The present invention relates to stable pharmaceutical composition comprising Candesartan Cilexetil.
In the field of therapy of hypertension, angiotensin II receptor antagonist has attracted attention as an effective agent for the therapy of hypertension following angiotensin I converting enzyme (ACE) inhibitor. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist. Candesartan Cilexetil is a prodrug and is hydrolyzed to Candesartan during absorption from the gastrointestinal tract. It falls in the class of benzimidazole -7- carboxylic acid and its derivatives thereof. These agents exhibit a strong and more effective hypotensive action and are less likely to cause coughing as side effect as compared to other class of ACE inhibitors.
Candesartan Cilexetil has low aqueous solubility i.e. it is hydrophobic in nature. Low bioavailability of hydrophobic drugs with extremely low water solubility can be a serious problem. Different approaches have been taken to achieve a desired level of drug solubility and dissolution rate. These approaches have been based on preparations with increased surface area (micronised powders), molecular inclusion complexes (cyclodextrines and derivatives), co-precipitates with water-soluble polymers (PEG, poloxamers, PVP, HPMC) and non-electrolytes (urea, mannitol, sugars etc.), micellar solutions in surfactant systems (Cremophor™, Tween™, Gellucires™), multilayer vesicles (liposomes and niosomes). Dispersed colloidal vehicles, such as oil-in-water, water-in-oil and multiple (O/W/O or W/O/W) emulsions, microemulsions and self-emulsifying compositions also have been used to improve bioavailability of poorly soluble molecules. None of these approaches has provided the efficiency for selected cases for bioavailability improvement of immediate drug release formulations.
Candesartan is stable against temperature, moisture and light when it is alone in the solid state, however when it is prepared into tablets with other ingredients, it has been observed that lowering of the content of the active ingredient has been observed with the lapse of time.
US Pat No 5,534,534 discloses that the reduction in the content of the Candesartan Cilexetil with the lapse of time, in pharmaceutical compositions can be reduced by incorporating oily substances having a low melting point in these compositions. This oily substance having a lower melting point is incorporated into the active component to form a stable composition in which decomposition with time caused by compression can be suppressed. Thus resulting in a stable composition in which the crystalline disorder is minimized.
The present invention is directed to Candesartan Cilexetil pharmaceutical composition comprising a mixture of fatty acid glyceride with a surfactant and a cosolvent. The present invention provide pharmaceutical compositions of Candesartan Cilexetil which is not only stable
but also achieves the same rate (Cmax) and extent of absorption (AUC) from the gastrointestinal tract as that achieved by the commercially available formulation of Candesartan sold under the trade name "ATACAND".
Since Candesartan Cilexetil has low water solubility the use of a co-solvent improves its bioavailability by increasing its solubility and dissolution rate in aqueous solutions. The cosolvent can be selected from propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, polyethylene glycol esters and mixtures thereof.
In one aspect it provides a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil and cosolvent wherein the concentration of Candesartan Cilexetil is in the range of 2% to 35%w/w and cosolvent is in the range of 1% to 10%w/w of the total weight of the composition.
In another aspect it provides a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil and propylene glycol wherein the concentration of Candesartan Cilexetil is in the range of 2% to 35%w/w and propylene glycol is in the range of 1 % to 10%w/w of the total weight of the composition.
In another aspect it provides a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil, fatty acid glyceride, surfactant and a cosolvent.
In another aspect it provides a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil, fatty acid esters, surfactant and a co-solvent wherein the concentration of Candesartan Cilexetil is in the range of 2% to 35%w/w, fatty acid ester is in the range of 0.5% to 5%w/w, surfactant is in the range of 0.1% to 2%w/w and propylene glycol is in the range of 1% to 10%w/w of the total weight of the composition.
In another aspect it provides a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil and propylene glycol, which achieves the same rate (Cmax) and extent of absorption (AUC) from the gastrointestinal tract as that achieved by its commercially available formulation of Candesartan sold under the trade name "ATACAND" by Astrazeneca.
In another aspect it provides a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil, fatty acid esters,
surfactant and a co-solvent which achieves the same rate (Cmax) and extent of absorption (ADC) from the gastrointestinal tract as that achieved by its commercially available formulation of Candesartan sold under the trade name "ATACAND" by Astrazeneca.
