CONTROLED RELEASE DRUG ADMINISTRATION:
During the last two decades there has been remarkable increase in interest in controlled release drug delivery system. This has been due to various factor viz. the prohibitive cost of developing new drug entities, expiration of existing international patents, discovery of new polymeric materials suitable for prolonging the drug release, and the improvement in therapeutic efficiency and safety achieved by these delivery systems. Now-a-days the technology of controlled release is also being applied to veterinary products.
Modified Release Dosage Forms2: According to the United States Pharmacopoeia the term 'modified release dosage forms' is used to denote the dosage forms for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic objectives not offered by the conventional dosage forms. Two types of modified release dosage forms are recognised.
1] Extended release dosage forms:
It is defined as the one that allows at least a two fold reduction in the dosing frequency as compared to that of conventional dosage form.
2] Delayed release dosage forms:
It is defined as one that releases the drug at a time other than “immediately” after administration.
Rationale of controlled drug delivery3
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.
Terminology3,4 Different terminologies have been used for the new drug delivery system by different authors.
A] Controlled Action:
In this type of dosage forms it provides a prolonged duration of drug release with predictability and reproducibility of drug release kinetics. In this case, the rate of drug absorption is equal to the rate of drug removal from body.
2] Sustained Action:
In this type of dosage forms, a sufficient amount of drug is initially made available to the body to cause a desired pharmacological response. The remaining fraction is released periodically and is required to maintain the maximum initial pharmacological activity for some desirable period of time in excess of time expected from usual single dose.
3] Prolonged Action:
These types of dosage form are designed in such a way that it release the drug over an extended period during which pharmacological response is obtained but does not necessarily maintain the constant blood level.
4] Site specific and receptor release:
It refers to targeting of drug directly to a certain biological location.
Potential advantages and disadvantages of controlled release dosage forms
i] Patient Compliance:
Lack of compliance is generally observed with long term treatment of chronic disease, as success of drug therapy depends upon the ability of patient to comply with the regimen. Patient compliance is affected by a combination of several factors, like awareness of disease process, patient faith in therapy, his understanding of the need to adhere to a strict treatment schedule. Also the complexity of therapeutic regimens, the cost of therapy and magnitude of local and or systemic side effect of the dosage form.
The problem of lack of patient compliance can be resolved to some extent by administering controlled release drug delivery system.
ii] Reduced 'see- saw' fluctuation:
Administration of a drug in a conventional dosage form [except via intravenous infusion at a constant rate] often results in 'see – saw' pattern of drug concentration in the systemic circulation and tissue compartments. The magnitudes of these fluctuations depend on drug kinetics such as the rate of absorption, distribution, elimination and dosing intervals. The 'see-saw' or 'peak and valley' pattern is more striking in case of drugs with biological half lives of less than four hours, since prescribed dosing intervals are rarely less than four hours. A well designed controlled release drug delivery system can significantly reduce the frequency of drug dosing and also maintain a more steady drug concentration in blood circulation and target tissue cells.
iii] Reduced total dose:
Controlled release drug delivery systems have repeatedly been shown to use less amount of total drug to treat a diseased condition. By reducing the total amount of drug, decrease in systemic or local side effects are observed. This would also lead to greater economy.
iv] Improved efficiency in treatment:
Optimal therapy of a disease requires an efficient delivery of active drugs to the tissues, organs that need treatment. Very often doses far in excess to those required in the cells have to be administered in order to achieve the necessary therapeutically effective concentration. This unfortunately may lead to undesirable, toxicological and immunological effects in non-target tissue. A controlled release dosage forms leads to better management of the acute or chronic disease condition.
i) Dose dumping:
Dose dumping is a phenomenon where by relatively large quantities of drug in a controlled release formulation is rapidly released, introducing potential toxic quantities of the drug into the systemic circulation. Dose dumping can lead to fatalities in case of potent drug, which have a narrow therapeutic index e.g. Phenobarbital.
ii) Less flexibility in accurate dose adjustment:
In conventional dosage forms, dose adjustments are much simpler e.g. tablet can be divided into two fractions. In case of controlled release dosage forms, this appears to be much more complicated. Controlled release property may get lost, if dosage form is fractured.
iii) Poor In Vitro – In Vivo correlation:
In controlled release dosage form, the rate of drug release is deliberately reduced to achieve drug release possibly over a large region of gastrointestinal tract. Here the so called ‘Absorption window’ becomes important and may give rise to unsatisfactory drug absorption in vivo despite excellent in-vitro release characteristics.
iv) Patient variation:
The time period required for absorption of drug released from the dosage form may vary among individuals. Co-administration of other drugs, presence or absence of food and residence time in gastrointestinal tract is different among patients. This also gives rise to variation in clinical response among the patient.
