Drug Delivery Systems:
A Review
Editor
A V Gothoskar
Acknowledgement:
SCES's Indira College of
Pharmacy, Pune
Men and medicine are inseparable from times immemorial. Although the physical forms of medication have not changed dramatically, the attitude of the public toward accepting medicines have changed with the passage of time. This fact is also reflected in the strategies adopted by the pharmaceutical companies in the field of research. The cost involved, both in terms of time and money, has made it mandatory for the companies to reconsider their research focus. In an attempt to reduce the cost of drug development process and advantageously reap the benefits of the patent regime, drug delivery systems have become an integral part of the said process.
Drug delivery system is a dosage form, containing an element that exhibits temporal and/or spatial control over the drug release. The ultimate aim of such systems is tailoring of the drug formulation to individual requirements under the control of pathophysiological or in-vivo conditions rather than in-vitro characteristics.
This field of drug delivery systems is dynamic and extensive. Probably it would need an encyclopedia to cover all the types of drug delivery systems. The aim of this book is to compile major drug delivery systems and offer a source of information for all those working in pharmaceutical academia as well as industry.
The book is made available free of charge to all who are interested in the subject for dissemination of knowledge. Authors feel proud to be a part of first of its kind of experiment wherein a technical book is offered for free download through a blog.
We welcome suggestions and criticisms for our readers.
A V Gothoskar
PhD, MBA
Bajaj Amruta Basrur Pooja Bhuruk Manisha
B.Pharm
B.Pharm
B.pharm, D.Pharm
Chavan Shankar Deshpande Tanvee Gothoskar Abhijit
B.Pharm
B.PharmPhD, MBA
Hastak Vishakha
Kamble Pranay
Katedeshmukh Ramesh
Khan Halimunnisa
Kulkarni Akshada
Maravaniya Pathik Kumar
B.Pharm
B.Pharm
B.Pharm
Mogal Rajendra
Patel Ruchita
Pawar Sandesh
M.Pharm (Pharmaceutics)
B.Pharm
B.Pharm, D.Pharm
Pawar Yogesh
Satam Madhavi
Sawant Sandip
M.Pharm (Pharmaceutics)
B.Pharm, D.Pharm
B.Pharm, D.Pharm
Wayal Abhijit
Zarikar Nitin
1. Fundamentals of Drug Delivery System - 10
Suryavanshi Kiran, Mogal Rajendra, Pawar Yogesh, Shaikh Aamir 2. Oral Controlled Drug Delivery System - 18
Bajaj Amruta, Katedeshmukh Ramesh 3. Gastroretentive Drug Delivery System - 43
Basrur Pooja, Hastak Vishakha 4. Colon Specific Drug Delivery System - 59
Bhuruk Manisha, Pawar Yogesh
5. Chronopharmaceutical Drug Delivery System - 83 Chavan Shankar, Shaikh Aamir
6. Self Dispersing Formulations-101 Deshpande Tanvee, Mogal Rajendra
7. Introduction To Bioadhesion/Mucoadhesion - 114 Kamble Pranay, Katedeshmukh Ramesh
8. Mucoadhesive Drug Delivery System - Nasal - 127 Khan Halimunnisa, Hastak Vishakha
9. Mucoadhesive Drug Delivery System - Rectal - 149 Kulkarni Akshasa, Pawar Yogesh
10. Mucoadhesive Drug Delivery System - Vaginal - 160 Deshpande Tanvee, Shinde Rohit, Pawar Yogesh 11. Parenteral Controlled Drug Delivery System – 182
13. Transdermal Drug Delivery System - 206 Pawar Sandesh, Katedeshmukh Ramesh
14. Particulate Drug Delivery System-Liposomes - 224 Satam Madhavi, Hastak Vishakha 15. Particulate Drug Delivery System- Microcapsules– 241
Sawant Sandip, Pawar Yogesh
16. Particulate Drug Delivery System- Microspheres -253 Sawant Sandip, Pawar Yogesh
17. Particulate Drug Delivery System-Resealed Erythrocytes-266 Shinde Rohit, Shaikh Aamir
18. Particulate Drug Delivery System-Monoclonal Antibodies -281 Suryavanshi Kiran, Mogal Rajendra
19. Intranasal Drug Delivery System - 291 Wayal Abhijit, Katedeshmukh Ramesh
20. Protein And Peptide Drug Delivery System - 302 Zarikar Nitin, Hastak Vishakha
21. Intraocular Drug Delivery System - 318
Maravaniya Pathikkumar , Zarikar Nitin , Pawar Yogesh 22. Pulmonary Drug Delivery System – 326
Kamble Pranay, Suryavanshi Kiran, Shaikh Aamir 23. Nanopharmaceuticals – 334
25. Oral Thin Film – 357
Bhuruk Manisha, Satam Madhavi, Hastak Vishakha 26. Nail Drug Delivery System – 367
Basrur Pooja, Suryavanshi Kiran, Katedeshmukh Ramesh 27. Regulatory Aspects of Drug Delivery System- 377
10
FUNDAMENTALS OF DRUG DELIVERY SYSTEMS
Suryavanshi Kiran, Mogal Rajendra, Pawar Yogesh, Shaikh AamirNeed for Controlled Release Systems:
(Kathryn E. Uhrich 1999)Controlled drug delivery technology represents one of the most rapidly advancing areas of science in which chemists and chemical engineers are contributing to human health care. Such delivery systems offer numerous advantages compared to conventional dosage forms including improved efficacy, reduced toxicity, and improved patient compliance and convenience. Such systems often use synthetic polymers as carriers for the drugs. By so doing, treatments that would not otherwise be possible are now in conventional use. Although the introduction of the first clinical controlled release systems occurred less than 25 years ago, 1997 sales of advanced drug delivery systems in the United States alone were approximately $14 billion dollars. Synthetic polymers used in the controlled release of drugs. Before considering the variety and the evolution of these polymeric structures, it is necessary to examine the motivation for achieving controlled release. This field of pharmaceutical technology has grown and diversified rapidly in recent years. Understanding the derivation of the methods of controlled release and the range of new polymers can be a barrier to involvement from the nonspecialist. All controlled release systems aim to improve the effectiveness of drug therapy. This improvement can take the form of increasing therapeutic activity compared to the intensity of side effects, reducing the number of drug administrations required during treatment, or eliminating the need for specialized drug administration (e.g., repeated injections).B. Methods of Controlled Release
In temporal control, drug delivery systems aim to deliver the drug over an extended duration or at as specific time during treatment.
