Dept. of Pharmaceutics, Viswanadha Institute of Pharmaceutical Sciences
The aim of the present study was to formulate and evaluate sustained release tablets of tranexamic acid. Xanthan gum and Guar gum were used as release rate controlling polymers. The prepared formulation mixtures were evaluated for preformulation parameters like bulk density, tapped density, angle of repose, Carr’s index and Hausner’s ratio. All the drug mixtures have shown the results within the limits. FTIR studies revealed that there are no incompatibilities among the formulation ingredients. The post compression parameter results of all the prepared tablets were found to be within the limits. The tablet releases the drug immediately without polymer. As the polymer concentration increases the rate of drug release decreases. The GF4 formulation containing 250 mg of Tranexamic acid, 150 mg of guar gum along with excipients, has sustained the release of drug for a period of 12 hours. GF4 formulation has shown the drug release of 100.0% in 12 hrs. The formulation, XF5 with drug:Xanthan gum 1 : 0.8 has shown 99.45% drug release in 12 hrs whereas the formulation, GF4 with drug : Guar gum 1 : 0.6 has shown 99.90% drug release in 12 hrs. Hence, the formulation GF4 containing less quantity of polymer was considered as optimized formulation with 99.90% drug release in 12 hrs. So, Guar gum is showing more drug release retardant property than Xanthan gum in the formulation of tranexamic acid SR tablets.
Oral sustained release systems continue to dominate the market despite the advancements made in other drug delivery systems in order to increase the clinical efficacy and patient compliance. From a practical pharmaceutical view point, numerous types of polymers are currently employed to control the drug release from the pharmaceutical dosage form. Oral sustained release systems are mainly grouped into three types, e.g. reservoir, monolithic and matrix types. Among these hydrophilic matrix tablets are preferred in the formulations since most display good compression characteristics, even when directly compressed and have adequate swelling properties that lead to a rapid formation of external layer, allowing drug release modification. Different natural gums and mucilages have been examined as polymers for sustained drug release, in the last few decades. The physical and structural properties and the drug release mechanisms and kinetics of these sustained release preparations determine the in vivo performance of these dosage forms. Now a day’s conventional dosage forms of drugs are rapidly being replaced by the new and the novel drug delivery systems. Amongst, these the controlled release/sustained release dosage forms have become extremely popular in modern therapeutics. Sustained release constitutes any dosage form that provides medication over an extended time or denotes that the system is able to provide some actual therapeutic control whether this is of a temporal nature, spatial nature or both.
A sustained release dosage form will provide a therapeutic concentration of the drug in the blood that is maintained throughout the dosing interval with a reduction in a peak concentration ratio. A sustained release dosage form will provide a therapeutic concentration of the drug in the blood that is maintained throughout the dosing interval with a reduction in a peak concentration ratio. Sustained release system generally do not attain zero order type release and usually try to mimic zero order release by providing drug in a slow first order. Repeat action tablets are an alternative method of sustained release in which multiple doses of drug are an alternative method of sustained release, are contained within a dosage form and each dose is released at a periodic interval. Delayed release system, in contrast, may not be sustaining, since often the function of these dosage forms is to maintain the drug in the dosage form for some time before release. A sustained release dosage form will provide a therapeutic concentration of the drug in the blood that is maintained throughout the dosing interval with a reduction in a peak concentration ratio. The term controlled release has become associated with those systems from which therapeutic agents may be automatically delivered at predetermined rates over a long period of time. Products of this type have been formulated for oral, injectable and topical use and inserts for placement in body cavities. Controlled release systems also denotes systems which can provide some control whether this be of a temporal or spatial nature or both, of drug release in the body. The system attempts to control drug concentrations in the target tissues or cells. Prolonged or sustained release systems only prolong therapeutic blood or tissue levels of the drug for an extended period of time. Sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. If the system is successful in maintaining constant drug levels in the blood or target tissue it is considered as controlled release system. If it is unsuccessful at this but nevertheless extends the duration of action over that achieved by conventional delivery, it is considered a prolonged release system. The oral route of administration for sustained release systems has received greater attention because of more flexibility in dosage form design. The design of oral sustained release delivery systems is subject to several inter related variables of considerable importance such as the type of delivery system, the disease being treated, the patient, the length of therapy and the properties of the drug.
Advantages:
Disadvantages
Limitations
Characteristics suitable for sustained release drug delivery system (DDS)
Physico-chemical characteristics2
For orally administered systems, there is an upper limit to the bulk size of the dose to be administered. In general, a single dose of 0.5-1.0 gm is considered maximal for a conventional dosage form. This also holds for sustained-release dosage forms. Those compounds that require large dosing size can sometimes be given in multiple amounts or formulated into liquid system. Another consideration is the margin of safety involved in administration of large amounts of a drug with narrow therapeutic range.
Compounds with very low solubility (less than 0.01mg/ml) are inherently sustained, since their release over the time course of a dosage form in the GI tract will be limited by dissolution of the drug. The lower limit for the solubility of a drug to be formulated in a sustained-release system has been reported to be 0.1mg/ml, so it is obvious that the solubility of the compound will limit the choice of mechanism to be employed in sustained delivery system. Diffusion systems will be poor choices for slightly soluble drugs, since the driving force for diffusion, which is the drug's concentration in solution, will be low.
