Project

Bioavailability Enhancement Methods
INTRODUCTION Bioavailability, one of the principal pharmacokinetic properties of drugs, is a term used by several branches of scientific study to describe the way chemicals are absorbed by humans and other animals. Bioequivalence indicates that the drug products, when given to the same patient in the same dosage regimen, result in equivalent concentrations of drug in plasma and tissues. Bioequivalence is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Chemical equivalence indicates that drug products contain the same compound in the same amount and meet current official standards; however, inactive ingredients in drug products may differ. Therapeutic equivalence indicates that drug products, when given to the same patient in the same dosage regimen, have the same therapeutic and adverse effects. Bioequivalent products are expected to be therapeutically equivalent. Therapeutic nonequivalence (eg. more adverse effects, less efficacy) is usually discovered during long-term treatment when patients who are stabilized on one formulation are given a nonequivalent substitute. Sometimes therapeutic equivalence is possible despite differences in bioavailability. For example, the therapeutic index (ratio of the minimum toxic concentration to the median effective concentration) of penicillin is so wide that efficacy and safety are usually not affected by the moderate differences in plasma concentration due to bioavailability differences in penicillin products. For drugs and other substances that act within the body (within the gut), it is generally considered to be the quantity or fraction of an administered dose of a substance that gets into the circulation and then is not metabolized, complexed or excreted before it can exert its intended biological effect. With nutrients, for which metabolism is usual and appropriate and the route of
1
administration is nearly always oral, the notion of bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed. Bioavailability, when used in environmental sciences, evaluates the rate and amount of toxic substances that may occur in the body. One example of this is the recent concern over mercury levels in fish. Some fish contain high levels of mercury, a poison, which can lead to severe illness when ingested in high quantities. People who eat a lot of fish may be subject to mercury poisoning. Recent recommendations by the US FDA suggest consuming mercury-high fish no more than once a week. Flow-chart - A systematic approach to ensure bioavailability of pharmaceutical products
DEFINITION Bioavailability is a measurement of the extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action. i.e. bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, It is expressed as the letter F. ASSESSING BIOAVAILABILITY Bioavailability is usually assessed by determining the maximum (peak) plasma drug concentration, peak time (when maximum plasma drug concentration occurs), and area under the plasma concentrationtime curve (AUCsee Fig.).
Maximum safe concentration
Therapeutic range
Minimum effective concentration
Onse t
Intensity
Fig. - Representative plasma concentrationtime relationship after a single oral dose of a drug Plasma drug concentration increases with extent of absorption; the peak is reached when drug elimination rate equals absorption rate. Peak time is the most widely used general index of absorption rate; the slower the absorption, the later the peak time. The most reliable measure of a drug's bioavailability is the AUC. The AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation. Drug products may be considered bioequivalent in extent and rate of absorption if their plasma concentration curves are essentially superimposable. Definition Related To The Area Under The Plasma Concentration Versus Time Curve
3
Minimum effective plasma concentration (MEC) The minimum concentration of drug must be achieved in the plasma before the desired therapeutic or pharmacological effect is achieved is called the minimum effective plasma concentration. Maximum safe concentration (MSC) The concentration of drug in the plasma above which side effects or toxic effects occur in a patient is known as the maximum safe concentration. Therapeutic range A range of plasma drug concentration over which the desired response is obtained yet toxic effects are avoided. This range of plasma drug concentration is known as the therapeutic range. Onset The time required to achieve the minimum effective plasma concentration. Duration The duration of the therapeutic effect of the drug is the period during which the concentration of drug in the plasma exceeds the minimum effective plasma concentration. Peak concentration (Cmax ) The highest concentration of the drug achieved in the plasma. Intensity The difference between the minimum effective plasma concentration and the peak concentration is a relative measure of the intensity. Area under the plasma concentration (AUC) The total amount of drug absorbed into the systemic circulation following the administration of a single dose that drug. It also gives a measure of the extent of absorption or the amount of drug that reaches the systemic circulation. Mean resident time (MRT) - Mean Residence Time (MRT ) is the average time the drug molecules introduced reside in the body.
OBJECTIVES OF BIOAVAILABILITY STUDIES : 1. Primary stages of development of a suitable dosage form for a new drug entity.
4
2. Determination of influence of excipients , patient related factors and possible interaction with other drugs on the efficiency of absorption. 3. Development of new formulation of the existing drugs. 4. Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage and stability on drug absorption.
FACTORS INFLUENCING BIOAVAILABILITY The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e. F<1). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation,Such factors may include : 1. Pharmaceutical factors related to physiochemical properties of the drug and characteristics of the dosage form. See fig.
Physical properties of the drug (hydrophobicity, pKa, solubility). The drug formulation (immediate release, excipients used, manufacturing methods, modified release - delayed release, extended release, sustained release, etc.).
2. Patient related factors.