Controlled release over an extended duration is highly beneficial for drugs that are rapidly metabolized and eliminated from the body after administration. An example of this benefit is shown schematically in Figure 1 in which the concentration of drug at the site of activity within
the body is compared after immediate release from 4 injections administered at 6 hourly intervals and after extended release from a controlled release system. Drug concentrations may fluctuate widely during the 24 h period when the drug is administered via bolus injection, and for only a portion of the treatment period is the drug concentration in the therapeutic window (i.e., the drug concentration that produces beneficial effects without harmful side effects). With the controlled release system, the rate of drug release matches the rate of drug elimination and, therefore, the drug concentration is within the therapeutic window for the vast majority of the 24 h period. Clinically, temporal control can produce a significant improvement in drug therapy. For example, when an opioids pain killer is administered to a patient with terminal cancer, any time that the drug concentration is below therapeutic concentrations the patient experiences pain. A temporally controlled release system would ensure that the maximum possible benefit is derived from the drug. In distribution control, drug delivery systems aim to target the release of the drug to the precise site of activity within the body. The benefit of this type of control is shown schematically in Figure 2 in which
Figure 1. Drug concentrations at site of
therapeutic action after delivery as a conventional injection (thin line) and as a temporal controlled release system (bold line). (Kathryn E. Uhrich 1999)
11
Figure 2. Drug delivery from an ideal distribution
controlled release system. Bold line: Drug concentrations at site of therapeutic action. Thin line: Systemic levels at which side effects occur. (Kathryn E. Uhrich 1999)
Drug concentrations at the site of activity and side effect production are compared. There are two principle situations in which distribution control can be beneficial. The first is when the natural distribution causes drug molecules to encounter tissues and cause major side effects that prohibit further treatment. This situation is often the cause of chemotherapy failure when bone marrow cell death prevents the patient from undergoing a complete drug treatment. The second situation is when the natural distribution of the drug does not allow drug molecules to reach their molecular site of action. For example, a drug molecule that acts on a receptor in the brain will not be active if it is distributed by the patient’s blood system but cannot cross the blood-brain barrier. A large number of classes of drugs can benefit from temporal or distribution controlled release. These classes include chemotherapeutic drugs, immunosuppressants, anti-inflammatory agents, Antibiotics, opioid antagonists, steroids, hormones, anesthetics, and vaccines. Recently, the need to develop new controlled release strategies has been intensified by advances in the design of peptide drugs and emergence of gene therapy. These biotechnology derived agents may dominate the next generation of drug design. However, their clinical success may be dependent on the design of controlled release devices that ensure that the drugs reach their target cells precisely at the required time. A discussion of the pharmacological and clinical motivations for controlling the release of the specific drug classes referred to above is beyond the limit of this article; however, a number of excellent reviews are available. In addition, it should be noted that controlled release technology is not confined to pharmaceutical applications but
has also proven beneficial in agricultural and cosmetic industries. (Kathryn E. Uhrich 1999)
Scope of Polymer Systems:
In this review, a number of polymer backbones that are potentially degradable are detailed in the text. This restriction certainly does not reduce the impact and significance of C-C backbones for controlled release applications but is simply a mechanism to focus on an important subset of materials. To illustrate the diverse range of functionalities available from nonbiodegradable systems based on C-C backbones to heteroatom-containing polymer backbones that may confer biodegradability. (Langer 1998)
Mechanisms of Controlled Drug Release Using Polymers:
A diverse range of mechanisms have been developed to achieve both temporal and distribution controlled release of drugs using polymers. This diversity is a necessary consequence of different drugs imposing various restrictions on the type of delivery system employed. For example, a drug that is to be released over an extended period in a patient’s stomach where the pH is acidic and environmental conditions fluctuate widely will require a controlled release system very different from that of a drug that is to be delivered in a pulsatile manner within the blood system. An important consideration in designing polymers for any controlled release mechanism is the fate of the polymer after drug release. Polymers that are naturally excreted from the body are desirable for many controlled release applications. These polymers may be excreted directly via the kidneys or may be biodegraded into smaller molecules that are then excreted. Nondegradable polymers are acceptable in applications in which the delivery system can be recovered after drug release (e.g., removal of patch or insert) or for oral applications in which the polymer passes through the gastrointestinal tract. From a polymer chemistry perspective, it is important to appreciate that different mechanisms of controlled release require polymers with a variety of physicochemical properties. This requirement has stimulated the evolution of the new polymers that will be discussed in section IV. Before consideration of these polymers, the major mechanisms of controlled release and polymeric characteristics that are required to carry out these mechanisms will be briefly. (Kathryn E. Uhrich 1999)
12
CLASSIFICATION
OF
DRUG
DELIVERY SYSTEM:
Classification of NDDS based on Physical means 1) Osmotic Pressure Activated
2) Hydrodynamic pressure activated 3) Vapor pressure activated
4) Mechanically activated 5) Magnetically activated 6) Sonophoresis
7) Iontophoresis 8) Hydration activated
Classification of NDDS based on Chemical means 1) Hydrolysis activated
2) Ion activated 3) pH activated
Polymers Generally Used for Controlled Drug Delivery System:
1) Poly(esters):
Poly (esters) is the best characterized and most widely studied biodegradable system. The synthesis of poly (esters) has received as much attention as the degradation of these materials. A patent for the use of poly (lactic acid) (PLA) as a resorbable suture material was first filed in 1967.34 The mechanism of degradation in poly (ester) materials is classified as bulk degradation with random hydrolytic scission of the polymer backbone
Polymerization of the cyclic lactone alone is usually too slow to produce high molecular weight material (>20 000 amu). The rate of ring opening for the cyclic lactone can be increased by activation of a Zn- or Snbased catalyst with the carbonyl ester. However, the introduction of a catalyst invites concerns over traces of potentially cytotoxic material. Thus, stannous octoate SnII (CO2CH(nBu)(Et))2 is commonly used because
has FDA approval as a food stabilizer.
Fig:3 Ring- opening polymerization of selected
cyclic lactones to give the following A) Poly(e-caprolactone)PCL B) Poly(glycolic acid) PGA
C) Poly(L-lactic acid)PLA (Kathryn E. Uhrich 1999)
1. Poly(lactic acid), Poly(glycolic acid), and Their Copolymers Poly(esters) based on poly(lactic acid) (PLA), poly- (glycolic acid) (PGA), and their copolymers, poly(lactic acid-co-glycolic acid) (PLGA), are some of the best defined biomaterials with regard to design and performance. Lactic acid contains an asymmetric R-carbon which is typically described as the D or L form in classical stereo chemical terms and sometimes as the R and S form, respectively. For homopolymers, the enantiomer forms are poly (D-lactic acid) (PDLA) and poly (L-lactic acid) (PLLA). The physicochemical properties of optically active PDLA and PLLA are nearly the same, whereas the racemic PLA has very different characteristics.41 For example, racemic PLA and PLLA have Tg’s of 57 and 56 °C, respectively, but PLLA is highly crystalline with a Tm of 170 °C and racemic PLA is completely amorphous.