When a drug is administered to the GI tract it must cross a variety of biological membranes to produce a therapeutic effect in another area of the body. It is common to consider that these membranes are lipidic, therefore, the partition coefficient of oil soluble drugs becomes important in determining the effectiveness of membrane barrier penetration. Partition coefficient is generally defined as the ratio of the fraction of drug in an oil phase to that of an adjacent aqueous phase. Accordingly, compounds with a relatively high partition coefficient are predominantly lipid-soluble and, consequently, have very low aqueous solubility.
d. Stability
Orally administered drugs can be subjected to both acid-base hydrolysis and enzymatic degradation. Degradation will proceed at a reduced rate for drugs in the solid state; therefore, this is the preferred composition of delivery for problem cases. For drugs that are unstable in the stomach, systems that prolong delivery over the entire course of transits in the GI tract are beneficial; likewise, for systems that delay release until the dosage form reaches the small intestine. Compound that is unstable in the small intestine may demonstrate decreased bioavailability when administered from a sustaining dosage form. This is because more drug is delivered in the small intestine and, hence, is subjected to degradation.
e.Protein Binding
It is well known that many drugs bind to plasma proteins with concomitant influence on the duration of drug action. Drug protein binding can serve as the depot for drug producing a prolonged release profile, especially if high degree of drug binding occurs. There are, however, other drug - protein interactions that have bearing on drug performance.
f. Drug pKa and pH
Drugs existing largely in ionized form are poor candidates for oral sustained release drug delivery system. Absorption of the unionized drugs are well whereas permeation of ionized drug is negligible because the absorption rate of ionized drug is 3-4 times less than that of the unionized drug. The pKa range for acidic drug whose ionization is pH sensitive is around 3.0-7.5 and pKa range for basic drug whose ionization is pH sensitive is around 7.0-11.0 are ideal for optimum positive absorption. Drug shall be unionized at the site to an extent 0.1-5.0%. If drug is administered in extended release dosage form that are unstable in small intestine may demonstrate decreased bioavailability. This occurs due to the fact that a greater quantity of drug is delivered in small intestine and is being subjected to more degradation.
g. Molecular size and diffusivity
Diffusivity depends on size & shape of the cavities of the membrane. The diffusion coefficient of intermediate molecular weight drug is 100-400 Daltons; through flexible polymer range is 10-6 – 10-9 cm2/sec. For drugs having molecular weight > 500 Daltons, the diffusion coefficient in many polymers are very less i.e. less than 10-12 cm2/sec. The examples of drugs which is difficult to control release rate of medicament from dosage form are proteins and peptides.
Biological characteristics
The elimination rate is quantitatively described by the half-life. Therapeutic compound with short halflives are excellent candidates for sustained release preparations, since this can reduce dosing frequency. However, this is limited, in that drug with very short half-lives may require excessively large amounts of drug in each dosage unit to maintain sustained effect, forcing the dosage form itself to become limitingly large. In general, drugs with half-lives shorter than 2 hours are poor candidates for sustained-release preparations. Compounds with long half-lives, more than 8 hours, are also generally not used in sustaining forms, since their effect is already sustained.
The characteristics of absorption of a drug can greatly affect its suitability as a sustained-release product. Since the purpose of forming a sustained release product is to place control on the delivery system, it is necessary that the rate of release much slower than the rate of absorption. If we assume that the transit time of most drugs and devices in the absorptive areas of the GI tract is about 8-12 hours, the maximum half-life for absorption should be approximately 3-4 hours; otherwise, the device will pass out of the potential absorptive regions before drug release is complete. This corresponds to a minimum apparent absorption rate constant of (0.17-0.23 hours-1) to give 80-95% over this time period. The absorption rate constant is an apparent rate constant, and should, in actuality, be the release rate constant of the drug from the dosage form. Compounds that demonstrate true lower absorption rate constants will probably be poor candidates for sustaining system.
The distribution of drugs into tissue can be an important factor in the overall drug elimination kinetics since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibration with blood and extracellular fluid. One aspect of this distribution is binding of drug to tissue and proteins in blood. The apparent volume of distribution of a drug is frequently used to describe the magnitude of distribution, including binding, within the body.
For design of sustained/controlled release products one would like to have as much information on drug disposition as possible but, in reality, decisions are usually based on only a few pharmacokinetic parameter, one of which is the apparent volume of distribution. Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzyme systems are saturable. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during specific period, allowing more complete conversion of the drug to its metabolites. Formulation of these enzymatically susceptible compounds as prodrugs is another viable solution.
d. Therapeutic index
Drugs with low therapeutic index are unsuitable for incorporation in sustained release formulations. If the system fails in the body, dose dumping may occur, which leads to toxicity.
Size of dose:
If the dose of a drug in the conventional dosage form is high, then it is less suitable candidate forsustained release drug delivery systems (SRDDS). This is because the size of a unit dose Sustained release oral formulation would become too big to administer without difficulty.
e.Absorption window
Design and formulation of SRDDS
The majority of oral sustained 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 sustained 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. Sustained (zero-order) drug release has been attempted to be achieved, by following classes of sustained drug delivery system.
A. Diffusion sustained system
B. Dissolution sustained system
C. Methods using Ion-exchange
D. Methods using osmotic pressure
E. pH independent formulations
F. Altered density formulations
A. Diffusion sustained 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.
Reservoir type:
In the system, a water insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media.
Characterization
Description:
Advantages:
Disadvantages:
Matrix type:
A solid drug is dispersed in an insoluble matrix and the rate of release of drug is dependent on the rateof 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 –eCs] Cst
Where;
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
Characterization
Description:
Homogenous dispersion of solid drug in a polymer mixture.
Advantage:
Disadvantage:
Release rate = AD / L = [C1- C2 ]
Where,
A = Area
D = diffusion coefficient
C1 = Drug concentration in the core
C2 = Drug concentration in the surrounding medium
L = diffusional path length
Thus diffusion sustained 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 sustained 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.
Reservoir type:
ii) Matrix type:
The more common type of dissolution sustained dosage form. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion.
Two types of dissolution- sustained pulsed delivery systems:
C. Methods using ion exchange:
It is based on the formation of drug resin complex 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 - + Cl- goes to Resin-Cl- + Drug-, where x- is cl-, conversely
Resin-- Drug + + Na+ goes to Resin- Na+ + Drug+
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 sustained 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 sustained by coating the drug resin complex by microencapsulation process.
D. Methods using osmotic pressure:
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.
Two types of osmotically sustained systems are
E. pH– independent formulations:
F. Altered density formulations:
These are as follows.
Evaluation of sustained release tablets
Before marketing a sustained 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 the correlation between two.