5
Fig.- effect of Gastric emptying on bioavailability
If the drug is administered in a fed or fasted state. Gastric emptying rate. Circadean differences. Enzyme induction/inhibition by other drugs/foods. Interactions with other drugs. (e.g. antacids, alcohol, nicotine). Interactions with other foods. (e.g. grapefruit juice, pomello, cranberry juice). Transporters: Substrate of an efflux transporter. (e.g. P-glycoprotein). Health of the GI tract. Enzyme induction/inhibition by other drugs/foods. Enzyme induction (increase rate of metabolism). e.g. Phenytoin (antiepileptic) induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4.
Enzyme inhibition (decrease rate of metabolism). e.g. grapefruit juice inhibits CYP3A --> higher nifedipine concentrations.
Individual Variation in Metabolic Differences. Age: In general, drugs metabolized more slowly in fetal, neonatal, and geriatric populations.
Phenotypic differences, enterohepatic circulation, diet, gender. Disease stages e.g. hepatic insufficiency, poor renal function. Sex also influence the absorption followed by bioavailability.
3. Route of administration.
The influence of route of administration on drugs bioavailability has following order : parenteral > oral > rectal > topical. Intravenous administrations of medications are considered to have 100% bioavailability
because they do not pass through the stomach. They are immediately in the circulatory system. Intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora and first pass metabolism alters the bioavailability of drug when administered orally. Graphical comparison of a drug when administered via different routes
The area under the plasma (serum, or blood) concentration versus time curve (AUC) has an number of important uses in toxicology, biopharmaceutics and pharmacokinetics.
TYPES OF BIOAVAILABILITY There are two types of bioavailability 1. Absolute bioavailability, 2. Relative bioavailability,. ABSOLUTE BIOAVAILABILITY Absolute bioavailability is the measurement of a medication once it passes through the gut and is released into the circulatory system. Absolute bioavailability compares the bioavailability (estimated as area under the curve, or AUC) of the active drug in systemic circulation following non-intravenous administration (i.e., after oral, rectal, transdermal, subcutaneous administration), with the bioavailability of the same drug following intravenous administration. It is the fraction of the drug absorbed through nonintravenous administration compared with the corresponding intravenous administration of the
8
same drug. The comparison must be dose normalized if different doses are used; consequently, each AUC is corrected by dividing the corresponding dose administered. In order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (IV) and nonintravenous administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the oral route (po) is given below.
Therefore, a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1) while drugs given by other routes usually have an absolute bioavailability of less than one.
RELATIVE BIOAVAILABILITY Relative bioavailability is a term used to compare different formulations of the same medication, for example brand name versus generic. Certain generic preparations are not equivalent in bioavailability to brand name versions of medications. One example of this is the drug Synthroid, which is usually marketed in generic form as thyroxidine. Many patients who use thyroid replacement therapy find that thyroxidine is not as effective as Synthroid. Technically, the two medications should be equivalent, but differences in the bioavailability of the two forms have been noted. This measures the bioavailability (estimated as area under the curve, or AUC) of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability.2,3
MEASUREMENT OF BIOAVAILABILITY A bioavailability measurement describes aspects like absorbency and half-life. The method used for measurement of bioavailability are following:
1. PHARMACOKINETIC METHODS:
Serum concentration method, Urine increment method, The Balance method, Tracer method
2. PHARMACODYNAMIC MTHODS: Target system effect method,
3. IN VITRO TESTS (E.G., THE DISSOLUTION AND DISINTEGRATION TEST
FOR CALCIUM SALTS). For non- metabolizable supplemental nutrients, bioavailability is effectively equivalent to absorbability. Factors which helps in determining the end point include source factors such as pharmaceutic formulation, subject factors such as mucosal mass and the need status of the absorbing subject, and co-ingested factors such as other foods or food constituents. Following approaches encompass most of the methods used for nutrients. Each will be described in just enough detail to show how its endpoints may be affected.
1. THE BALANCE METHOD
It refers to total body balance, but to intestinal balance, i.e., the difference between what goes in at the mouth and what comes out in the feces. In this conceptually simple form, the method is cumbersome, imprecise, time consuming and expensive. Additionally, its endpoint is subject to the influence of bacterial action on the nutrient concerned in the colon (a problem for organic
10
compounds, although not for minerals). A much simplified form, largely eliminating bacterial interference, is the method of intestinal lavage , in which the gut is first thoroughly emptied of all of its contents by drinking a large volume of an isosmotic solution, then feeding a test meal containing the nutrient for which bioavailability information is sought along with a nonabsorbable marker, then several hours later following with a second lavage and measuring the content of the test nutrient in the effluent. The method directly yields the quantity absorbed. It measures net rather than gross absorption and, thus, provides nutritionally relevant information, particularly for minerals, such as calcium, which enter the gut with digestive juices, as well as leave it in the process of absorption.
2. SERUM CONCENTRATION METHOD
The measurement of serum concentration of the nutrient after ingestion is based on the fact that serum concentration rises as the nutrient is introduced into the circulation during its absorption. It yields an area under the curve (AUC), as well as the other traditional pharmacokinetic measures.. Unless parallel AUC determinations are made for intravenously administered doses of the same substance, this method does not yield absolute bioavailability values and is better suited to the comparison of two (or more) preparations. It tends to be relatively expensive because of the number of analyses required and because of the time involved, for which volunteers must be compensated. It also tends to have a very low signal-to-noise ratio, particularly for minerals. This is because, in contrast to drugs, the test substance is normally present in the serum, and its level often tightly regulated. The absorptive increment tends to be a small fraction of what is already present and homeostatic forces actively damp the absorptive rise. Hence, this method exhibits limited sensitivity.
3. TRACER METHOD
When intrinsic labeling of a source is possible, tracer methods are generally the most accurate and precise. The tracer methods are highly sensitive and reproducible and depending upon the tracer used, can be very quick and inexpensive . The tracers used may be either radioactive or stable (the former tending to be cheaper and easier to use). Like the balance methods, the tracer methods yield the
11
absolute quantity absorbed, but in this instance, it is gross absorption (i.e., unidirectional flux out of the lumen and into the circulation), rather than net absorption, which is measured. This can be a nutritionally less relevant measure, but it is always a better test of the inherent absorbability of the nutrient source. The method has very high sensitivity because the normal background for the tracer (particularly if radioactive) is usually very low; hence, the signal-to-noise ratio is usually very favorable. Also, homeostatic forces do not damp the rise in tracer concentration as they damp the rise in carrier. The limitation of the method is that it requires that the source can be intrinsically labeled, i.e., every atom or molecule of the test nutrient in the ingestate must have the same probability of containing the isotopic tracer as every other atom or molecule.
4. URINE INCREMENT METHOD
For drugs excreted primarily unchanged in urine, bioavailability can be estimated by measuring the total amount of drug excreted after a single dose. Ideally, urine is collected over a period of 7 to 10 elimination half-lives for complete urinary recovery of the absorbed drug. After multiple dosing, bioavailability may be estimated by measuring unchanged drug recovered from urine over a 24-h period under steady-state conditions.
12
The urine increment method is based on the fact that as the serum concentration of the nutrient rises, some of the nutrient spills over into the urine. A timed urine collection represents a time integral of the serum concentration, i.e., it reflects the AUCt. It is a much less expensive method than the classical serum AUC method, but it is also much less precise, because it adds another layer of biological variability (variable renal clearance). Hence, it is even less sensitive than the serum method. It has, accordingly, a very low signal-to-noise ratio, and like the serum method, it does not yield absolute bioavailability values.
5. TARGET SYSTEM EFFECT METHOD The effect of the nutrient on target systems is intuitively attractive, because methods with such endpoints get directly at the reason for taking the supplement in the first place. Their weaknesses lie in the fact that they are not easily calibrated and are often ill-suited for the testing of nutrients, because the biological response will be a function not only of the bioavailability of the product being tested. For example, the increment in serum 25-hydroxycholecalciferol that can be produced by a given oral dose of a vitamin D preparation is an inverse function both of the basal 25hydroxycholecalciferol status and of the dose itself.
6. IN VITRO METHODS
The in vitro methods are inexpensive and attractive for that reason and are often able to identify bad pharmaceutical formulations before going on to more expensive clinical tests, but they also often yield misleading information, particularly for calcium. This is because solubility of calcium salts is very poorly related to their absorbability because acid is not needed for absorption, because the test conditions create artifacts in their own right, and finally because the test conditions do not mimic the conditions within the human intestinal lumen.
13
Fig - plasma concentration v/s time when in vitro study is carried out using different formulation formula.
