Sustained Release Products: A Review on Formulation Technologies and Regulatory Aspects

 

Anjan K. Mahapatra¹*, P.N. Murthy², Ranjit P. Swain¹, Y. Sravani¹, G. Sagar¹

¹Maharajah’s College of Pharmacy, Phool Baugh, Vizianagaram - 535 002, INDIA

²Royal College of Pharmacy and Health Sciences, Berhampur-760 002, Odisha, INDIA

 

ABSTRACT:

The aim of authors in this review is to provide an updated hypothetical and technological outlook on designing a sustainable drug product to meet the patients need. An appropriately designed sustained release (SR) drug delivery system can have major advance towards solving problems concerning the targeting of a drug to specific organ or tissue and controlling the rate of drug delivery to the target tissue. The principal goal of sustained release formulations is to improve the drug therapy assessed by the relationship between advantages and disadvantages of its use. Usually drugs with short biological half life and requiring repeated dosing are formulated into sustained release products. The most important factors to taken into account when selecting the polymers in the formulation of SR  products are they should be inert, biodegradable, biocompatible and they should have release retarding property, they may be synthetic or natural origin. Polymer drug ratio, drug or polymer solubility, drug particle size and compression force are important among the formulation factors to be considered in the design of SR products. The authors review on novel and established methods to develop sustained release products. Here updates and basics are presented with special reference to materials, design and development, release mechanism etc. for a researcher to newly imagine working on formulation and development of SR products. A description of drug and polymers physicochemical or biopharmaceutical characteristics, Preparation methods and regulatory considerations is also presented and reviewed in this manuscript. 

 

INTRODUCTION:

Sustained release medication may be defined as a specific type of programmed release medication which contains in one dosage form the equivalent of several single doses of a drug, and which is released to the body over an extended period of time and there by produces a sustained clinical effect. ^[1]The advantages of administering a single dose of a drug that is released over an extended period of time, instead of numerous doses, have been obvious to the pharmaceutical industry for some time. The desire to maintain a near-constant or uniform blood level of a drug often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use.^[2-3]Usually sustained release products provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period.^[4]

 

The basic rationale of a sustained drug delivery system is to optimize the biopharmaceutic, pharmacokinetic and pharmacodynamic properties of a drug in such a way that its utility is maximized through reduction in side effects.^[5]  The expense and complication involved in marketing new entities have increased with concomitant recognition of the therapeutics advantages of sustained drug delivery, greater attention has been focused on development of sustained drug delivery.^[6] Comparison of plasma drug concentration versus time profile of immediate release, sustained release and zero order is shown in Figure 1. In case of immediate release formulations a rapid peak plasma concentration is achieved and the same is not maintained for prolonged period of time. Where as in case of sustained release medication a peak plasma concentration is achieved within therapeutic range and is maintained for a prolonged period of time following zero order kinetic for its release profile i.e., a constant rate of release independent of concentration or amount of drug.

 

Merits of Sustained Release Dosage Form ^[7-9]

Clinical benefits:

·        Reduced local and systemic side effects

·        Better drug utilization

·        Improved efficacy in treatment

·        Better patient compliance

·        Economical to the health care providers and the patients.

 

Commercial benefits:

·           Extension of product life-cycle.

·           Differentiation of product.

·           Expansion of market and patent.

 

Limitations of sustained release dosage forms: ^[4]

·        Possible toxicity of the materials used.

·        Dose dumping.

·        Higher manufacturing costs for design and development of sustained release delivery systems.

·        Poor in vitro - in vivo correlation.

 

Limitations of conventional release dosage form:

·        Repeated dosing, so chances of missing a dose.                                   

·        Sea-saw plasma concentration time profile.

·        Under or over medication.

·        Poor patient compliance.

