Over the past 30 years, as the expense & complications involved in marketing new drug entities have increased with concomitant recognition of the therapeutic advantages of controlled drug-delivery, greater attention has been focused on development of sustained or extended release drug delivery systems. There are several reasons for the attractiveness of these dosage forms. It is generally recognized that for many disease states, a substantial number of therapeutically effective compounds already exist. The effectiveness of these drugs however, is often limited by side effects or the necessity to administer the compound in a clinical setting. The goal in designing extended or sustained-release drug delivery systems is to reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery.
If one were to imagine the ideal drug delivery system, two prerequisites would be required. First, it would be a single dose for the duration of treatment, whether it be for days or weeks, as with infection, or for the lifetime of the patient, as in hypertension or diabetes. Second, it should deliver the active entity directly to the site of action, thereby minimizing or eliminating side effects. This may necessitate delivery to specific receptors or to localization to cells or to specific areas of the body.
The goal of any drug-delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. That is, the drug delivery system should deliver drug at a rate dictated by the needs of the body over a specified period of treatment. This idealized objective points to the two aspects most important to drug delivery, namely, spatial placement and temporal delivery of a drug. Spatial placement relates to targeting a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue. An appropriately designed controlled-release drug-delivery system can be a major advance towards solving these two problems. It is for this reason that the science and technology responsible for development of controlled-release pharmaceuticals has been, and continues to be, the focus of a great deal of attention in both industrial and academic laboratories (Robinson JR et al, 2005).
In the last two decades, sustained-release dosage forms have made significant progress in terms of clinical efficacy and patient compliance (Merkus F.W.H.M., 1986).
The objective of this work is to evaluate the comparative efficiency of some market preparations of metformin ER by using in vitro dissolution methods.
Metformin ER (a long-acting, extended-release version of metformin) is used to treat type 2 diabetes. The drug works by decreasing the amount of sugar that the liver makes and by decreasing the amount of sugar absorbed into the body. The medication comes in the form of a tablet that should be taken once a day with evening meal (Princeton NJ, 2006; FDA, 2007).
Dissolution method was carried out in two medium: 0.1N HCl & phosphate buffer (pH=6.8).
1.1. History of Extended Release dosage forms:
The history of extended-release technology can be divided roughly into three time periods. From 1950 to 1970 is the period of sustained drug release. A number of systems containing hydrophobic polymers and waxes were fabricated with drugs into dosage forms with the aim of sustaining drug levels and hence drug action for an extended period of time. However, a lack of understanding of anatomical and physiological barriers imposed impediments on the development of efficient delivery systems. The period 1970 to 1990 was involved in the determinations of the needs in controlled drug delivery and to understand the barriers for various routes of administration. Post 1990 is the modern era of controlled release technology and represents the period in which an attempt at drug optimization is emphasized. Recently, considerable effort has been expended to develop biocompatible polymers, polymer carriers etc. There currently exist numerous products on the market, formulated for both oral and parenteral routes of administration, that claim sustained on controlled drug delivery. The bulk of research has been directed towards oral dosage forms that satisfy the temporal aspects of drug delivery. In addition, some of the newer approaches under investigation may allow for spatial placement as well (Robinson JR et al, 2005).
1.2. Concept of ER dosage forms:
Extended release, sustain release, sustain action, prolonged action, controlled release, timed release dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. In the case of injectable dosage forms, this period may vary from days to months. In the case of orally administered forms, however, this period is measured in hours and critically depends on the residence time of the dosage form in the gastrointestinal tract. The term “Controlled release” has become associated with those systems from which therapeutic agents may be automatically delivered at predefined rates over a long period of time. Products of this type have been formulated for oral, injectable, and topical use and include inserts for placement in body cavities as well.
The pharmaceutical industry provides a variety of dosage forms and dosage levels of particular drugs, thus enabling the physician to control the onset and duration of drug therapy by altering the dose and mode of administration. In some instances, control of drug therapy can be achieved by taking advantages of beneficial drug interactions that affects drug disposition and elimination, e.g. the action of probencid, which inhibits the excretion of penicillin, thus prolonging its blood level. Mixtures of drugs might be utilized to potentiate, synergize, or antagonize given drug actions. Alternatively, drug mixtures might be formulated in which the rate or extent of drug absorption is modified. Sustained release dosage form design embodies this approach to the control of drug action, i.e., through a process of either drug modification or dosage form modification, the absorption process and subsequently drug action, can be controlled (Lordi NG, 1986).
1.3. The Rationale for Extended- Release Pharmaceuticals:
Some drugs are inherently long lasting & require only once-a-day oral dosing to sustain adequate drug blood levels & the desired therapeutic effect. These drugs are formulated in the conventional manner in immediate release dosage forms. However, many other drugs are not inherently long lasting & require multiple daily dosing to achieve the desired therapeutic results.
Multiple daily dosing is inconvenient for the patient & can result in missed doses, made-up doses, & noncompliance with the regimen. When conventional immediate release dosage forms are taken on schedule & more than once daily, they cause sequential therapeutic blood level peaks & valleys associated with the taking of each dose. However when doses are not administered on schedule, the resulting peaks & valleys reflect less than optimum drug therapy. For example, if doses are administered too frequently, minimum toxic concentrations (MTC) of drug may be reached, with toxic side effects resulting. If doses are missed, periods of subtherapeutic drug blood levels or those below the minimum effective concentration (MEC) may result, with no benefit to the patient.
Extended-release tablets & capsules are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to be taken three or four times daily to achieve the same therapeutic effect. Typically, extended-release products provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period. The sustained plasma drug levels provided by extended-release products oftentimes eliminates the need for night dosing, which benefits not only the patient but the caregiver as
well (Ansel HC et al., 2005).
1.4. Extended- Release technology:
Extended Release dosage forms are those in which drug is released slowly, so that plasma concentrations are maintained at a therapeutic level for a prolonged period of time (usually between 8 & 2 hrs) (Moreton C et al, 2002).
Ideally, the ultimate criterion for a sustained release tablet is to achieve a blood level of the drug comparable to that of a liquid product administered every 4 hr. To this end, extended release dosage forms are designed to release the drug so as to provide a drug level within the therapeutic range for 8 to 12 hr. They are intended as a convenience so that the patient needs to take only one dose morning & evening & need not get up in the night.
Extended drug forms are not without disadvantages. Since gastrointestinal tracts are not all uniform, certain individuals may release too much drug too soon & experience toxic or exaggerated response to the drug, whereas others may liberate the drug more slowly & not receive the proper benefit or response anticipated. This is especially true of older people whose GIT is less active than that of younger. Also, where liberation is slow, there is danger of accumulation of the drug after several days resulting in high blood levels & a delayed exaggerated response.
Extended release tablets must be tested for the rate of drug release by the prescribed in vitro laboratory method. Each product has an inherent release rate based on properly designed clinical trials of blood concentration & excretion in humans which is compared to the concentration & pharmacological activity resulting from the usual single-dose schedule of the drug administered in solution (Bandelin FJ, 1989).