Because the naturally occurring lactic acid is L (or S), PLLA is considered more biocompatible. The polymers are derived from monomers that are natural metabolites of the body; thus degradation of these materials yields the corresponding hydroxy acid, making them safe for in vivo use. Biocompatibility of the monomer is the foundation for biocompatibility of degradable polymer systems. To this end, the degradation products often define the biocompatibility of a polymers not necessarily the polymer itself. Even though PLGA is extensively used and represents the gold standard of degradable polymers, increased local acidity due to the degradation can lead to irritation at the site of the polymer
13
employment. Introduction of basic salts has been investigated as a technique to control the pH in local environment of PLGA implantsFrom a physical level of understanding, poly (esters) undergo bulk degradation. PLA homopolymers degrade slower than PGA homopolymers on the basis of crystallinity as well as stearic inhibition by the pendent methyl group of PLA to hydrolytic attack. However, the complexity of PLA, PGA, and PLGA degradation has been demonstrated by Vert45 and does not conform to a simple model. Vert and coworkers have demonstrated that size dependence for hydrolytic degradation exists for PLA systems. Other research efforts suggest that PLA-derived micro particles will degrade faster than nanoparticles derived from PLA. This is modeled on diffusion reaction phenomena. An autocatalytic effect at the interior of larger devices is thought to contribute to the initial heterogeneous degradation of larger devices as acidic byproducts cannot readily diffuse out from the interior as is the case for smaller constructs. Extensive degradation studies have also been reported for PLA, poly (caprolactone) (PCL), and their copolymers both in vitro and in vivo. Studies in hydrolytic degradation for poly (esters) have focused on understanding the effects of changes in polymer chain composition. A distinguishable effect based on end group composition for poly (ester) degradation demonstrated that terminal carboxyl groups have a catalytic effect on hydrolysis for PGA. The ability to tailor rates of protein release from PLGA microspheres was derived from the understanding of end-group effects. The commercial developmental process for formulating poly (esters) with selected drug candidates has been reviewed. The aforementioned review highlights the development of poly (ester) matrices containing human growth hormone that sustained levels of a therapeutic protein in humans for 1 month from a single dose. (Kathryn E. Uhrich 1999)
2. Poly (ethylene glycol) Block Copolymers: Poly (ethylene glycol) (PEG) is also referred to as poly (ethylene oxide) (PEO) at high molecular weights. Biocompatibility is one of the most noted advantages of this material. Typically, PEG with molecular weights of 4000 amu is 98% excreted in man. One of the emerging uses for inclusion of PEG in a controlled release system arises from its protein resistivity. The hydrophilic nature of PEG is such that water hydrogen bonds
tightly with the polymer chain and thus excludes, or inhibits, protein adsorption. Many research groups are investigating attachment of PEG chains to therapeutic proteins; PEG chains at the surface allow for longer circulation of the protein in the body by prolonging biological events such as endocytosis, phagocytosis, liver uptake and clearance, and other adsorptive processes.
Fig.4 Synthesis of PLA-PEG Copolymer (Kathryn
E. Uhrich 1999)
PEG can be made with a range of terminal functionalities which lends to its easy incorporation into copolymer systems. PEG is commonly terminated with chain-end hydroxyl groups which provide a ready handle for synthetic modification. Diblock PLA/ PEG and triblock PLA/PEG/PLA systems have been synthesized and characterized with various PLA contents. The free hydroxyl groups of PEG are ring-opening initiators for lactide in forming the diblock or triblock materials (Figure 5a, b). Recently, Chen et al. have synthesized PLA-PEG multiblock copolymers from L-lactide and ethylene oxide, the monomer precursors for PLA and PEG, respectively (Figure 5c). This approach is different in two respects: (i) use of bimetallic catalysts which proceed by anionic mechanisms; (ii) multiblock polymers are generated. Han and Hubbell further demonstrated the synthetic utility for PLA-PEG systems by introducing acrylate moieties to form cross-linked systems. Similarly, Jeong et al. prepared thermo sensitive PLA-PEO hydrogels that exhibit temperature-dependent gel-sol transition for use as injectable drug delivery systems.
Poly (ortho esters):
The motivation for designing poly (ortho esters) for drug delivery was the need to develop biodegradable polymers that inhibited drug release
14
by diffusion mechanisms and allowed drug release only after the hydrolysis of polymer chains at the surface of the device.70 Most research on poly (ortho esters) has focused on the synthesis of polymers by the addition of polyols to diketene acetals. For example, Heller et al. have described the synthesis and application of the 3, 9-diethylidene-2, 4, 8, 10-tetraoxaspiro [5.5] undecane (DETOSU)-based poly (ortho esters).71 The basic structure is formed by the addition of the DETOSUmonomer to a diol to form the chemical structure. The DETOSU-based poly (ortho esters) contain acid labile ortho ester linkages in their backbone structure. Within aqueous environments, the ortho ester groups are hydrolyzed to form Pentaerythritol dipropionate and diol monomers as breakdown products. The Pentaerythritol dipropionate is further hydrolyzed to Pentaerythritol and acetic acid. Acid-catalyzed hydrolysis of these polymers can be controlled by introducing acidic or basic Excipients into matrixes. Rates of hydrolysis can be increased by the addition of acidic excipients, such as suberic acid, as demonstrated by the zero-order release of 5-fluorouracil over a 15 day period.72 Alternatively, basic excipients stabilize the bulk of the matrix but diffuse out of the surface region, thereby facilitating surface-only erosion. This approach has been employed in the temporal controlled release of tetracycline over a period of weeks in the treatment of periodontal disease.Fig.5: Degradation of 3, 9(bis ethylidene-2, 4,8,10
Tetraoxaspiro undecane (DETOSU) based poly ortho ester (Kathryn E. Uhrich 1999)
A useful feature of the DETOSU systems is the ability to control the mechanical properties by changing the diol monomer ratios within the final polymeric structure. For example, Heller et al. have shown that the glass transition temperature of polymers containing a rigid diol monomer (transcyclohexanedimethanol) and a flexible
monomer (1, 6- hexanediol) could be varied between 20 and 105° by increasing the proportion of the rigid diol. This control can also be achieved with the glycolide containing polymers.