The chyme is largely a complex suspension, and dispersion of its constituents may be much more important for absorption than true dissolution, particularly because the latter usually refers to what can be measured in dilute solution in a laboratory under conditions very different from those in the gut. The dissolution of two calcium carbonate preparations in vitro was a function of the vigorousness of the agitation of the system. With mild agitation, neither substance met the disintegration and dissolution standard; with intermediate agitation, one source was completely dissolved and the other incompletely, and with vigorous agitation both were completely dissolved. The in vitro test in this case was calibrated with the intestinal lavage method, which revealed that one product was 32% absorbed and the other, 19%. It turned out that intermediate agitation yielded about the same proportion between the two dissolution values, but it would have been very difficult to predefine those conditions or to select from the three different in vitro experiments without having performed the in vivo study. A closely related issue is the tendency, with some CaCO3 preparations, for the CO2 released in an acid medium to adhere to the particles, thus, floating them to the top of the reaction vessel and insulating them from the acid in the solution phase. CAUSES OF LOW BIOAVAILABILITY
14
Orally administered drugs must pass through the intestinal wall and then through the portal circulation to the liver; both are common sites of 1st-pass metabolism (metabolism of a drug before it reaches systemic circulation). Thus, many drugs may be metabolized before adequate plasma concentrations are reached. Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. Insufficient time for absorption in the GI tract is a common cause of low bioavailability. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (eg, if it is highly ionized and polar), time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, physical activity, genetic phenotype, stress, disorders (eg, achlorhydria, malabsorption syndromes), or previous GI surgery (eg, bariatric surgery) can also affect drug bioavailability. Lipophilic Drugs: - A poorly water soluble compound has classically been defined as one dissolving in less than 1part per 10000 part of water 1 A poorly water soluble drug, more recently, has been defined in general terms to require more time to dissolve in the gastrointestinal fluid than it take to be absorbed in the gastrointestinal tract2. Thus a greater understanding of dissolution and absorption behaviors of drugs with low aqueous solubility is required to successfully formulate them into bioavailable drug products. Poorly water-soluble (hydrophobic) drug present significant challenges due to their inadequate solubilisation in digestive liquids:
Poor bioavailability leading to high dose . Inter and intra-individual variability leading to inadequate therapy and/or safety concerns. Significant food effects on bioavailability. Enhancing bioavailability has become a vital need within the pharmaceutical and
biopharmaceutical industries. This need is growing as rational drug design and high throughput screening generate thousands of new chemical entities (NCEs) for disease targets. These NCEs are usually hydrophobic in nature, with increased receptor binding affinities.
15
Up to 40% of lipophilic drugs are not prepared , meanwhile, some lipophilic drugs are to be administered at high doses. Thereby, various formulation strategies have been investigated to improve the solubility and the rate of dissolution and hence the oral bioavailability of lipophilic drugs.These strategies include the solubilization and surfactants, the use of different polymorphic/amorphic drug forms, the reduction of drug particle size, the complexation (e.g., cyclodextrins) and the formation of solid drug solutions/dispersions. Examples of active ingredients that are considered hydrophobic, poorly water-soluble or waterinsoluble include benzodiazepines, clofibrate, chlorpheniramine, dinitirate, digoxin, digitoxin, ergotamin tartate, estradiol, fenofibrate, griseofulvin, hydrochlorothiazide, hydrocortisone, isosorbide, medrogeston, oxyphenbutazone, prednisolone, prednisone, polythiazide, progensterone, spironolactone, tolbutamide.8
16
METHODS OF ENHANCEMENT OF BIOAVAILABILITY
A. ENHANCEMENT OF SOLUBILITY The active ingredient's post-ingestion dissolution rate and its corresponding bioavailability can be optimized by intimately mixing a micronized hydrophobic drug with suitably sized inert particlesto form a dispersion that will facilitate desired bioavailability. For drugs that are hydrophobic or poorly soluble in water, increased wettability upon exposure to biological fluids can become a goal for those formulating and manufacturing these agents. One approach to increase the bioavailability of lipophilic drugs is the solubilization of the drugs by means of pH adjustment, cosolvent, microemulsification, self-emulsification, micelles, liposomes and emulsions.
1. pH ADJUSTMENT: -
pH adjustment is the simplest and most commonly method to increase water solubility of ionizable compounds. However, this salt formation is infeasible for unionized compounds. The formed salts may also converse to respective acid or base forms in gastrointestinal-tract (GIT). The influence of the changes in pH within the gastrointestinal tract upon the bioavailability of pharmaceuticals is well documented. The absorption of a drug is largely dependent upon diffusion, which varies with the pKa of the drug and the pH of the individual regions within the gastrointestinal tract, and permeability, which is not only moderated by the surface area of the region in which it is released, but also the regional pH effects upon drug ionisation.
2. COSOLVENT / SOLUBILISING EXCIPIENTS: -
Cosolvents are the mixtures of miscible solvents often used to solubilize lipophilic drugs. The solubilizing excipients used in commercially available oral and injectable formulations are listed in Table.
17
Table : Solubilizing excipients used in commercially available oral and injectable formulations. Currently, the water-soluble organic solvents are polyethylene glycol 400 (PEG 400), ethanol, propylene glycol, and glycerin. For example, Procardia (nifidipine) was developed by Pfizer contains glycerin, peppermint oil, PEG 400 and sodium saccharin in soft gelatin capsules. The water-insoluble solvents include long-chain triglycerides (i.e. peanut oil, corn oil, soybean oil, sesame oil, olive oil, peppermint oil, hydrogenated vegetable oil & hydrogenated soybean oil), medium-chain triglycerides (Miglyol 812), beeswax, d-- tocopherol (vitamin E) and oleic acid. Progesterone is a water-insoluble steroid and is solubilized in peanut oil (Prometrium). The use of surfactants is to improve the dissolution performance of poorly soluble drug products. The presence of surfactants may lower the surface tension and increase the solubility of the drug within an organic solvent. The surface-active agents enhance dissolution rate primarily by promoting wetting and penetration of dissolution fluid into the solid drug particles. They are generally used in concentration below their critical micelle concentration (CMC) values since
18
above CMC, the drug entrapped in the micelle structure fails to partition in the dissolution fluid. Nonionic surfactants like polysorbates are widely used. Surfactants are also often used to stabilize microemulsions and suspensions into which drugs are dissolved.10
The presence of surfactants within a drug product formulationmay result in an incompatibility with drug delivery technologieswhich rely upon well-regulated hydration, dissolution and erosion of a matrix or coating to achieve controlled release.
19
The use of a surfactant, such as sodium lauryl sulfate, in a formulation of an active principle may improve absorption of the drug, and hence improve its bioavailability. Microcrystalline cellulose has been used as an excipient in the manufacture of pharmaceuticals. However, it reportedly interfered with the bioavailability, or reduced the activity, of ampicillin and amoxycillin when used as acarrier. On the other hand, microcrystalline cellulose has been mixed with diethylstilbestrol to improve the dispersability of that hydrophobic drug in animal feed. Microcrystalline cellulose has also been included as an excipient in formulations comprising water-soluble n-acetyl-paminophenol and fumed silica.While the importance of salt selection and pH adjustment has been stressed as a critical parameter of pre-formulation, the use of pH-altering excipients within drug delivery systems is also of significant utility. Solubilised excipients that increase environmental pH within a dosage form, such as a tablet or capsule, to a range higher than pKa of weakly-acidic drugs increases the solubility of that drug, those excipients which act as alkalising agents may increase the solubility of weakly basic drugs. One example of such a use of pH-inducing excipients is SCOLR Incs self-correcting hydrogel systems. One or more electrolytes are included within the dosage form whose pKa is complementary to the drug; as the dosage form hydrates, the electrolyte is wetted simultaneously with the active compound, creating a microenvironment independent of gastrointestinal pH. Micro-environmental pH may be modulated to enhance dissolution of poorly soluble drugs via salting-in effects through the inclusion of electrolytes of varying hydrophobic character; conversely, intra-dosage form pH may induce precipitation of highly soluble drugs, thereby slowing dissolution through salting-out effects.
Fig- effect of different surfactant
20
e.g. A capsule formulation, including the carrier particle and hydrophobic active ingredient, may be manufactured by intimately mixing the micronized active ingredient(s) with the suitably sized particles, such as lactose or microcrystalline cellulose, with or without a disintegrant or other excipients, for a period of time sufficient to maximize dispersion of the active ingredient to the carrier. Dispersion may be monitored optically, for example. The granulate mixture is then wetted with an appropriate granulation solution, with or without surfactant or other excipients. After the wet granules are dried, they are milled to desirable granule size. The milled granules may be blended with a suitable lubricant or other non-lubricant excipient. The final blend is then filled into capsules of suitable size.11 3. MICROEMULSION Microemulsion is a thermodynamically stable isotropical dispersion composed of a polar solvent, an oil, a surfactant and a co-surfactant. The formation of microemulsions is spontaneous and does not involve the input of external energy. One theory considers negative interfacial tension while another considers swollen micelles. The surfactant and the cosurfactant alternate each other forming a mixed film at the interface contributing to the stability of the microemulsion. Microemulsions are potential drug delivery systems for poorly water soluble drugs due to their ability to solubilize the drugs in the oil phase, thus increasing their dissolution rate. Even if the microemulsions are diluted after oral administration below the critical micelles concentration (CMC), the resultant drug precipitates have a fine particle size allowing enhanced absorption. 4. SELF-EMULSIFICATION In the absence of external phase (water), the mixture of oil, surfactant, cosurfactant, one or more hydrophilic solvents and cosolvent forms a transparent isotropic solution that is known as the self-emulsifying drug delivery system (SEDDS). This forms fine O/W emulsions or microemulsions spontaneously upon dilution in the aqueous phase and is used for improving lipophilic drug dissolution and absorption. The self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. The ease of emulsification could be associated with the ease of water penetrating into the various liquid crystalline or gel phases formed on the surface of the droplet. A