Criteria to be met by drug proposed to be formulated in controlled release dosage forms.5,6
a) Desirable half-life.
b) High therapeutic index
c) Small dose
d) Desirable absorption and solubility characteristics.
e) Desirable absorption window.
f) First past clearance.
a) Desirable half-life:
The half life of a drug is an index of its residence time in the body. If the drug has a short half life (less than 2 hours), the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from, and controlled release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours.
b) High therapeutic index:
Drugs with low therapeutic index are unsuitable for incorporation in controlled release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg. Digitoxin.
c) Small dose:
If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for controlled release is seriously undetermined. This is chiefly because the size of a unit dose controlled release formulation would become too big, to administer without difficulty.
d) Desirable absorption and solubility characteristics:
Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into controlled release formulations is therefore unrealistic and may reduce overall absorption efficiency.
e) Desirable absorption window:
Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the ‘absorption window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable.
f) First pass clearance:
As discussed earlier in disadvantages of controlled delivery system, delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in controlled release forms.
DESIGN AND FORMULATION OF ORAL CONTROLLED RELEASE DRUG DELIVERY SYSTEM AND THE FACTORS AFFECTING THEREOF:7,8,9,10
The oral route of administration is the most preferred route due to flexibility in dosage form, design and patient compliance. But here one has to take into consideration, the various 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. The majority of oral controlled release systems rely on dissolution, diffusion or a combination of both mechanisms, to generate slow release of drug to the gastrointestinal milieu.
Theoretically and desirably a controlled release delivery device, should release the drug by a zero-order process which would result in a blood-level time profile similar to that after intravenous constant rate infusion.
Controlled (zero-order) drug release can be schematically illustrated as follows:7
Plasma drug concentration-profiles for conventional tablet or capsule formulation, a sustained release formulation, and a zero order controlled release formulation.
Controlled (zero-order) drug release has been attempted to be achieved, by following classes of controlled drug delivery system.8
A) Diffusion controlled system.
i) Reservoir type.
ii) Matrix type
B) Dissolution controlled system.
i) Reservoir type.
ii) Matrix type
C) Methods using Ion-exchange.
D) Methods using osmotic pressure.
E) pH independent formulations.
F) Altered density formulations.
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. 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.
J= - D dc/dx.
D = diffusion coefficient in area/ time
dc/dx = change of concentration 'c' with distance 'x'
In common form, when a water insoluble membrane encloses a core of drug, it must diffuse through the membrane, the drug release rate dm/ dt is given by,
dm/ dt= ADK C/L
Where A = area
K = Partition coefficient of drug between the membrane and drug core
L= diffusion path length [i.e. thickness of coat]
c= concentration difference across the membrane.
1] Reservoir type:
Schematic representation of diffusion controlled drug release: reservoir system.
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.
Description: Drug core surrounded by polymer membrane which controls release rate.
Advantages: Zero order delivery is possible, release rates variable with polymer type.
Disadvantages: System must be physically removed from implant sites. Difficult to deliver high molecular weight compound, generally increased cost per dosage unit, potential toxicity if system fails.
Products Drug Manufacturer
Duotrate Pentaerythritol tetranitrate Marion
Histospan Chlorpheniramine maleate USV
Nitrospan Nitroglycerin USV
Bronkodyl Theophylline Breon
ii] Matrix type:
A solid drug is dispersed in an insoluble matrix and the rate of release of drug is dependent on the rate of drug diffusion and not on the rate of solid dissolution.
Higuchi has derived the appropriate equation for drug release for this system,
Q = D/ T [2 A –Cs] Cst ½
Q = weight in gms of drug released per unit area of surface at time t
D = Diffusion coefficient of drug in the release medium
= porosity of the matrix
Cs = solubility of drug in release medium
T= Tortuosity of the matrix
A = concentration of drug in the tablet, as gm/ ml
Description: Homogenous dispersion of solid drug in a polymer mixture.
Advantages: Easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds.
Disadvantages: Cannot provide zero order release, removal of remaining matrix is necessary for implanted system.
Products Drug Manufacturer
Desowyn Methamphetamine hydrochloride Abott
Procaine SR Procainamide hydrochloride Parke Davis
Priscoline Tolazoline hydrochloride CIBA
Schematic representation of diffusion controlled drug release: matrix system.