In another aspect it provides a process for preparation of a stable pharmaceutical composition for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil and propylene glycol wherein the process comprises the step of dispersing Candesartan Cilexetil, surfactant and a fatty acid ester in a solution of cosolvent in water.
In another aspect it provides a stable pharmaceutical composition for oral administration for the preparation of a medicament for the treatment of hypertension comprising an effective amount of Candesartan Cilexetil and cosolvent.
In another aspect it provides a stable pharmaceutical composition for oral administration for the preparation of a medicament for the treatment of hypertension comprising an effective amount of Candesartan Cilexetil, fatty acid esters, surfactant and co-solvent.
In another aspect it provides a stable tablet for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil and a cosolvent wherein the tablet is coated with a coating composition comprising a film forming polymer and polyethylene glycol.
In another aspect it provides process for preparation of a stable tablet of Candesartan wherein the process comprises the step of:
a) dispersing Candesartan Cilexetil in a solution of cosolvent in water
b) granulating the blend of diluents and disintegrant with above dispersion,
c) optionally further granulating with binder solution
d) lubricating the granules of step b) or step c), and
e) compressing into suitable size solid dosage form,
f) coating the above solid dosage form with a coating composition comprising a film
forming polymer and polyethylene glycol.
In another aspect it provides stable tablet for oral administration for the treatment of hypertension comprising comprising a therapeutically effective amount of Candesartan Cilexetil and a cosolvent, wherein the tablet is coated with a coating composition comprising a film forming polymer and polyethylene glycol.
In another aspect it provides a stable tablet for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil, fatty acid glyceride, surfactant and a cosolvent
wherein the tablet is coated with a coating composition comprising a film forming polymer and polyethylene glycol.
In another aspect it provides a stable tablet for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil and propylene glycol wherein the composition is coated with a coating composition comprising a film forming polymer and polyethylene glycol and the concentration of Candesartan Cilexetil is in the range of 2% to 35%w/w and propylene glycol is in the range of 1 % to 10%w/w of the total weight of the composition.
In another aspect it provides a stable tablet for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil, fatty acid esters, surfactant and a co-solvent wherein the composition is coated with a coating composition comprising a film forming polymer and polyethylene glycol and the concentration of Candesartan Cilexetil is in the range of 2% to 35%w/w, fatty acid ester is in the range of 0.5% to 5%w/w, surfactant is in the range of 0.1% to 2%w/w and propylene glycol is in the range of 1% to 10%w/w of the total weight of the composition.
In another aspect it provides process for preparation of a stable tablet of Candesartan wherein the process comprises the step of:
a) dispersing Candesartan Cilexetil, surfactant and fatty acid ester in a solution of cosolvent
in water
b) granulating the blend of diluents and disintegrant with above dispersion,
c) optionally further granulating with binder solution
d) lubricating the granules of step b) or step c), and
e) compressing into suitable size solid dosage form,
f) coating the above solid dosage form with a coating composition comprising a film forming
polymer and polyethylene glycol.
In another aspect it provides a coated tablet for oral administration comprising a therapeutically effective amount of Candesartan Cilexetil wherein the coating composition comprises a film forming polymer, polyethylene glycol, coloring agent, and lubricants/glidants.
Polyethylene glycol in the formulation serves the dual purpose of acting as enhancer for the absorption of Candesartan and as plasticizer in the coating layer. Various authors have described the enhancement mechanism of polyethylene glycol. For example, according to Hugger et al (Hugger, E. D., Kenneth L. A., Ronald T. B., Journal of Pharmaceutical Sciences, Vol. 91,NO. 9, September 2002, pp. 1980-1990) PEG 300 is capable of inhibiting efflux transporter activity mediated by p-glycoprotein. Similarly, Johnson et al (Johnson, B. M.,
Charman, W. N., and Porter, C. J. H., AAPS PharmSci 2002; 4(4), pp. 1-13), studied the effect of PEG 400 and other excipients on p-glycoprotein mediated efflux of certain drugs. Thereby the formulation is stable due to stabilizer present in the core as well as would be bioequivalent due to polyethylene glycol present in the coating layer.
Polyethylene glycol may be present alone or in combination of other plasticizer and it may be present in the concentration 10-75% by weight of the coating composition.