1. In – vitromethods
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
3. Stability studies :
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 sustained 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 sustained release product useless. The in-vitro and in-vivo release rates of sustained release product may be altered by atmospheric or accelerated conditions such as temperature & humidity. The stability programmes of a sustained 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 vivocorrelations
The requirement of establishing good in-vitro in-vivo correlation in the development of sustained 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 sustained 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 sustained 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-vivo in-vitro correlation factor is derived.
Levy has classified in-vivo – in-vitro correlation in to:
While most of the published correlations are of semi-quantitative nature, the most valuable are those based on absorption kinetics.
Bioavailability testing:
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. 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 sustained 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.
Regulatory requirements:
In India, the sustained release drug products in legal sense are considered to be "New Drugs" as per the Drugs and Cosmetic Act 1940, and Rules there under, 1945. The guidelines and requirements are given under the schedule 'Y.1,2
Description of fibrinolysis
Until the 1990s investigations of the fibrinolytic system were focused mainly on the study of the mechanisms of activation of plasminogen (Pg) and plasminmediated degradation of intravascular fibrin depositions, probably because for a long time it was wellknown that impairments in this system are associated with bleedings or thrombotic complications in patients. However, in the last decade, when methods of gene inactivation in mice were applied for the study of the physiological role of proteins, it became evident that functions of components of the fibrinolytic system are not restricted to the dissolution of fibrin. Now the participation of this system in the regulation of cellular activity and tissue development is under intensive exploration. Fibrinolysis is a key component of the haemostatic processes that maintain patency of the vascular system. Circulating plasminogen is converted to the serine protease plasmin by the enzyme tissue plasminogen activator (tPA), causing the breakdown of fibrin to fibrin degradation products (FDPs). Fibrinolysis is regulated by a complex series of interactions and feedback mechanisms.
Fibrinolysis has been implicated in the pathogenesis of coagulopathy after severe tissue damage, or trauma. It is postulated that hypoperfusion, hypoxia, and up-regulation of tPA contribute to drive the balance of haemostasis towards ‘hyperfibrinolysis’ and subsequent coagulopathy. Plasmin also activates monocytes, neutrophils, and the complement pathway, leading to the development of inflammation and is not simply involved in fibrinolytic systems. This highlights the close interaction between coagulation, inflammation, and immunological processes as part of the host defence mechanism. Fibrinolysis can be monitored via changes in blood markers (e.g. D-dimer, FDPs, Plasminogen activator inhibitor-1), by measuring the euglobulin lysis time, or by viscoelastic tests (e.g. thromboelastometry, thromboelastography).
Main components of the fibrinolytic system
The fibrinolytic system comprises of a proenzyme (plasminogen), enzymes that proteolytically activate plasminogen, and several inhibitors that regulate activation of plasminogen, activity of plasmin, and stepwise degradation of fibrin.
The timing of antifibrinolytic therapy
Antifibrinolytic therapy functions primarily through the lysine binding site of plasminogen or plasmin by interfering with plasminogen activation or the effector mechanism of plasmin. The effect of t-PA is enhanced more than 400-fold in the presence of fibrin, therefore, to prevent locally excessive activity of t-PA and plasmin, antifibrinolytic drugs should optimally be present as the coagulation cascade, with its fibrin formation during CPB, is initiated. Otherwise, antiplasmin will instantly begin degrading plasmin, and the decreased concentration ofantiplasmin may contribute to excessive bleeding.3
Antifibrinolytics
These are the drugs which inhibit plasminogen activation and dissolution of clot.
It is an analogue of the amino acid lysine it combines with the lysine binding sites of plasminogen and plasmin so that the latter is not able to bind to fibrin and lyse it. It is a specific antidote for fibrinolytic agents and has been used in many hyperplasminaemic states associated with excessive intravascular fibrinolysis resulting in bleeding, e.g;
Like EACA, it binds to the lysine binding site on plasminogen and prevents its combination with fibrin and is 7 times more potent. It has been used for prevention of excessive bleeding in
It is a polypeptide isolated from bovine tissues with polyvalent serine protease inhibitory activity: trypsin, chymotrypsin, kallikrein and plasmin are inhibited. It can be administered only i.v. and has a half life of 2hr.