21
few parameters have been proposed to characterize the self-emulsifying performance including the rate of emulsification, the emulsion size distribution and the charge of resulting droplets. Among them, emulsion droplet size is considered to be a decisive factor in self emulsification/dispersion performance, since it determines the rate and extent of drug release and absorption. In addition, positively charged emulsion droplets could be obtained by incorporation of a small amount of cationic lipid (oleylamine) into such system. The oral bioavailability of progesterone was significantly enhanced in rats by forming positively charged emulsion in comparison to the corresponding negatively charged formulation. One of the advantages of SEDDS in relation to scale-up and manufacture is that they form spontaneously upon mixing their components under mild agitation and they are thermodynamically stable. The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates GIT. Consequently, the safety aspect of the surfactant vehicle had to be considered. Moreover, volatile cosolvents in the conventional self-emulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs. As an example of self-emulsification, Neoral is composed of ethanol, corn oil-mono-ditriglycerides, Cremophor RH 40 and propylene glycol. It exhibits less variability and better drug uptake compared to Sandimmune. B. SELECTIVE ADSORPTION ON INSOLUBLE CARRIERS The object of this method is to provide a delivery composition that provide formulations from being spoonable to a rigid gel, to provide a delivery system which is of low cost to allow use with various herbs, vitamin and nutritional supplements and to provide a good tasting delivery system which masks the taste of the delivered substances. These and other objects are achieved by a delivery composition comprising a gel base, water and a bioavailability enhancing composition. Agar is a preferred gelling agent, most preferably used with gelatin to form a base. Agar is a phycocolloid derived from red algae, that is strongly hydrophilic. Agar is preferred to pectin because its smaller molecular structure helps in absorption of the delivered component. The gelatin/agar base provides a flexible base that can cover a full
22
range of consistency, from spoonable suspension to a rigid gel. The base provides a stable environment for both water and lipid soluble substances. The bioavailability enhancing substance is preferably a surfactant such as a mixture of lecithin and Vitamin E which promotes absorption of the carried substance. Other ingredients, such as flavoring agents, coloring agents or thickeners, among others, can be incorporated. This is a gel delivery system which uses a combination of mechanisms to enhance substance absorption. The mechanisms involve micellar solubilization, solid dispersion, and in situ emulsification. These improve the surfactant qualities of the gel preparation. The gel preferably has an all natural composition for delivering substances such as vitamins and minerals in a way that bypasses the poor disintegration or dissolution problems associated with solid dosage forms such as tablets or capsules. The gel system represents a convenient dosage form for delivering a wide variety of substances such as vitamins, minerals, herbs, food, supplements, medicaments, nutrients and further enhances their bioavailability. Use of the gel permits smaller dosages of vitamins and other nutrients to be used since greater uptake can be achieved. For convenience, the system can be packaged in a unit dose form. The gel may be formulated to include multiple vitamins and mineral preparations with their own enhanced bioavailability. The consistency of the gel can be changed to make it more fluid for beverage use or more solid for gummy type chewables. Absorption occurs by one of three methods, either passive diffusion, active transport or facilitated active transport. Passive diffusion is simply the passage of molecules across the mucosal barrier until the concentrations of the molecules reach osmotic balance on both sides of the membrane. This is the primary method used by water, small ions and glucose. The other two transport mechanisms require energy to pump them against a concentration gradient or against an electrical potential. In active transport, the molecule is actively pumped across the mucosa. In facilitated transport, a carrier, generally a protein, is required to convey the nutrient across the membrane for absorption. Carrier systems are required by many nutrients including minerals, peptides and lipids. With such a vast absorptive area, a vehicle that increases the time of contact with the micro villi enhances absorption. In other words, an ideal absorption enhancer acts as a spreading factor allowing more of the micro villi access to nutrients before they are swished away by the peristaltic action of the intestines. Delivery systems that enhance surfactant qualities improve the
23
bioavailability of fat soluble nutrients such as vitamin A and vitamin E. As a result, lower doses of these vitamins are required to reach optimum serum levels. The pharmacokinetic behavior of water soluble vitamins such as riboflavin, pyridoxine and vitamin C suggest these normally bombard the upper absorptive areas in the intestines which rapidly become saturated. As a result, mega doses of these vitamins normally by-pass the proximal segment of the jejunum and exit the body. In the case of vitamin C, gastrointestinal complaints such as bloating and flatulence are common, as unabsorbed vitamins can be irritating to the intestines. Nausea is a common side effect of Bvitamins taken on an empty stomach and unabsorbed riboflavin causes the bright yellow urine noted by those taking mega doses of the vitamin. Increased absorption with the gel depends on two functions. Improving surfactant qualities utilizing micellar solubilization, solid dispersions, and in situ emulsification improving intestinal function by supporting growth of beneficial gut flora and use of ingredients with enhanced bioavailability The gel composition exhibits a two dimensional functionality for enhancing absorption of the nutrients in it. The first function facilitates the disposition of nutrients to the intestinal mucosa by means of self emulsification and colloidal dispersion associated with the use of the gel base. The second function supports the microflora that stabilizes and normalize permeability of the intestinal mucosa and influence the gut barrier system. The semi-solid consistency of the gel system maintains the constituents in a readily absorbable form. These may be in solution (dissolved), present in a colloidal micro particulate suspended state, or in an emulsified form. The constituents are exposed to a maximum amount of intestinal surface area for absorption. Furthermore, the gel imparts stability to twophase preparations, whether they are water/solid (colloidal) or water/oil (emulsified) suspensions. The use of gelatin and agar as gelling agents is preferred as it provides a smooth gel of desired consistency that can vary from being a viscous liquid suitable for drinking or pouring, to being a rigid non-flowing gel. The consistency of the example below is one that facilitates administration
24
from a spoon or an appropriate container such as a small plastic cup. Of course, other hydro colloid gelling agents can be used other than or in addition to those used in the example. These include carrageenan, acacia, guar, arabic, ghatti, karaya, tragacanth, terra, pectin, tamarind seed, larch arabinogalactan, alginates, locust bean, xanthin, starch, veegum, and colloidal silica. Modified cellulose products such as sodium carboxymethylcellulose, hyroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, methylethylcellulose, and hydroxyelthylcellulose can also be used. Surfactant properties of the gel account for improvement in vitamin bioavailability and this has been documented for lipid soluble vitamins such as vitamin E or those with limited water solubility such as riboflavin. The preferred surfactant is a vitamin Ellecithin self emulsifiable system that does not require oil for functional stabilization of the emulsion. The micellar solubilization component of the gel is effective for emulsifying vitamins A and D as well as E. The constituents for the surfactant system facilitate the transport of nutrients across the intestinal wall by increasing the surface area of the lipophilic vitamins. The improved bioavailability characteristics of the gel depend on in situ liposome formation from lecithin and a unique form of vitamin E with surfactant properties. Liposome formation is one of the newer technologies used by the supplement, cosmetic and drug industries to improve uptake of ingredients with both water soluble and fat soluble characteristics. Liposomes change the surfactant properties of the ingredients and thus improve their absorbability in the intestines or on the skin surface. Lecithin, a common choice for liposome formation, is a phospholipid with polar heads and non-polar tails that forms conglomerates with herbs and other mixed soluble ingredients. Liposomes are described as a complex with the polar tails of the phospholipid pointing inward and the non-polar heads facing outward. Such formation effectively sequesters water soluble fractions and makes them more lipid friendly, hence attractive to mucosal villi. Liposome technology has been widely used in the drug and cosmetic industry, and to a lesser degree in the dietary supplement industry, to improve absorption of mixed fat and water soluble ingredients. Solubilized vitamin E is used as an excipient in the gel to improve its overall surfactant qualities. This vitamin E forms liquid crystals in water at body temperature and functions to enhance drug, vitamin and mineral solubility in an aqueous environment by forming amphophilic micelles around
25
hydrophobic nutrients in the gel. It has been described as forming a self-emulsifying system in the stomach. The vitamin E micelles facilitate transport across the intestinal wall by blocking the natural tendency to reject supplemented vitamins, minerals, herbs or drugs.
C. FORMATION OF POROUS MATRIX The porous matrix with low aqueous solubility drugs yields upon contact with an aqueous medium microparticles having a mean diameter between about 0.1 and 5 m and a total surface area greater than about 0.9 m 2 /mL. The dry porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL and/or having a total surface area (sum of internal and external surface area) of greater than or equal to 0.2 m 2 /g The method and apparatus of this method involve spraying the solution into a supercritical antisolvent using a spray nozzle. to form an emulsion, suspension, and removing the volatile solvent and pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to nonporous matrix forms of the drug. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. If the pore forming agent is a solid, the agent is (i) dissolved in the drug solution, (ii) dissolved in a solvent that is not miscible in tile drug solvent and then emulsified with the drug solution, or (iii) suspended as solid particulates in the drug solution. Optionally, hydrophilic excipients, wetting agents, and/or tonicity agents mall be added to the drug solvent, the pore forming agent solvent, or both. The porous matrices that contain the drug are preferably made using a process that includes (i) dissolving a drug in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution from the emulsion, suspension to yield the porous matrix of drug. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster
