SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM: A METHOD …

www.wjpr.net Vol 5, Issue 7, 2016.

578

Ghule et al. World Journal of Pharmaceutical Research

SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM: A

METHOD FOR ENHANCEMENT OF BIOAVAILABILITY

Poonam Kailas Ghule*, Sadik F. Sayyad and Dr. Sanjay R. Chaudhari

Savitribai Phule Pune University, Pune, Amrutvahini Sheti and Shikshan Vikas Sanstha’s,

Amrutvahini College of Pharmacy, Amrutnagar, Sangamner, Maharashtra 2015 – 2016.

ABSTRACT[1-3]

Most of the modern drugs are poorly aqueous soluble, having high

molecular weight, pre systemic first pass effect, enzymatic degradation

and limited dissolution rate shows low bioavailability. The newer and

novel technologies developed in recent year to overcome such

problems. One of the most new way for such a mentioned problem is

the Self microemulsifying drug delivery system (SMEDDS). The

SMEDDS are the isotropic mixture of oil, surfactant and co-surfactant.

SMEDDS solve the problem of all BCS class of drug such as

solubility, high molecular weight, pre systemic first pass effect,

enzymatic degradation, gastric irritation and also increase the

bioavailability and stability of drug. SMEDDS are complex mixtures in

which drug quantification can become a challenging task. The

hypothesis behind dissolution rate enhancement with SMEDDS is the

spontaneous formation of the emulsion in the gastrointestinal tract which presents the drug in

solubilized form, and the small size of the formed droplet provides a large interfacial surface

area for drug absorption.. This article gives a complete overview of SMEDDS as a promising

approach to effectively tackle the problem of poorly soluble molecules.

KEYWORDS: Self micro emulsifying drug delivery system, oral bioavailability, lipid based

formulations, poorly water soluble drugs.

INTRODUCTION[2-4]

Self micro emulsifying drug delivery system (SMEDDS) are defined as isotropic mixtures of

natural or synthetic oils, solid or liquid surfactants, or alternatively, one or more hydrophilic

solvents and co-solvents/surfactants that have a unique ability of forming fine oil-in-water

World Journal of Pharmaceutical Research SJIF Impact Factor 6.805

Volume 5, Issue 7, 578-590. Review Article ISSN 2277– 7105

*Corresponding Author

Poonam Kailas Ghule

Savitribai Phule Pune

University, Pune,

Amrutvahini Sheti and

Shikshan Vikas Sanstha’s,

Amrutvahini College of

Pharmacy, Amrutnagar,

Sangamner, Maharashtra

2015 – 2016.

Article Received on

13 May 2016,

Revised on 03 June 2016,

Accepted on 24 June 2016

DOI: 10.20959/wjpr20167-6613


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(o/w) micro emulsions upon mild agitation followed by dilution in aqueous media, such as GI

fluids.[1]

SMEDDS spread readily in the GI tract, and the digestive motility of the stomach

and the intestine provide the agitation necessary for self-emulsification. SMEDDS form

transparent micro emulsions with a droplet size of less than 50 nm also the concentration of

oil in SMEDDS is less than 20 % as compared to 40-80% in SEDDS. When compared with

emulsions, which are sensitive and metastable dispersed forms, SMEDDS are physically

stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that

exhibit dissolution rate-limited absorption, these systems may offer an improvement in the

rate and extent of absorption and result in more reproducible blood-time profiles. SMEDDS

formulation is in theory, comparatively simple. The key step is to find a suitable oil surfactant

mixture that can dissolve the drug within the required therapeutic concentration. The

SMEDDS mixture can be filled in either soft or hard gelatin capsules. A typical SMEDDS

formulation contains oils, surfactants and if required an antioxidants. Often co-surfactants

and co-solvents are added to improve the formulation characteristics.