Extended-Release dosage form is also called:
Prolonged-Release dosage form
Sustained-Release dosage form
Controlled-Release dosage form
Modified-Release dosage form
Delayed-Release dosage form
Timed-Release dosage form
Retarded-Release dosage form
Repeat action dosage form (Moreton C et al, 2002; Bandelin FJ, 1989).
1.5. Factors to be considered in Extended-Release technology:
Extended-release oral drug products remain in the GI tract longer than conventional, immediate release drug products intended for rapid absorption. Thus, drug release from an extended-release drug product is more affected by the anatomy & physiology of the gastrointestinal tract & its contents compared to an immediate-release oral drug product (Shargel L et al, 2005).
Table-1.1. Factors to be considered in Extended-release technology
1. Physicochemical properties of the drug • Aqueous solubility of the drug.
• Stability of the drug.
• Partition co-efficient of the drug.
• pKa value of the drug.
• Protien binding of the drug.
• Molecular size and diffusivity.
2. Biological properties of the drug • Absorption characteristics of the drug.
• Distribution characteristics of the drug.
• Metabolism of the drug.
• Biological half-life and elimination of the drug.
• Duration of action of the drug.
• Role of disease state and tissue injury.
• Side-effects of the drug.
• Dose size.
3. Patient or disease factors • Acute or chronic therapy required.
• Age and physiological state of the patients.
• Ambulatory or bed ridden patient.
• Duration of drug action desired.
• Location of the target area.
• Pathology of disease state.
(Robinson JR et al, 2005).
1.6. Physiology of Gastrointestinal tract:
Several extended release & delayed release drug products are formulated to take advantage of physiologic conditions of the GI tract. Enteric coated beads have been found to release drug over 8 hrs when taken with food, because of the gradual emptying of the beads into the small intestine. Specially formulated “floating tablets” that remain in the top of the stomach have been used to extend the residence time of the product in the stomach. None of these methods, however, is consistent enough to perform reliably for potent medications.
In most mammals, the stomach is a hollow muscular organ of the gastrointestinal tract involved in the second phase of digestion, following mastication. The word stomach is derived from the Latin stomachus, which derives from the Greek word stomachos. The words gastro- and gastric (meaning related to the stomach) are both derived from the Greek word gaster.
The stomach lies between the esophagus and the duodenum (the first part of the small intestine). It is on the left side of the abdominal cavity. The top of the stomach lies against the diaphragm. Lying beneath the stomach is the pancreas, and the greater omentum which hangs from the greater curvature. Two smooth muscle valves, or sphincters, keep the contents of the stomach contained. They are the esophageal sphincter (found in the cardiac region) dividing the tract above, and the Pyloric sphincter dividing the stomach from the small intestine.
In humans, the stomach has a relaxed volume of about 45 ml, it generally expands to hold about 1 liter of food (Sherwood et al, 1997), but can hold as much as 4 liters.
The stomach is a highly acidic environment due to hydrochloric acid production and secretion which produces a luminal pH range usually between 1 and 2 depending on the species, food intake, time of the day, drug use, and other factors, but fasting pH is 3-5. Combined with digestive enzymes, such an environment is able to break down large molecules (such as from food) to smaller ones so that they can eventually be absorbed from the small intestine. A zymogen called pepsinogen is secreted by chief cells and turns into pepsin under low pH conditions and is a necessity in protein digestion (Maton et al, 1993).
The human stomach can produce and secrete about 2.2 to 3 liters of gastric acid per day with basal secretion levels being typically highest in the evening. The stomach can expand to hold between 2-4 liters of food. It is a temporary food storage area, and in the process of digestion, the food goes into the stomach first.
The stomach is a “mixing & secreting” organ, where food is mixed with digestive juices & emptied periodically into the small intestine. Gastric empting occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states:
1. Interdigestive phase (fasting state), alternating cycles of activity known as the mi-grating motor complex (MMC) act as a propulsive movement that empties the upper GI tract that is divided into 4 phases such as-
Phase-I, it lasts for 30-60 mins with rare contractions.
Phase-II, it lasts for 20-40 mins with irregular contractions. Bile secretion begins & onset of particles & mucus discharge may occur.
Phase-III, it lasts for 5-15 mins with regular contractions. Particle & mucus discharge continuously occur. It is due to the wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.
Phase-IV, it lasts for 0-5 mins with irregular contractions.
2. Digestive phase (fed state); food is present in the stomach, regular, frequent contractions, but wave is lower than phase III (Rubinstein et al, 1988).
Feldman M et al (1984) observed that soft drink, digestible solid, & undigestible solid were 50% emptied from the stomach in 30 minutes, 154 minutes, & 3-4 hrs, respectively. Large particles including tablets & capsules are delayed from emptying for 3-6 hrs by the presence of food in the stomach.
The intestines consist of the small intestine and the large intestine. The intestines look like a very long, curvy tube wound up snugly in the lower to middle abdomen of the body. The small intestine is where nutrients are absorbed from food and the process of digestion is completed. Then the nutrients are carried throughout the body through the blood.
There are three parts to the small intestines: the duodenum, the jejunum, and the ileum. The duodenum is the first section and is the shortest and the widest part of the small intestines. The small intestine is just over 9 meters long. The duodenum is sterile, while the terminal part of the small intestine that connects the cecum. The proximal part of the small intestine has a pH of about 6, because of neutralization of acid by bicarbonates secrete-d by the duodenal mucosa & the pancreas. The small intestine provides an enormous surface area for drug absorption because of the presence of microvilli. It is also called “absorption window”. The transit time interval for most of the drugs is 3-6 hrs, but extended release dosage forms that last up to 12 hrs, unless the drug is to be absorbed in the colon (Hofmann et al, 1983).
The large intestine is about 4-5 feet long. It consists of the cecum, the ascending & descending colons, & eventually ends at the rectum. Little fluid is in the colon, & drug transit is slow. It absorbs fluids from the solid mass received from the small intestine and stores the leftover, unused part of the food. After most of the fluid has been absorbed from the mass, it enters the rectum and then exits the body through the anus. Not much is known about drug absorption in this area, although unabsorbed drug that reaches this region may be metabolized. PH of it 6.8-7.0. Presumably, drugs formulated for 24 hrs duration-on must remain in this region to be absorbed (Shareef et al, 2003).
1.7. Advantages of sustained release dosage forms:
1) Improved control over the maintenance of therapeutic plasma drug concentration of drugs permits:-
# Improved treatment of much chronic illness. e.g., Asthma, depressive illness.
# Maintenance of the therapeutic action of drug during overnight management of pain in terminally ill patients improved sleep.
# Less fluctuation in drug blood levels.
# Frequency reduction in dosing – SR products frequently deliver more than a single dose hence may be taken loss often conventional forms.
2) Enhanced convenience and patient compliance:-
With less frequency of dosing a patient is less to neglect taking a dose also greater convenience with day and night administration. e.g., one per oral SR product every 12hrs contributes to the improved control of therapeutic drug conc. achieved with products.
3) Reduction in adverse side effects:-
There is a reduction in the incidence and severity of localized gastrointestinal side effects produced by “dose dumping” of irritant drugs from conventional dosage forms, e.g., potassium chloride.