It has been employed in selected situations:
LITERATURE REVIEW
Prakash B. Mote et al.,has prepared sustained release tablets of Salbutamol sulphate matrix tablets, for the treatment of chronic obstructive pulmonary disease (COPD).To prepare the matrix tablets, different concentration of Hydroxy propyl methyl cellulose K100M (HPMC K100M), HPMC K15M and ethyl cellulose (EC)used. Prepared formulations were subjected to pre-compression parameters. Tablets were subjected to in-vitro drug release in 0.1 N HCl (pH 1.2) for first 2 hours followed by phosphate buffer (pH 6.8) for remaining 10 hours. In-vitro drug release followed zero order release kinetics obeying Higuchi mode of drug release. Swelling study suggested that when the matrix tablets come in contact with the dissolution medium, they take up water and swells, forming a gel layer around the matrix and simultaneously erosion also takes place.5
AfsarC. Shaikhet al., formulated was “once daily” sustained release tablets of aceclofenac (200mg) by wet granulation usinghydrophilic polymer like hydroxy propyl methyl cellulose K ?100. The drug excipient mixtures were subjected to preformulation studies. Results of the study indicated the suitability of hydrophilic polymers in the preparation of matrix based sustained release formulation of aceclofenac.6
KunalJ. Patilet al. Developed sustained release, matrix tablets of Ritonavir by using different polymers like hydroxyl propyl methylcellulose(K100M), Eudragit RS 100, chitosan, in different ratios. Formulations were compressed by wet granulation method. Drug in combination with chitosan were found to be effective in retarding the release of Ritonavir.7
Jin Sunet al., prepared azithromycin (AZI) sustained-release products inorder to allow for a high dose to be administered, reduce gastrointestinal side-effects and increase the compliance of patients. AZI sustained-release tablets with different release performance (F-I and F-II in pH 6.0 phosphate buffer) were successfully prepared by wet granulation. The in vitro release rate and drug release mechanism were studied. The release rate of F-I was affected by dissolution media with different pH, but not for F-II. Hixson Crowell model was the best regression fitting model for F-I and F-II. Additionally, F-I and F-II both belonged to non-Fick diffusion. Oral pharmacokinetics of the two tablets and one AZI dispersible tablet as reference were studied in six healthy beagle dogs after oral administration. Compared with the reference, the Cmax of F-I and F-II were decreased, and the Tmax were prolonged, in that case which meet therequirement of sustained-release tablet. The relative bioavailability of F-I and F-II were 79.12%and respectively. T-test ofAUC0e144, and AUC0eN for F-I and F-II indicated that there was no significant difference between F-I and F-II. These mean that the extended release rate did not induce different pharmacokinetics in vivo.8
N. Hingaweet al.,prepared sustained release tablets of cephalexin by using different polymers like HPMC K4M, HPMC K15M, HPMC K100M, HPMC K 100LV, ethyl cellulose, Carbopol 971P, Carbopol 974P, Eudragit RS100, Eudragit RL100 and Eudragit L100. The results of the studies indicated that the polymers used have significant release-retarding effect on the formulation. The results of the accelerated stability study of best formulation K4 for two months revealed no significant changes in formulation. It is concluded that Carbopol, Eudragit and HPMC were found to be suitable as bases for preparing tablet matrices containing cephalexin but only Carbopol 971and HPMC K4M were able to produce release profile similar to that of marketed preparation.9
Charu Bharti et al., studied different concentrations of natural and synthetic polymers on in vitro drug release from sustained release matrix tablets. The tablets were prepared by using diclofenac sodium with different polymers like HPMC K4M and acacia gum. The release mechanism of matrix tablet followed zero order release kinetics. The finding of current investigation clearly indicates that the synthetic polymer was given a more sustained release profile than natural polymer on different concentration.On comparing in vitro release of optimized formulation with marketed preparation, it was concluded that F3 was found to be more efficient and promising than marketed preparation.10
S. Lakshmana Prabhuet al., have prepared diltiazem HCl tablets by using direct compression method. Matrix tablets were prepared by using rosin as matrix forming material in different proportions and with different diluent combinations. The method of preparation of matrix system and its concentration were found to have pronounced effect on the release of diltiazem HCl. The release was found to follow both the first order kinetics and Fickian diffusion. The drug delivery was analyzed using the paddle method according to USP XXIII. The matrix tablets were evaluated. The results suggest that the rosin is useful in developing sustained release matrix tablets, prolong release of water soluble drug for up to 24h. Rosin thus promises considerable utility in the development of oral sustained releasedrug delivery system.11
Basavarajaet al.,formulatedtablets of flurbiprofen by using natural and syntheticpolymers. All the formulations showed compliance with Pharmacopeial standards. The release data was fitted to different mathematical models such as, Higuchi, Korsmeyer-Peppas, First-order and Zero order to evaluate the kinetics and mechanism of the drug release. The stability studies were carried out according to ICH guideline which indicates that the selected formulations were stable.12
K. J. Wadheret al., developed oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The data obtained was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.13
Kamlesh J. Wadher.et al., prepared floating matrix tablets of metformin HCl tablets by using HPMC K100M, Eudragit RL 100 as polymers and sodium bicarbonate as gas generating agent.Metformin HCl is an oral anti-diabetic drug and it comes under biguanide class. Absorption of the metformin HCl is limited to upper part of the GI tract and therefore its bioavailability from both immediate and sustained release marketed dosage forms is 50-60%. So,metformin is suitable for gastro retentive drug delivery system, which may improve bioavailability. The prepared formulations were evaluated for hardness, weight variation, friability and drug content, floating time and in vitro drug release characteristics. Comparison between optimized and marketed formulation by similarity factor (ƒ2) divulged similarity in release profile between both. Release kinetic study showed that all batches followed Fickian diffusion.14
V. N. Deshmukhet al.,the objective of this study was to design and evaluate oral sustained drug delivery system for Metoprolol succinate using natural hydrophilic gums such as karaya gum and xanthan gum as a release modifier. The kinetic treatment showed that the optimized formulation followed zero order kinetic with release exponent (n) 0.7656 and having good stability as per ICH guidelines. No chemical interaction between drug and gums was seen as confirmed by IR studies. The matrix formulation F8 showed sustained release of metoprolol succinate by the diffusion mechanism.15
D. Krishnarajan. et al., developed matrix tablets of levofloxacin for sustained release. Xanthan gum, guar gum, karaya gum are used as natural polymers and studied the effect of various formulation factors such as polymer proportion and effect of filler type on the in vitro release of the drug. Levofloxacin matrix tablets were prepared by direct compression technique with average weight of drug of 250 mg. The prepared tablets were evaluated for weight variation, friability, hardness, thickness and in vitro dissolution studies. All the granules of formulations showed compliance with Pharmacopoeial standards. From the in vitro dissolution studies it is clear that by increasing the amount of polymer drug release is decreased. The formulation F7 is selected as the optimized formulation by in vitro drug release for 12 hrs with the release of 99.26%. The kinetic treatment showed that mechanism of drug release followed non Fickian transport mechanism which having n < 1>
ShantveerV Salger.et al., studied the development of sustained release matrix tablets of anti-hypertensive drugPropranolol hydrochloride. Hydroxypropyl methyl cellulose K100M used as a rate retarding polymerwhereas lactose and dibasic calcium phosphate are used as diluents. The results of the present study point out that the rate ofPropranolol hydrochloride release from HPMC K100M matrices are mainly controlled by the drug –HPMC ratio. When the influence of excipients on the release of drug was examined, the excipientslactose enhanced the release rate of propranolol hydrochloride, however the dibasic calcium phosphate (DCP) demonstrated slower release rate. The prepared sustained release matrix tablets were evaluated for different parameters like hardness, friability, uniformity of weight, uniformity of drug content, in-vitro drug release and short term stability studies. The dissolution t50% and t90% values for the co-excipients were in the order of lactose>dibasic calcium phosphate.17
MATERIALS AND METHOD
Drug Profile18,19
Drug name : Tranexamic acid
Description : Antifibrinolytichemostatic used in severe haemorrhage
Synonyms : Acidetranexamique, Acidotranexamico, Acidumtranexamicum, Cyklokapron, Tranexamsaeure, Tranexmic acid, Tranexamic, Trans AMCHA, trans-4-(Aminomethyl)cyclohexanecarboxylicacid, trans-Amcha, trans-Tranexamic acid.