ADVANTAGES OF SMEDDS

1. Enhanced oral bioavailability enabling reduction in dose[18]

2. Selective targeting of drug(s) towards specific absorption window in GIT.[2]

3. Protection of drug(s) from the hostile environment in gut.[9]

4. Reduced variability including food effects.[13]

5. Protection of sensitive drug substances.

6. Liquid or solid dosage forms.

7. In SMEDDS, the lipid matrix interacts readily with water, forming a fine particulate oil-

in-water (o/w) emulsion. The emulsion droplets will deliver the drug to the

gastrointestinal mucosa in the dissolved state readily accessible for absorption. Therefore

increase in AUC i.e. bioavailability and C max is observed with many drugs when

presented in SMEDDS.

8. Fine oil droplets empty rapidly from the stomach and promote wide distribution of drug

throughout the intestinal tract and thereby minimizing irritation frequently encountered

with extended contact of drugs and gut wall.[9]

9. Ease of manufacture and scale up is one of the most important advantage that make

SMEDDS unique when compared to other drug delivery system like solid dispersion,

liposomes, nanoparticles etc.


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10. SMEDDS has potential to deliver peptides that are processed to enzymatic hydrolysis in

GIT.

11. When polymer is incorporated in composition of SMEDDS it gives prolonged release of

medicament.[5]

12. SMEDDS formulation is composed of lipids, surfactants and co-solvents. The system has

the ability to form an oil-on-water emulsion when dispersed by an aqueous phase under

gentle agitation. SMEDDS present drugs in a small droplet size and well-proportioned

distribution and increase the dissolution and permeability. Furthermore, because drugs

can be loaded in the inner phase and delivered to the lymphatic system, can bypass first

pass metabolism. Thus SMEDDS protect drugs against hydrolysis by enzymes in the GI

tract and reduce the presystemic clearance in the GI mucosa and hepatic first-pass

metabolism.

DISADVANTAGES OF SMEDDS[1-5]

1. One of the obstacles for the development of SMEDDS and other lipid-based formulations

is the lack of good predicative in vitro models for assessment of the formulations.

2. Traditional dissolution methods do not work, because these formulations potentially are

dependent on digestion prior to release of the drug.

3. This in vitro model needs further development and validation before its strength can be

evaluated.

4. Further development will be based on in vitro - in vivo correlations and therefore different

prototype lipid based formulations needs to be developed and tested in vivo in a suitable

animal model.

5. The drawbacks of this system include chemical instabilities of drugs and high surfactant

concentrations in formulations (approximately 30-60%) which irritate GIT.

6. Moreover, volatile co solvents in the conventional self-micro emulsifying formulations

are known to migrate into the shells of soft or hard gelatin capsules, resulting in the

precipitation of the lipophilic drugs.

7. The precipitation tendency of the drug on dilution may be higher due to the dilution effect

of the hydrophilic solvent.

8. Formulations containing several components become more challenging to validate.


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COMPOSITION OF SMEDDS[2-5]

The SMEDDS composed of the oil and surfactant. The ratio of concentration of the oil and

surfactant depends upon the solubility of the drug and self emulsifying ability. The nature of

oil, concentration of surfactant and the temperature at which self emulsification occur is also

important during the formulation of SMEDDS. Preformulation studies are carried out for the

selection of oil, surfactant and co-surfactant as these are specific for a particular SMEDDS.

First we govern solubility of drug in various oils and surfactant/co-surfactant then prepare a

series of SMEDDS system containing drug in various oils and surfactants/co-surfactants. By

constricting the Pseudo-ternary phase diagram we identify the efficient self -emulsification

region.

1. OILS

One of the most important excipients because oil can solubilise the lipophilic drug in a

specific amount and it can facilitate self emulsification and increase the fraction of lipophilic

drug transported via the intestinal lymphatic system, mainly the long chain and medium chain

triglycerides are use. The concentration of oil present in SMEDDS is about the 40 to 80 % the

modified and hydrolyzed vegetable oils widely because they show the more solubility and

good self emulsifying property. Solvent capacity for less hydrophobic drugs can be improved

by blend in gtriglycerides with mono- and di-glycerides.

2. SURFACTANTS

The surfactant is the important for the solubilisation of the drug in the oil and they commonly

use as the emulsifier in this system. The various surfactants are using in this system mainly

the non-ionic surfactants. The non-ionic surfactants have the ability to from the self

emulsification in gastric medium also the non ionic surfactant having the less toxicity. The

non-ionic surfactant cause the reversible changes in the permeability of the intestinal lumen.