26
rate of dissolution following administration to a patient, as compared to non-porous Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration. Since the dissolution rate of a drug particle is directly related to its surface area available to contact the aqueous media at the site of administration or site of absorption, methods of preparing drugs in nanoparticulate form have been developed in an effort to maximize the drug surface area. Nanoparticles however, can be difficult to produce and maintain in a stable form due to the tendency of the nanoparticles to flocculate or agglomerate, particularly without the presence of surface modifying agents adsorbed or coated onto the particles. Milling or wet grinding techniques are typically employed for nanonization. Other efforts for enhancing the rate of dissolution have focused on delivering the drug as a dispersion in a water-soluble or biodegradable matrix, typically in the form of polymeric microparticles. For example, the dissolution rate of dexamethasone reportedly was improved by entrapping the drug in chitosan microspheres made by spray-drying. Similarly, others have reported enhanced dissolution rates by mixing a poorly soluble drug powder with a water-soluble The formulations can also be administered parenterally. In one embodiment, the matrix further includes a pegylated excipient, such as pegylated phospholipid, with the drug. The pegylated excipient shields the drug from macrophage uptake, which prolong its half-life or enhance bioavailability of the drug.
27
The rate of dissolution of drugs can be enhanced by making the drug into a porous matrix form, substantially increasing the surface area of the drug available to contact aqueous biological fluids at the site of administration of the drug composition. In a preferred embodiment, the drug has low aqueous solubility. I. Drug Matrix Compositions The matrices also may contain hydrophilic excipients such as water soluble polymers or sugars, wetting agents such as surfactants, and tonicity agents. The form of the drug matrix (drug powder) is critical to the dissolution rate. The matrix must contain microparticles of drug, which preferably have a diameter between about 100 nm and 5 m, more preferably between about 500 nm and 5 m. The average total surface area of the microparticles contained within the porous matrix, which typically is in the form of a dry powder, is 0.9 m 2 /mL or greater. 1. Drugs Drugs contemplated for use in the compositions described herein include the following categories and examples of drugs and alternative forms of these drugs such as alternative salt forms, free acid forms, free base forms, and hydrates: e.g., aspirin, acetaminophen, ibuprofen, neomycin, streptomycin, chloramphenicol, , tetracycline, and ciprofloxacin heparin, valproic acid, phenytoin, clonazepam, phenobarbitol, carbamazepine, ethosuximide, amantadine hydrochloride, acyclovir, dextrothyroxine sodium, atorvastatin, cimetidine, and ranitidine hydrochloride, meclizine hydrochloride, scopolamine, vitamins A, D, E, K. 2. Excipients The matrices may contain hydrophilic excipients such as water soluble polymers or sugars which can serve as bulking agents or as wetting agents, wetting agents such as surfactants or sugars, and tonicity agents. Upon contact with an aqueous medium, water penetrates through the highly porous
28
matrix to dissolve the water soluble excipients in the matrix. In the case of low aqueous solubility drugs, a suspension of drug particles in the aqueous medium is left. The total surface area of the resultant low aqueous solubility drug microparticles is increased relative to the unprocessed drug and the dissolution rate of the drug is increased. One of skill in the art can select appropriate excipients for use in the drug matrix compositions, considering a variety of factors, such as the drug to be administered, the route of administration, the dosage, and the preferred dissolution rate. For example, the excipients can function as bulking agents, release-modifiers, wetting agents, tonicity agents, or combinations thereof. Preferred excipients include hydrophilic polymers, wetting agents, and sugars. The amount of excipient in the drug matrix is less than about 95%, more preferably less than about 80%, by weight of the drug matrix. The hydrophilic excipients, wetting agents, and tonicity agents may be added to the drug solution, the pore forming agent, or both, during production of the matrix. (i) Hydrophilic Polymers The hydrophilic polymer can be used as a bulking agent or as a wetting agent. The polymers that can be used in the drug matrices described herein include both synthetic and natural polymers, either non-biodegradable or biodegradable. Synthetic polymers include polyethylene glycol (PEG), polyvinyl alcohol, polyacrylic acid, polyethylene oxide, and polyethyoxazoline. Natural polymers include albumin, alginate, gelatin, acacia. (ii) Sugars Representative sugars that can be used in the drug matrices include mannitol, sorbitol, xylitol, fructose, sorbose, glucose, dextrose, galactose, ribose, xylose, sucrose, maltose, lactose, lactulose, etc. are adjusted to provide osmolality or to provide wetting of the porous drug matrix or the drug microparticles within the matrix.
29
(iii) Wetting Agents Wetting agents can be used to facilitate water ingress into the matrix and wetting of the drug particles in order to facilitate dissolution. Representative examples of wetting agents include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, polyethylene glycols, polyoxyethylene stearates. polyvinylpyrrolidone, polyethylene glycol, (iv) Tonicity or Osmolality Agents The porous drug matrices may include one or more tonicity agents, such as salts (e.g., as sodium chloride or potassium chloride) or sugars (such as mannitol, dextrose, sucrose, or trehalose) to adjust a hypotonic solution of a drug to isotonic so that the drug, when in solution, is physiologically compatible with the cells of the body tissue of the patient. The type and amount of tonicity agent can be selected by one of skill in the art using known techniques. (v) Pegylated Excipients In one embodiment, the matrix further includes a pegylated excipient. Such pegylated excipients include, pegylated proteins, pegylated peptides, pegylated sugars, pegylated polysaccharides. The pegylated excipient beneficially envelops or shields the drug from macrophage uptake, which prolongs its half-life or enhances bioavailability of the drug. Representative examples of pegylated phospholipids include 1,2-diacyl 1-sn-glycero-3phosphoethanolamine-N-[Poly(ethylene glycol) 2000] (PEG 2000 PE) and 1,2-diacyl-snglycero-3 -phosphoethanolamine-N-[Poly(ethylene glycol) 5000](PEG 5000 PE), where the acyl group is selected, for example, from dimyristoyl, dipalmitoyl, distearoyl, diolcoyl, and 1palmitoyl-2-oleoyl. Other polyalkyleneoxides can be used in the place of the polyethylene glycol moiety. II. Volatile Solvents
30
The choice of solvent depends on the drug. In a preferred embodiment, the solvent is an organic solvent that is volatile, has a relatively low boiling point, or can be removed under vacuum, and which is acceptable for administration to humans in trace amounts. Representative solvents include acetic acid, acetone, chloroform, chlorofluorocarbons, dichloromethane, dipropyl ether, diisopropyl ether, N,N-dimethlyformamide (DMF), foramide, demethyl sulfoxide (DMSO), dioxane, ethanol, ethyl acetate, ethyl formate, ethyl vinyl ether, glycerol, heptane, hexane, isopropanol, methanol, isopropanol, butanol, toluene, water, xylene etc. In general, the drug is dissolved in the volatile solvent to form a drug solution having a concentration of between 0.01 and 80% weight to volume (w/v), more preferably between 0.025 and 30% (w/v). When the drug is a water soluble drug, aqueous solvents or mixtures of aqueous and organic solvents, such as water-alcohol mixtures, can be used to dissolve the drug. III. Pore Forming Agents Pore forming agents are volatile materials that are used during the process to create porosity in the resultant matrix. The pore forming agent can be a volatilizable solid or volatilizable liquid. 1. Liquid Pore Forming Agent The liquid pore forming agent must be immiscible with the drug solvent and volatilizable under processing conditions compatible with the drug. To effect pore formation, the pore forming agent first is emulsified with the drug solvent, Then, the emulsion is further processed to remove the drug solvent and the pore forming agent simultaneously or sequentially using evaporation, vacuum drying, spray drying, fluid bed drying, lyophilization, or a combination of these techniques. The selection of liquid pore forming agents will depend on the drug solvent. Representative liquid pore forming agents include water; dichloromethane; alcohols such as ethanol, methanol, or isopropanol, acetone, ethyl acetate, toluene, xylene, ethers such as THF, diethyl ether, triethylamine, acetic acid, pyridine, hexane, water etc. The liquid pore forming agent is used in an amount that is between 1 and 50% (v/v), preferably between 5 and 25% (v/v), of the drug solvent emulsion.
31
2. Solid Pore Forming Agent The solid pore forming agent must be volatilizable under processing conditions which do not harm the drug compositions. The solid pore forming agent can be (i) dissolved in the drug solution, (ii) dissolved in a solvent which is not miscible with the drug solvent to form a solution which is then emulsified with the drug solution, or (iii) added as solid particulates to the drug solution. The solution, emulsion, or suspension of the pore forming agent in the drug solution then is further processed to remove the drug solvent, the pore forming agent, and, if appropriate, the solvent for the pore forming agent simultaneously or sequentially using evaporation, spray drying, fluid bed drying, lyophilization, vacuum drying, or a combination of these techniques. In a preferred embodiment, the solid pore forming agent is a volatile salt, such as salts of volatile bases combined with volatile acids. Volatile salts are materials that can transform from a solid or liquid to a gaseous state using added heat and/or vacuum. Examples of volatile bases include ammonia, methylamine, ethylamine, dimethylamine, diethylamine, methylethylamine, trimethylamine, triethylamine, and pyridine. Examples of volatile acids include carbonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, formic acid, acetic acid, propionic acid, butyric acid, and benzoic acid. Preferred volatile salts include ammonium bicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate and mixtures thereof. Other examples of solid pore forming agents include iodine, phenol, benzoic acid (as acid not as salt), and naphthalene. The solid pore forming agent is used in an amount between 5 and 1000% (w/w), preferably between 10 and 600% (w/w), and more preferably between 10 and 100% (w/w), of the drug. IV. Method of Making the Porous Drug Matrix The porous drug matrices preferably are made by (i) dissolving a drug, preferably one having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution. In a preferred embodiment, spray drying, optionally followed by lyophilization or