 

Polymers Used:

These polymers have been broadly grouped into two categories, hydrogels and the hydrophilic polymers. Hydrogels are swellable polymers that are water insoluble, whereas the hydrophilic polymers are swellable and water soluble. The increasing need for suitable polymers to achieve a desired drug release has facilitated screening of a large variety of both synthetic and natural polymers for their ability to retard the release of specific drug substances. Since the cost of synthesizing a new polymeric substance and testing for its safety is enormous, a new focus has been directed towards investigating the use of polymer blends of pharmaceutically approved polymeric materials as matrix excipients to retard drug release.^[10] The use of natural polymers and their semi-synthetic derivative in drug delivery continues to be an area of active research.^[11] Polymers commonly used in sustained release matrices are given in Table 1. ^[12-21]

 

Biodegradable polymers:

Over the past decade the use of biodegradable polymers for the administration of pharmaceuticals and biomedical agents has increased, most important biomedical applications of biodegradable polymers are in the areas of sustained drug delivery systems. ^{[29, 30]} In general synthetic polymers offer greater advantages than natural ones in that they can be tailored to give a wide range of properties. However, toxicity is associated with these synthetic polymers. Therefore, safer carrier natural polymers are used. Thus, natural polymers have certain advantages as drug delivery carriers. ^[31] At present the application of the various types of biodegradable polymers in therapy, surgery, and pharmacology is considered. An absorbable polymer may also play the role of a drug depot providing a more or less long-term supply of drug to the blood at a constant rate.

 

Few examples of biodegradable polymers used in sustained drug delivery are Polylactides (PLA), Polyglycolides (PGA), Poly (lactide-co-glycolides) (PLGA), Polyanhydrides, Polyorthoesters, Polycaprolactones, Polyphosphazens, Pseudo-polyamino acids etc. Natural polymers include collagen, gelatin and albumin and polysaccharides like starch and dextran etc.

Siepmann  et al., were published a review in which they classify the mathematical models used to study drug release in sustained release formulations as a function of the different processes involved in it. Some of these models are given in Table 3. ^{[32, 33]}

 

Table 1: Polymers commonly used in sustained release matrices.

Synthetic                                                       Natural

Xanthan gum 1.Cellulosic                                                      Chitosan Methylcellulose                                                Carrageenan Hydroxypropylmethylcellulose                       Guar gum (Hypromellose, HPMC)                                           Hydroxypropylcellulose (HPC)                         Pectin Hydroxyethylcellulose (HEC)                            Hibiscus mucilage Ethylhydroxyethylcellulose (E-HEC)                   Aloe mucilage Sodium carboxymethylcellulose (Na-CMC)       Fenugreek mucilage

2.Non-cellulosic                                                Karaya gum Sodium alginate                                                 Hakea gum Cross-linked high amylose starch                       Tamarind gum Polyethylene oxide                                            Okara gum Homopolymers and copolymers of acrylic acid   Mimosa pudica Water-insoluble and hydrophobic polymers Ethylcellulose Hypromellose acetate succinate Cellulose acetate Cellulose acetate propionate Methacrylic acid copolymers Polyvinyl acetate

 

And combinations of polymers studied to modulate the dissolution profiles of drugs are given in Table 2. ^[22-28]

 

Properties of Drug Candidates for SR Formulation:

There are some considerations on physicochemical properties for the selection of drugs to be formulated in sustained release dosage forms, which mainly includes the absorption mechanism of the drug form the gastro intestinal (GI) tract, absorbability, molecular weight, solubility at different pH and apparent partition coefficient are given in Table 4.

 

Table 2: Combinations of polymers studied to modulate the dissolution profiles of drugs.

Polymer mixture	Drugs
HPMC+Na-CMC	Losartan potassium Atenolol Diltiazem HCl Zidovudine Naproxen sodium Captopril Thiamine hydrochloride                                                                   Metronidazole
HPMC+HPC	Acetaminophen
HPMC+EC	Metoprolol tartrate                                                             Glipizide                                                              Propranolol hydrochloride                                                                 Captopril                                                             Metronidazole Tramadol
HPMC+PVP	Diltiazem sodium HCl Theophylline                                                              Diclofenac
HPMC+ Carrageenan	Ibuprofen Naproxen sodium                                                               Salbutamol sulfate                                                              Clorpheniramine maleate
HPMC+ Xanthan gum	Glipizide
HPMC+carbopol 940	Diclofenac sodium
EC+NaCMC	Propranolol hydrochloride
HPMC+Poly-ethyloxazoline	Dyphylline
HPMC+EC+carbopol-971P	Zidovudine

Table 3: Mechanistic mathematical models used to study drug release in sustained release    formulations as a function of the mechanism involved.