The term 'Candesartan Cilexetil' used herein refers to a prodrug that is hydrolyzed to Candesartan during absorption from the gastrointestinal tract.
The term "therapeutically effective amount" used herein refers to a nontoxic but sufficient amount of the agent to provide the desired effect.
The term 'co-solvent' relates to a substance, which is miscible with water and gastrointestinal fluid and increases the solubility and dissolution rate of Candesartan Cilexetil in aqueous solutions and gastrointestinal fluids.
The term 'stable' as used herein refers to negligible lowering of the content of active ingredient with the lapse of time.
Examples of cosolvents include propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol esters, polyethylene glycol esters and mixtures thereof.
Examples of fatty acid esters include glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glyceryl caprylate/caprate, glycerol oleate, glycerol linoleate, glyceryl lauropalmitoleate or mixtures thereof.
Examples of surfactants include sodium lauryl sulphate, poloxamer, Polysorbate 80 Cremophor and the like.
The composition may contain other pharmaceutically acceptable excipients in addition to Candesartan Cilexetil, fatty substance, surfactant and co-solvent.
The term 'other pharmaceutically acceptable excipient' refers to ingredients of the composition, excluding the active drug substance.
Examples of other pharmaceutically acceptable excipients as used herein include fillers, binders, disintegrants, lubricants, glidants, colors and the like.
The fillers can be selected from the group comprising of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Examples of disintegrants include calcium carboxymethyl cellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like.
Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
The coloring agents of the present invention may be selected from any FDA approved colors for oral use.
Candesartan Cilexetil can be present in the range of 2% to 35%w/w and most particularly about 3% to about 30% (w/w), based on the total weight of the composition.
The cosolvent can be present in the range of 1 to 10% w/w. Propylene glycol can be present in the range of 1% to 10%w/w and most particularly about 1% to about 5% (w/w), based on the total weight of the composition.
The fatty acid esters can be present in the range of 0.5% to 10%w/w and most particularly about 1 % to about 5% (w/w), based on the total weight of the composition.
The surfactant can be present in the range of 0.1% to 2%w/w and most particularly about 0.2% to about 1% (w/w), based on the total weight of the composition.
The pharmaceutical composition can be prepared by processes known in the prior art such as wet granulation, dry granulation or direct compression and the final dosage form may be in the form of tablets or capsules.
In one of the embodiments Candesartan Cilexetil tablet may be prepared by dispersing Candesartan Cilexetil, Polysorbate 80 and Glyceryl caprate in a solution of propylene glycol in water, adding this drug dispersion to lactose, microcrystalline cellulose and calcium carboxymethyl cellulose by spraying and making granules; drying the granules; sizing; lubricating and compressing the lubricated granules.
The tablets prepared by the present invention may be coated with one or more additional layers comprising film forming agents and/or pharmaceutically acceptable excipients.
The coating composition may further comprise other coating additives such as plasticizers, coloring agents, gloss producer and lubricants/glidants.
The coating composition may comprise another plasticizer in combination with polyethylene glycol. The plasticizer may be selected from the group comprising of diethyl phthalate, dibutyl phthalate and triethyl citrate.
The coating layers over the tablet may be applied as solution/ dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating and the like.
Example of solvents used for preparing a solution/dispersion of the coating ingredients include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof.
Example of film forming agents include ethyl cellulose, Hydroxypropyl methylcellulose, Hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like and mixture thereof. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
In one of the embodiments Candesartan Cilexetil tablet may be prepared by dispersing Candesartan Cilexetil, Polysorbate 80 and Glyceryl caprate in a solution of propylene glycol in water, adding this drug dispersion to lactose, microcrystalline cellulose and calcium carboxymethyl cellulose by spraying and making granules; drying the granules; sizing; lubricating and compressing the lubricated granules into tablet; coating the tablet with a dispersion of a film forming polymer, polyethylene glycol, titanium dioxide and talc.
The following examples are illustrative of the invention, and are not to be construed as limiting the invention.
EXAMPLE 1
(Table Removed)
PROCEDURE:
1. Candesartan Cilexetil, Polysorbate 80 and Glyceryl caprate are dispersed in a solution
of propylene glycol in water.