Structure
Molecular weight : Average: 157.2102
Monoisotopic: 157.11027872
Chemical formula : C8H15NO2
Melting point : >300 °C
Solubility : Soluble in water at 18.2 mg/mL
Absorption Absorption of tranexamic acid after oral administration in humans represents approximately 30 to 50% of the ingested dose and bioavailability is not affected by food intake.
Volumeof distribution : 9 to 12 L
Protein binding : The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen (does not bind serum albumin).
Metabolism : Only a small fraction of the drug is metabolized (less than 5%).
Route of elimination : Urinary excretion is the main route of elimination via glomerular filtration.
Half life : Biological half-life in the joint fluid is about 3 hours
Clearance : 110-116 ml/min
Mechanism of action
Tranexamic acid competitively inhibits activation of plasminogen (via binding to the kringle domain), thereby reducing conversion of plasminogen to plasmin (fibrinolysin), an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII. Tranexamic acid also directly inhibits plasmin activity, but higher doses are required than are needed to reduce plasmin formation.
Pharmacodynamics
Tranexamic acid is an anti-fibrinolytic that competitively inhibits the activation of plasminogen to plasmin. Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a non-competitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid. Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. Tranexamic acid in a concentration of 1 mg per mL does not aggregate platelets in vitro. In patients with hereditary angioedema, inhibition of the formation and activity of plasmin by tranexamic acid may prevent attacks of angioedema by decreasing plasmin-induced activation of the first complement protein (C1).
Indications and usage:
Tranexamic acid is indicated in patients with haemophilia for short-term use (two to eight days) to reduce or prevent haemorrhage and reduce the need for replacement therapy during and following tooth extraction.
Contraindications
Tranexamic acid
Injection is contraindicated
Adverse reactions
Gastrointestinal disturbances (nausea, vomiting, diarrhoea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 ml per minute.
Worldwide post marketing reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than haemorrhage prevention in patients with haemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined
Storage
Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°- 86°F)
Dosage
Adults
Injectable solution
100mg/mL
Dental extraction in patients with haemophilia
Indicated in patients with haemophilia for short-term use (i.e., 2-8 days) to reduce/prevent haemorrhage and reduce the need for replacement therapy during and following tooth extraction 10 mg/kg IV immediately before surgery 10 mg/kg IV q6-8hr 1 day before surgery 25 mg/kg PO q6-8hr 1 day pre-surgery 2-8 days post-surgery
Coronary artery bypass graft (CABG)
10-15 mg/kg IV over 20 minutes, 1 mg/kg/hr continuous infusion for 6-10 hrs.
Hereditary angioedema
Long-term prophylaxis:
1000-1500 mg per os (PO) q8-12hr; reduce dose to 500 mg/dose PO qDay or q12hr when frequency of attacks reduces.
Short term prophylaxis:
75 mg/kg/day PO divided q8-12hr for 5 days before and after the event.
Treatment of acute hereditary angioedema (HAE) attack:
25 mg/kg/dose PO/IV; not to exceed 1000 mg/dose q3-4hr; not to exceed 75 mg/kg/day or 1000 mg PO q6hr for 48 hr
Total knee replacement surgery, blood loss reduction
10 mg/kg IV over 30 min before inflation of tourniquet and 3 hr after first dose
Hyphema
25 mg/kg PO q8hr for 5-7 days
Renal impairment
Dental extraction
Paediatric
Injectable solution
100mg/mL
Dental Extraction in Patients with Haemophilia
10 mg/kg IV immediately before surgery 10 mg/kg IV q6-8hr 1 day before surgery
25 mg/kg PO q6-8hr 1 day pre-surgery 2-8 days post-surgery
Hyphema
25 mg/kg PO q8hr for 5-7 days
Hereditary Angioedema
Long term prophylaxis:
20-40 mg/kg/day PO divided q8-12hr; reduce dosing frequency to every other day or twice weekly when frequency of attacks reduces
Short term prophylaxis:
20-40 mg/kg/day PO divided q8-12hr; initiate 2-5 days before and continue for 2 days after the procedure
Uses:
This medication is used to treat heavy bleeding during your menstrual period. Tranexamic acid works by slowing the breakdown of blood clots, which helps to prevent prolonged bleeding. It belongs to a class of drugs known as antifibrinolytics.
XANTHAN GUM20
Description :
Xanthan gum occurs as a cream or white-colored, odourless, free lowing, fine powder.
Synonyms
Corn sugar gum; Keltrol, merezan; Polysaccharide B-1459; Rhodigel
Functional category :
Stabilizing agent, suspending agent, viscosity increasing agent
Molecular formula :
(C35H49O29) n
Molecular weight :
2 × 106 – 50 × 106 Daltons
Molecular structure :
Melting point :
270ºC
Ph :
7±1.5
Colour :
Cream or white-coloured powder
Solubility :
Practically insoluble in ethanol and ether, soluble in cold or warm water.
Source
Xanthan gum is a polymer prepared commercially on a large scale (>30,000 tons per year) by aerobic submerged fermentation from xanthomonascampestris. It is naturally produced to stick the bacteria to the leaves of cabbage-like plants. It is relatively expensive by weight but becoming rather less so. As the media used to grow the xanthomonas may contain corn, soy or other plant material, manufacturers should make clear if any residues may remain.