The concentration of surfactant is most important parameter because the self emulsification

of SMEDDS is depends up on the concentration ratio of oil and surfactant. The concentration

of surfactant is about the 30 to 60 % in SMEDDS and the HLB value of non ionic surfactant

is about >12. The large quantity of the surfactant may cause the gastric irritation. The droplet

size depends up on the concentration of surfactant. The mean droplet size is increase with

increasing the surfactant concentration. This could be attributed to the interfacial disruption

elicited by enhanced water penetration into the oil droplet mediated by the increased

surfactant concentration and leading to ejection of oil droplets into the aqueous phase. The


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surfactants used in these formulations are known to improve the bioavailability by various

mechanisms including: improved drug dissolution, increased intestinal epithelial

permeability, increased tight junction permeability.

3. CO-SURFACTANT

For the fabrication of an optimum SMEDDS, high concentration of surfactant is required in

order to reduce interfacial tension sufficiently, which can be harmful, so co-surfactants are

used to shrink the concentration of surfactants. Co-surfactants together with the surfactants

afford the sufficient litheness to interfacial film to take up different curvatures required to

form micro-emulsion over a wide range of composition. Selection of proper surfactant and

co-surfactant is necessary for the efficient design of SMEDDS and for the solubilisation of

drug in the SMEDDS. Organic solvents like ethanol, propylene glycol, polyethylene glycol

are able to dissolve large amount of either drug or hydrophilic surfactant in lipid base and are

suitable for oral delivery, so they can be used as co-surfactant for SMEDDS. Alternately

alcohols and other volatile co-solvents show a disadvantage that by evaporation they get

entered into soft/hard gelatin capsule shells resulting in precipitation of drug. On the other

hand formulations which are free from alcohols have limited lipophilic drug dissolution

ability. Hence, appropriate choice of components has to be made for formulation of efficient

SMEDDS. Hydrophilic co-surfactants are preferably alcohols of intermediate chain length

such as hexanol, pentanol and octanol, which are known to reduce the oil/water interface and

allow the spontaneous formulation of micro emulsion.

CONSTRUCTION OF TERNARY PHASE DIAGRAMS[15-18]

Ternary phase diagram is useful to identify best emulsification region of Oil, Surfactant and

Co-Surfactant combinations. Ternary phase diagram of surfactant, co-surfactant and oil will

plot; each of them, representing an apex of the triangle. The methods are used to plot Ternary

phase diagrams are namely Dilution method and Water Titration method.

DILUTION METHOD

Ternary mixtures with varying compositions of surfactant, co-surfactant and oil will be

equipped. The surfactant concentration will diverge from 30 to 75% (w/w), oil concentration

will diverge from 25 to 75% and co-surfactant concentration will diverge from 0 to 30%

(w/w). For any mixture, the total of surfactant, co-surfactant and oil concentrations always

added to 100%. For example, in the experiment, first mixture consisted of 75% of surfactant,

25% of the oily phase and 0% of co-surfactant. Further, the co-surfactant was increased by


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5% for each composition, oily phase concentration will keep constant and the surfactant

concentration will adjust to make a total of 100%. Forty-two such mixtures with varying

surfactant, co-surfactant and oil concentrations will prepare. The percentage of surfactant, co-

surfactant and oil used herein will decide on the basis of the requirements. Compositions are

evaluated for nanoemulsion formation by diluting appropriate amount of mixtures with

appropriate double distilled water. Globule size of the resulting dispersions will be

determined by using spectroscopy technique. Dispersions, having globule size 200 nm or

below will consider desirable. The area of nanoemulsion formation in Ternary phase diagram

will identified for the respective system in which nanoemulsions with desire globule size

were obtain.