A number of applications have been described for cross-linked poly (ortho esters) formed by the substitution of 1, 2, 6-hexanetriol for 1, 2-hexanediol, for example. The triol monomer allows cross-linked materials to be formed that are semisolid materials. It has been envisaged that these materials could be injected into the patient as a viscous liquid at slightly elevated temperatures that form nondeformable depot implants upon cooling. (V. Balmurlidhara 2011)
Poly (anhydrides)
To obtain a device that erodes heterogeneously, the polymer should be hydrophobic yet contain water sensitive linkages. One type of polymer system that meets this requirement is the poly (anhydrides). Poly- (anhydrides) undergoes hydrolytic bond cleavage to form water-soluble degradation products that can dissolve in an aqueous environment, thus resulting in polymer erosion. Poly (anhydrides) are believed to undergo predominantly surface erosion due to the high water liability of the anhydride bonds on the surface and the hydrophobicity which prevents water penetration into the bulk. This process is similar to the slow disappearance of a bar of soap over time. The decrease in the device thickness throughout the erosion process, maintenance of the structural integrity, and the nearly zero-order degradation kinetics suggest that heterogeneous surface erosion predominates. The majority of poly (anhydrides) are prepared by melt-condensation polymerization. Starting with a dicarboxylic acid monomer, a prepolymer of a mixed anhydride is formed with acetic anhydride. The final polymer is obtained by heating the prepolymer under vacuum to remove the acetic anhydride byproduct. The most widely studied poly (anhydrides) are based on sebacic acid (SA), p-(carboxyphenoxy) propane (CPP), and p-(carboxyphenoxy) hexane (CPH) Degradation rates of these polymers can be controlled by variations in polymer composition. The more hydrophobic the monomer, the more stable the anhydride bond is to hydrolysis. Aliphatic poly- (anhydrides) (e.g., SA) degrade within days whereas aromatic poly (anhydrides) (e.g., CPH) degrade over several years.
15
Fig: 6 Structure of widely used aromatic poly
(anhydrides) based on monomer of p-carboxy phenoxy propane (Kathryn E. Uhrich 1999) The biocompatibility of copolymers of SA and CPP has been well established. Evaluation of the toxicity of poly (anhydrides) show that they possess excellent in vivo biocompatibility.81 Recent clinical trials have demonstrated that an intracranial device of SA/CPP copolymers improves the therapeutic efficacy of an antitumor agent, bischloronitrosourea, for patients suffering from a lethal type of brain cancer.
Poly (anhydride-esters)
Other modifications of poly (anhydrides) include poly (anhydride-esters), which include two different types of hydrolytically cleavable bonds in the polymer backbone. In one example, low molecular weight carboxylic acid-terminated prepolymer of poly (_- caprolactone) were coupled via anhydride linkages. The intent of this research was to design polymers that displayed two-stage degradation profiles: anhydride bonds rapidly hydrolyzed to the poly (ester) prepolymer which degraded much more slowly. In another example, carboxylic acid-terminated monomers that contain ester bonds are activated and then polymerized using the same chemistry described for the poly (anhydrides). A unique aspect of these poly (anhydride-esters) is that hydrolytic degradation of the polymer backbone yields a therapeutically useful compound, salicylic acid. Polymer’s degradation products are potentially beneficial
Fig: 7 Poly (anhydride ester that undergo into
salicylic acid, an anti inflammatory agent (Kathryn E. Uhrich 1999)
Poly (amides):
The most interesting class of poly (amides) for controlled release are the poly (amino acids). The synthetic ability to manipulate amino acid sequences has seen its maturity over the last two decades with new techniques and strategies continually being introduced. An excellent review of the histo4ry of amino acid-derived polymers is given by Nathan and Kohn.93 Poly(amino acids) have been used predominantly to deliver low molecular weight drugs, are usually tolerated when implanted in animals,94 and are metabolized to relatively nontoxic products. These results suggest good biocompatibility, but their mildly antigenic nature makes their widespread use uncertain. Another concern with poly (amino acids) is the intrinsic hydrolytic stability of the amide bond which must rely upon enzymes for bond cleavage. The dependence on enzymes generally results in poor controlled release in vivo. The expense and difficulty in production of elaborate polypeptide sequences has limited the composition to homopolymers, predominantly poly (glutamic acid) and poly (aspartic acid). Poly(amino acids) are generally hydrophilic with degradation rates dependent upon hydrophilicity of the amino acids.96,97 Amino acids are attractive due to the functionality they can provide a polymer. For example, poly (lactic acid-co lysine) (PLAL) was synthesized using a stannous octoate catalyst from lactide and a lysine-containing monomer analogous to lactide. Inclusion of the amino acid lysine provides an amino group that allows for further modification of the PLAL system. Recently, peptide sequences that promote cell adhesion have been attached to PLAL.
16
Fig.8 Poly (lactic acid-co-amino acid) PLAL
Polymer system (Kathryn E. Uhrich 1999)
Currently marketed oral controlled-release
systems:
Advances in oral controlled-release technology are attributed to the development of novel biocompatible polymers and machineries that allow preparation of novel design dosage forms in a reproducible manner. The main oral drug-delivery approaches that have survived through the ages are as follows:
● Coating technology using various polymers for coating tablets, nonpareil sugar beads, and granules ● Matrix systems made of swell able or nonswellable polymers
● Slowly eroding devices ● Osmotically controlled devices.
Conventional tablet formulations are still popular in the design of single-unit, matrix-type controlled release dosage forms. The advancement of granulation technology and the array of polymers available with various physicochemical properties (such as modified cellulose or starch derivatives) have made the development of novel oral controlled release systems possible. Matrix devices made with cellulose or acrylic acid derivatives, which release the homogeneously dispersed drug based on the penetration of water through the matrix, have gained steady popularity because of their simplicity in design. The drawback of matrix-type delivery systems is their first-order drug delivery mechanism caused by changing surface area and drug diffusional path length with time. This drawback has been addressed by osmotic delivery systems, which maintain a zero-order drug release irrespective of the pH and hydrodynamics of the GI tract. Multiparticulate systems are gaining favor over single-unit dosage forms because of their desirable distribution characteristics, reproducible transit time, and reduced chance of gastric irritation owing to the localization of drug delivery.
Although several technologies for the production of microparticulate systems have been designed, thus
far the mainstream technologies are still based on spray-drying, spheronization, and film-coating technology.
