Zero order release approximation

• A design consisting of a loading dose and zero order release maintained dose.

• If a zero order release characteristic can be implemented in a partial formulation, the release process becomes independent of the magnitude of the maintenance dose and does not change during the effective maintenance period

First order release approximation

The rate of release of drug from the maintaince portion of the dosage form should be zero- order if the amount of drug at the absorption site in to remain constant.

Most currently sustained release formulation, how ever don't release drug at constant rate and consequently do not maintain the relative constant activity.Observed blood level decreases over time until the next

dose is administered

The rate of appearance of drug at the absorption site

can be approximated be an exponential or first order process, in which the rate of drug release is a function of the amount of the drug remaining in the dosage form.

• The expression that can be used to estimate the design parameter for optimized first under release method.

Method 1: Dm not delayed (simultaneous release of Dm & Di)

Method 2: Dm delayed when Tm=Tp

Method 3: Dm delayed release when Tm > Tp

• D1 = initial loading dose or immediately available portion of dose. • Dm = Maintenance dose or slowly available portion of dosage

• Tm = Time at which release of maintenance dose.

• Kr = Specific rate of release of maintenance dose

• Tp = Peak level time

• Kr = Specific rate of release of maintenance dose

• H = Total time after administration in which the drug is effectively absorbed

• Method 1: Simultaneous release of Dm and Di or Dm not delayed

The crossing time, Ti is the time at which the blood level profile produced by administration of separate loading and maintain doses intersect. The closest approximation to the ideal profile is obtained if the crossing point is made at least equal is the desired maintenance period (h-Tp)

Method 2: Delayed release of Dm (Tm=Tp)

If Dm is large and Kr is made small, maintenance dose may be released on a pseudo zero order process.

As a first approximation Kr1 may be estimated as the reciprocal of the maintenance time . Dm is then calculated as in method 1.

Method 3: Delayed release of Dm (Tm > Tp)

Increasing the delay time Tm allows the use of faster release rates, A period equal to the time at which 99% of the loading dose has been absorbed is selected.

Multiple Dosing:

Like conventional dosage form, sustained release form are administrated as multiple dosing release, with the objective is to maintain the required avg. drug level for the duration of therapy with a minimal fluctuation b/w doses. If the dosing interval is made equal to (or less than) the total anticipated drug release time (fig ) accumulation results from formulation designed with loading doses.

Significant blood level peaks may be observed with the zero-order release model:

How ever minimal fluctuation b/w administered

Fig on next page

dose can be obtained if the dosing is set equal to (h+4) as shown by curve B.

Increasing the dosing interval further while diminishing the peak also deepens the trough in the drug level profile, defeating one of the objective of dosage form design.

In sustained release therapy only the dosing interval is adjustable. If two units are initially administered followed by a single unit subsequently doses, as common in therapy with non-sustained form, a slow fall in overall drug level accur .There are several strategies for attaining approximation of ideal profile in the multiple dosing of different sustained release designs based on both cumulative and non cumulative approaches.

Alternatively administration of formulation designed without loading doses can result in minimal fluctuation during the long term therapy.

in fig Curve-c shows the result of this type of multiple dosing regimen where a zero-order based design consisting only slow release maintenance dose is administrated at interval of h hours.

if absorption is consistent, profile obtained are equivalent to those resulting from administration of drug by constant rate infusion.

APPROACHES BASE ON DRUG MODIFICATION:

Two general set of method have been developed for implementation of practical sustained release dosage form design.

Method based on the modification of the physical/or chemical properties of the drug and method based on modification of drug release rate characteristics of the dosage that affect bioavailability.

Design A: the physicochemical properties of a drug may be altered through complex formation, drug adsorb ate preparation, or prodrug synthesis possible where functional gp present .The principle advantages of this approach to sustain release is that it is independent of the dosage form design. Drug so modified may be formulated as the liquid suspension, capsules or tablets. Loading doses of

Implementation of Design

unmodified drug may also be incorporated in formulations that are ordinarily formulated to release both unmodified and modified drugs without significant delay.

Mechanism:

method involved in controlling the release of drug form complexes, adsorbates and pro-drugs. In the case of drug complexes, the effective release rate is a function of two processes: the rate of the dissolution of solid complex into the biological fluids and rate of dissociation or break down, of the complex in the solution.