4) Reduction in overall health care cost:-
Although initial cost of extended release dosage forms may be greater than for conventional forms, overall cost of the treatment may be less because of enhanced therapeutic benefit, fewer side effects, reduced time for health care personnel to dispense and administer drug and monitor patients (Lordi NG, 1986).
1.8. Disadvantages of sustained release dosage forms:
1) Administration of sustained release medication does not permit the promt termination of therapy.
2) The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form design.
3) Sustained releease forms are designed for the normal population, e.g., on the basis of average drug biologic half-lives. Consequently, disease states that alter during drug disposition, significant patient variation, and so forth are not accommodated.
4) Variable physiological factors such as GI pH, enzyme activities, gastric & intestinal transit rates, food and severity of disease which may influence the absorption of drugs from SR forms.
5) More costly processes and equipments are involved in manufacturing many sustained release dosage forms (Moreton C. et al, 2002).
1.9. Drug candidates for extended release products:
To be a successful extended release product, the drug must be released from the dosage form at a predetermined rate, dissolved in the gastrointestinal fluids, maintain sufficient gastrointestinal residence time, and be absorbed at a rate that will replace the amount of drug being metabolized and excreted.
In general, the drugs best suited for incorporation into an extended release product have the following characteristics:
1) They exhibit neither very slow nor very fast rates of absorption and excretion.
2) They are uniformly absorbed the gastrointestinal tract. Drugs prepared in extended-release forms must have good aqueous solubility & maintain adequate residence time in the gastrointestinal tract.
3) They are administered in relatively small doses, e.g., Ketoprofen 100mg cap.
4) They possess a good margin of safety. The larger the therapeutic index, the safer the drug.
5) Drugs that are administered in very small doses or possess very narrow therapeutic index are poor candidates for formulation into extended release formulation because of technological limitations of precise control over the release rates & the risk of dose dumping due to a product defect. Patient misuse also could result in toxic drug levels (Lordi NG, 1986). e.g. LD50 of chemotherapeutic drug is 16, and ED50 is 4, so TI=4. Again, LD50 of anticancer drug is 16, and ED50 is 8, so TI=2. So, chemotherapeutic drug is safer than anticancer drugs (Khan AR, 1998).
6) They are used in the treatment of chronic rather than acute conditions, e.g., Asthma.
1.10. Drugs unsuitable for SR forms:
1) Drugs that are not effectively absorbed in the lower intestine, e.g., Riboflavin, ferrous salts.
2) Absorbed & excreted rapidly; short biologic half-life (2hrs), e.g., Penicillin G, furosemide.
3) Long biologic half-life (>12hrs), e.g., diazepam, phenytoin.
4) Large doses required (>1g), e.g., Sulfonamides.
5) Cumulative action & undesirable side effects; drugs with low therapeutic indexes, e.g., Phenobarbital, digitoxin.
6) Precise dosage titrated to individual is required, e.g., Anticoagulants, cardiac glycosides.
7) No clear advantage for sustain release dosage formulation, e.g., Griseofulvin (Lordi NG, 1986).
1.11. Principle / Mechanism of SR dosage form design:
There are two general methods have been developed for implementation of SR dosage form design such as-
1) Methods based on drug modification.
-Drug-resin complex / drug-adsorbate preparation.
2) Methods based on dosage form modification.
1.11.1. Methods based on drug modification:
126.96.36.199. Drug-complex formation:
Some drugs substances when chemically combined with certain other chemical agents, form complexes that may be only slowly soluble in body fluids, depending on the pH of the environment.
In case of drug complexes the effective release rate is a function of two processes:
-the rate of dissolution of the solid complex into the biologic fluids, and
-the rate of dissociation or breakdown of the complex in solution
Slow dissolution rate provides ER of the drug. For example, tannate complexes of
bases are hydrolyzed in both acidic & basic media, the dissociation of the complex being more rapid at the gastric pH.
188.8.131.52. Drug-resin complex / drug-adsorbate preparation:
Drug adsorbats represents a special case of complex formation in which the product is essentially insoluble. Drug availability is determined only by the rate of dissociation (desorption) and therefore, access of the adsorbent surface to water as well as the effective surface area of the adsorbate. Styrene/ divinyl benzene moiety of the resin are used.
A solution of a cationic drug may be passed through a column containing an ion exchange resin, forming a complex by the replacement of hydrogen atoms. The resin drug complex is washed and may be tableted, encapsulated or suspended in an aqueous vehicle.
Drug release from cationic ion-exchanges resin complexes depends on sodium ion conc. in GI fluids, and although a stearate salt of a weak base resists the action of gastric fluid, natural digestive processes in the intestine act to dissociate the complex.
184.108.40.206. Prodrug synthesis:
Prodrugs are therapeutically inactive drug derivatives that regenerate the parent drug by enzymatic or non-enzymatic hydrolysis. The solubility, absorption rate, and elimination rate constant of an effective Prodrug should be significantly lower than that of the parent compound.
The pharmacokinetics of a Prodrug in which the sustain blood level is determined by the metabolic rate, e.g., by formation of the active moiety after absorption. Some drugs from which Prodrugs designed are- Isoproterenol, isoniazid, and penicillin.
1.11.2. Methods based on dosage form modification:
Microencapsulation is a process by which solids, liquids, or even gases may be enclosed in microscopic particles by formulation of thin coatings of wall material around the substance.
The typical encapsulation process usually begins with dissolving the wall material, say gelatin in water. The material to be encapsulated is added and the two phase mixture thoroughly stirred with the material to be encapsulated broken up to the desired particle size, a solution of a second material, usually acacia is added. This additive material concentrates the gelatin (polymer) into tyni liquid droplets. These droplets (the coacervate) form a film or coat around the particles of the substance to be encapsulated as a consequence of the extremely low interfacial tension of the residual water or solvent in the wall material so that a continuous tight film coating remains on the particle, e.g., Potassium chloride.
220.127.116.11. Osmotic pump system:
In osmotic pump system, a drug is included in a tablet core which is water soluble, and which will solubilize or suspend the drug in the presence of water. The tablet core is coated with a semi-permeable membrane which will allow water to pass through into the core, which then dissolves. As the core dissolves, a hydrostatic pressure builds up and forces (pumps) drug solution (or suspension) through a hole drilled in the coating. The system is designed such that only a few drops of water are drawn into the tablet each hour that govern the release rate.
18.104.22.168. Matrix system:
A matrix system will be embedded in the polymer matrix. This system depends on barrier concept.
There are 3 systems, considered based on 3 types of materials which are used to design SR dosage forms.
I. Insoluble, Inert & non-erodable system.
Components: -Active drug
-Inert excipients: polyethylene, polyvinyl chloride, ethyl cellulose, poly amide.
II. Insoluble but erodible system (water insoluble).
Components: -Active drugs
-Lipid excipients: Carnauba wax, stearyl alcohol, hydrogenated vegetable oil, castor wax, poly ethylene glycol monostearate, triglycerides.
III. Hydrophilic matrix system.
Components: -Active drug.
-Hydrophilic excipients: Sodium alginates, gelatin, hydroxyl propyl methyl cellulose, methyl cellulose, carboxy polymethylene.