Sr. No	Mechanism	Equations
1	Fickian diffusion	Thin film                                                                                                              Mt and M∞ are amounts of drug  released at time t and infinity      n is a dummy variable,      D is the diffusion coefficient of the drug       L is the thickness of the film Spherical   Mt and M∞ are the amounts of drug released at time t and infinity.         n is a dummy variable       D is the diffusion coefficient of  the drug       R is the radius of the sphere.  Cylindrical      Mt and M∞ are the amounts of drug released at time t and                infinity                    n and p denote dummy variables    qn are the roots of the Bessel function,    R and H denote the radius and height of the cylinder.    Monolithic dispersions:   Mt is the amount of drug released at time t, A is the surface area of  the film, D is the drug diffusivity C0 and Cs are the initial drug concentration and the solubility of the drug
2	Polymer swelling	D1 is the diffusion coefficient of water, C1 is the normalized water concentration.  Cw is the water concentration in the film at a particular position, e is the equilibrium water concentration in the system.   D2 is the diffusion coefficient of the drug, C2 is the normalized drug concentration CS the drug concentration in the film, CS, is the initial drug concentration in the system.
3	Polymer swelling	dt, ρi and Di are the mass concentration and diffusivity  of the species  and drug and polymer dissolution wi is the weight fraction, r and t are the radial position and time V is the volume of the matrix.
4	Polymer erosion and Degradation	Mt and M∞ are the cumulative absolute amounts of drug released time t and at infinite time δ is the relative separation between the diffusion and erosion         fronts                                         B is the surface erosion rate constant a is the half-thickness of the film, D is the drug diffusivity within the  system, τ is the dimensionless time.

 

Table 4: Physicochemical parameters for drug selection

Parameter	Preferred value
Molecular weight/size	< 500 Daltons
Solubility	> 0.1 mg/ml for pH 1 to pH 7.8
Apparent partition coefficient	High
Absorption mechanism	Diffusion
General absorbability	From all GI segments
Release	Should not be influenced by pH and enzymes

 

The pharmacokinetic parameters like drug’s elimination half- life, total clearances etc are given in Table 5. ^[34-36]

 

Table 5: Pharmacokinetic parameters for drug selection

Parameter	Comment
Elimination half-life	Preferably between 2 to 4 hrs
Total clearance	Should not be dose dependent
Elimination rate constant	Required for design
Apparent volume of distribution  (Vd)	The larger Vd and MEC, larger will be the required dose size
Absolute bioavailability	Should be 75% or more
Intrinsic absorption rate	Must be greater than release rate

 

Pharmacokinetic and pharmacodynamic factor:

Biological half life:

The goal of an oral sustained release product is to maintain therapeutic blood levels over an extended period. To this, drug must enter the circulation at approximately the same rate at which it is eliminated it is described by the half-life. Each drug has its own elimination rate, the sum of all elimination processes like metabolism, urinary excretion etc. Drugs with short half lives (less than 2h) and high dose impose a constraint on formulation into sustained release systems and drugs with long half lives (more than 8h) are inherently sustained.

 

Absorption:

The rate, extent and uniformity of absorption of a drug is considered when it's formulated into a sustained -release dosage forms as the rate limiting step  is its release, rather than absorption, in this case  Kr<<< Ka  becomes most critical. Assuming that the transit time of a drug through the absorption half life should be 4 h. This corresponds to a minimum absorption rate constant Ka of 0.17 to 0.23 h necessary for about 80 to 95 % absorption over a 9 to 12 h transit time. For a drug with a rapid rate of absorption, (i.e., Ka >>0.23 h ^-1), this implies that a first order release rate constant Kr < 0.17 h^-1 is likely to result in unacceptable poor bioavailability in many patients. Therefore, slowly absorbed drugs are difficult to formulate into sustained release systems.