FDA regulation of oral
Controlled-release drugs:
In the 1980s, FDA introduced rigorous regulations governing bioequivalence and in vitro– in vivo correlations for controlled-release products. Required pharmacokinetic evaluations involve ● relative bioavailability following single dose ● relative bioavailability following multiple doses ● effect of food
● dose proportionality
● unit dosage strength proportionality ● single-dose bioequivalence study
(Experimental versus marketed formulations at various strengths)
● In vivo–in vitro correlation
●Pharmacokinetic/pharmacodynamic (PK/PD) relationship.
In general, for drugs in which the exposure– response relationship has not been established or is unknown, applications for changing the formulation from immediate release to controlled release requires demonstration of the safety and efficacy of the product in the target patient population. When an NME is developed as a controlled-release dosage form, additional studies to characterize its absorption, distribution, metabolism, and excretion (ADME) characteristics are recommended.
The future of Drug Delivery System:
The future of controlled-release products is promising, especially in the following areas that present high promise and acceptability:● Particulate systems: The micro particle and nanoparticle approach that involves biodegradable polymers and is aimed at the uptake of intact drug-loaded particles via the Peyer’s patches in the small intestine could be useful for delivery of peptide drugs that cannot, in general, be given orally. ● Chronopharmacokinetic systems: Oral controlled drug delivery with a pulsatile release regimen could effectively deliver drugs where need exists to counter naturally occurring processes such as bacterial/parasitical growth patterns (e.g., the once-daily oral Pulsys system introduced by Advancis Pharmaceutical Corp., which could potentially inhibit the emergence of resistant strains of microorganisms).
● Targeted drug delivery: Oral controlled drug delivery that targets regions in the GI tract and
17
releases drugs only upon reaching that site could offer effective treatment for certain disease states (e.g. colon-targeted delivery of antineoplastics in the treatment of colon cancer).● Mucoadhesive delivery: This is a promising technique for buccal and sublingual drug delivery, which can offer rapid onset of action and superior bioavailability compared with simple oral delivery because it bypasses first—pass metabolism in the liver. (Das 2003)
Advantages of controlled drug delivery
systems:
1. Improved patient convenience and compliance
2. Reduction in fluctuation in steady state levels.
3. Increased safety margin of high potency drugs.
4. Reduction in dose.
5. Reduction in health care cost.
Disadvantages
of
controlled
drug
delivery systems:
1. Decreased systemic availability 2. Poor invitro-invivo correlations 3. Chances of dose dumping 4. Dose withdrawal is not possible. 5. Higher cost of formulation
Applications of controlled drug delivery
system:
1) Mucoadhesive drug delivery system
2) Colon drug delivery system 3) Pulmonary drug delivery system 4) Ocular drug delivery system 5) Oral thin films
6) Nasal drug delivery system 7) Gastro retentive drug delivery
system
8) Vaginal drug delivery system 9) Resealed erythrocytes
References:
1. Www.Farmacist.Blogspot.Com.
2. Blanco Md, Alonso Mj. "Development And Characterization Of ." Eur J. Pharma Biopharm, 1997: 387-422.
3. Brouwers. "J. R. B. J." Pharm. World Sci, 1998.
4. Das, Nandita G. Das And Sudip K. "Controlled-Release Of Oral Dosage Forms." 2003: 10-16.
5. Kathryn E. Uhrich, Scott M. Cannizzaro And Robert S. Langer,Kevin M. Shakesheff. "Polymeric Systems For Controlled Drug Release." 1999: 3181-3198.
6. Katre, N. "Adv. Drug Delivery Review." 1993.
7. Langer, R. Nature 1998. 1998: 392.5. 8. Mehreganym, Gabriel KJ, Trimmer WSN.
1998: 35:719.
9. Paolino, Donatella. "Drug Delivery System." Encyclopedia Of Medical Devices And Instrumentation, 2006: 437-485.
10. Ranade VV, Hollinger MA. "Drug Delivery Systems." CRC Press, 1996. 11. Shivkumar, Vishal Gupta N. And.
"Development Of Drug Delivery System." Trop J. Pharma, 2009.
12. Smith BR, Et Al. "A Biological Perspective Of Particulate Nanoporous." 2004: 19-16.
13. V. Balmurlidhara, T.M. Pramodkumar. "Ph Sensitive Drug Delivery System- A Review." American Journal Of Drug Delivery And Development, 2011: 24-48.
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ORAL CONTROLLED DRUG DELIVERY SYSTEM
Bajaj Amruta, Katedeshmukh RameshIntroduction:
Oral drug delivery is the most widely utilized route of administration among all the routes [nasal, ophthalmic, rectal, transdermal and Parenteral routes] that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, uncomplicated, convenient and safe [in respect to Parenteral route] due to its ease of administration, patient acceptance, and cost-effective manufacturing process. Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption. These immediate release dosage forms have some limitations such as:
1) Drugs with short half-life requires frequent administration, which increases chances of missing dose of drug leading to poor patient compliance.
2) A typical peak-valley plasma concentration-time profile is obtained which makes attainment of steady state condition difficult.
3) The unavoidable fluctuations in the drug concentration may lead to under medication or overmedication as the CSS values fall or rise beyond the therapeutic range.
4) The fluctuating drug levels may lead to precipitation of adverse effects especially of a drug with small therapeutic index, whenever overmedication occurs.
In order to overcome the drawbacks of conventional drug delivery systems, several technical advancements have led to the development of controlled drug delivery system that could revolutionize method of medication and provide a number of therapeutic benefits. (Hemnani M. 2011)
TABLE 1:-Benefit Characteristics Of Oral Controlled-Release Drug Delivery System. (Das N. 2003)
Benefit Reason
Therapeutic advantage
Reduction in drug plasma level fluctuations; maintenance of a steady plasma level of the drug over a prolonged time period, ideally simulating an intravenous infusion of a drug.
Reduction in adverse side effects and improvement in tolerability
Drug plasma levels are maintained within a narrow window with no sharp peaks and with AUC of plasma concentration versus time curve comparable with total AUC from multiple dosing with immediate release dosage forms. This greatly reduces the possibility of side effects, as the scale of side effects increase as we approach the MSC.
Patient comfort and compliance
Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance.
Reduction in healthcare cost
The total cost of therapy of the controlled release product could be comparable or lower than the immediate-release product. With reduction in side effects, the overall expense in disease management also would be reduced.
Controlled Drug Delivery Systems: (Hemnani M.