A third possible diffusional mechanism is the system where a partially soluble membrane encloses a drug core. Dissolution of part of membrane allows for diffusion of the constrained drug through pores in the polymer coat.
The release rate can be given by following equation:-
Release rate = AD / L = [ C1- C2 ]
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 of some sort. 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.
B] 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 employed 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 natural or alkaline media is used. This inhibits release of drug from the device until it reaches the higher pH of the intestine. In most cases, enteric coated dosage forms are not truly sustaining in nature, but serve as a useful function in directing release of the drug to a special site. The same approach can be employed for compounds that are degraded by the harsh conditions found in the gastric region.
i) 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, 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. 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. This is shown in figure. 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 capsule. Cellulose nitrate phthalate was synthesized and used as an enteric coating agent for acetyl salicylic acid tablets.
Product Drug Manufacturer
Spansule capsule Amphetamine sulphate Smith kline
Sequel capsule Acetazolamide Lederle
Diamox Ferrous fumarate
Matrix type: The more common type of dissolution controlled dosage form as shown in figure. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion.
Product Drug Manufacturer
Timespan raniacol Nicotinyl alcohol Roche
Dimetane Brompheniramine Robins
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.
C] Methods using lon Exchange:
It is based on the formation of drug resin complex formed when a ionic solution is kept in contact with ionic resins. The drug from these complex gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract
Resin + - Drug - + x- goes to resin + x- + Drug-
Where x- is cl- conversely
Resin - - drug+ + Y +goes resin – Y+ + Drug
Where Y +is Na +
These systems generally utilize resin compounds of water insoluble cross – linked polymer. They contain salt – forming functional group in repeating positions on the polymer chain. The rate of drug diffusion out of the resin is controlled by the area of diffusion, diffusional path length and rigidity of the resin which is function of the amount of cross linking agent used to prepare resins .The release rate can be further controlled by coating the drug resin complex by microencapsulation process.15 The resins used include Amberlite Indion, polysterol resins and others.
D] Methods using osmotic pressure:9
A semi permeable membrane is placed around a tablet, particle or drug solution that allows transport of water into the tablet with eventual pumping of drug solution out of the tablet through a small delivery aperture in tablet coating.
Description: Drug surrounded by semi permeable membrane and release governed by osmotic pressure.
Advantages: Zero order release rates are obtainable. Reformulation is not required for different drugs. Release of drug is independent on the environment of the system.
Disadvantages: System can be much more expensive than conventional counterparts. Quality control is more extensive than most conventional tablets.
Two types of osmotically controlled systems are:-
Type A contains an osmotic core with drug
Type B contains the drug in flexible bag with osmotic core surrounding.
E] pH– Independent formulations:8,12
The gastrointestinal tract present some unusual features for the oral route of drug administration with relatively brief transit time through the gastrointestinal tract, which constraint the length of prolongation, further the chemical environment throughout the length of gastrointestinal tract is constraint on dosage form design. Since most drugs are either weak acids or weak bases, the release from sustained release formulations is pH dependent. However, buffers such as salts of amino acids, citric acid, phthalic acid phosphoric acid or tartaric acid can be added to the formulation, to help to maintain a constant pH thereby rendering pH independent drug release. A buffered controlled release formulation is prepared by mixing a basic or acidic drug with one or more buffering agent, granulating with appropriate pharmaceutical excipients and coating with gastrointestinal fluid permeable film forming polymer. When gastrointestinal fluid permeates through the membrane, the buffering agents adjust the fluid inside to suitable constant pH thereby rendering a constant rate of drug release e.g. propoxyphene in a buffered controlled release formulation, which significantly increase reproducibility.12
F] Altered density formulations:3
It is reasonable to expect that unless a delivery system remains in the vicinity of the absorption site until most, if not all of its drug contents is released, it would have limited utility. To this end, several approaches have been developed to prolong the residence time of drug delivery system in the gastrointestinal tract.
High density approach
In this approach the density of the pellets must exceed that of normal stomach content and should therefore be at least 1-4gm/cm3.
Low density approach:
Globular shells which have an apparent density lower than that of gastric fluid can be used as a carrier of drug for sustained release purpose.
Factors Influencing Design of Controlled Release Dosage Forms:3,8,9
The therapeutic efficacy of drug under clinical conditions is not simply a function of its intrinsic pharmacological activity but also depends upon the path of the drug molecule from the site of administration to the target site. Different conditions encountered by the drug molecule while traversing the path of distribution may alter either the effectiveness of the drug or affect the amount of the drug reaching the receptor site.