 

Metabolism:

Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the intestine can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specific period allowing more complete conversion of drug to its metabolite. Formulation of these enzymatically susceptible compounds as prodrug is viable solution.

 

Drug properties relevant to sustain release formulation

Dose size:

A dose size of 500-1000 mg is used for a conventional dosage form and for sustained release dosage forms. Since dose size consideration serves to be a parameter for the safety involved in administration of large amounts with narrow therapeutic range.

 

Molecular weight:

Drugs with a low molecular weight tend to diffuse through the gel layer more easily than those of high molecular weight. Studies performed to compare the mean dissolution times (MDT) of drugs with different molecular weights have shown that those with a lower molecular weight have a lower MDT than high-molecular weight compounds.

 

Aqueous solubility and pKa:

A drug to be absorbed it must be dissolved in the aqueous phase surrounding the site of administration and then partition into the absorbing membrane. Important Physicochemical properties of a drug that influence its absorption are its aqueous solubility and its pKa if it is a weak acid or base. The dissolution rate is constant if surface area is constant; initial rare is directly proportional to aqueous solubility Cs. Therefore, aqueous solubility of a drug can be used as a first approximation of its dissolution rate. Drugs with low aqueous solubility have low dissolution rates and have oral bioavailability problems. Formulation of such a drug into a sustained release system may not provide considerable benefits over conventional dosage forms. Any system upon diffusion of drug through a polymer as the rate - limiting step in release would be unsuitable for a poorly soluble drug, since the driving force for diffusion is the concentration of drug in the polymer or solution, and this concentration would be low. For a drug with very high solubility and a rapid dissolution rate, it is difficult to decrease its dissolution rate to slow its absorption. Preparing a slightly soluble form of a drug with normally high solubility is one method for preparing controlled release dosage forms.

 

Partition Coefficient:

For a drug to be absorbed in the body and to show bioavailability, it must diffuse through biological membranes that act primarily as lipid like barriers. A major criteria in evaluation of the ability of a drug to penetrate these lipid membranes is its apparent oil/water partition coefficient defined as

Where;

C_o= Equilibrium concentration of the drug in organic phase.

C_w= Equilibrium concentration of all forms in aqueous phase.

 

In general, drugs with large values of ‘K’ are oil soluble and will partition into membrane readily.

 

Drug stability:

One important factor for oral dosage forms is the loss of drug by acid hydrolysis or metabolism in the GI tract. It is possible to improve the relative bioavailability of a drug that is unstable in the stomach, the controlling unit is release its content only in the intestine. The reverse in the case for those drugs that are unstable in the environment of the intestine, the controlling unit in this case would be one that releases its contents only in the stomach, so, drugs with significant stability problems in any particular area of the GI tract are less suitable for formulation into controlled release systems that deliver their content uniformity over the length of the GI tract. Sustained drug delivery systems may provide benefits for highly unstable drugs because the drug may be protected from enzymatic degradation by incorporation into a polymeric matrix.

 

Process Variables: ^[37]

Compression force:

The compression force had a significant effect on tablet hardness; it could be assumed that the variation in compression force is closely related to a change in the porosity of the tablet. Increased dissolution rates were observed when the tablets were found to be extremely soft, and this is due to a lack of powder compaction.

 

Tablet shape:

The size and shape of tablet for matrix system undergoing diffusion and erosion might impact the drug dissolution rate. Researchers says that for maximum uniformity of extended release characteristics, tablet should be manufactured to be as spherical as possible, in order to produce the minimum release rate with regard to tablet shape varying the aspect ratio(radius/height) of HPMC tablet is a very easy and effective tool to modify the release rate of the matrix systems.