22.214.171.124.1. Insoluble but non-erodable system:
An inert matrix system is one in which a drug is embedded in an inert polymer which is not soluble in the GIT fluid. The drug is slowly released from the inert plastic matrix by diffusion. The compression creates the matrix or plastic form that retains its shape during leaching of the drug & during its passage through the alimentary tract. An immediate release portion of the drug may be compressed onto the surface of the tablet. The inert tablet matrix expended of drug, is excreted with the feces.
Drug release from insoluble matrix by 4 ways-
Drug molecularly dissolved in the matrix and drug diffusion occurs by a solution-diffusion mechanism.
Drug dissolved in the matrix & then, dissolution of the drug, diffusion occurs via a solution-diffusion mechanism.
Drug dissolved in the matrix and drug diffusion occurs through water-filled pores in the matrix.
Drug dispersed in the matrix & then, after dissolution of the drug, diffusion occurs through water-filled pores in the matrix, e.g., Ferro gradumet.
The matrix compacts are prepared from the blends of powdered components. The active compound is contained in a hydrophobic matrix that remains intact during drug release.
Release depends on an aqueous medium dissolving the chennelling agent (polyols, NaCl) which leaches out of the compact so forming a porous matrix of tortuous capillaries. The active agent dissolves in the aqueous medium, and by way of the water-filled capillaries, diffuses out of the matrix.
Figure 1.7: Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems.
126.96.36.199.3. Hydrophilic matrix system:
This Delivery System is also called swellable soluble matrix. In general they comprise a compressed mixture of drug and water-swellable hydrophilic polymer. The systems are capable of swelling on contact with water followed by-
-gel formation erosion, e.g., triple helix formation in gelatin gel.
-dissolution in aqueous media (viscolized matrix),e.g., HPMC & Na-alginate in water.
Advantages of Matrix system:
• Easy to manufacture using direct compression and wet granulation method.
• Possible to release zero order, first order.
Disadvantages of Matrix system:
• Drug-polymer ratio should be maintained carefully.
• Need optimal rate-controlling polymers for different active (Lordi NG, 1986; Moreton C. et al, 2002).
It was found that the choice of matrix material, amount of drug incorporated in matrix additives, hardness of the tablet, density variation and tablet shape cold markedly affect the release of drug. Several other workers have also reported that the rate of drug release from matrix is affected by:
• Drug solubility
• Composition of the matrix.
• PH of the dissolution fluid.
• External agitation
• Mass of the drug.
• Porosity of the matrix.
More recently Potter et al (1992) observed that the particle size of drug and excipients as well as the drug loading of the tablets exert a great deal of effect on the release of behavior.
1.12. Primary Controlled-Release Mechanisms:
There are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion. Any or all of these mechanisms may occur in a given release system. Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale—as through pores in the polymer matrix—or on a molecular level, by passing between polymer chains. Examples of diffusion-release systems are shown in Figures 1.9 & 1.10.
A polymer and active agent have been mixed to form a homogeneous system, also referred to as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release.
For the reservoir systems shown in Figures 1.10a and 1.10b, the drug delivery rate can remain fairly constant. In this design, a reservoir—whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix—is surrounded by a film or membrane of a rate-controlling material. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. Since this polymer coating is essentially uniform and of a non-changing thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system. The system shown in Figure 1.10a is representative of an implantable or oral reservoir delivery system, whereas the system shown in Figure 1.10b illustrates a transdermal drug delivery system, in which only one side of the device will actually be delivering the drug (Vert M et al, 1991).
1.12.1. ENVIRONMENTALLY RESPONSIVE SYSTEMS:
It is also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment. Swelling-controlled release systems are initially dry and, when placed in the body, will absorb water or other body fluids and swell. The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. It is also called floating drug delivery system. The figure 1.11 shows this system.
One of the most remarkable, and useful, features of a polymer’s swelling ability manifests itself when that swelling can be triggered by a change in the environment surrounding the delivery system. Depending upon the polymer, the environmental change can involve pH, temperature, or ionic strength, and the system can either shrink or swell upon a change in any of these environmental factors.
The diagrams in Figure 1.12 illustrate the basic changes in structure of these sensitive systems. Once again, for this type of system, the drug release is accomplished only when the polymer swells. Because many of the potentially most useful pH-sensitive polymers swell at high pH values and collapse at low pH values, the triggered drug delivery occurs upon an increase in the pH of the environment. Such materials are ideal for systems such as oral delivery, in which the drug is not released at low pH values in the stomach but rather at high pH values in the upper small intestine (Kim SW, 1996).
1.13. Mathematical expression of drug release mechanism from controlled release dosage forms:
The release of drug from controlled dosage form is controlled by several processes. These are extraction or diffusion of drug from matrix alternatively; drug may be dissolved in the matrix material and be released by diffusion through membrane. Matrices may be prepared from soluble, insoluble or erodable materials. In some cases drug may be released by osmotic process.
The release of drug is determined by the diffusion through the polymeric membrane. It can be mathematically expressed as-
J = – D dc/ dx ………………………………………………… (1)
J= is the flux of drug in amount/area-time
D= is diffusion coefficient in area/time
C= is the concentration
X= is the diffusion path length
Assuming Steady-state level equation (1) can be integrated as-
J= – DC/ I
When water insoluble membrane is employed then the equation is
dM/dt = – ADK AC/I
dM/dt= the amount of drug that diffuses
A= cross sectional area
K= partition coefficient
I= diffusion path length
AC= the concentration gradient across the membrane.
1.13.2. First Order Release:
Most sustained release formulation tends to give first order release pattern. This release equation is based on pick’s law, described as
dc/ dt = -DA (Cm-Cr)/h
Dc/dt= the mass of drug which diffuses in unit time.
A = cross sectional area
D= diffusion constant
Cm = the initial concentration in the dosage form
Cr= the concentration in the dissolution time
H= thickness of the barrier
Under sink condition, the equation becomes
dCm/ dt = -KtCm
Kt = constant
Integration of the above equation gives the first order equation
Log Cm = logC°m – Kt/ 2.303
Cm = the concentration at time t
K = the first order release rate constant
1.13.3. Zero Order Release:
A zero order release of drug is needed for the dosage form, which means that the rate of drug is independent of drug concentration, expressed by the following equations-
Dc/ dt = kro
dM/ dt = kro
At times it is not possible to generate a constant release product & a slow first-order release of drug is employed.
1.13.4. Higuchi Release:
Obviously, 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 dissolute drug leaving the matrix. Deviation of mathematical model to describe this system involves the following assumption:
– A pseudo-steady state is maintained during drug release.
– The diameter of drug particles is less than the average distance of drug dissolution through the matrix.
– The bathing solution provides sink conditions at all times.
– The diffusion coefficient of drug in the matrix remains constant.
Higuchi has derived the rate of drugs dispersed in an inert matrix system.
This equation is-
dM/dh = Co.dh – Cs/2
dM= Change in the amount of drug release per unit area.
Dh= Change in the thickness of the zone of matrix that been depleted of the drug.
Co= Total amount of drug in a unit volume of the matrix.
Cs= Sustained concentration of the drug within the matrix.
1.14. Metformin HCl ER:
• Chemical structure:
• Chemical name: 1, 1-Dimethylbiguanide HCl.