In general dissolution step may be described following expression:

Rate Dissolution: Ks(solubility) (surface area)

Where Ks is the dissolution rate constant, a function of the hydrodynamic state as well as factor influencing the diffusion process (e.g. viscosity)

Technicalities: the formulator has the option of altering surface area through particle size control/ and solubility of the drug complex through selection of the complexing agent.

while both processes are dependent on the pH and composition of the gastric and intestinal fluids, the dissociating step is critically so, since its rate may be pH dependent, may be determined by the ionic composition of the fluid and may be affected by the natural digestive processes including enzymatic and bile salt action.

The formulator should select the appropriate complex for preparation with the knowledge of the specific in vivo processes involved in the control of drug release from the complex. E.g. tannate complex of bases are hydrolyzed in both acidic and basic media.

the dissociation of the complex being more rapid at the gastric pH. Drug release from cationic ion-exchange resin complexes depends on Na ion concen in GI fluids and although a stearate salt of a weak base resists the action of gastric fluid, natural digestive processes in the intestine act to dissociate the complex.

If the rate of dissolution is greater than the rate of dissociation, then the dissolution of the complex is rate determining.

P. size of the complex should be adjusted to establish the most appropriate rate of release with sufficient excess solid phase, zero order release may also be approximated.

Design B: Drug absorbate represent a special case of complex formation, in which product is essentially insoluble, drug availability in determined only by the rate of dissociation and there for, acess of the adsorbent surface to water as well as the effective surface area of adsorbate.

prodrug are therapeutically in active drug derivatives that regenerate the parent drug by enzymatic or non enzymatic hydrolysis.

Fig shown the scheme that identifies the potential process for achieving sustained action. Dissolution Dissocation Absorption

D.C (Solid). D.C (Solution) D

(Drug absorbate) Desorption Absorption

A.D. D(Solid)

Pro drugDissolution Absorption metabolism Excretion

P.D (Solid). P.D (Solution) P.D P.D

Plasma

Factors: the solubility, specific absorption rate, and / or elimination rate constant of an effective prodrug should be significantly lower then that of the parent compound.

Approaches based on dosage form modification.

Most per oral sustained release product have been formulated as encapsulation or tablet.

Formulation based on modification of physicochemical properties of these dosage form can be classed into three product type.

1- Encapsulated slow release beads (or granules)

2- Tabletted mixed or slow release granulation

3- Slow release (core) tablet.

• One layer or the other coat of the tablet is prepared from a potentially rapid disintegration granulation leaving the less quickly disintegrating layer or core which contains the maintenance dose.

System prepared as tabletted mixed released granulation, may or may not be designed to disintegrate quickly, simulating the administration of an encapsulated form in the latter case.

Advantages encapsulated s. released dosage form have two specific advantages over core tablet dosing

1- Undisintegrated tablet may remain in the stomach for extended period of time, excessively delaying absorption of the maintenance dose.

Disintegration of the capsule shell in the gastric fluid release particle that can pass unimpeded through the pyloric valve.

2- there is statistical assurance of drug release with encapsulated form , since release of drug by a significant fraction of the granule is highly probable, if a core tablet fail to release drug, all of the maintaince dose is lost.

Product evaluation and testing

In vitro measurement of drug availability:

it is not possible to simulate in a single in vitro test system the range of variables that affect drug release during the passage of sustained release medication through GIT.

Properly designed in vitro test for drug release serve two important functions.

1- Data from such test are required as guide to formulation during the development stage prior to clinical test

2- in vitro testing is necessary to ensure batch to batch uniformity in the production of a proven dosage form.

Methods: different method are usually required by these two distinctly different testing solution .

Ideal characteristics of Method: method used to measure drug release profile should have the following characterstics.

1- The analytical technique should be automated so that the complete drug release profile can be directly recorded.

2- Allowance should be made for changing the release media from simulated gastric to simulated intestinal fluid at reliable programmed time interval to establish the effect of the retention dosage form in gastric fluid as well as to approximate more closely the pH shift, that the dosage form is likely to encounter in vivo.

3- The hydrodynamic state in the dissolution vessel should be controllable and capable of variation.