 

Tablet size:

For tablets having the same aspect ratio and drug concentration, the tablet size had a strong influence on the release rate within 24 hours. It was hypothesized that the smaller tablet released drug more rapidly due to an increased surface area per volume and larger difussional pathways existed in the larger tablet leading to a decrease in drug release.

 

Design of Oral Sustained Release Drug Delivery Systems ^[38-42]:

 The oral route of administration is the most preferred route due to flexibility in dosage form, design and patient compliance. The various factors like pH that the dosage form would encounter during its transit, the gastrointestinal motility, the enzyme system and its influence on the drug and the dosage form.

 

Approaches to sustain release drug delivery systems:

·        Diffusion controlled system.

i) Reservoir type.

ii) Matrix type

·        Dissolution controlled system.

i) Reservoir type.

ii) Matrix type. 

·        Dissolution and diffusion controlled release systems.

 

Diffusion controlled system:

 Basically diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration. The flux of the drug J (in amount / area -time), across a membrane in the direction of decreasing concentration is given by Fick’s law.

Where, D is diffusion coefficient in area/ time
dc/dx = change of concentration 'c' with distance 'x'

The drug release rate dm/ dt is given by,

Where, A = area

 K   = Partition coefficient of drug between the membrane and drug core

L = diffusion path length [i.e. thickness of coat]

D c= concentration difference across the membrane.  

 

Reservoir type:

In the system, a water insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media. The release of drug to the medium through diffusion and  partitioning through the insoluble or permeable membrane is shown under Figure 2.

 

Matrix type:

Here a solid drug is dispersed in matrix or gum of insoluble or soluble or swell-able characteristics .The rate of drug release is dependent on the rate of drug diffusion. Release of drug to the medium by diffusion from the matrix type formulations is shown in Figure 3.

 

Higuchi has derived the appropriate equation for drug release for this system,

Where-

Q = weight in grams of drug released per unit area of surface at time t

D   = Diffusion coefficient of drug in the release medium 

e    = porosity of the matrix

Cs = solubility of drug in release medium

T   = Tortuosity of the matrix

A  = concentration of drug in the tablet, as g/ mL

 

The release rate can be given by following equation-

Release rate =   -------------Eq-5
Where,
A=Area
D=Diffusion coefficient

C₁=Drug concentration in the core
C₂=Drug concentration in the surrounding medium
L = Diffusional path length.

 

Thus diffusion controlled products are based on two approaches the first approach entails placement of the drug in an insoluble matrix. The eluting medium penetrates the matrix and drug diffuses out of the matrix to the surrounding pool for ultimate absorption. The second approach involves enclosing the drug particle with a polymer coat, in this case the portion of the drug which has dissolved in the polymer coat diffuses through an unstirred film of liquid into the surrounding fluid.

 

Matrix tablets can be classified as:

·           Hydrophilic matrix tablet.

·           Fat wax matrix tablet.

·           Plastic matrix tablet (hydrophobic matrix).

ü   Biodegradable matrices.

ü   Mineral matrices.

Matrix system can be classified according to their porosity as:

·        Macro porous systems.

·        Micro porous systems.

·        Non-porous systems.

 

Dissolution controlled systems:

A drug with a slow dissolution rate is inherently sustained and for those drugs with high water solubility, one can decrease dissolution through appropriate salt or derivative formation. These systems are most commonly used in the production of enteric coated dosage forms. To protect the stomach from the effects of drugs such as Aspirin, a coating that dissolves in neutral or alkaline media is used. This inhibits release of drug from the device until it reaches the higher pH of the intestine.

Reservoir type:

Drug is coated with a given thickness, which is slowly dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats a pulsed delivery can be achieved.  The outer layer will release bolus dose of the drug, initial levels of the drug in the body can be established with pulsed intervals. Although this is not a true controlled release system, the biological effects can be similar. An alternative method is to administer the drug as group of beads that have coating of different thickness. Since the beads have different coating thickness, their release occurs in a progressive manner. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be achieved from those with thicker coating.  This is the principle of the spansule or capsule. A reservoir type of sustained release formulation containing a soluble drug and its release from a slowly dissolving matrix or slowly dissolving coat is shown in Figure 4.