A] Pharmaceutics: This refers to the development/manufacturing of an efficient delivery system in which the drug has maximum physiological stability and optimum bioavailability.
B] Biopharmaceutics/ pharmacokinetics: This involves the study of absorption, distribution, metabolism and excretion of the drug, before and after reaching the target site and evaluation of the relationship between delivery system and therapeutic response.
C] Pharmacodynamics/ Clinical Pharmacology:It is the study of the mechanism of action and clinical efficacy of a drug administered in dosage form in terms of onset, intensity and duration of pharmacological activity.
Drug properties influencing the design of sustained or controlled release drug delivery system are classified as:
1] Physicochemical properties of the drug
These include dose size, aqueous solubility, protein binding, molecular size, drug stability and partition coefficients.
2] Biological factors
These include absorption, distribution, metabolism, duration of action, margin of safety, side effects of drug, disease state and circadian rhythm.
Methods to achieve oral controlled drug delivery:8
There are various methods employed for the fabrication of oral controlled release delivery systems. Ritschel has given a detailed report of these techniques. These are as follows.
a. Hydrophilic matrix
b. Plastic matrix
c. Barrier resin beads
d. Fat embedment
e. Repeat action
f. Ion exchange resin
g. Soft gelatin depot capsules
h. Drug complexes
In the following discussion, controlled release dosage form using method of matrix is discussed.
Historically, the most popular drug delivery system has been the matrix because of its low cost and ease of fabrication. Methods of altering the kinetics of drug release from the inherent first order behavior especially to achieve a constant rate of drug release from matrix devices have involved several factors.
Requirements of matrix materials:
The matrix materials must comply with the following conditions,
1. They must be completely inert and non- reactive with the drug and additives in the tablet.
2. They must be able to form a stable and strong matrices when compressed either directly or more often as granules prepared by the addition of a binding agent.
3. They must be non-toxic.
Hydrophilic matrix system:
Carboxymethylcellulose sodium, hydroxymethyl cellulose, polyethylene oxide, polyvinyl-107, molidones and natural gums can be used as matrix materials. The matrix may be tableted by direct compression of the blend of active ingredient and certain hydrophilic carriers or from a wet granulation containing the drug and hydrophilic matrix material.
Upon immersion in water the hydrophilic matrix quickly forms a gel layer around the tablet. Drug release is controlled by a gel diffusional barrier and /or tablet erosion.
Evaluation of controlled release Tablets:
Before marketing a controlled release product, it is must to assure the strength, safety, stability and reliability of a product by forming in-vitro and in-vivo analysis and correlation between the two. Various authors have discussed the evaluating parameters and procedures for controlled release formulations.
1. In – Vitro Methods
a. Beaker method
b. Rotating disc method
c. Rotating Bottle method
d. Rotating Basket method
e. Stationary Basket Method
f. Oscillating tube method
g. Dialysis method
h. USP dissolution method.
2. In–Vivo Methods
Once the satisfactory in-vitro profile is achieved, it becomes necessary to conduct in-vivo evaluation and establish in-vitro in-vivo correlation. The various in-vivo evaluation methods are:-
a. Clinical response
b. Blood level data
c. Urinary excretion studies
d. Nutritional studies.
e. Toxicity studies
f. Radioactive tracer techniques
3.Stability Studies :6,14
Adequate stability data of the drug and its dosage form is essential to ensure the strength, safety, identity, quality, purity and in-vitro in-vivo release rates, that they claim to have at the time of use. A controlled release product should release a predetermined amount of the drug at specified time intervals, which should not change on storage. Any considerable deviation from the appropriate release would render the controlled release product useless. The in-vitro and in-vivo release rates of controlled release product may be altered by atmospheric or accelerated conditions such as temperature & humidity.
The stability programmes of a controlled release product include storage at both nominal and accelerated conditions such as temperature & humidity to ensure that the product will withstand these conditions.
In vitro- In vivo Correlations:6,13
The requirement of establishing good in-vitro in-vivo correlation in the development of controlled release delivery systems is self evident. To make a meaningful in-vitro in-vivo correlation one has to consider not only the pharmaceutical aspect of controlled release drug delivery system but also the biopharmaceutics and pharmacokinetics of the therapeutic agent in the body after its release from the drug delivery system and also the pharmacodynamics of therapeutic agent at the site of drug action.