Stability and storage conditions
Xanthan gum is a stable material. Aqueous solutions are stable over a wide pH range (pH 3-12) and temperature between 10-60ºC. Solutions are also stable in the presence of enzymes, salts, acids and bases. The bulk material should be stored in a well-closed container in a cool, dry place.
Safety
Xanthan gum is used widely in oral and topical pharmaceutical formulations, cosmetics and food products and it is generally regarded as non-toxic and non-irritant at the levels employed as pharmaceutical excipients.
Incompatibility
Xanthan gum is an anionic material and is not usually compatible with cationic surfactants, polymers or preservatives. It is compatible with most synthetic and natural viscosity increasing agents.
Applications
Xanthan gum is widely used in oral and topical formulations, cosmetics, and foods as a suspending and stabilizing agent. It has also been used to prepare sustained release matrix.
GUAR GUM21
Non-proprietary names :
BP: Guar galactomannan
PhEur: Guar galactomannanum
USPNF: Guar gum
Synonyms :
E412, Galactosol; guar flour; jaguar gum; Meyprogat; Meyprodor; Meyprofin.
Chemical Name :
Galactomannan polysaccharide
Empirical Formula :
(C6 H12 O6)n
Molecular Weight :
2,20,000
Functional Category :
Suspending agent; tablet binder; tablet disintegrant; viscosity increasing agent.
Functional Category :
Suspending agent; tablet binder; tablet disintegrant; viscosity increasing agent.
Molecular structure
pH :
5.0-7.0
Solubility :
Practically insoluble in organic solvents. In cold or hot water, guar gum disperses and swells almost immediately to form a highly viscous, thixotropic sol.
Description
The USPNF 23 describes guar gum as a gum obtained from the ground endosperms of Cyamopsistetragonolobus (L.) Taub. (Fam. Leguminosae). It consists chiefly of a high-molecular weight hydrocolloidal polysaccharide, composed of galactan and mannan units combined through glycoside linkages, which may be described chemically as a galactomannan. The PhEur 2005similarly describes guargalactomannans being obtained from the seeds of Cyamopsistetragonolobus (L.) Taub by grinding the endosperms and subsequent partial hydrolysis. The main components are polysaccharides composed of D-galactose and D-mannose in molecular ratios of 1:1.4 to 1:2. The molecule consists of a linear chain of ?-(1,4)-glycosidically linked manno-pyranoses and single ?-(1,6)-glycosidically linked galacto-pyranoses. Guar gum occurs as an odorless or nearly odorless, white to yellowish-white powder with a bland taste.
Stability and storage conditions
Aqueous guar gum dispersions have a buffering action and are stable at pH 4.0–10.5. However, prolonged heating reduces the viscosity of dispersions. The bacteriological stability of guar gum dispersions may be improved by the addition of a mixture of 0.15% methylparaben and 0.02% propylparaben as a preservative. In food applications, benzoic acid, citric acid, sodium benzoate, or sorbic acid may be used. Guar gum powder should be stored in a well-closed container in a cool, dry place
Incompatibilities:
Safety:
Applications
Guar gum is a galactomannan, commonly used in cosmetics, food products, and pharmaceutical formulations. It has also been investigated in the preparation of sustained-release matrix tablets in the place of cellulose derivatives such as methylcellulose. In pharmaceuticals, guar gum is used in solid-dosage forms as a binder and disintegrant, in oral and topical products as a suspending, thickening, and stabilizing agent; and also as a controlled-release carrier. Guar gum has also been examined for use in colonic drug delivery. Guar-gum-based three-layer matrix tablets have been used experimentally in oral controlled-release formulations. Therapeutically, guar gum has been used as part of the diet of patients with diabetes mellitus. It has also been used as an appetite suppressant, although its use for this purpose, in tablet form, is now banned in the UK.
LACTOSE22
Non-proprietary names :
BP: Anhydrous lactose
JP: Anhydrous lactose
PhEur: Lactosumanhydricum
USPNF: Anhydrous lactose
Synonyms :
Anhydrous Lactose NF 60M; Anhydrous Lactose NF Direct Tableting; Lactopress Anhydrous; lactosum; lattioso; milk sugar; Pharmatose DCL 21; Pharmatose DCL 22; saccharumlactis; Super-Tab Anhydrous.
Chemical name :
O-?-D-galactopyranosyl-(1,4)-?-D-glucopyranose
Empirical formula :
C12 H22 O11
Molecular weight :
342.30
Functional category :
Binding agent; directly compressible tableting excipient; lyophilization aid; tablet and capsule filler.
Structural formula:
Solubility :
Soluble in water; sparingly soluble in ethanol (95%) and ether.
Description
Lactose occurs as white to off-white crystalline particles or powder. Several different brands of anhydrous lactose are commercially available which contain anhydrous?-lactose and anhydrous?-lactose. Anhydrous lactose typically contains 70–80% anhydrous ? -lactose and 20–30% anhydrous lactose.
Stability and storage conditions
Mold growth may occur under humid conditions (80% RH and above). Lactose may develop a brown coloration on storage, the reaction being accelerated by warm, damp conditions. At 8080C and 80% RH, tablets containing anhydrous lactose have been shown to expand 1.2 times after one day. Lactose anhydrous should be stored in a well-closed container in a cool, dry place.
Incompatibilities
Lactose anhydrous is incompatible with strong oxidizers. When mixtures containing a hydrophobic leukotriene antagonist and anhydrous lactose or lactose monohydrate were stored for six weeks at 40ºC and 75% RH, the mixture containing anhydrous lactose showed greater moisture uptake and drug degradation. Studies have also shown that in blends of roxifiban acetate (DMP-754) and lactose anhydrous, the presence of lactose anhydrous accelerated the hydrolysis of the ester and amidine groups.
Safety
Lactose is widely used in pharmaceutical formulations as a diluent and filler-binder in oral capsule and tablet formulations. It may also be used in intravenous injections. Adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactase, and is associated with oral ingestion of amounts well over those in solid dosage forms.