 

Matrix type:

This method involves compression of the drug with a slowly dissolving carrier in a tablet form. Here the rate of drug availability is controlled by the rate of penetration of the dissolution fluid into the matrix. This in turn, can be controlled by porosity of the tablet matrix, the presence of hydrophilic additives and the wettability of the tablet and particle surface.

 

Two types of dissolution- controlled pulsed delivery systems:

a]     Single bead – type device with alternating drug and rate- controlling layer. 

b]    Beads containing drug with differing thickness of dissolving coats.

 

Regulatory Consideration ^[43-44]

Essential characteristics for a research based pharmaceutical industries is its continued commitment to discovery, development and marketing of new medicines. Rationale for controlled release dosage forms include:

a.       Increase in the time interval required between doses(reduce dose frequency)

b.      Reduction in fluctuation of drug blood levels about the mean.

Potential pharmacodynamic problems with continuous release products:

A constant blood level is not necessarily the most advantageous.

Examples are:

a.       Corticosteroids- suppresses endogenous Adrenocortico tropic hormone (ACTH) Adreno cortico trophy (alternating blood level every other day is better)

b.      Bactericidal effect of penicillin- more effective given as pulses rather than continuously

c.       Nitroglycerin transdermal drug delivery systems (TDDS) – continuous nitroglycerin plasma levels appear to lead the development of tolerance. When use chronically most biological systems show diurnal a cyclical behavior.

 

Controlled drug delivery is one which delivers drug at predetermined rate, for locally or systemically for a specified period of time. An appropriately designed CDDS can improve the safety and therapeutic efficacy of drug by precise temporal and spatial placement in the body thereby reducing both size and number of doses required.

 

The regulatory requirements related to controlled release dosage forms first appeared in a regulation that was really a statement of policy and was published 30 years ago by the FDA. It defined the conditions under which drugs delivered to patients in a controlled release formulation over a period would be regarded as new drugs within the meaning of the Federal Food, Drug and Cosmetics Act, Section 201(p). Since then, there has been a proliferation of controlled release dosage forms for pharmaceutical products that may have little rationale and provide advantage over the same drugs in conventional dosage forms.

 

The regulatory approval of a controlled release product requires submission of scientific documents from pharmaceutical firms to

1.       Demonstrate the safety and efficacy of CDDS.

2.       Demonstrate its controlled release characteristics.

 

Controlled clinical studies may be required to demonstrate the safety and efficacy of drugs in controlled release formulations. Bioavailability data of drugs delivered in controlled release formulations are also required and may be acceptable in lieu of clinical trials. Bioavailability studies performed under steady state conditions to demonstrate comparability to an approved immediate release drug product are acceptable for supporting labeling for dosage administration.

 

The bioavailability data are required by law to be included in submission of new drug application in accordance with the “Bioavailability requirements for controlled release formulations” as specified in the Federal Register, C.25 (f).

 

FDA bioavailability regulations:

1      The product meets the controlled release claims made to it.

2      The bioavailability profile established for the product rules out the occurrence of dose dumping.

3      The product’s steady state performance is equivalent to that of currently marketed non-controlled release or controlled release pharmaceutical products that contain the same ingredient (or therapeutic moiety) and is subject to and approved, complete new drug application.

4      The product’s formulation provides consistent pharmacokinetic performance between individual dosage units.

 

Recommended reference standards:

1      Either an intravenous solution or an oral solution or suspension containing same active ingredient or therapeutic moiety.

2      A currently marketed, approved, conventional release drug product with defined bioavailability, reproducibility containing same active ingredient.

3      A specified currently marketed controlled release product with defined reproducible bioavailability.

4.     In some instances (1, 2, and 3) may be required.

5.     In order to avoid selection of an inappropriate reference, the director, division of biopharmaceutics should be consulted before initiating studies.