A simple in vitro-in vitro relationship can be established by conducting in-vitro and in-vivo evaluations of a potential drug delivery system simultaneously to study and compare the mechanism and rate profiles of controlled drug release. When the in-vivo drug release mechanism is proven to be in good agreement with that observed in the in-vitro drug release studies, then in-vitro in-vivo correlation factor is derived. For capsule type drug delivery system the factor can be represented as:
Where Q/t = Rate of release
‘Q’ values are dependent profiles of drug delivery systems. upon the sites of administration and environmental conditions to which the animals are exposed during treatment (study). The above relationship can be used for optimization of controlled release Levy has classified in-vivo – in-vitro correlation in to:
a] Pharmacological correlations based on clinical observations;
b] Semi-quantitative correlations based on blood levels or urinary
c] Quantitative correlation arising from absorption kinetics. While most of the published correlations are of semi-quantitative nature, the most valuable are those based on absorption kinetics.
Bioavailability Testing: 6,15
Bioavailability is generally defined as the rate and extent of absorption of unchanged drug from its site of application to the general circulation. Bioavailability is defined in terms of a specific drug moiety, usually active therapeutic entity, which may be the unchanged drug or as with prodrug, for instance, a metabolite. In contrast, the term "absorption" often refers to net transport of drug related mass from its site of application into the body. Hence, a compound may be completely absorbed but only partially bioavailable as would occur, when low bioavailability is caused by incomplete absorption. Pharmaceutical optimization of the dosage form may be warranted to improve absorption characteristics of the drug and thereby also its bioavailability. Bioavailability studies are ordinarily single dose comparisons of tested drug product in normal adults in a fasting state. A crossover design, in which all subjects receive both, the product and reference material on different days is preferred. Guidelines for clinical testing have been published for multiple dose studies. Correlation of pharmacological activity or clinical evidence of therapeutic effectiveness with bioavailability may be necessary to validate the single significance of controlled release claims. While single dose studies are usually sufficient to establish the validity of sustained release dosage form design; multiple dose studies are required to establish optimum dosing regimen. They are also required when difference may exist in the rate but not the extent of absorption. When there is excessive subject to subject variation or when the observed blood levels after a single dose are too low to be measured accurately. A sufficient number of doses must be administered to attain steady state blood levels. According to an extensive study of sustained release Theophylline products; for example, encapsulated forms showed less peaking during multiple dosing and therefore better control of blood level within the desired limits.
Regulatory Requirements: 15,16
In India, the controlled release drug products in legal sense are considered to be "New Drugs" according to schedule 'Y' of Drugs and Cosmetic Act and Rules. The guidelines given under Drugs and Cosmetic Act 1940, and Rules thereunder, 1945, under the schedule 'Y' inserted by notification no. GSR 944 (E), dated September 29, 1988, gives the data required to be submitted with application for permission to market a new drug.
The data is as follows:
1) Introduction: a brief description of the drug, the therapeutic class in which it belongs.
2) Chemical and pharmaceutical information.
a) Chemical name: Code number or name if any, non-proprietary or generic name, structure, physicochemical properties.
b) Dosage form and its composition.
c) Specification of active and inactive ingredients.
d) Tests for identification of active ingredients and method of its assay.
e) Outline of the method of manufacture of the active ingredient.
f) Stability data.
3) Animal Pharmacology
4) Animal toxicology
b) Acute toxicity
c) Long term toxicity
d) Reproduction studies
e) Local toxicity
f) Mutagenicity and carcinogenicity
5) Human clinical pharmacology (Phase I)
a) General pharmacological effects
6) Exploratory clinical trials
b) Investigator wise reports
7) Confirmatory clinical trials
b) Investigator wise report
8) Special studies
b) Bioavailability and dissolution studies
c) Investigator wise report
9) Regulatory status in other countries
a) Countries where,
iii) Under trial, with phase
iv) Withdrawn, reasons
b) Restriction in use, if any, in countries where marketed/approved.
c) Free sale certificate from country or origin.