2011)
Controlled drug delivery systems have been developed which are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of
drug to a tissue. Controlled drug delivery or modified drug delivery systems are conveniently divided into four categories.
1) Delayed release 2) Sustained release
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3) Site-specific targeting4) Receptor targeting
More precisely, controlled delivery can be defined as:
1) Sustained drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects.
2) Localized drug action by spatial placement of a controlled release system adjacent to or in the diseased tissue.
3) Targeted drug action by using carriers or chemical derivatives to deliver drug to a particular target cell type.
4) Provide a physiologically/therapeutically based drug release system. In other words, the amount and the rate of drug release are determined by the physiological/ therapeutic needs of the body. A controlled drug delivery system is usually designed to deliver the drug at particular rate. Safe and effective blood levels are maintained for a period as long as the system continues to deliver the drug. Controlled drug delivery usually results in substantially constant blood levels of the active ingredient as compared to the uncontrolled fluctuations observed when multiple doses of quick releasing conventional dosage forms are administered to a patient.
Figure 1: A hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of sustained and controlled delivery formulations. Rationale of Controlled Drug Delivery
The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery system or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration. It is desirable that the
duration of drug action become more a design property of a rate controlled dosage form, and less, or not at all, a property of the molecule’s inherent kinetic properties. Thus optimal design of controlled release systems necessitates a thorough understanding of the pharmacokinetics and pharmacodynamics of the drug. The primary objectives of 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. The dose and dosing interval can be modified in case of conventional dosage forms. However, therapeutic window of plasma concentration below which no therapeutic effect is exhibited and above which undesirable effects are manifested. Therapeutic index is the prime parameter for development of a controlled delivery system of a particular drug candidate.
Factors Affecting the Design and
Performance
of
Controlled
Drug
Delivery:
(Hemnani M. 2011) 1. Drug Properties:Partition coefficient Drug stability Protein binding
Molecular size and diffusivity
2. Biological Properties:
Absorption Metabolism
Elimination and biological half life Dose size
Route of administration Target sites
Acute or chronic therapy Disease condition
Advantages of Controlled Drug Delivery
System: (Patel H. Nov Dec 2011):
1. Avoid patient compliance problems. 2. Employ less total drug
3. Minimize or eliminate local side effects 4. Minimize or eliminate systemic side
effects
5. Obtain less potentiating or reduction in drug activity with chronic use.
6. Minimize drug accumulation with chronic dosing.
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7. Improve efficiency in treatment8. Cures or controls condition more promptly.
9. Improves control of condition i.e., reduced fluctuation in drug level. 10. Improves bioavailability of some drugs. 11. Make use of special effects, E.g.
Sustained-release aspirin for morning relief of arthritis by dosing before bed time.
12. Economy i.e. reduction in health care costs. The average cost of treatment over an extended time period may be less, with less frequency of dosing, enhanced therapeutic benefits and reduced side effects.
13. The time required for health care personnel to dispense and administer the drug and monitor patient is also reduced.
Disadvantages: (Kamboj S 2009)
1) Decreased systemic availability in comparison to immediate release conventional dosage forms, which may be due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site specific absorption, pH dependent stability etc.
2) Poor in vitro – in vivo correlation. 3) Possibility of dose dumping due to food,
physiologic or formulation variables or chewing or grinding of oral formulations by the patient and thus, increased risk of toxicity.
4) Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.
5) Reduced potential for dosage adjustment of drugs normally administered in varying strengths.
6) Stability problems. 7) Increased cost.
8) More rapid development of tolerance and counseling.
9) Need for additional patient education and counseling
Oral Controlled Drug Delivery Systems:
(Hemnani M. 2011)
Oral controlled release drug delivery is a drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit and also the system that target the delivery of a drug to a specific region within the GI tract for either a local or systemic action. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (immediate, sustained or controlled release) and the design of dosage form (either solid dispersion or liquid), must be developed within the intrinsic characteristics of GI physiology. Therefore the scientific framework required for the successful development of oral drug delivery systems consists of basic understanding of
(i) physicochemical, pharmacokinetic and pharmacodynamic characteristics of the drug
(ii) the anatomic and physiologic characteristics of the gastrointestinal tract
(iii) physicochemical characteristics and the drug delivery mode of the dosage
form to be designed. The main areas of potential challenge in the
development of oral controlled drug delivery systems are:-
1) Development of a drug delivery system: To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment.
2) Modulation of gastrointestinal transit time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for a prolonged period of time to maximize the delivery of a drug dose.
3) Minimization of hepatic first pass elimination: If the drug to be delivered is subjected to extensive hepatic first-pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.
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Methods Used To Achieve Controlled Release Of Orally Administered Drugs:
A. Diffusion Controlled System:
Basically diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration. This system is of two types:
a) Reservoir type: A core of drug surrounded by
polymer membrane, which controls the release rate, characterizes reservoir devices.
b) Matrix type: Matrix system is characterized by
a homogenous dispersion of solid drug in a polymer mixture.
B. Dissolution Controlled Systems:
a) Reservoir type: Drug is coated with a given thickness coating, which is slowly dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats as shown in figure no.2, a pulsed delivery can be achieved. If the outer layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can be quickly established with pulsed intervals
Figure 2: Schematic representation of diffusion controlled drug release reservoir system.
b) Matrix type: The more common type of
dissolution controlled dosage form as shown in figure .3. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion.
Figure 3: Schematic representation of diffusion controlled drug release matrix system.
C. Bioerodable and Combination of Diffusion
and Dissolution Systems:
It is characterized by a homogeneous dispersion of drug in an erodible matrix. (Shown in figure.4)
Figure 4: Drug delivery from (a) bulk-eroding and (b) surface-eroding Bio erodible systems.
D. Methods using Ion Exchange: It is based on the drug resin complex formation when an ionic solution is kept in contact with ionic resins. The drug from these complexes gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract. E. Methods using osmotic pressure: It is characterized by drug surrounded by semi permeable membrane and release governed by osmotic pressure.
F. pH– Independent formulations: A buffered controlled release formulation as shown in figure 5, is prepared by mixing a basic or acidic drug with one or more buffering agents, granulating with appropriate pharmaceutical excipients and coating with GI fluid permeable film forming polymer. When GI fluid permeates through the membrane the buffering agent adjusts the fluid inside to suitable constant pH thereby rendering a constant rate of drug release.
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Figure 5: Drug delivery from environmentally pH sensitive release systems.
G. Altered density formulations: Several approaches have been developed to prolong the residence time of drug delivery system in the gastrointestinal tract.