 

The bioavailability data, which consist of blood levels and/or urinary excretion rate profiles performed under steady state conditions, may be acceptable in lieu of clinical trials if it can be demonstrated that the blood levels and/or urinary excretion profiles are comparable to those achieved by the administration of multiple doses of the same drug in appropriate conventional dosage form or to an equivalent dose of the same drug in the appropriate controlled release dosage forms.

 

Demonstration of controlled release characteristics:

To demonstrate the controlled release characteristics delivered from a controlled release pharmaceutical product, the manufacturer should submit the following information:

 

1.       In vitro drug release data:

The in vitro test developed should be utilized to access the bioavailability of the CR drug formulations by “red flagging” possible lot-to-lot in vitro performance differences includes:

·        Reproducibility of the method

·        Proper choice of the media

·        Maintenance of sink condition

·        Control of hydrodynamics

·        Dissolution rate

The dissolution procedure should establish:

·        Controlled release characteristics

·        Complete drug release indicated by a 75 to 80% minimum release specification at the lost sampling interval

2. In vivo bioavailability data includes:

·        Pharmacokinetic profile, including profile of fraction of amount absorbed (wagner-nelson, loo-reigelman method)

·        Safety and efficacy data is required

·        Data indicating “therapeutic occupancy time”

               C_Max- C_Min

%F  = _{------------------------------}

              (C_Max+ C_Min)/2

·        Reproducibility of in vivo performance

 

In considering the regulatory requirements for controlled release pharmaceutical products, one needs to take into account each of the following factors in the development and evaluation of any controlled release formulation:

 

I. Pharmacokinetic properties of the drug:

a)     Hepatic first pass metabolism

b)    Michaelis-Menten kinetics

c)     Biological half life

d)    Rate of absorption

 

II. Pharmacological properties of the drug:

a)     Minimum therapeutic effective concentration

b)    Influence of peaking (C_max) versus steady state plasma concentration

c)     Desirability of steady state plasma levels

d)    Conventional dosing regimen

 

III. Toxicological properties of the drug:

a)     Minimum toxic level

b)    Frequency and type of toxicity encountered.

 

In addition to safety and efficacy of CDDS, biopharmaceutics and pharmacokinetic issues are to be addressed by the manufacturers. The key elements that need to be established are as follows-

1      Reproducibility of the drug release kinetics.

2      A defined bioavailability profile that rules out the possibility of dose dumping.

3      Demonstration of reasonably good absorption relative to standard.

4.     A well defined pharmacokinetic profile that supports the drug labeling.

Recent developments and perspectives:

1      NIFEDIPINE releasing gastrointestinal therapeutic system for the once a day management of stable angina or treatment of hypertension. (Procardia XL, Pfizer)

2      PILOCARPINE releasing ocular inserts for a weekly management of glaucoma. (Ocusert system, Ciba)

3      NITROGLYCERIN releasing transdermal therapeutic system for the treatment and prevention of angina pectoris.

4      LEVONORGESTROL releasing sub dermal implants for 5years fertility regulation in females. (NORPLANT)

5      PROGESTRONE releasing intrauterine device for 1year intrauterine contraception. (Progestasert IUD)

6      GOSERELIN ACETATE releasing biodegradable implant for a once-a-day management of advanced carcinoma of prostate gland. (Zoladex)

 

CURVE FITTING AND RELEASE KINETICS: ^{[4, 45-47]}

In order to establish the mathematical modeling of drug release, the experimental data are fitted to different kinetic models. The commonly used mathematical models for evaluating the release kinetics of drug are shown in     Table 6.

 

 

Table 6: Commonly used mathematical model for evaluating the release kinetics of drug.