Applications
Anhydrous lactose is widely used in direct compression tableting applications and as a tablet and capsule filler and binder. Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content.
Magnesium stearate23
Non-proprietary names :
BP: Magnesium stearate
JP: Magnesium stearate
PhEur: Magnesiistearas
USPNF: Magnesium stearate
Synonyms : Magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt
Chemical name : Octadecanoic acid magnesium salt
Empirical formula : C36H70MgO4
Molecular weight : 591.34
Structural formula : [CH3(CH2)16COO]2Mg
Molecular structure :
Functional category : Tablet and capsule lubricant
Solubility : Practically insoluble in ethanol, ethanol(95%),ether and water; slightly soluble in warm benzene and warm ethanol (95%).
Description
Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odour of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin.
Stability and storage conditions
Magnesium stearate is stable and should be stored in a wellclosed container in a cool, dry place.
Incompatibilities
Incompatible with strong acids, alkalis, and iron salts. Avoid mixing with strong oxidizing materials. Magnesium stearate cannot be used in products containing aspirin, some vitamins, and most alkaloidal salts.
Applications
Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams.
METHODOLOGY
Preformulation testing is the first step in the rationale development of dosage forms of a drug. It can be defined as an investigation of physical and chemical properties of drug substance, alone and when in combined with excipients. The overall objective of the preformulation testing is to generate information useful to the formulator in developing stable and bio available dosage forms which can be mass produced.
The goals of preformulation studies are:
Hence, preformulation studies on the obtained sample of drug include colour, taste, solubility analysis, melting point determination and compatibility studies.
B. CHARECTERIZATION OF TRANEXAMIC ACID:
1. Melting point determination:
The melting point of tranexamic acid was determined by using melting point apparatus
2. Spectroscopic studies:
a. FT-IR spectrum interpretation:
The infrared spectrum of the pure tranexamic acid sample was recorded and the spectral analysis was done. The dry sample of drug was directly placed after mixing and triturating with dry potassium bromide.The polymers were also subjected to FT-IR studies alone and in combination with drug, to study he interference of polymer with drug.
b. UV spectroscopy
A. Construction of calibration curve of tranexamic acid in 0.1N HCL buffer solution
Accurately Weighed 10 mg of tranexamic acid and dissolved in 5 ml of methanol and volume was made up to 10 ml with 0.1N HCL buffer accordingly the mark to give stock solution and transfer 100µg/ml. Further dilutions were made and absorbance was measured at 220nm. The standard graph is plotted with concentration on X-axis and absorbance on Y-axis.
Bulk density(Db):
It is the total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder (passed through standard sieve #20)into a measuring cylinder and the powder weight was noted. This initial volume is called the bulk volume. From this bulk density is calculated according to the formula mentioned in beow.it is expressed in g/ml and is given by,
Db=M/Vb
Where, M is the mass of powder
Vbis the bulk volume of the powder.
Tapped density (Dt):
It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was measured by tapping the powder for 750 times and the tapped volume was noted, if the between these two volumes is less than 2%.if it is more than 2%,tapping is continued for 1250 times and tapped volume was noted. Tapping was continued until the difference between successive volumes is less than 2%(in a bulk density apparatus).it is expressed in g/ml and is given y,
Dt= M/Vt
Where, M is the mass of powder
Vt is the tapped volume of the powder
Angle of repose:
The friction forces in a loose power can be measured by the angle of repose ?. It is an indicative of the flow properties of the powder. It is defined as maximum angle possible between the surfaces of the pile of powder and the horizontal plane.
Tan ? = h/r
Where, ? is the angle of repose
his height in cm
r is the radius in cm
The powder maximum was allowed to flow through the funnel fixed to a stand at definite height(h).The angle of repose was then calculated by measuring the height and radius of the heap of powder formed. Care was taken to see that the powder particles slip and roll over each other through the slides of the funnel. Relationship between angle of repose and powder flow property
Carr’s index (or) compressibility index:
It indicates powder flow properties. It is expressed in percentage and is given by,
I=(Dt– Db)/ Dtx100
Where, Dtis the tapped density of the powder
Db is the bulk density of the powder.
Hausner’s ratio:
It is an indirect index of ease of powder flow. It is calculated by the flowing formula.
Hausner’s ratio= Dt /Db
Where, Dtis the tapped density
Db is the bulk density
C. FORMULATION OF SUSTAINED RELEASE TABLETS
The development of formulation in the present study was mainly based on the system chosen and drug selected. The solubility characteristics were considered more important in the development of formulations. Sustained release tablets of tranexamic aid were prepared by direct compression technique method. Required amount of drug tranexamic acid, polymers and mcc pH 101 and magnesium stearate, talc were taken into the modern and pestle and mix it properly. Then the required amount of the samples were weighed and punched with a punching machine.
D. POST FORMULATION PARAMETERS
1. Weight variation:
20 tablets were selected randomly from the lot and weighed individually to check for weight variation. Weight variation specifications as per I.P. are show
2. Hardness:
Hardness or tablet crushing strength (fc),the force required to break a tabletin a diametric compression was measured using Monsanto tablet hardness tester. It is expressed in Kg/cm2. Three tablets from each batch of formulation are tested for their hardness.
3. Thickness:
Three tablets were selected randomly from each batch and Thickness was measured by using Vernier caliper.
Friability of the tablet was determined using rochefriabilator. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a tablet at the height of 6 inches in each revolution. pre weighed sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. Tablets were de dusted and re weighed. The friability (F)is given by the formula.
F = (Winitial- Wfinal)/Winitialx 100
In vitro release of the rug from tablets, was determined by estimating the dissolution profile.
Dissolution test:
Apparatus:
USP type-2dissolution rate test apparatus
rpm: 50
Dissolution medium: 0.1N HCl
Volume: 900
Samples were taken at periodic intervals and the percentage drug release was calculated by extrapolating the absorbance values on standard graph.