• Molecular formula: C4 H11 N5, HCl.
• Molecular weight: 165.6.
• Content: 98.5 to101.0 %
Appearance- White crystals.
Solubility- Freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone & in methylene chloride.
Melting point- 222-226°C (BP, 2003).
Antidiabetic drug, for the treatment of type-2 diabetes.
It is available as an extended release tablet containing 500mg, 750mg, 850mg, or 1000mg of metformin.
1.15. History of metformin:
The biguanide class of anti-diabetic drugs, which also includes the withdrawn agents phenformin and buformin, originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus (Witters L, 2001).
Metformin was first described in the scientific literature in 1957 (Ungar G et al, 1957). It was first marketed in France in 1979, but did not receive approval by the U.S. Food and Drug Administration (FDA) for Type 2 diabetes until 1994 (U.S. Food and Drug Administration , December 30, 1994). Bristol-Myers Squibb’s Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995 (U.S. Food and Drug Administration, 2008). Generic formulations are now available.
Metformin absorption is relatively slow and may extend over about 6 hours.
Metformin is not bound with plasma protein. So its volume of distribution is high.
Metformin is not metabolized. Its main sites of concentration are the intestinal mucosa and the salivary glands. The plasma concentration at steady-state ranges about 1 to 2 µg/mL.
The drug is excreted in an unchanged form in urine at high renal clearance rate of about 450 mL/min. The initial elimination of metformin is rapid with a half-life varying between 1.7 and 3 hours. The terminal elimination phase accounting for about 4 to 5 % of the absorbed dose is slow with a half-life between 9 and 17 hours.
Metformin is a biguanide derivative producing an antihyperglycemic effect which can only be observed in man or in the diabetic animal and only when there is insulin secretion. Metformin, at therapeutic doses, does not cause hypoglycemia when used alone in man or in the non-diabetic animal, except when using a near lethal dose. Metformin has no effects on the pancreatic beta cells. It has been postulated that metformin might potentiate the effect of insulin or that it might enhance the effect of insulin on the peripheral receptor site. This increased sensitivity seems to follow an increase in the number of insulin receptors on cell surface membranes (Roussel HM, 2007).
1.17. Mechanisms of action of metformin:
Currently proposed mechanisms of action include:
Direct stimulation of glycolysis in tissues, with increased glucose removal from blood;
Reduced hepatic & renal gluconeogenesis;
Slowing of glucose absorption from the gastrointestinal tract, with increased glucose to lactate conversion by enterocytes; &
Reduction of plasma glucagons levels (Karam JH et al, 2004).
1.18. Benefits of metformin:
PREVENTION OR DELAY OF ONSET OF DIABETES:
Type 2 diabetes is the most common type of diabetes. It is also sometimes called adult-onset diabetes or noninsulin-dependent diabetes. Type 2 diabetes is a condition involving insulin resistance. With insulin resistance, the cells of the body do not respond to insulin as well as they normally should. As a result, the cells of the body do not remove sugar from the blood very well. This is why type 2 diabetics have high blood sugar.
Over time, high blood sugar can lead to a number of problems, including diabetic impotence, diabetic neuropathy, kidney failure, and heart disease. The cause of type 2 diabetes is not fully understood, although it is known that obesity and genetics play an important role.
There are many ways to treat high blood sugar in people with type 2 diabetes. Some diabetes medications force the pancreas to produce more insulin. These medications are effective, but can cause dangerously low blood sugar (hypoglycemia). Metformin works differently, having several effects in the body. The drug lowers blood sugar by the following actions:
• Decreasing the amount of sugar (glucose) made by the liver
• Decreasing the amount of sugar absorbed into the body (from food)
• Making insulin receptors more sensitive, helping the body responds better to insulin (Lauderdale FL, 2005; Princeton NJ, 2006; Menlo Park CA, 2006; Jacksonville FL, 2004).
REDUCED RISK OF GESTATIONAL DIABETES:
Gestational diabetes is diabetes that is found for the first time when a woman is pregnant. It is one of the most common health problems for pregnant women. The condition affects about 5 percent of all pregnancies, which means there are about 200,000 cases each year. If not treated, gestational diabetes can cause health problems for the mother and the fetus (Lauderdale FL, 2005; Princeton NJ, 2006; Menlo Park CA, 2006; Jacksonville FL, 2004).
In another study at Jewish Hospital in Cincinatti, gestational diabetes risk was evaluated in two groups of Polycystic Ovarian Syndrome (PCOS) women. The first group was 33 non-diabletic women who had conceived while taking metformin or took it during their pregnancy. This group was compared to a group of 39 PCOS women who did not take it. Only 3% of the metformin group developed gestational diabetes as compared to 31% in the non-metformin group (Glueck CJ et al, 2002).
LOWERING OF INSULIN, TESTOSTERONE, AND GLUCOSE LEVELS:
Quite a number of studies indicate Glucophage reduces insulin, testosterone and glucose levels — which reduces acne, hirsutism, abdominal obesity, amenorrhea and other symptoms. In one study conducted at Virginia Commonwealth University, 24 obese PCOS women were given metformin or placebo. The 11 women who received the metformin experienced a reduction in insulin levels, which slowed the activity of an enzyme in the ovaries that stimulates excess production of testosterone. As a result, testosterone levels also dropped ( Nestler JE et al, 1996).
Metformin ER can suppress the TSH level with no accompanying symptoms of hyperthyroidism or changes in measured thyroid hormone levels (Vigersky RA et al, 2006).
Metformin ER appears to do the same for non-obese PCOS women, according to a study from the University of Medical Sciences in Poznan, Poland. Thirty nine PCOS women were given it for 12 weeks. They had improvements in insulin, testosterone, hirsutism and acne (Kolodziejezyk B et al, 2000).
RESTORATION OF NORMAL MENSTRUAL CYCLE:
A number of studies have shown that menstruation can be restored in many women with PCOS. For example, in a study at Jewish Hospital in Cincinnati, 43 women who were not having periods took Glucophage, and 39 of them resumed normal menses (Glueck CJ et al, 1999). In another study at Jewish Hospital, 11 teenage girls with PCOS were put on metformin and a high-protein, low-carbohydrate diet. Ten of the 11 girls resumed regular periods (Glueck CJ et al, 2001).
IMPROVED CHANCE OF PREGNANCY:
Metformin is generally considered safe to take during pregnancy (Briggs GG et al, 2005).A study of 48 women with PCOS and infertility was conducted at the Baylor College of Medicine. They were first given metformin and 19 of them resumed menstruating and showed indications of ovulation. But 10 required clomiphene (a fertility drug) in addition to metformin in order to show evidence of ovulation. Twenty women of the 48 (42%) became pregnant. However, 7 of the 20 miscarried (Heard MJ et al, 2002).
Metformin can be used by women who are breastfeeding. There are three published studies of metformin in breast milk. The milk:serum or milk:plasma ratio varied between 0.18 and 1.00, while the estimated mean infant dose as a percentage of the mother’s weight-adjusted dose varied between 0.18% and 1.08%. This dose is much less than the usual 10% level of concern (Briggs GG et al, 2005). Women can be reassured that it is unlikely that there will be any significant effect on their babies. In particular, there is no risk of neonatal hypoglycaemia, in contrast to the use of drugs stimulating insulin release, such as the sulfonylureas. Maintenance of maternal euglycaemia during lactation remains an important principle to reduce the risk of subsequent obesity in the child (Plagemann A et al, 2002).