WATER TITRATION METHOD

The pseudo-ternary phase diagrams were also constructed by titration of homogenous liquid

mixtures of oil, surfactant and co-surfactant with water at room temperature. Oil phase,

Surfactant and the co-surfactant (surfactant: co-surfactant ratio) were prepared varied from

9:1 to 1:9 and weighed in the same screw-cap glass tubes and were vortexed. Each mixture

was then slowly titrated with aliquots of distilled water and stirred at room temperature to

attain equilibrium. The mixture was visually examined for transparency. After equilibrium

was reached, the mixtures were further titrated with aliquots of distilled water until they

showed the turbidity. Clear and isotropic samples were deemed to be within the

microemulsion region. No attempts were made to completely identify the other regions of the

phase diagrams. Based on the results, appropriate percentage of oil, surfactant and co-

surfactant was selected, correlated in the phase diagram and were used for preparation of

SMEDDS.

PREPARATIONS OF SMEDDS FORMULATIONS

SMEDDS was prepared according to recently reported method. Variable proportions of oil,

surfactant and co-surfactant were added into a 10 ml screw capped glass tube, and the

components were mixed by gentle stirring. After complete dissolution, SMEDDS, a clear and

transparent solution, was obtained. Based on the results of above experiment and the reported

concentration scope of three ingredients forming SMEDDS, the contents of surfactant, co-

surfactant and oil were chosen at the range of 30-65%, 30-65% and 5-40%, respectively, in

order to obtain the optimal formulation of SMEDDS. Now a days for optimization and design


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of SMEDDS the surface methodology, modified simplex method and box- bechnken design

optimization techniques use.

ABSORPTION OF SMEDDS[2-4]

Generally the SMEDDS causes the stimulation of intestinal lymphatic transport. For highly

lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase

bioavailability directly or indirectly via a reduction in first‐pass metabolism. Increases in

effective luminal drug solubility. The presence of lipids in the GI tract stimulates an increase

in the secretion of bile salts (BS) and endogenous biliary lipids including phospholipids (PL)

and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles and an

increase in the solubilisation capacity of the GI tract. However, intercalation of administered

(exogenous) lipids into these BS structures either directly (if sufficiently polar), or secondary

to digestion, leads to swelling of the micelle structures and a further increase in solubilisation

capacity. Changes in the biochemical barrier function of the GI tract. It is clear that certain

lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated

by the p‐glycoprotein efflux pump, and may also reduce the extent of enterocyte ‐based

metabolism. -Rapid dispersion of self-emulsifying systems -Increased solubility and

promotion of super saturation - Inceasesing residence time - Potential effects on intestinal-

based efflux and permeability - Potential influence of drug metabolism in the intestine.

Potential effect of lipid drug delivery system on oral drug absorption


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MECHANISM OF SELF EMULSIFICATION[5-7]

In emulsification process the free energy (ΔG) associated is given by the equation: ΔG =

ΣNiπri2σ In which “N” is number of droplets with radius “r” and “σ” is interfacial energy. It

is apparent from equation that the spontaneous formation of the interface between the oil and

water phase is energetically not favored. The system commonly classified as SEDDS have

not yet been shown to emulsify spontaneously in the thermodynamic sense. The process of

self-emulsification was observed using light microscopy. The emulsification process may be

associated with the ease with water penetrates the oil-water interface with the formation of

liquid crystalline phases resulting in swelling at the interface thereby resulting in greater ease

of emulsification. The additional mechanisms by which lipid based delivery systems enhance

the absorption of lipophilic drugs are.

ENHANCED DISSOLUTION/SOLUBILIZATION

The presence of lipids in the GI tract stimulates gallbladder contractions and biliary and

pancreatic secretions including bile salts (BS), phospholipids (PL) and cholesterol. These

products, along with the gastric shear movement, form a crude emulsion which promotes the

solubilization of the coadministered lipophilic drug. Lipids in the GI tract provoke delay in

gastric emptying, i.e. gastric transit time is increased. As a result, the residence time of the

co-administered lipophilic drug in the small intestine increases that enables better dissolution

of the drug.