32
vacuum drying, is used to remove the solvents and the pore forming agent. The removal of the pore forming agent can be conducted simultaneously with or following removal of enough solvent to solidify the droplets. Production can be carried out using continuous, batch, or semi-continuous processes. First, the selected drug is dissolved in an appropriate solvent. The concentration of the drug in the resulting drug solution typically is between about 0.01 and 80% (w/v), preferably between about 0.025 and 30% (w/v). Next, the drug solution is combined, typically under mixing conditions, with the pore forming agent or solution thereof. If a liquid pore forming agent is used, it is first emulsified with the drug solution to form droplets of pore forming agent dispersed throughout the drug solution. If a solid pore forming agent is used, it is dissolved either directly in the drug solution to formic a solution of drug/pore forming agent, or it is first dissolved in a second solvent which is immiscible with the drug solvent to form a solution which subsequently is emulsified with the drug solution to form droplets of the pore forming agent solution dispersed throughout the drug solution. A solid pore forming agent alternatively can be added directly to the drug solution as solid particulates, preferably between about 100 nm and 10 m in size, to form a suspension of pore forming agent in the drug solution. Subsequently, the solid pore forming agent particle size can be reduced by further processing the resulting suspension, for example, using homogenization or sonication techniques known in the art. Then, the solution, emulsion, or suspension is further processed to remove the drug solvent and the pore forming agent simultaneously or sequentially, using evaporation, spray drying, fluid bed drying, lyophilization, vacuum drying, or a combination of these techniques. In a preferred embodiment, the solution, emulsion, or suspension is spray-dried. As used herein, spray dry means to atomize the solution, emulsion, or suspension to form a fine mist of droplets (of drug solution having solid or liquid pore forming agent dispersed throughout), which immediately enter a drying chamber (e.g., a vessel, tank, tubing, or coil) where they contact a drying gas. The solvent and pore forming agents evaporate from the droplets into the drying gas to solidify the droplets, simultaneously forming pores throughout the solid. The solid (typically in a powder, particulate form) then is separated from the drying gas and collected.
33
V. Porous Drug Matrix Applications The porous drug matrices described herein are useful in formulations for administration to a patient in need of the drug. As used herein, patient refers to animals, including mammals, preferably humans. The formulations deliver a therapeutically or prophylactically effective amount of the drug to the patient. The porous matrices, or formulations thereof, are suitable for administration of drug by a variety of routes, for example, parenteral, mucosal, oral, topical/transdermal administration, for local, regional, or systemic effect. Examples of parenteral routes include intraveneous, intraarterial, intracardiac, intrathecal, intraosseous, intraarticular, intrasynovial, intracutaneous, subcutaneous, and intramuscular administration. Examples of mucosal routes include pulmonary (intrarespiratory), buccal, sublingual, intranasal, rectal, and vaginal administration. The porous matrices also can be formulated for intraocular, conjunctival, aural, urethral, intracranial, intralesional, and intratumoral administration. In a preferred embodiment, the drug matrix is in the form of powder, which can be reconstituted with an aqueous medium, such as physiological saline, and administered parenterally, such as intramuscularly, subcutaneously, or intravenously. An advantage of the formulations described herein is that they can be used to convert drugs which must be infused (e.g., to avoid precipitation of the drug following bolus injection) to a bolus formulation, avoiding unacceptable precipitation of drug in vivo or for local delivery. Alternatively, the matrix can be further processed using standard techniques into tablets or capsules for oral administration, into rectal suppositories, into a dry powder inhaler for pulmonary administration, or mixed/processed into a cream or ointment for topical administrationThe present invention will be further understood with reference to the following non-limiting examples. D. SOLID DISPERSION Solid dispersion is drug dispersed in a biologically inert matrix. Drug in soluble hydrophilic carrier improves the dissolution rate by reducing particle size, higher porosity, drug is in amorphous state,
34
improving wettability and hence possibly bioavailability for poorly water soluble drugs. Polymers used are Polyethylene glycol, polyvinyl pyrollidone of low molecular weight material such as sugars. The mechanism of improving dissolution was not yet understood. Recently surfactants have been included to stabilize the formulations, this avoiding drug recrystallisation and potentiating their solubility. DEFINITION The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles. Chiou and Riegelman defined the term solid dispersion asa dispersion involving the formation of eutectic mixtures of drugs with water soluble carriers by melting of their physical mixtures.
The term solid dispersion refers to the dispersion of one or more active ingredient in an inert carrier or matrix at solid state prepared by melting (fusion), solvent, or the melting solvent method. Sekiguchi and Obi suggested that the drug was present in a eutectic mixture in a microcrystalline state, after few years Goldberg et.al. reported that all drug in solid dispersion might not necessarily be presents in a microcrystalline state, a certain fraction of the drug might be molecular dispersion in the matrix, thereby forming a solid solution. Once the solid dispersion was exposed to aqueous media & the carrier dissolved, the drug was released as very fine, colloidal particles. Because of greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs were expected to be high. The commercial use of such systems has been limited primarily because of manufacturing problems with solid dispersion systems may be overcome by using surface active and self-emulsifying carriers. The carriers are melted at elevated temperatures and the drugs are dissolved in molten carriers. Surface active carriers used in solid dispersion:
35
The advantage of a surface-active carrier over a non-surface-active one in the dissolution of drug from a capsule formulation is shown schematically in Figure 1. The physical state of drug if a solid dispersion must, however, is carefully considered an evaluating the advantage of a surfaceactive vehicle. As mentioned earlier, the drug can be molecularly dispersed in the carrier to form a solid solution or it can be dispersed as particles. It can also be both partially dissolved and partially dispersed in the carrier. The potential for the formation of a continuous drug rich surface layer is possibly greater if the drug is molecularly dispersed, whereas the drug dispersed, as particulates may be more prone to dissociation from the water-soluble matrix. It is however, rare that the drug is dispersed just as particulates and is not at least partially dissolved in the vehicle. Therefore, a surface-active carrier is preferably in almost all cases for the solid dispersion of poorly watersoluble drugs.
Figure 1. A schematic representation of the comparative dissolution of a poorly water-soluble drug from surface-active versus non surface-active vehicle. Co-precipitation-
36
Solute and solid carrier solvent are dissolving in a common volatile liquid solvent such as alcohol. The liquid solvent is removed by evaporation under reduced pressure or by freeze-drying which result in amorphous precipitation of solute in a crystalline carrier. Example: amorphous sulfathiazole in crystalline urea. Such dispersions are often called as co-evaporates or co-precipitates. The method is suitable for thermolabile substances but has a number of disadvantages like higher cost of processing, use of large quantities of solvent, difficulty in complete removal of solvent, etc The methods of preparation of solid dispersion: (i) Melting (fusion) (ii) Solvent or melting solvent method.
Manufacturing Process used to produce solid dispersions:
37
Limitations of Surface active carrier based Solid Dispersions: 1. The solid state structure 2. The mechanism by which dissolution enhancement occurs 3. The stability of the dispersions on storage 4. Poor understanding of IVIVC. Solid dispersion in surface-active carriers may not be the answer to all bioavailability problems with poorly water-soluble drug. One of the limitations of bioavailability enhancement by this method might be the low solubility of drug in available carriers. The desired dose of a drug cannot be solubilized and filled into the hard gelatin capsules if adequate solubility in a carrier cannot be obtained. Dordunoo et al reported that the particle size of a drug in a solid dispersion remained unchanged if it is just mixed with the carrier instead of dissolving in it. On the other hand, if the drug is dissolved by heating in excess of its solubility in a carrier under normal storage condition, it may subsequently crystallize out from the solid dispersion. Either situation would defect the purpose of bioavailability enhancement of poorly water-soluble drugs by solid dispersion. Another limitation of the use of surface-active carrier reported by Aungst et al. is that the bioavailability of a drug may vary depending on the amount of carrier administered along with it. This variation is because different amounts of a surface-active carrier may have different solubilization or dispersion effects on a drug in the gastrointestinal fluid.
38