10) Marketing information
a) Proposed product monograph
b) Drafts of labels and cartons
RECENT WORK REVIEW ON CONTROL DRUG RELEASE SYSTEM:
LEE et al.,(1999)17prepared A hydroxypropyl methylcellulose (HPMC) matrix tablet containing melatonin (MT) was formulated as a function of HPMC viscosity, drug loading, type and amount of disintegrant, lubricant and glidant, and aqueous polymeric coating level and was compared with two commercial products. The release characteristics of the HPMC matrix tablet were investigated in the gastric fluid for 2 hr followed by study in intestinal fluid. The surface morphology of an uncoated HPMC matrix tablet using scanning electron microscopy (SEM) was crude, showing aggregated particles and rough crystals or pores, but it became smoother as the coating levels increased. As the HPMC polymer viscosity increased, the release rate had a tendency to decrease. As the drug loadings increased, the release rate slightly decreased. When Polyplasdone XL, Primojel, and Ac-Di-Sol, except Avicel, were incorporated in the HPMC matrix tablet, the release rate was markedly increased. There was no significant difference in release profiles when a mixture of lubricants and glidants (magnesium stearate, talc, and Cab-O-Sil), except for magnesium stearate alone, was incorporated into low and high viscosity grade HPMC matrix tablets. As the coating level increased, the release rate gradually decreased, giving an increased lag time. The sustained-release HPMC matrix tablet with optimizing formulations may provide an alternative for oral controlled delivery of MT and be helpful in the future treatment of circadian rhythmic disorders OCHOA L et al.,(2008)18 prepare theophylline sustained release matrix tablets based on the combination of hydroxypropyl methylcellulose (HPMC K4M and K100M) and different meltable binders by melt granulation in a high-shear mixer. METHODS: Dissolution profiles of each formulation were compared to those of TheoDur 200 mg tablets and the mean dissolution time (MDT) and similarity factor (f2 factor) were calculated. The matrices swelling behavior was investigated by texture analysis. RESULTS: The results obtained show that the type of excipient influenced the drug release rate. In particular, the dissolution rate was delayed when lipophilic binders were used and only formulations containing Gelucire 50/13 or PEG 6000 with HPMC K4M had a profile similar to the commercial formulation. The release mechanism of theophylline from the formulations was described by Peppas's equation showing a non-Fickian release mechanism. The investigation of matrices swelling behavior showed that the gel layer thickness increased continuously over the time period studied. Moreover, a correlation between gel layer thickness and strength with the percentage released was found. CONCLUSIONS: These results suggest that melt granulation could be an easy and fast method to formulate sustained release tablets.
DONG W et al.,(2005)19 developed Enteric microparticles were prepared by a novel microencapsulation method in order to improve the oral bioavailability of lipophilic drugs. This method involved the addition of an aqueous polymer solution to an organic enteric polymer solution containing lipophilic drugs. In contrast to classical coacervation microencapsulation methods, the drugs were initially also dissolved and not dispersed in the organic polymer solution. The hydrophilic polymer (hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and Poloxamer 407) was dissolved in the aqueous phase and acted as a stabilizer for the coacervate droplets, preventing their coalescence and leading to the formation of enteric microparticles. The size of the enteric microparticles decreased with higher concentrations of the hydrophilic polymers, a higher pH of the aqueous polymer solution, a higher content of carboxyl groups of the enteric polymer and with better polymer solvents. Amide-containing lipophilic drugs, such as carbamazepine, lidocaine and cyclosporine A, were successfully encapsulated in the enteric microparticles in a non-crystalline state and were physically stable for 5 months. The high solubility of carbamazepine in the enteric polymer (>30%, w/w), a high partition coefficient between polymer-rich/-poor regions and strong drug/polymer interactions contributed to the high drug encapsulation efficiency (90%, w/w). In contrast, carboxyl-containing drugs (indomethacin, ibuprofen) and hydroxyl-containing drug (17beta-estradiol hemihydrate) crystallized inside or outside the polymeric matrix due to their low solubility in the enteric polymer.
DI COLO et al.,(2007)20 prepared a system able to sustain release of high MF-HCl doses in compliance with the above requirement. Matrices (6 mm diameter; 50 mg weight) comprising varying drug-Precirol ATO 5 ratios were prepared by compression. The matrix containing 70% drug was coated on one face with Eudragit L100-55. Drug release to simulated gastric (SGF), jejunal (SJF) and ileal (SIF) fluids in sequence was studied using a modified USP rotating basket method. Release depended on drug load whereas it was independent of dissolution medium pH and hydrodynamics. Release kinetics were of radical t type and were determined by drug diffusion in aqueous pores created in the matrix by drug dissolution. An equation correlating rate-determining factors was developed, whereby the release pattern could be optimized. The half-coated matrix started release in SGF and completed it in SJF. The half-coated matrix, synchronizing drug release and matrix transit across the small intestine, may improve drug bioavailability and reduce side effects.