RECENT ADVANCEMENTS IN SMEDDS SELF-EMULSIFYING SUSTAINED/

CONTROLLED-RELEASE TABLETS[10-15]

Numerous potent drugs exhibit low oral bioavailability due to their poor aqueous solubilities

or presystemic metabolism. Carvedilol one of those drug having low bioavailability, low

solubility and having pre systemic metabolism. The novel self-emulsifying osmotic pump

tablet (SEOPT) containing carvedilol has many advantages. It improves the bioavailability of

carvedilol, controls the release rate and makes the plasma concentrations more stable. The

results of dissolution experiment showed that the release of carvedilol from self-made EOPT

was controlled and complete and its profile was close to zero order releas.

SELF-EMULSIFYING CAPSULE

It is a capsules containing liquid or semisolid form of self emulsifying system. In the GIT, the

capsules get dispersed to SES uniformly in the fluid to micron size, enhancing bioavailability.

Second type of self emulsifying capsule is solid SES filled into capsule.


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SELF-EMULSIFYING SUPPOSITORIES

Some investigators proved that Solid-SEDDS could increase not only GI adsorption but also

rectal/vaginal adsorption. Glycyrrhizin, which, by the oral route, barely achieves therapeutic

plasma concentrations, can obtain satisfactory therapeutic levels for chronic hepatic diseases

by either vaginal or rectal SE suppositories. The formulation included glycyrrhizin and a

mixture of a C6–C18 fatty acid glycerol ester and a C6–C18 fatty acid macrogol ester.

SELF-NANO MULSIFYING DRUG DELIVERY SYSTEM (SNEDDS) /SELF-

EMULSIFYING NANOPARTICLES

Nanoparticle techniques have been useful in the production of SE nanoparticles. Solvent

injection is one of these techniques.In this method, the lipid, surfactant, and drugs were

melted together, and injected drop wise into a stirred non-solvent. The resulting SE

nanoparticles were thereafter filtered out and dried. E.glacidipine loaded SNEDDS

formulation so to contain minimum amount of surfactant, maximum amount of lipid, highest

emulsification and dissolution rates.

SELF-EMULSIFYING SUSTAINED/CONTROLLED-RELEASE PELLETS

Pellets, as a multiple unit dosage form, possess many advantages over conventional solid

dosage forms, such as flexibility of manufacture, reduction of intra subject and inter subject

variability of plasma profiles and minimizing GI irritation without lowering drug

bioavailability. Thus, it seems very appealing to combine the advantages of pellets with those

of SEDDS by SE pellets. Spherical pellets with low friability and self-emulsifying properties

can be produced by the standard extrusion/ spheronization technique. E.g Lipid mixtures

composed of Solutol® HS 15 and medium chain glycerides were optimized with respect to

their self-emulsifying properties. The liquid SE lipid was mixed with microcrystalline

cellulose and transformed into pellets by extrusion/spheronization. The pellets were

characterized for size, shape, surface characteristics and friability. The combinations of

coating and SES could control in vitro drug release by providing a range of release rates and

the presence of the SEDDS did not influence the ability of the polymer film to control drug

dissolution.

SELF-EMULSIFYING SOLID DISPERSIONS

Although solid dispersions can increase the dissolution rate and bioavailability of poorly

water-soluble drugs, some manufacturing problems involving stability are continuing targets

for pharmaceutical research. These difficulties could be overcome by the use of SE


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excipients. SE excipients, likeGelucire1 44/14, Gelucire 50/02, Labrasol, Transcutol and

TPGS (tocopheryl polyethylene glycol 1000succinate), have been widely used to solve the

same problem. Gupta et al. prepared SE solid dispersion granules using the hot-melt

granulation method for seven drugs, including four carboxylic acid containing drugs, a

hydroxyl-containing drug, an amide containing drug (phenacetin) and a drug with no proton

donating groups (progesterone) in which Gelucire 50/13was used as the dispersion carrier,

while Neusilin US2was used as the surface adsorbent. Self-emulsifying beads Solidification

of liquid systems has been a challenge that has attracted wide attention due to handling

difficulties and machinability and stability problems that are often encountered with liquids.