Serajuddin et al. reported a method whereby the rate and efficiency of dispersion of drug in aqueous media from different formulations can be studied. NEWER TECHNIQUES The two important breakthrough in formulation of solid dispersion are, the development of technologies to fill solid dispersions directly in to hard gelatin capsule and the ability of surface active & self-emulsifying agents carriers. The technique to fill solid dispersion directly into hard gelatin capsule as melts, which gets solidify at room temperature, was first described by Francols & Jones in 1978. But the potential application of that technique was fully realized by Chatham. For ease of manufacturing the carriers must be amenable to liquid filling into hard gelatin capsules as melts. The melting temperature of carriers should be such that the solutions do not exceed ~70C which is the maximum acceptable temperature for hard gelatin capsule shells. The water soluble carriers dissolves more rapidly than the drug, the drug rich layer has to form over the surface of dissolving plug, which prevent further dissolution of drug from solid dispersion because of this directly filled hard gelatin capsule is not a good method of preparation of solid dispersion unless the formation of drug rich layer on the surface of dissolving plug can be prevented. The self-emulsifying agent will act as dispersing or self emulsifying agent on drug through which the dissolution of drug can be increase by preventing the formation of any water insoluble surface layer, although the liberated drug remain undissolved in the dissolution medium. When its concentration exceeded its saturation solubility, it will disperse or emulsify into a finely divided state because of the surface activity of the dissolved vehicle the high surface area will be made available which will facilitate its dissolution in gastrointestinal fluid. Serajuddin et al. has also studied improve dissolution of dispersions of REV-5901. He prepared solid dispersion of poorly water-soluble REV-5901 (alpha-pentyl-3- (2 quinolinylmethoxy) benzene methanol) in various PEGs & in Gelucire 44/14 filled in to hard gelatin capsule, Gelucire 44/14 formulation were able to promote complete & rapid drug dispersion in water & simulated gastric fluid. The most commonly used surface-active carrier is Gelucire 44/14.
39
Table- Examples of surface-active carriers used for solid dispersion.
Sr. No. Carrier 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Poloxamer 188 Poloxamer 188 Poloxamer 407 Poloxamer 188, Gelucire 50/13 Gelucire 44/14 Gelucire 44/14 Mixture Gelucire 44/14-lecithin Gelucire 44/14 and PEG 6000
Drug Ibuprofen ABT-963 Nifedipine Nifedipine REV 5901 LAB-687 Ubidecarenone Glibenclamide
Scientist Passerini et al Chen et al Chutinawarapan et al Vippagunta et al Sheen et al Serajuddin et al Pozi et al Tashtoush Squillanate et al Seong-Wan CHO et al Aungst et al
Gelucire 44/14, Vitamin E TPGS Carbamazepine Gelucire, Capmul, Capmul MCM Ceftriaxone C10 Polyethylene glycol DMP 323
Mixture of Gelucire 50/13, Polysorbate 80, Polyoxyl 35 Ritonavir castor oil
---
40
13. 14.
PEG 3350- Labrasol-Polysorbate RP 80 PEG, Myrj 2, Eudragit E 100 Indomethacin
69698 Sheen et al Hadi et al
E. PARTICLE SIZE REDUCTION The bioavailability of low solubility drugs is often intrinsically related to drug particle size. By reducing particle size, the increased surface area may improve the dissolution properties of the drug to allow a wider range of formulation approaches and delivery technologies. DEFINITION Nanosizing: Reducing drug particle size to below submicron level i.e., 100-200nm. This reduction of particle size leads to significant increase in the dissolution rate of drug. Elans nanomilling technology is utilized, which works on two approaches Top down (Wet milling technology) and bottom up (Precipitation, crystallization).16 Micronization: The process involves reducing the size of the solid drug particles to 1 to10 microns commonly by spray drying or by use of air attrition methods (fluid energy mill). Examples of drugs whose bioavailability have been increased by micronization include griseofulvin and several steroidal and sulfa drugs. Greater the surface area, faster the dissolution, can be increased by micronization of drug "Micronization" means the production of particles having an average diameter of 1-100 m."Nanonization" means the production of particles having an average diameter of less than 1 m. Methods For Particle Size Reduction: -
1. Pearl milling
41
NanoCrystals involves filling an aqueous suspension of drug into a pearl mill containing glass or zirconium oxide pearls as milling media. The drug microparticles are ground to nanoparticles (< 400 nm) in between the moving milling pearls over a few days. The milling efficiency is dependent on the properties of the drug, the medium and the stabilizer. Rapamune, an immune suppressant agent, is the first FDA approved nanoparticle drug using NanoCrystals technology developed by Elan Drug Delivery. Emend is another product containing 80 or 125 mg aprepitant formulated by this technique. The limitation of the pearl milling process is the introduction of contamination to the product from the grinding material, batch-to-batch variations and the risk of microbiological problems after milling in an aqueous environment for a few days.
2. High pressure homogenizationDissoCubes manufacture involves dispersing a drug powder in an aqueous surfactant solution and passing through a high pressure homogenizer, subsequently nanosuspensions are obtained. The cavitation force experienced is sufficient to disintegrate drug from microparticles to nanoparticles. The particle size is dependent on the hardness of the drug substance, the processing pressure and the number of cycles applied. The possible interesting features of nanosuspensions are (Mller et al., 2001): Increase in saturation solubility and dissolution rate of drug Increase in adhesive nature, thus resulting in enhanced bioavailability Increase the amorphous fraction in the particles, leading to a potential change in the crystalline structure and higher solubility Possibility of surface modification of nanosuspensions for site specific delivery Possibility of large-scale production, the prerequisite for the introduction of a delivery system to the market. However, only brittle drug candidates might be broken up into nanoparticles by this technique. A few points have to be considered, such as chemical instability of fragile drugs under the harsh production conditions, Ostwald ripening in long-term storage, toxicity of surfactants, redispersibility of the dried powder, batch-to-batch variation in crystallinity level and finally the difficulty of quality control and the stability of the partially amorphous nanosuspensions.
42
3. Solution enhanced dispersion by the supercritical fluids (SEDS)The SEDS process was developed and patented by the University of Bradford (Hanna and York, 1998). The use of a coaxial nozzle provides a means whereby the drug in the organic solvent solution mixes with the compressed fluid CO2 (antisolvent) in the mixing chamber of the nozzle prior to dispersion, and flows into a particle-formation vessel via a restricted orifice. Such nozzle achieves solution breakup through the impaction of the solution by a higher velocity fluid. The high velocity fluid creates high frictional surface forces, causing the solution to disintegrate into droplets. A wide range of materials has been prepared as carriers of microparticles and nanoparticles using the SEDS process (York, 1999; Hanna and York, 1998). A key step in the formation of nanoparticles is to enhance the mass transfer rate between the droplets and the antisolvent before the droplets coalesce to form bigger droplets. In another study, a significant decrease in the particle size is achieved by using the ultrasonic nozzle-based supercritical antisolvent process (Subramaniam et al., 1997A; 1997B).
4. Rapid expansion from supercritical to aqueous solution (RESAS)This process induces rapid nucleation of the supercritical fluid dissolved drugs and surfactants resulting in particle formation with a desirable size distribution in a very short time. The surfactants in the supercritical fluid stabilize the newly formed small particles and suppress any tendency of particle agglomeration or particle growth when spraying this solution (drug + surfactant + CO2) into an aqueous solution containing a second surface modifier (Young et al., 2000; Pace et al., 2001). The low solubility of poorly water soluble drugs and surfactants in supercritical CO2 and the high pressure required for these processes restrict the utility of this technology in pharmaceutical industry.
5. Spray freezing into liquid (SFL)The SFL technology was developed and patented by the University of Texas at Austin in 2003 and commercialized by the Dow Chemical Company. This technique involves atomizing an aqueous, organic, aqueousorganic cosolvent solution, aqueous-organic emulsion or suspension containing a
43
drug and pharmaceutical excipients directly into a compressed gas (i.e. CO2, helium, propane, ethane), or the cryogenic liquids (i.e. nitrogen, argon, or hydrofluoroethers). The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders (Williams et al., 2003). Using of acetonitrile as the solvent increased the drug loading and decreased the drying time for lyophilization. The dissolution rate was remarkably enhanced from the SFL powder contained amorphous nanostructured aggregates with high surface area and excellent wettability (Rogers et al., 2002; 2003; Hu et al., 2002; 2003).
6. Evaporative precipitation into aqueous solution (EPAS)The EPAS process utilizes rapid phase separation to nucleate and grow nanoparticles and microparticles of lipophilic drugs. The drug is first dissolved in a low boiling point organic solvent. This solution is pumped through a tube where it is heated under pressure to a temperature above the solvents boiling point and then sprayed through a fine atomizing nozzle into a heated aqueous solution. Surfactants are added to the organic solution and the aqueous 15 solution to optimize particle formation and stabilization. In EPAS, the surfactant migrates to the drug-water interface during particle formation, and the hydrophilic segment is oriented towards the aqueous continuous phase (Chen et al., 2002). The hydrophilic stabilizer on the surface inhibits crystallization of the growing particles and therefore facilitates dissolution rates. OTHER METHODS: Lyophilization: The material to be dried is first frozen and then subjected under a high vacuum to heat (supplied by conduction or radiation or by both), so that the frozen liquid sublimed leaving only the solid, dried components of the original liquid. The four components of freeze driers are vacum chamber for drying, vacum source, heat source and vapor removal system. Gole et al32 and Lawrence et al33 describes the inventive preparation of lyophilized matrix with gelatin, pectin, soy fibre protein and mannitol. The low soluble and bitter actives like risperidone and ibuprofen are coated by particulate coating with natural or synthetic polymer and organic solvents and dried by vapor
44
removal system. The Matrix disperses rapidly with in 10 seconds in water and thus improves dissolution. Use of Salt forms: Salts have improved solubility and dissolution characteristics in comparison to the original drug. Alkali metals salts of acidic drug like penicillins and strong acid salts of basic drugs like atropine are more water-soluble than the parent drug. Use of more soluble metastable polymorphs: the B form of chlorampheical palmitate is more water-soluble than the A and the C forms. Solute-solvent complexation: solvates of drugs with organic solvents (also called as pseudopolymorphs) generally have higher aqueous solubility than their respective hydrates or the original drug. Much higher solubility can be Solvent deposition: In this method, the poorly aqueous soluble drug such as nifedipine is dissolved in an organic solvent like alcohol and deposited on an inert, hydrophilic, solid matrix such as starch or microcrystalline cellulose by evaporation of solvent. Solid solutions : A solid solution is a binary system comprising of a solid solute molecularly dispersed in a solid solvent by fusion method whereby physical mixture of solute and solvent are melted together followed by rapid solidification. Griseofulvin-succinic acid . Eutetic Mixtures :Eutetic melts differ from solid solution in that the fused melt of solute-solvent show complete miscibility but negligible solid-solid solubility i.e. such systems are basically intimately blended physical mixture of two crystalline components. Paracetamol-urea, grisefulvin-urea. The methods cannot be applied for drugs which fail to crystallize from the mixed melt, thermolabile drugs and