METFORMIN USE IN CHILDREN:
Metformin is approved for use in children who are at least 10 years old. The long acting form, metformin ER, is approved for use in individuals who are age 17 or older. Talk to your healthcare provider about the benefits and risks of using metformin for type 2 diabetes in children (Lauderdale FL, 2005; Princeton NJ, 2006; Menlo Park CA, 2006; Jacksonville FL, 2004).
WEIGHT LOSS AND OTHER BENEFITS:
Metformin may contribute to weight loss in some diabetics (Greenway F, 1999). However, weight loss does not appear to be one of its primary benefits. Metformin may also be of some value improving success with in vitro fertilization, lowering cholesterol, and improving energy.
1.19. Side Effects of Metformin:
About 3 of every 100,000 people who take metformin will develop a medical emergency called “lactic acidosis”. Lactic acid is a metabolic byproduct that cans become toxic if it builds up faster than it is neutralized. Lactic acidosis is most likely to occur in people who with diabetes, kidney or liver disease, multiple medications, dehydration, or severe chronic stress.
Lactic acidosis can gradually build up. Symptoms to watch for include a need to breathe deeply and more rapidly, a slow, irregular pulse, a feeling of weakness, muscle pain, sleepiness, and a sense of feeling very sick. Treatment requires intravenous administration of sodium bicarbonate. Contact with the doctor or go immediately to a hospital emergency room if they have these symptoms (Boss A et al, 2001; Salpeter S et al, 2003).
10%- 25% of women who take metformin ER just don’t feel well. They experience a general malaise, fatigue and occasional achiness that last for varying lengths of time. Malaise a signal for the physician to closely monitor body systems affected by metformin, including liver, kidneys, and GI tract. A blood count should be taken from time to time, because metformin can induce B vitamin insufficiencies that can lead to a form of anemia.
The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea, vomiting and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs (Bolen S et al, 2007). In a clinical trial of 286 subjects, 53.2% of the 141 who were given immediate-release metformin (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo (Drug Facts and Comparisons, 2005).
Gastrointestinal upset can cause severe discomfort for patients; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common (Wulffele MG et al, 2003).
VITAMIN B12 MALABSORPTION:
Of patients who take this drug, 10%-30% show evidence of reduced vitamin B12 absorption. A substance formed in the stomach called “intrinsic factor” combines with B12 so that it can be transferred into the blood. Metformin interferes with the ability of their cells to absorb this intrinsic factor-vitamin B12 complex (Adams JF et al, 1983; Andrès E et al, 2002; Gilligan M, 2002).
Over the long term, vitamin B12 insufficiency is a significant health risk. B12 is essential to the proper growth and function of every cell in their body. It’s required for synthesis of DNA and for many crucial biochemical functions. There is also a link between B12 insufficiency and cardiovascular disease (Ting R et al, 2006).
At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people (McCarty MF, 2000). The apparent cause is continued problems with availability of intrinsic factor, which is required for B12 absorption.
People who take metformin ER tend to have higher homocysteine levels (Desouza C et al, 2002). Women with PCOS also tend to have elevated homocysteine (Vrbikova J et al, 2002).
Homocysteine is an amino acid in the blood. A normal amount is OK. But an elevated level means that your metabolic processes are not working properly. Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia, (Regland B et al, 1997) cognitive impairment (Parsons RB et al, 1998), and cervical cancer (Weinstein SJ et al, 2001).
Vitamin B12, along with vitamin B6 and folic acid (another B vitamin), is responsible for metabolizing homocysteine into less potentially harmful substances (Selhub JF, 2002). Therefore, when metformin reduces absorption of vitamin B12, you lose one of the nutrients needed to reduce homocysteine and thus reduce the risk of cardiovascular disease.
ELEVATED HOMOCYSTEINE & PREGNANCY COMPLICATIONS:
Pre-eclampsia is a complication of pregnancy characterized by increasing blood pressure and edema. If left untreated, pre-ecampsia can lead to eclampsia, a serious condition that puts you and your baby at risk. In a study conducted at the Center for Perinatal Studies at Swedish Medical Center in Seattle, a second trimester elevation of homocysteine was associated with a 3.2 fold increased risk of pre-eclampsia (Sorensen TK et al, 1999).
The Dept. of Obstetrics and Gynecology, Nijmegen, The Netherlands, reviwed a series of studies on the linkage between elevated homocysteine and early pregnancy loss. They concluded that high homocysteine levels are a risk factor for recurrent early pregnancy loss (Nelen WL et al, 2000).
Ovarian follicular fluid contains detectable amounts of homocysteine along with B12, B6, and folic acid. The follicular fluid provides nourishment to the egg by facilitating transport of nutrients from blood plasma. High levels of homocysteine as well as an insufficiency of B vitamins may adversely influence the process of fertilization and early fetal development (Steegers-Theunissen RP et al, 1993).
Many women use metformin ER in their pursuit of a successful pregnancy. However, it is a category B drug, meaning its safety for use while pregnant has not been established. It is found in breast milk so it’s not advisable to breast feed while taking metformin.
By preventing optimal absorption of vitamins B12 and folic acid, metformin could induce or contribute to megaloblastic anemia (Callaghan TS et al, 1980). Megaloblastic anemia occurs when patient’s bone marrow doesn’t have enough B vitamins to manufacture red blood cells. Their bone marrow then releases immature and dysfunctional red blood cells into circulation.
Although anemia is not common among people taking metformin, it remains a risk for those whose B12 and folic acid levels were already low when metformin therapy was started.
LIVER OR KIDNEY PROBLEMS:
If patients have liver or kidney problems of any kind, metformin could pose a problem, because it alters liver function and is excreted through the kidneys. A healthy liver and kidneys will improve their outcome with metformin. Liver and kidney function should be assessed before starting metformin and rechecked at least once a year while taking it. A blood chemistry screen and a complete blood count will tell the physician how well their system is doing with this drug.
Patients may be at risk for health problems or symptoms if they take metformin in addition to other medications. The more drugs they take, and the higher the dosage, the greater the probability there will be some kind of interaction between the drugs or some unexpected effect from the combined drugs. The effect of combined drugs also depends on the state of their health, genetic uniqueness, and diet and lifestyle. Always consult with the doctor if they add or change any medication, or if they develop any symptoms.
Metformin may contribute to male pattern hair loss at the temples and top of head. Although there’s nothing in the medical literature to support this linkage, some women have reported that hair loss was made worse by metformin (Boss A et al, 2001).
Bile is produced by the liver, stored in the gallbladder, and secreted into the intestines in order to absorb fats into the bloodstream. One possible reason for the GI problems is that metformin reduces normal reabsorption of bile from the intestines back into the bloodstream, which causes elevated bile salt concentrations in the colon (Scarpello JH et al, 1998). Most studies suggest that colonic bile salts cause free radical damage to DNA and may contribute to colon cancer (Allgayer H et al, 2002; Barone M et al, 2002).