SrNo.                    1	Mathematical model      Zero order	Mathematical equation	Terms used in equation Qt =amount of drug remaining                                                                                                                         as a solid state at time t  Q0 = initial amount of drug in                                                                                                                            the pharmaceutical dosage form   K0= zero-order release rate   constant
2	First-order		Qt =amount of drug remaining                                                                                                                          as a solid state at time t Q0 = initial amount of drug in                                                                                                                             the pharmaceutical dosage form  K1= First-order release rate   constant
3         4	Higuchi                                            Hixson-Crowell		Qt =amount of drug released in  time t  =Higuchi’s release rate   constant Qt =amount of drug remaining as                                                                                                                      a solid state at time t Q0 = initial amount of drug in  the  dosage  form                                                                                                                                                              Ks= Release rate constant
5	Baker–Lonsdale		Mt= amount of drug released    at  time t                                                                                    Ma =amount of  drug released at   an initial time;                                                            Dm=diffusion coefficient Cms =drug solubility in the   matrix                                                                                                               r0 = radius of the spherical   matrix C0= initial concentration of  drug  in the matrix
6	Korsmeyer–peppas		Mt/M∞= fraction of drug  released at time t                                                                                                                    a=kinetic constant                                                                                                                    n=diffusional  release  exponent
7           8	Hopfenberg           Poiseuille’s law       of laminar flow		Mt/M∞= fraction of drug dissolved K0 =erosion rate constant                                              C0 =initial concentration of drug in the matrix a0= initial radius for matrix  n =1, 2 and 3 for a slab, cylinder and sphere, respectively.                                                                                                                                                                        dM/dt=drug release rate c=concentration of drug in matrix r=radius of orifice g= viscosity of matrix                                                                                                               P1– P2 =pressure difference                                                                                                                                      between inside and out                                                                                                            side of  membrane
9	Weibull		m =fraction of the drug in  solution at time t             a= time scale of the process                                                                                        b= shape parameter Ti =lag time

 

 

Different kinetic plots for drug release form sustained release formulations i.e., Zero order, First order, Korsmeyer peppas, Hixson-Crowell, Higuchi are shown under     Figure 5.

 

FUTURE PROSPECTS AND CONCLUSIONS:

The development of SR products is currently one of the most important challenges in pharmaceutical research. From the above review we conclude that SR products by virtue of formulation and product design provide drug release in a modified form distinct from that of the conventional dosage forms. The release models with major application and best describing drug release phenomena are

 

Higuchi (Describes drug release from polymer matrix/matrices), Zero order (Concentration independent for amount release), First order, Korsemeyer-Peppas models etc. The physicochemical properties of the drug, polymer and the drug to polymer ratio govern the release of drug from the formulation. The use of one kind of polymer or another can affect the release kinetics, the presence of burst effect and the mechanisms involved in the release. Other factors have been shown to be involved in the release of drugs, such as the percentage and mixtures of polymer and the dimensions of the matrix (geometry and thickness). The compression force is important to the extent that it determines the amount of air trapped in the matrix. All this, together with the use of mathematical models as tools for estimating the kinetics of drug release allows sustained action formulations to be optimized and the pre-formulation phases during drug development to be shortened. However some disadvantages of SR products are retrieval of the dose is difficult in case of toxicity  and extremes of drug properties like aqueous solubility, oil/water partition coefficient, tissue binding, narrow therapeutic index etc., are limiting factors in formulating SR products these can be overcome by using physical, chemical and biomedical engineering approaches.   

 

Justification for the regulatory approval of controlled release formulations of established and new drug entities should be solely based on scientific documentation of the drugs in terms of safety and efficacy. Regulatory approval of a CDDS in terms of bioavailability requirements requires demonstration of bioavailability, controlled release characteristics, reproducibility of   in vivo performance, evidence to support clinical safety and efficacy as well as rationale as reflected in labeling.

 

ACKNOWLEDGEMENTS:

We thank Dr. Sudarsan Biswal (Drugs control Department, Govt. of Odisha) for his discussions on some aspects of the manuscript. 

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Received on 30.09.2013       Modified on 24.10.2013

Accepted on 04.11.2013      © RJPT All right reserved