45
carriers such as succininc acid that decompose at their melting point. The eutectic product is often tacky, intractable or irregular crystal. Molecular encapsulation and cyclodextrins: The beta and gamma cyclodextrins and several of their derivatives are unique in having the ability to form molecular inclusions complexes with hydrophobic drug having poor aqueous solubility. These cyclodextrin molecules are versatile in having a hydrophobic cavity of size suitable enough to accommodate the lipophilic drugs as guest; the outside of the host molecule is relatively hydrophilic. Thiazide diuretics, barbiturates, benzodiazepines Delayed release : A modified release product in which the release of active substance is delayed for a finite lag time, after which release is unhindered [e.g. enteric coated or Gastro resistant (Ph.Eur.) oral tablets or capsules which remain intact in the stomach and only disintegrate in the higher pH of the small intestine]. Delayed release results in a longer Tmax but with Tmax and elimination half life unchanged. In delayed release component, the drug may not be sufficiently protected for residence time greater than 2 hours in the gastric pH of 1.2. Low pH may also alter the performance by causing chemical reactions of the materials used in the dosage for modifying the release of drug. Therefore, while the final dissolution test may only require a 1-2 hour presoak at gastric pH, the dosage form should be thoroughly evaluated at gastric pH if there is potential for long gastric residence times. If the goal of the dosage form is to release the drug in the duodenum, e.g., target transport through tight junctions, then the dissolution test should reflect the possibility of a short residence time. This is especially true if the mechanism for targeting the release is enteric coating. Further hampering of drug release can occur if the enteric coating erodes at pH 6.5, since the pH at the proximal duodenum is closer to 5.5 than 6.5. Therefore, an appropriate dissolution test for pH sensitive release mechanism such as enteric-coated dosage forms may require several pHs simultaneously taking into consideration the potential in vivo residence time at each pH.
46
Coated particles/beads currently used in both extended release and delayed release dosage forms offer advantages over larger, non-disintegrating delivery systems. Depending on the design of the delivery system, dissolution tests for bead formulations may consist of 2-3 hours in simulated gastric fluid at pH 1.2, followed by 15-30 minutes in simulated intestinal fluid at pH 5.5, and then simulated intestinal fluid at pH 6.8 or pH 8.0. Extended Release: The FIP -Guideline and European Pharmacopeia demand at least 3 specification points, the first after 1-2 hours (around 20-30% drug release) to provide assurance against premature drug release. The second specification point has to be around 50 % drug release to define the dissolution pattern. At the last point, the dissolution limit should be at least 80 % drug release to ensure almost quantitative release. Alternatively, a dissolution of <80% has to be justified and should be supported by a test duration of at least 24 hours. As can be seen, there are slight differences with regard to the United States Pharmacopeia17, where only > 2 test points are demanded considering the individual monograph. In-vitro-In-vivo Correlation: Invitro-invivo correlation is the demonstration of the direct relationship of in vitro dissolution rate of drugs and their in vivo bioavailability. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed28. Correlation is used to ensure batch-to-batch consistency in the physiologic performance of a drug product by use of such in vitro values and to serve as a tool in the development of a new dosage form with desired in vivo performance. There are two basic approaches by which a correlation between dissolution testing and bioavailability can be developed. 1. By establishing a relationship, between the in vitro dissolution and the in vivo bioavailability parameters. If this relationship becomes linear with a slope of 1, then curves are super imposable, and there is a 1:1 relationship which is defined as point-to-point or level A correlation.
47
2. By using the data from previous bioavailability studies to modify the dissolution methodology in order to arrive at meaningful in vitro-invivo correlation. Application of an IVIVC Biowaivers: Recent research has lead to the use of in-vitro tests to waive additional in vivo bioequivalency studies for some pharmaceutical products. The use of in vitro testing to achieve a waiver of in vivo studies is commonly referred to as a biowaiver. The FDA guidance outlines five categories of biowaivers: 1) biowaivers without an IVIVC, 2) biowaivers using an IVIVC: non-narrow therapeutic index drugs, 3) biowaivers using an IVIVC: narrow therapeutic index drugs, 4) biowaivers when in vitro dissolution is independent of dissolution test conditions and 5) situations for which an IVIVC is not recommended for biowaivers.
Biowaivers for new drug : Biowaivers of a higher strength will be determined to be appropriate based on (i) clinical safety and/or efficacy studies including data on the dose and the desirability of the higher strength, (ii) linear elimination kinetics over the therapeutic dose range, (iii) the higher strength being proportionally similar to the lower strength, and (iv) the same dissolution procedures being used for both strengths and similar dissolution results obtained. A dissolution profile should be generated for all strengths. Biowaiver of Generic drug: (i)Waiver of in vivo BE studies based on BCS: Recommended for a solid oral test product that exhibit rapid (85% in 30 mints) and similar in vitro dissolution under specified conditions to an approved reference product when the following conditions are satisfied: Products are pharmaceutical equivalent
48
Drug substance is highly soluble and highly permeable and is not considered have a narrow therapeutic range Excipients used are not likely to effect drug absorption;
(ii). Waiver of invivo BE for IR oral dosage form: bioequivalence studies may be waived for compositionally similar strengths when one strength in a range has been studied, under these conditions the following conditions are satisfied Product are manufactured by the same manufacturer and process Linear pharmacokinetics The qualitative composition of the different strengths is the same; except in the case of
flavours/colours The ratio between amounts of drug and excipients is the same or in case of preparations
containing a low concentration of the drug (less than 5%), the ratio between the amounts of excipients is similar the dissolution profile should be similar for additional strengths and the strength of the batch
used in BE study Waivers for Scale-up and Post approval changes: Biowaivers may be granted for manufacturing site changes, equipment changes, manufacturing process changes, and formulation composition changes according to a predictive and reliable IVIVC.19
49
REFERENCES 1. Textbook of Biopharmaceutics and Pharmacokinetics- A treaties by Brahmankar D.M., Jaiswal S.B. 2. Text book The Theory and Practice of Industrial Pharmacy by Leon Lachman, Herbert A. Lieberman, and Joseph L. Kanig., 3rd Indian, edition. 3. Text book of Anatomy and Physiology in Health and Illness, 9th edition, by Ross and Willson. 4. H.Abdou, dissolution bioavailability and bioequivalence, mack publishing 5. European Pharmacopoeia, 6th edition.
50
company.
6. In-Vitro-In-Vivo Correlations and Definitions and Regulatory Guidances published in http://www.locumusa.com (International journal of generic drugs) 7. Guidance for Industry Bioavailability and Bioequivalence studies for orally administered drug productsGeneral Considerations available online in http://www.fda.gov/cder/ guidance/4964dft.htm. 8. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs by Jennifer B.Dressman, Christos Reppas published in European Journal of Pharmaceutical Sciences 11 Suppl.2 (2000) S73-S80. 9. International pharmaceutical federation(FIP); Guidelines for Dissolution Testing of Solid Oral Product. 10. J.W.Moore and H.H.Flanner, Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles. Pharm. Tech. 20(6), : 64-74, 1996. 11. http://seacoast.sunderland.ac.uk/~hs0dad/qm/ctinew/v2bthumb.htm 12. http://www.tsrlinc.com/services/bcs/search.cfm 13. International pharmaceutical federation(FIP); Guidelines for Dissolution Testing of Solid Oral Products in www.fip.org 14. Solid dispersion as strategy to improve oral bioavailability of poor water soluble drugs by Teofilo vasconcelos, Bruno sarmento and Paluo costa publised in Drug discovery today 12 numbers 23/24 Dec 2007. 15. The mechanism of drug release from solid dispersions in water soluble polymers by Duncan Q.M Craig, Published in International journal of Pharmaceutics 231 (2002) 131-144. 16. Nanosizing oral formulation development and biopharmaceutical evaluatin by Flippos kesisoglon, Santipharp Pannai, Yunhui wu published in Advance drug delivery reviews 59(2007) 631-644. 17. Application of In Vitro-In Vivo correlations (IVIVC) in setting Formulation Release Specifications by Nishit B.Modi et al published in Biopharm. Drug Dispos. 21:321-326(2000).
51
52

Project

Diunggah oleh

Informasi Dokumen

Deskripsi Asli:

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Project

Diunggah oleh

Hak Cipta:

Format Tersedia

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Maximum safe concentration

Minimum effective concentration

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

2. Patient related factors.

Bioavailability Enhancement Methods

Fig.- effect of Gastric emptying on bioavailability

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

2. PHARMACODYNAMIC MTHODS: Target system effect method,

3. IN VITRO TESTS (E.G., THE DISSOLUTION AND DISINTEGRATION TEST

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

4. URINE INCREMENT METHOD

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

METHODS OF ENHANCEMENT OF BIOAVAILABILITY

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Fig- effect of different surfactant

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Manufacturing Process used to produce solid dispersions:

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Table- Examples of surface-active carriers used for solid dispersion.

Mixture of Gelucire 50/13, Polysorbate 80, Polyoxyl 35 Ritonavir castor oil

Bioavailability Enhancement Methods

PEG 3350- Labrasol-Polysorbate RP 80 PEG, Myrj 2, Eudragit E 100 Indomethacin

69698 Sheen et al Hadi et al

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods

Bioavailability Enhancement Methods