In addition, bile acids may stimulate cells in the colon to produce leukotriene B4 (LTB4), a highly inflammatory substance. LTB4 would be a contributor to any intestinal inflammatory condition (Dias VC et al, 1994). Byproducts of bacterial action on bile salts may lead to intestinal cell damage and absorption of “foreign” molecules such as food or bacteria particles into the bloodstream, possibly causing allergies and other immune responses (Fegundes-Neto U et al, 1981).
Moreover, many PCOS women have switched to a high-protein diet. If that protein consists of beef and other meats, bile acid concentration in the intestines is increased (Goldin BR et al, 1994). A diet high in meats is also linked to a higher risk of colon cancer.
Metformin is contraindicated in people with any condition that could increase the risk of lactic acidosis, including kidney disorders (creatinine levels over 150 μmol/l, [Jones G et al, 2003] although this is an arbitrary limit), lung disease and liver disease. Heart failure has long been considered a contraindication for metformin use, although a 2007 systematic review showed metformin to be the only anti-diabetic drug not associated with harm in people with heart failure (Eurich DTet al, 2007).
It is recommended that metformin be temporarily discontinued before any radiographic study involving iodinated contrast (such as a contrast-enhanced CT scan or angiogram), as contrast dye may temporarily impair kidney function, indirectly leading to lactic acidosis by causing retention of metformin in the body. It is recommended that metformin be resumed after two days, assuming kidney function is normal (Weir J, 1999; Thomsen HS et al, 2003).
A review of intentional and accidental metformin overdoses reported to Poison control centers over a 5-year period found that serious adverse events were rare, though elderly patients appeared to be at greater risk (Spiller HA et al, 2004). Intentional overdoses with up to 63 g of metformin have been reported in the medical literature (Gjedde S et al, 2003). The major potentially life-threatening complication of metformin overdose is lactic acidosis. Treatment of metformin overdose is generally supportive, but may include sodium bicarbonate to address acidosis and standard hemodialysis or continuous venovenous hemofiltration to rapidly remove metformin and correct acidosis (Harvey B et al, 2005; Guo PY et al, 2006).
1.22. Combinations with other drugs:
Metformin is also available in combination:
Metformin/rosiglitazone (GlaxoSmithKline, 2002).
1.23. Metformin Drug Interactions
Metformin drug interactions with other medications (such as calcium channel blockers, and diuretics) can potentially lead to problems. Some of these drug interactions can make metformin less effective, increasing the chance of high blood sugar, or can increase the level of metformin in patient’s blood, increasing the risk of side effects. Therefore, be sure to talk to the doctor about any metformin drug interactions that may apply.
Some of the drugs that may lead to metformin interactions include:
• Calcium channel blockers, such as:
• Corticosteroids, such as:
• Diuretics, such as:
Chlorothiazide (Lexi-comp, Inc., 2007).
1.24. Some Metformin Warnings and Precautions:
Some metformin warnings and precautions to be aware of include:
• Very rarely, metformin may cause a life-threatening condition called lactic acidosis. The risk of lactic acidosis increases with other medical conditions, including congestive heart failure (CHF), kidney failure, and liver problems, including liver failure and cirrhosis.
• Drinking alcohol can increase the risk of lactic acidosis. Drinking large amounts of alcohol on a regular basis or drinking a large amount of alcohol at once (binge drinking) should be avoided while taking metformin.
• Since liver disease (including liver failure and cirrhosis) can increase the risk of lactic acidosis, they should not take metformin their liver is not functioning norm-ally.
• Their kidney function needs to be monitored while they are taking metformin. This means that they should have blood tests to check their kidneys before they start metformin and then at least once every year. If their kidney function is very poor, they should not take metformin due to increased risk of lactic acidosis.
• Fever, infections, injury, or surgery can temporarily increase your blood sugar, even in people with well-controlled diabetes. Metformin may not be enough to treat your diabetes at these times, and the use of insulin may be required. Contact with healthcare provider if they have a fever, infection, injury, or will be having surgery. Also, make sure they know the symptoms of high blood sugar and how to check their blood sugar levels.
• Metformin can decrease the levels of vitamin B12. The healthcare provider should monitor their vitamin B12 levels, especially if they have a vitamin B12 deficiency (including pernicious anemia).
• Metformin is considered a pregnancy Category B medication. This means that it is probably safe for use in pregnant women, although the full risks of metformin during pregnancy are not known. Talk to their healthcare provider before taking metformin during pregnancy.
• Metformin passes through breast milk. Therefore, if they are breastfeeding or plan to start breastfeeding, be sure to talk with their healthcare provider about this (Lauderdale FL, 2005; Princeton NJ, 2006; Menlo Park CA, 2006; Jacksonville FL, 2004).
Dissolution study was done with two samples of available market preparations & after that compared with another by calculating the percentages of release. Dissolution test was carried out in two medium such as 0.1N HCl for 2 hr & phosphate buffer (pH= 6.8) for 3 to 8 hrs. For this test, six vessel tablet dissolution tester PHARMA TEST Mo-del-DT 70 was used.
2.1. Dissolution Study for Metformin HCl 500 XR
The time takes for the drug to dissolve from the dosage form is dissolution time. Numerous factors affect dissolution. Thus the dissolution medium, agitation, temperature are carefully controlled. The dissolution medium may be water, simulated gastric juice. The temperature is usually 37.5°C. The apparatus & specifications may be found in the U.S.P.
The U.S.P. methods are official however there is a wide variety of methods based on other apparatus. These are used because they may be faster, cheaper, easier, sensitive to a particular problem for a particular drug, or developed by a particular investigator.
Dissolution tests are used as quality control to measure variability between batches which may be reflected by in vivo performance. Thus the in vitro test may be a quick method of ensuring in vivo performance. Thus there has been considerable work aimed at defining the in vitro/in vivo correlation.
2.3. Physicochemical & physiological factors affecting drug dissolution in the gastrointestinal tract:
There are various physicochemical & physiological factors that affecting drug dissolution in gastrointestinal tract are given below:
Table: 2.1. Factors affecting drug dissolution.
|Factor||Physicochemical parameter||Physiological parameter|
|Effect of surface area of drug||Particle size, wet ability||Surfactants in gastric juice & bile|
|Solubility in diffusion layer||Hydrophilicity, crystal structure, solubilization||PH, buffer capacity, bile, food components|
|Amount of drug already dissolved||Permeability, transit|
|Diffusivity of drug||Molecular size||Viscosity of luminal contents|
|Boundary later thickness||Motility patterns & flow rate|
|Volume of solvent available||Gastrointestinal secretions, co-administered fluids|
2.4. Drug Dissolution System:
A drug with slow dissolution rate will yield an inherently sustained blood level. In principle, then it would seem possible to prepare controlled release products by controlling the dissolution rate of drugs that are highly water soluble. This can be done by preparing an appropriate salt or derivative, by coating the drug with a slowly soluble material, or by incorporating it into a tablet with a slowly soluble carrier. Ideally, the surface area available for dissolution must remain constant to achieve a constant release rate.
So far we have looked at the transfer of drugs in solution in the GIT, through a membrane, into solution in the blood. However, many drugs are given in solid dosage forms, & therefore must dissolve before absorption can take place.