10 tablets were weighed and triturated. The tablet triturate equivalent to 100 mg of the drug was weighed accurately, dissolved in small amount of methanol and diluted to 100 ml with 0.1N HCl. Further dilutions were done suitably to get a concentration of 10 µg/ml with 0.1N HCl. Absorbance was read at 220 nm against the reagent blank, and the concentrations of tranexamic acid in µg/ml was determined by using standard graph.
E. Kinetics of drug release:
The results of in-vitro dissolution studies of matrix tablets were fitted with various kinetic models, like
The zero order rate describes the systems where the drug release rate is independent of the concentration.
Qt = Q0 +K0 t
Where, Qt= the amount of drug dissolved in time, ‘t’
Q0 = the initial amount of drug in the solution (most of the time, Q0 = 0)
K0 = the zero order release constant expressed in units of concentration time.
A plot of amount of drug released versus time will be linear for zero-order kinetics. This relation can be used to determine the drug dissolution from various types of modified release dosage forms such as matrix tablets with low soluble drugs, coated tablets and capsules and osmotic systems.
The first order equation describes the release of drug from system where release rate is concentration dependent.
log C0 - log Ct =Kt / 2.303
Where, C0= initial concentration of the drug
Ct= amount of drug released in time, ‘t’
Kt= first order constant.
The data obtained is plotted as log cumulative percentage of drug remaining versus time which would yield a straight line with a slope of –K / 2.303.
This model is used to study the release of water soluble and poorly soluble drugs incorporated in semi-solid and /or solid matrices.
Q = KH t1/2
Where, Q = amount of drug released in time t per unit area
KH = Higuchi dissolution constant
The data obtained is to be plotted as cumulative percent drug release versus square root of time. Higuchi describes drug release as diffusion process based on the Fick’s Law, square root time dependent.
d. Hixson – Crowell erosion equation
Hixson and Crowell recognized that the particles regular area is proportional to the cube root of its volume.
W01/3 – Wt1/3 = Kt
Where, W0 = initial amount of drug in the dosage form.
Wt = remaining amount of drug in the dosage form at time t
Kt = rate constant
Thus a plot between (1 – Q)1/3 versus time will be linear.
e.Korsmeyer – Peppas equation
Korsmeyer derived a simple relationship which described the drug release from a polymeric system. To find out the mechanism of drug release, first 60% drug release data is fitted in Korsmeyer – Peppas model.
Mt / M? = ktn
Where, Mt / M ? = fraction of a drug released at time, ‘t’
K = release rate constant
n = diffusional exponent
The ‘n’ value is used to characterize different release for a cylindrical shaped matrices. In this model, the value of n characterizes the release mechanism of drug as described in the below table. To study the release kinetics, data obtained from in vitro drug release studies is plotted as log cumulative percentage drug release versus log time.
Compatibility studies
FTIR technique was commonly used to investigate the compatibility between the drug and the various excipients used in the formulation. The samples were prepared by physical mixture of drug and excipients (1:1) using a clean dried glass mortar and subjected to analysis by FTIR and spectral scanning was done in the range of 4000 – 400cm-1.
RESULTS AND DISCUSSIONS
Calibration curve of tranexamic acid:
Calibration curve of Tranexamic acid was established by preparing the concentrations of 20, 40, 60, 80 and 100 mcg/ml in 0.1N HCl and estimating the values at 220 nm using UV spectroscopy against blank. Calibration curve was constructed by taking concentration on X-axis and absorbance on Y-axis. It has obeyed the Beer Lamberts law in the concentration range of 20 to 100 mcg/ml with regression line y=0.0008x and r2 value of 0.9986.
Post compression parameters
1. Weight variation test:
10 tablets of each batch were randomly selected and subjected to weight variation test. Difference in average weight and percent deviation was calculated for each tablet.
2. Hardness test:
Three tablets of each batch was checked for hardness by using Monsanto hardness tester.
3. Thickness:
Three tablets of each batch was checked for thickness by using vernier callipers
4. Friability:
5 tablets of each batch were evaluated for percentage friability by using Roche friabilator.
The different post compression evaluation parameters were estimated and tabulate
Note:All values are expressed as mean ±S.D. a) n=10; b) n=3
In vitro dissolution studies:
Finally, the tablets were evaluated for in vitro dissolution studies in 0.1N HCl buffer for 12 hours. The results were shown in the table 4.4&4.5
In vitro dissolution profile of formulation
DISCUSSION
Compatibility studies
FTIR spectra of pure drug (Tranexamic acid)
C-H out plane bending was observed at 841.01cm-1
FTIR spectra of Xanthan gu
An ether bond (C-O-C) is observed at 1373.73cm-1
FTIR spectra of Guar gum
FTIR spectra of Tranexamic acid and Xanthan gum
A peak was observed at 1637.85 cm-1 indicating the presence of C=O (ketone) group
FTIR spectra of Tranexamic acid and Guar gum
A bend was observed at 1155.71 cm-1 indicating the presence of OH group
DISCUSSION
FTIR studies revealed that there are no interactions between drug and polymers. Hence, they are compatible with each other.
SUMMARY AND CONCLUSION
SUMMARY
CONCLUSION:
From the present investigation it was found that Xanthan gum and Guar gum can be used for the preparation of sustained release tablets of tranexamic acid. However, the formulation, XF5 with drug : Xanthan gum 1 : 0.8 has shown 99.45% drug release in 12 hrs whereas the formulation, GF4 with drug : Guar gum 1 : 0.6 has shown 99.90% drug release in 12 hrs. Hence, the formulation GF4 containing less quantity of polymer was considered as optimized formulation with 99.90% drug release in 12 hrs. So, Guar gum is showing more drug release retardant property than Xanthan gum in the formulation of tranexamic acid SR tablets.
REFERENCE
D. Aswani , M. Bhagyasree , Formulation And Evaluation Of Tranexamic Acid Sustained Release (Sr) Tablets, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 9, 1381-1419. https://doi.org/10.5281/zenodo.13854247
10.5281/zenodo.13854247