Bailey CJ et al .,(2008)21 Combined of two or more oral agents with different mechanisms of action are often used for the management of hyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, several fixed-dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets, giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply to each active component. Fixed-dose combinations can offer convenience, reduce the pill burden and simplify administration regimens for the patient. They increase patient adherence compared with equivalent combinations of separate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabetic fixed-dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor or meglitinide as well as thiazolidinedione-sulphonylurea combinations, each at a range of dosage strengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management is likely to increase the use of fixed-dose single tablet combinations.
LEE BJ et al.,(2008)22 A dual drug-loaded hydroxypropylmethylcellulose (HPMC) matrix tablet simultaneously containing drug in inner tablet core and outer coated layer was formulated using drug-containing aqueous-based polymeric Eudragit RS30D dispersions. Effects of coating levels, drug loadings in outer layers, amount and type of five plasticizers and talc concentration on the release characteristics were evaluated on the characteristics in simulated gastric fluid for 2 h followed by a study in intestinal fluids. Melatonin (MT) was selected as a model drug. The surface morphology of dual drug-loaded HPMC tablets using scanning electron microscope (SEM) was smooth, showing the distinct coated layer with about 75-microm coating thickness at the 15% coating level.. The time for the first linear release was also advanced. However, the biphasic release pattern was not changed. The biphasic release profiles of dual drug-loaded HPMC matrix tablet were highly modified, depending on the amount and type of five plasticizers. Talc (10-30%) in coating dispersion as an anti-sticking material did not affect the release profiles. The current dual drug-loaded HPMC matrix tablet, showing biphasic release profiles may provide an alternative to deliver drugs with circadian rhythmic behaviors in the body but needs to be further validated in future in human studies. The dual drug-loaded coating method is also interesting for the modified release of poorly water-soluble drugs because solubilizers and other additives can be added in drug-containing polymeric coating dispersions.
TALUKDER MM et al.,(2008)23 prepared a swelling matrix core containing pectin, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose and 5-aminosalicylic acid was developed. This was subjected to a dual coating operation: an inner pH-sensitive enteric and an outer semi-permeable membrane coat with a pore former. In-vitro dissolution studies were carried out in USP apparatus-I using sequential pH media. The first 2 h of dissolution studies were done in HCl buffer at pH 1.5, the next 2 h in pH 5.5 and, finally, in phosphate buffer at pH 6.8 with and without pectinolytic enzyme present. Less than 2% drug was released in the first 6 h and about 90% released in the following 12 h in a controlled manner. The stability studies of the coated systems were performed for 90 days under various conditions and it was found that drug release was not adversely affected. Results indicate that this delivery system has potential for site-specific delivery of drugs to the colon irrespective of transit time and rapid changes in the proximal pH of the gastrointestinal tract.
CONTOAR SL et al., (2004)24 to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit(R) RS 30D were developed and beads were produced by extrusion-spheronization. Drug beads were coated using 15% wt/wt Surelease(R) or Eudragit(R) NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm(3) and size of 855 mum were quite close to Surelease(R)-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease(R)-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease(R) films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.
Vueba ML et al.,(2006)25 study of different ketoprofen:excipient formulations, in order to determine the effect of the polymer substitution and type of diluent on the drug-release mechanism. Substituted cellulose-methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose were used as polymers, while lactose monohydrate and beta-cyclodextrin were tested as diluents. Distinct test formulations were prepared, containing 57.14% of ketoprofen, 20.00% of polymer, 20.29% of diluent, and 1.71% of talc/0.86% of magnesium stearate as lubricants. The tablets were tested for their drug content, weight variation, hardness, thickness, tensile strength, friability, swelling and release ratio. Polymers MC25 and HPC were found not to be appropriate for the preparation of modified release ketoprofen hydrophilic matrix tablets, while HPMC K15M and K100M showed to be advantageous. The analysis of the release profiles in the light of distinct kinetic models (zero-order, first-order, Higuchi and Korsmeyer-Peppas) led to the conclusion that the type of polymer did not influence the release mechanism of the drug. The mean dissolution time (MDT) was determined, the highest MDT value being obtained for HPMC formulations. Moreover, the drug-release process was found to be slightly influenced by the type of diluent, either lactose or beta-cyclodextrin
Corti G et al., (2007)26 develop a MH sustained-release formulation in compliance with these requirements. The strategy proposed is based on direct-compressed matrix tablets consisting of a combination of MH with the hydrophobic triacetyl-beta-cyclodextrin (TAbetaCD), dispersed in a polymeric material. Different polymers were tested as excipients, i.e. hydroxypropylmethylcellulose, xanthan gum, chitosan, ethylcellulose, Eudragit L100-55, and Precirol. Compatibility among the formulation components was assessed by DSC analysis. All the tablets were examined for drug release pattern in simulated gastric and jejunal fluids used in sequence to mimic the GI transit. Release studies demonstrated that blends of a hydrophobic swelling polymer (hydroxypropylmethylcellulose or chitosan) with a pH-dependent one (Eudragit L100-55) were more useful than single polymers in controlling drug release. Moreover, the main role played by the MH-TAbetaCD system preparation method (i.e. grinding or spray-drying) in determining the behaviour of the final formulation was evidenced. In fact, for a given matrix-tablet composition, different sustained-release effects were obtained by varying the relative amounts of MH-TAbetaCD as ground or spray-dried product. In particular, the 1:1 (w/w) blend of such systems, dispersed in a Eudragit-chitosan polymeric matrix, fully achieved the prefixed goal, giving about 30% released drug after 2h at gastric pH, and overcoming 90% released drug within the subsequent 3h in jejunal fluid.