One of the solidification is to transform into SES beds form with minimum amounts of

solidifying excipients, investigated SES as microchannels of porous polystyrene beads (PPB)

using the solvent evaporation method. PPB with complex internal void structure is typically

produced by copolymerizing styrene and divinyl benzene. Porous polymer structures such as

macroporous high internal phase emulsion (HIPE) polymers were used as high-capacity

reservoirs for included liquids and as carriers for active pharmaceuticals for sustained

delivery.

SELF-EMULSIFYING SUSTAINED-RELEASE MICROSPHERES

Zedoary turmeric oil (ZTO) exhibits potent pharmacological actions including tumor

suppression, and antibacterial, and antithrombotic activity. With ZTO as an oil phase, the

solid SE sustained-release microspheres were prepared by the quasi-emulsion-solvent-

diffusion method involving spherical crystallization. The ZTO release behaviour was

controlled by the ratio of hydroxyl- -propyl methyl cellulose acetate succinate to Aerosil 200

in the formulation, and the plasma concentration time-profiles after oral administration to

rabbits showed a bioavailability of 135.6%compared with the conventional liquid SEDDS.

POSITIVELY CHARGED SELF-EMULSIFYINGDRUG DELIVERY SYSTEM

One of the most persistent problems faced by the formulation scientists has been to find

methods of improving the oral bioavailability of poorly water-soluble drugs. This positively

charged SEDDS gives several fold increase in the bioavailability than the negatively charged

one. Cationic lipids are use in this type of system. E.g positively charged Meloxicam SEDDS

were prepared using oil components (ethyl oleate, sunflower oil and arachis oil), cationic

lipid (oleylamine) and surfactants (combination of Tween 80 and Span 80).


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SELF-DOUBLE-EMULSIFYING DRUG DELIVERY SYSTEM (SDEDDS)

SDEDDS can spontaneously emulsify to water-in-oil in-water (w/o/w) double emulsions in

the mixed aqueous gastrointestinal environment, with drugs encapsulated in the internal water

phase of the double emulsions. We employed SDEDDS to improve the oral absorption of

pidotimod, a peptide-like drug with high solubility and low permeability.

SUPER SATURATABLE SELF-EMULSIFYING DRUG DELIVERY SYSTEM (S-

SEDDS)

The potential for supersaturated drug formulations in improving drug absorption was first

proposed by the T, Higuchii. The polyvinyl pyrrolidone and water soluble cellulosic

polymers such as HPMC, methyl cellulose, hydroxyl propyl methylcellulose phthalate are

useful in generating a super saturatable state with number of poorly water soluble drug. A

high payload super saturatable self-emulsifying drug delivery system (S-SEDDS) was

explored to improve the oral bioavailability of silybin, a poorly water-soluble drug candidate,

employing hydroxyl propyl methyl cellulose (HPMC) as a precipitation inhibitor.

SELF-MICRO EMULSIFYING FLOATING DOSAGE FORM

The main problem regarding the low bioavailability is low solubility, presystemic

metabolism; eradicate absorption of drug throughout GIT. The floating system increases the

residence time of drug in the stomach and develop prolonged-release forms. The novel

floating dosage form of Furosemide (FUR) to enhance its solubility by formulating a self

microemulsifying drug delivery system (SMEDDS) of FUR, followed by its adsorption onto

a mixture of high functionality excipient, matrix forming polymers (HPMC K4M and HPMC

E50 LV) and a gas-generating agent (NaHCO3) to achieve a buoyant matrix with a controlled

release profile.

CONCLUSION

Self - emulsifying drug delivery systems are a promising approach for the formulation of

drug compounds with poor aqueous solubility, having high molecular weight, pre systemic

first pass effect, enzymatic degradation, gastric irritation, having limited dissolution rate and

low bioavailability. This is the method suited for all BCS class drugs where resulting

emulsification gives faster dissolution rates and absorption. With future development of this

technology, SEDDS will continue to enable novel applications in drug delivery and solve

deficiency associated with the delivery of poorly water soluble, high molecular weight, pre


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systemic first pass effect, enzymatic degradation, gastric irritation, having limited dissolution

rate and low bioavailability.

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