If absorption is slow relative to dissolution then all we are concerned with is absorption. However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process. This is a more common problem with drugs which have a low solubility (below 1g/100 ml) or which are given at a high dose, e.g. griseofulvin (Robinson JR et al, 2005).
Table: 2.2. Materials used in project work.
|Serial no.||Name||Category||Source||Country of origin|
|1||Metformin HCl||Active Drug||Maneesh pharmaceuticals pvt. ltd||India|
|2||Comet 500 XR||Tablet (Market preparation)||Square pharmaceuticals ltd.||Bangladesh|
|3||Glucomet 500 XR||Tablet (Market preparation)||Aristopharma ltd.||Bangladesh|
Table: 2.3. List of Instruments & Equipments used in Experiment.
|1||UV- Visible Spectrophotometer|| HACH Spectrophotometer.|
|2||Tablet Dissolution Tester|| PHARMA TEST|
|3||Electric Balance|| Denver Instrument|
|4||PH Meter||LIDA Instrument Model-PHS-25|
Table: 2.4. List of Apparatus/Glass wares used in this Project.
|Serial No||Name||Serial No||Name|
|1||Plastic container (10 L)||8||Measuring flask (1000ml)|
|3||Volumetric flask (50ml & 100ml)||10||Disposable syringes (10ml)|
|4||Volumetric pipette||11||Glass rod|
|7||Measuring cylinder (25ml, 50ml, 1000ml)||14||Mortar & pastels|
Table: 2.5. List of reagents & Solvents.
|Serial No.||Name||Source||Country of origin|
|1||Potassium dihydrogen ortho phosphate||Technopharma||Bangladesh|
|3||Concentrated HCl (37%)||Merck||Germany|
|4||Purified water||Research Laboratory||Bangladesh|
2.6.1. Preparation of Dissolution Media:
188.8.131.52. Purified Water:
Purified water in bulk is prepared by distillation or by any other suitable method from water that complies with the regulations on water intended for human consumption laid down by the competent authority.
184.108.40.206. Preparation of 0.1N HCl:
For preparing 7L 0.1N HCl, 69.02ml of 37% conc. HCl was taken in a plastic container & then purified water was added up to 7L.
220.127.116.11. Preparation of Phosphate buffer:
For preparing 9L phosphate buffer, 61.2g of potassium dihydrogen ortho phosphate (K H2 PO4) was taken in a plastic container, dissolved in & diluted with distilled water up to the mark & then NaOH solution was added for pH (6.8) adjust.
2.7. Methods of dissolution study:
The dissolution of metformin HCl XR tablets from market preparation was monitored using standard BP apparatus paddle equipment with the tablet positioned 3mm above the bottom & UV spectrometer, at 232 nm. The compendially recommended stirring speed of 100 rpm for the paddle apparatus was used. The temperature was maintained at 37±0.5°C throughout. The apparatus was within specification for all six positions with regard to shaft wobble, alignment, rotation speed, vibration & temperature. Firstly, 0.1N HCl (about 900ml) was taken into six vessels & for each run, 3 tablets of Square Pharma & 3 tablets of Aristo Pharma were placed into six vessels respectively for 2 hr. These tablets were tested in basic buffer for 3to 8 hrs. At every interval, 10ml samples were withdrawn from the dissolution medium & 10ml of fresh buffer solution was added to each glass vessel to compensate the volume loss. The process was performed for 8 hrs to get a simulated picture of the drug release in the in vivo condition. The amount of drug released from the samples was then calculated with the help of appropriate calibration curve constructed from reference standard.
2.8. Assay Method:
Drug content of the sample solution i.e., the quantity of drug released in the dissolution medium from the metformin HCl XR tablet was determined after appropriate dilution (where necessary) by spectrophotometric analysis using a UV-Visible spectrophotometer, at 232 nm. 0.1N HCl & Phosphate buffer were used as the blank solution. From each value of absorbance, the concentration of the corresponding sample solution was calculated by using the equation of the standard curve for metformin HCl & then the amount of drug released in each vessel was determined. The percentages of drug release from the tablets were then calculated & plotted against time.
2.9. Theory of standard curve preparation:
The greater the number of molecule capable of absorbing light of a given wave length. The greater will be the extent of light absorption. Furthermore, the more effective a molecule is in absorbing light of a given wave length, the greater will be the extent of light absorption. From these guiding ideas the following empirical expression, which is known as the Beer-Lambert law, may be formulated:
Log (Io/I) = ε C l for a given wave length.
Io=Intensity of the light incident upon the cell.
I= Intensity of the light leaving the sample cell.
C=Molar concentration of solute.
L=Length of sample cell (cm).
2.9.1. Preparation of standard curve of metformin HCl:
- In case of Acidic Media:
- 50mg pure metformin HCl powder was dissolved in 0.1N HCl & made the
volume 100ml. So the concentration was 500μg/ml. It is called stock solu-
2. Different concentration of 5μg/ml, 10μg/ml, 15μg/ml, 20μg/ml, 25μg/ml,
30μg/ml, 35μg/ml were done to prepare a standard curve.
- To prepare these concentrations 1, 2, 3, 4, 5, 6, & 7ml of stock solution were taken, & made the volume 100ml with 0.1N HCl.
- The absorbance of these standard solutions of different concentration was measured at 232nm to construct the standard curve.
- In case of Basic Media:
1. 50mg pure metformin HCl powder was dissolved in phosphate buffer &
made the volume 100ml. So the concentration was 500μg/ml. It is called
2. Different concentration of 2μg/ml, 4μg/ml, 6μg/ml, 8μg/ml, 10μg/ml
were done to prepare a standard curve.
- To prepare these concentrations 0.4, 0.8, 1.2, 1.6, & 2ml of stock solution were taken, & made the volume 100ml with phosphate buffer.
- The absorbance of these standard solutions of different concentration was measured at 232nm to construct the standard curve.
Table: 2.6. Absorbance of Metformin HCl for different concentration of standard solution (Acidic Media).
|Concentration (μg/ml)||Absorbance (232nm)|
Table: 2.7. Absorbance of Metformin HCl for different concentration of standard solution (Basic Media).
|Concentration (μg/ml)||Absorbance (232nm)|
Metformin HCl is required 500 mg, 2 or 3 times daily in conventional dosage form. Sometimes the number and the frequency of doses are required to increase considering disease state. Repeated medication via rapid absorption causes side effects and toxicities along patient non-compliance and nocturnal harassment can be avoided by administering metformin HCl extended release dosage form, preferably once daily.
The influence of dissolution media on the release rate was significant found to be highest in phosphate buffer than in acidic media. The release data were then treated in different mathematical model to identify the release mechanism.
The approach of the present study was to make a comparative evaluation among the percent of drug release of two sample of metformin HCl XR tablets from two different companies. The study reveals the release of metformin HCl (water soluble drug) in acidic & basic media. The data generated in this study also shows that, the release pattern of drug closer to zero order & Higuchi release mechanism.
From the above discussion, the experiment indicates that, metformin HCl XR tablet delivered drug at desired rate. The rate and extent of drug release of different companies were different but was fully meet the BP specification.
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