High-density approach Low-density approach
Matrix Tablet: (Patel H. Nov Dec 2011) Advantages of matrix tablet:
Easy to manufacture
Versatile, effective and low cost
Can be made to release high molecular weight compounds
The sustained release formulations may maintain therapeutic concentrations over prolonged periods.
The use of sustain release formulations avoids the high blood concentration.
Sustain release formulations have the potential to improve the patient compliance.
Reduce the toxicity by slowing drug absorption.
Increase the stability by protecting the drug from hydrolysis or other derivative changes in gastrointestinal tract.
Minimize the local and systemic side effects.
Improvement in treatment efficacy.
Minimize drug accumulation with chronic dosing.
Usage of less total drug.
Improvement the bioavailability of some drugs.
Improvement of the ability to provide special effects. Ex: Morning relief of arthritis through bed time dosing.
Disadvantages of matrix tablet: (Patel H. Nov
Dec 2011)
The remaining matrix must be removed after the drug has been released.
High cost of preparation.
The release rates are affected by various factors such as, food and the rate transit through the gut. The drug release rates vary with the square root of time. Release rate continuously diminishes due to an increase in diffusional resistance and/or a decrease in effective area at the diffusion front. However, a substantial sustained effect can be produced through the use of very slow release rates, which in many applications are indistinguishable from zero-order.
Classification Of Matrix Tablets:
On the Basis of Retardant Material Used: Matrix tablets can be divided in to 5 types.
1. Hydrophobic Matrices (Plastic matrices):
The concept of using hydrophobic or inert materials as matrix materials was first introduced in 1959. In this method of obtaining sustained release from an oral dosage form, drug is mixed with an inert or hydrophobic polymer and then compressed in to a tablet. Sustained release is produced due to the fact that the dissolving drug has diffused through a network of channels that exist between compacted polymer particles. Examples of materials that have been used as inert or hydrophobic matrices include polyethylene, polyvinyl chloride, ethyl cellulose and acrylate polymers and their copolymers. The rate-controlling step in these formulations is liquid penetration into the matrix. The possible mechanism of release of drug in such type of tablets is diffusion. Such types of matrix tablets become inert in the presence of water and gastrointestinal fluid.
2. Lipid Matrices:
These matrices prepared by the lipid waxes and related materials. Drug release from such matrices occurs through both pore diffusion and erosion. Release characteristics are therefore more sensitive to digestive fluid composition than to totally insoluble polymer matrix. Carnauba wax in combination with stearyl alcohol or stearic acid has been utilized for retardant base for many sustained release formulation.
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3. Hydrophilic Matrices:Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost effectiveness, and broad regulatory acceptance. The formulation of the drugs in gelatinous capsules or more frequently, in tablets, using hydrophilic polymers with high gelling capacities as base excipients is of particular interest in the field of controlled release. Infect a matrix is defined as well mixed composite of one or more drugs with a gelling agent (hydrophilic polymer). These systems are called swellable controlled release systems. The polymers used in the preparation of hydrophilic matrices are divided in to three broad groups,
A. Cellulose derivatives: Methylcellulose 400 and
4000cPs, HEC; HPMC 25, 100, 4000 and 15000cPs; and Sodium carboxymethylcellulose.
B. Non cellulose natural or semi synthetic polymers: Agar-Agar; Carob gum; Alginates;
Molasses; Polysaccharides of mannose and galactose, Chitosan and Modified starches.
4. Biodegradable Matrices: These consist of the
polymers which comprised of monomers linked to one another through functional groups and have unstable linkage in the backbone. They are biologically degraded or eroded by enzymes generated by surrounding living cells or by nonenzymetic process in to oligomers and monomers that can be metabolized or excreted. Examples are natural polymers such as proteins and polysaccharides; modified natural polymers; synthetic polymers such as aliphatic poly (esters)
and poly anhydrides.
5. Mineral Matrices: These consist of polymers
which are obtained from various species of seaweeds. Example is Alginic acid which is a hydrophilic carbohydrate obtained from species of brown seaweeds (Phaephyceae) by the use of dilute
alkali.
On the Basis of Porosity of Matrix: Matrix
system can also be classified according to their porosity and consequently, Macro porous; Micro
porous and Non-porous systems can be identified:
1. Macro porous Systems: In such systems the
diffusion of drug occurs through pores of matrix, which are of size range 0.1 to 1 μm. This pore size
is larger than diffusant molecule size.
2. Micro porous System: Diffusion in this type of
system occurs essentially through pores. For micro
porous systems, pore size ranges between 50 – 200 A°, which is slightly larger than diffusant
molecules size.
3. Non-porous System: Non-porous systems have
no pores and the molecules diffuse through the network meshes. In this case, only the polymeric phase exists and no pore phase is present.
Polymers used in matrix tablet:
Hydrogels: Polyhydroxyethylemethylacrylate (PHEMA), Cross-linked polyvinyl alcohol (PVA), Cross-linked polyvinyl pyrrolidone (PVP),
Polyethylene oxide (PEO), Polyacrylamide (PA)
Soluble polymers: Polyethyleneglycol (PEG),
polyvinyl alcohol (PVA), Polyvinylpyrrolidone
(PVP), Hydroxypropyl methyl cellulose (HPMC)
Biodegradable polymers: Polylactic acid (PLA),
Polyglycolic acid (PGA), Polycaprolactone (PCL),
Polyanhydrides, Polyorthoesters
Non-biodegradable polymers: Polyethylene vinyl
acetate (PVA), Polydimethylsiloxane (PDS), Polyether urethane (PEU), Polyvinyl chloride (PVC), Cellulose acetate (CA), Ethyl cellulose
(EC)
Mucoadhesive polymers: Polycarbophil, Sodium
carboxymethyl cellulose, Polyacrylic acid,
Tragacanth, Methyl cellulose, Pectin
Natural gums: Xanthan gum, Guar gum, Karaya
gum, Locust bean gum
Components of matrix tablets: (ME. 2005)
These include:
Active drug
Release controlling agent(s): matrix formers
Matrix Modifiers, such as channelling agents and wicking agents
Solubilizers and pH modifiers
Lubricants and flow aid
Supplementary coatings to extend lag time further reduce drug release etc.
Density modifiers (if required)
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Mechanism Of Drug Release From Matrix Tablet:
Drug in the outside layer exposed to the bathing solution is dissolved first and then diffuses out of the matrix. This process continues with the interface between the bathing solution and the solid drug moving toward the interior. It follows that for this system to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be much faster than the diffusion rate of dissolved drug leaving the matrix. Derivation of the mathematical model to describe this system involves the following assumptions:
a) A pseudo-steady state is maintained during drug release,
b) The diameter of the drug particles is less than the average distance of drug diffusion through the matrix,
c) The bathing solution provides sink conditions at all times.