Kapat et al., (2004)27 this work has focused on the effects of different hydroxypropylmethylcellulose (HPMC) types and HPMC :direct tabletting agent (DC-agent) ratio on Verapamil Hydrochloride (VRP HCl) release from monolayered and three-layered matrix tablets. Investigated polymers were Methocel K100LV, K15M, K100M and DC-agent was Ludipress® LCE. Eight formulations were prepared as monolayered matrix tablets while four formulations were prepared as three-layered matrix tablets by direct compression method. Drug release studies were carried out according to the method given for Delayed Release Articles in USP XXVII. HPMC types and ratios were found to be effective on drug release. Increasing amount and viscosity grade of HPMC resulted in a decrease in release of drug from the matrices. Tablets containing low viscosity grade HPMC at inner and outer layers presented release profiles close to or within the limits of pharmacopeia. Release data of three-layered matrix tablet (F12) and the reference product (Isoptin® -KKH) which were in agreement with USP XXVII criteria, were evaluated by mathematical models (zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas), difference factor (f1) and similarity factor.
Md. Selim Reza et al., (2003)28 undertaken to investigate the effect of plastic, hydrophilic and hydrophobic types of polymers and their content level on the release profile of drug from matrix systems. As the physico-chemical nature of the active ingredients influence the drug retarding ability of these polymers, three different drugs were used to evaluate their comparative release characteristics in similar matrices. Matrix tablets of theophylline, diclofenac sodium and diltiazem HCl using Kollidon SR, Carnauba wax and Hydroxypropyl methylcellulose (HPMC-15cps) were prepared separately by direct compression process Release profile showed a tendency to follow zero-order kinetics from HPMC matrix systems whereas Fickian (Case I) transport was predominant mechanism of drug release from Kollidon SR matrix system. The mean dissolution time (MDT) was calculated for all the formulations and the highest MDT value was obtained with Carnauba wax for all the drugs under investigate. The results generated in this study showed that the profile and kinetics of drug release were functions of polymer type, polymer level and physico-chemical nature of drug. A controlled plasma level profile of drug can be obtained by judicious combination of polymers and modulation of polymer content in the matrix system.
Heinz R et al., (2000)29using Ludipress greatly simplifies formulation development and the manufacturing process because only the active ingredient Ludipress and a lubricant need to be mixed briefly before being compressed into tablets. The studies described here were designed to investigate the scale-up of Ludipress-based formulations from laboratory to production scale, and to predict changes in tablet properties due to changes in format, compaction pressure, and the use of different tablet presses. It was found that the tensile strength of tablets made of Ludipress increased linearly with compaction pressures up to 300 MPa. It was also independent of the geometry of the tablets (diameter, thickness, shape). It is therefore possible to give an equation with which the compaction pressure required to achieve a given hardness can be calculated for a given tablet form. The equation has to be modified slightly to convert from a single-punch press to a rotary tableting machine. Tablets produced in the rotary machine at the same pressure have a slightly higher tensile strength. The production of tablets based on Ludipress can be scaled up from one rotary press to another without problem if the powder mixtures are prepared with the same mixing energy. The tensile strength curve determined for tablets made with Ludipress alone can also be applied to tablets with a small quantity (< 10%) of an active ingredient.
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