin are still the most commonly used resins today.

· The principle of ion exchange has been used for a long time in analytical and protein chemistry. It is an attractive method for sustained drug delivery because, in theory, drug release characteristics largely depends only on the ionic environment of the resin containing drug and should therefore be less susceptible to environmental conditions. Such as

· Enzyme contents and

· PH, at the site absorption.

· Because this approach of sustained release requires the presence of ions in solution, it would not be applicable to the skin, the external ear canal, or other areas with limited quantities of eluting ions.

· In contrast the SC and IM routes, where the pool of available ions is more controlled, would appear better suited for this approach. However the resin may undergo biodegradation with an attendent alternation in the “pre-programmed” release rate.

· While the GIT appears to possess a rather constant ionic content, the variability in diet, water intake, and GI content composition make this constant ionic content unlikely.

· The Resins are water insoluble materials containing anionic or cationic groups in repeating position on the resin chain.

· The drug charged resin is prepared by mixing the resin with drug solution either by repeated exposure of the resin to drug in chromatographic column or by keeping the resin in contact with the drug solution for extended period of time.

· When a high concentration of drug charged ions is in contact with the ion exchange group, the drug molecules is exchange and diffuse out of the resin to bulk solution according following scheme.

Resin [N (CH3)] + X¯ + Z - Resin [N (CH3)] + Z + X-

(Drug-charged resin)

The release rate can be controlled by coating the drug resin complex using the one of the micro-encapsulating process.

TYPES:

1 Cation exchange resins

2 Anion exchange resins

1. Cation Exchange Resins:

These are synthesised by copolymerization of divinyl benzene and styrene. Polymerization reaction involves initially the formation of linear chains of polystyrene, which are subsequently attached to each other at intermittent points by divinylbenzene cross links results in the formation of three-dimensional insoluble hydrocarbon network. when this is treated with sulphuric acid, sulphonic acid groups (-SO3-H+) are introduced into most of the benzene rings of the copolymer ultimately producing a cation exchange resin.

2. Anion Exchange Resins:

These are synthesised by chioromethylation of benzene rings of 3dimensional styrene-divinyl benzenecopolymer network leading to the insertion of -CH2CL groups allowing these to react with a tertiary amine viz, trimethyl amine resulting in formation of strong anion exchange resin.

Mechanism of drug release:

Cation exchange resins contain acidic functional groups, generally they contain polystyrene polymer with either phenolic, carboxylic or sulphonicgroups. on the other hand anion exchange resins involve basic functional groups capable of extracting anions from acidic solutions.

Ion exchange resins are used to sustain the effects of drugs based on the concept that negatively or positively charged drug moities combine with appropriate resins producing insoluble polysaltresinates.

Where R-SO3-H+ and R-NH3+OH- represents cationic and anionic resins, respectively, where as H2N-A and HOOC-B depicts basic and acidic drug respectively. whereadmistered orally resins come in contact with acidic fluid that contains HCL with a following reaction takes place

R-SO3-H+ + H2N-A → R-SO3- + H3N+ -A

R-N+H3 OH- + HOOC-B→ R-N+H3- OOC-B + H2O

Drugs that are suitable for the preparation of controlled release resinates should have

· Acidic or basic nature.

· Biological half-life between 2-6 hrs.

· Absorption window in all regions of the GI tract.

REFERENCES:

1. Sahilhusen IJ. Pharmaceutical Controlled Release Drug Delivery System: A Patent Review. Aperito journal of Drug Designing, and Pharmacology, 2014;1(2):1-22.

2. Dr. Tiwari G, Bhati L. Drug delivery System: An Updated review. International Journal of Pharmaceutical Investigation, 2012;2(1):2-11.

3. Patel N et.al. Controlled Drug delivery System: A Review. Indo American journal of Pharmaceutical Sciences. 2016;3(3):227-233.

4. Patil SS, Patel ND. A review of Control drug delivery system International Journal of Pharmaceutical, Chemical and Biological Sciences, 2014;4(3):529-536.

Received on 30.08.2020 Modified on 19.09.2020

Res. J. Pharma. Dosage Forms and Tech.2021; 13(1):41-53.

DOI: 10.5958/0975-4377.2021.00008.2