The release behaviour for the system can be mathematically described by the following equation:
dM/dh = Co. dh - Cs/2 ……… (1)
Where, dM = Change in the amount of drug
released per unit area
dh = Change in the thickness of the zone of matrix that has been depleted of drug
Co = Total amount of drug in a unit volume of matrix
Cs = Saturated concentration of the drug within the matrix.
Additionally, according to diffusion theory:
dM = ( Dm. Cs / h) dt... (2) Where, Dm = Diffusion coefficient in the matrix.
h = Thickness of the drug-depleted matrix dt = Change in time
By combining equation 1 and equation 2 and integrating:
M = [Cs. Dm (2Co −Cs) t] ½ ……… (3)
When the amount of drug is in excess of the saturation concentration then:
M = [2Cs.Dm.Co.t] 1/2 ……… (4)
Equation 3 and equation 4 relate the amount of drug release to the square-root of time. Therefore, if a system is predominantly diffusion controlled, then it is expected that a plot of the drug release vs. square root of time will result in a straight line. Drug release from a porous monolithic matrix involves the simultaneous penetration of surrounding liquid, dissolution of drug and leaching out of the drug through tortuous interstitial channels and pores.
The volume and length of the openings must be accounted for in the drug release from a porous or granular matrix:
M = [Ds. Ca. p/T. (2Co – p.Ca) t] 1/2 ………. (5)
Where, p = Porosity of the matrix
t = Tortuosity Ca = solubility of the drug in the release medium
Ds = Diffusion coefficient in the release medium. T = Diffusional path length For pseudo steady state,
the equation can be written as:
M = [2D.Ca .Co (p/T) t] ½ ……….. (6)
The total porosity of the matrix can be calculated
with the following equation:
p = pa + Ca/ ρ + Cex / ρex ………
(7)
Where, p = Porosity ρ = Drug density
pa = Porosity due to air pockets in the matrix ρex = Density of the water soluble excipients Cex = Concentration of water soluble excipients For the purpose of data treatment, equation 7 can be reduced to: M = k. t 1/2 ………..
(8)
Where, k is a constant, so that the amount of drug
released versus the square root of time will be linear, if the release of drug from matrix is diffusion-controlled. If this is the case, the release of drug from a homogeneous matrix system can be controlled by varying the following parameters: • Initial concentration of drug in the matrix • Porosity
• Tortuosity
• Polymer system forming the matrix
• Solubility of the drug.
Effect Of Release Limiting Factor On Drug Release:
The mechanistic analysis of controlled release of
drug reveals that partition coefficient; diffusivity; diffusional path thickness and other system parameters play various rate determining roles in the controlled release of drugs from either capsules, matrix or sandwich type drug delivery systems.
A. Polymer hydration: It is important to study
polymer hydration/swelling process for the maximum number of polymers and polymeric combinations. The more important step in
polymer dissolution include
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accessible places, rupture of polymer-polymer linking with the simultaneous forming of water-polymer linking, separation of polymeric chains, swelling and finally dispersion of polymeric chain in dissolution medium
B. Drug solubility: Molecular size and water
solubility of drug are important determinants in the release of drug from swelling and erosion controlled polymeric matrices. For drugs with reasonable aqueous solubility, release of drugs occurs by dissolution in infiltrating medium and for drugs with poor solubility release occurs by both dissolution of drug and dissolution of drug particles through erosion of the matrix tablet.
C. Solution solubility: In view of in vivo (biological) sink condition maintained actively by hem perfusion, it is logical that all the in vitro drug release studies should also be conducted under perfect sink condition. In this way a better simulation and correlation of in vitro drug release profile with in vivo drug administration can be achieved. It is necessary to maintain a sink condition so that the release of drug is controlled solely by the delivery system and is not affected or
complicated by solubility factor.
D. Polymer diffusivity: The diffusion of small
molecules in polymer structure is energy activated process in which the diffusant molecules moves to a successive series of equilibrium position when a sufficient amount of energy of activation for diffusion Ed has been acquired by the diffusant is dependent on length of polymer chain segment, cross linking and crystallinity of polymer. The release of drug may be attributed to the three factors viz,
i. Polymer particle size ii. Polymer viscosity
iii. Polymer concentration.
i. Polymer particle size: Malamataris
stated that when the content of hydroxyl propyl methylcellulose is higher, the effect of particle size is less important on the release rate of propranolol hydrochloride, the effect of this variable more important when the content of polymer is low. He also justified these results by considering that in certain areas of matrix containing low levels of
hydroxyl propyl methylcellulose led to the burst release.
ii. Polymer viscosity: With cellulose ether
polymers, viscosity is used as an indication of matrix weight. Increasing the molecular weight or viscosity of the polymer in the matrix formulation increases the gel layer viscosity and thus slows drug dissolution. Also, the greater viscosity of the gel, the more resistant the gel is to dilution and erosion, thus
controlling the drug dissolution.
iii. Polymer concentration: An increase in
polymer concentration causes an increase in the viscosity of gel as well as formulation of gel layer with a longer diffusional path. This could cause a decrease in the effective diffusion coefficient of the drug and therefore reduction in drug release. The mechanism of drug release from matrix also changes from erosion to diffusion as the polymer concentration increases.
E. Thickness of polymer diffusional path: The
controlled release of a drug from both capsule and matrix type polymeric drug delivery system is essentially governed by Fick’s law of diffusion:
JD = D dc/dx
Where, JD is flux of diffusion across a plane
surface of unit area
D is diffusibility of drug molecule, dc/dx is concentration gradient of drug molecule across a
diffusion path with thickness dx.
F. Thickness of hydrodynamic diffusion layer: It
was observed that the drug release profile is a function of the variation in thickness of hydrodynamic diffusion layer on the surface of matrix type delivery devices. The magnitude of drug release value decreases on increasing the
thickness of hydrodynamic diffusion layer δd.
G. Drug loading dose: The loading dose of drug
has a significant effect on resulting release kinetics along with drug solubility. The effect of initial drug loading of the tablets on the resulting release kinetics is more complex in case of poorly water soluble drugs, with increasing initial drug loading the relative release rate first decreases and then increases, whereas, absolute release rate monotonically increases. In case of freely water soluble drugs, the porosity of matrix upon drug depletion increases with increasing initial drug