2. Povidone K-30 is dissolved in water separately.
3. Lactose, microcrystalline cellulose, and calcium carboxymethyl cellulose are mixed in a
high shear mixer and granulated with the dispersion of Step 1 and Step 2.
4. The wet granules are dried in a fluid bed drier, passed through a screen and
then subjected to sizing.
5. The extragranular calcium carboxymethyl cellulose is passed through a screen and
blended with the granules of step 4.
6. The magnesium stearate is passed through a screen, blended with the blend of step 5
and compressed to tablets.
EXAMPLE 2
(Table Removed)
PROCEDURE:
1. Candesartan Cilexetil and Glyceryl caprylate are dispersed in a solution of propylene
glycol in water.
2. Povidone K 30 is dissolved in water separately.
3. Lactose, microcrystalline cellulose, and calcium carboxymethyl cellulose are mixed in a
high shear mixer and granulated with the dispersion of Step 1 and Step 2.
4. The wet granules are dried in a fluid bed drier, passed through a screen and
then subjected to sizing.
5. The extragranular calcium carboxymethyl cellulose is passed through a screen and
blended with the granules of step 4.
6. The magnesium stearate is passed through a screen, blended with the blend of step 5
and compressed to tablets.
In vitro dissolution study
In vitro release of Candesartan Cilexetil from tablets as per composition of Example 1 and 2 were studied in 900 ml, pH 6.8 Phosphate buffer and 0.35% polysorbate-20, using USP apparatus - II, at 50 rpm. The results are listed in Table 1.
Table 1: In vitro release of Candesartan Cilexetil from tablets
(Table Removed)
In Vivo Bioavailabilitv Study
In vivo performance of Candesartan Cilexetil from tablets prepared as per the composition of Example 1 were evaluated with respect to the ATACAND in 15 healthy male volunteers under fasting condition. The study protocol followed was open randomized, three treatment, three period, three sequence and single dose crossover study on Candesartan Cilexetil under fasting condition with a wash out period of at least 4 days. Pharmacokinetic parameters Cmax (Maximum plasma concentration), AUC0-t (Area under the plasma concentration vs. time curve from 0 hours to the time of last sample collected) and AUCo-∞ (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. The results of the study are given in Table 2.
Table 2: Comparative Pharmacokinetic data for tablets of Candesartan Cilextil tablet and ATACAND® tablet.
(Table Removed)
The tablets of example 1 demonstrated comparable extent of absorption when compared to the reference ATACAND.
Cosolvent shows a stabilizing effect on Candesartan Cilexetil. Table 3 shows comparative stability data at various intervals (40°C/75%RH) with reference to the amount of Desethyl Candesartan and total related substances found.
Table 3: Comparative stability data at various intervals (40°C/75%RH) with reference to the amount of Desethyl Candesartan and total related substances
(Table Removed)
Table 3 clearly indicates that the use of cosolvent stabilizes the Candesartan Cilexetil compositions.
EXAMPLE 3
(Table Removed)
PROCEDURE:
1. Propylene glycol and Polysorbate 80 were mixed with a part of water to form clear
solution.
2. Candesartan Cilexetil and Glyceryl caprate are dispersed in above solution.
3. Povidone K 30 is dissolved in water separately and mixed with above drug dispersion.
4. Lactose, microcrystalline cellulose, and calcium carboxymethyl cellulose are mixed in a
high shear mixer and granulated with above dispersion.
5. The wet granules are dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
6. The extragranular calcium carboxymethyl cellulose is passed through a screen and
blended with the granules of step 5.
7. The magnesium stearate is passed through a screen, blended with the blend of step 6
and compressed to tablets.
8. Ingredients of the coating composition are dispersed in water and coated on the above
tablets.
In vitro dissolution study
In vitro release of Candesartan Cilexetil from tablets as per composition of Example 3 were studied in 900 ml, pH 6.8 Phosphate buffer and 0.35% polysorbate-20, using USP apparatus -II, at 25 and 50 rpm. The results are listed in Table 4.
Table 4: In vitro release of Candesartan Cilexetil from tablets
(Table Removed)
While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

WE CLAIM:
1. A stable tablet for oral administration comprising a therapeutically effective amount of
Candesartan Cilexetil and a cosolvent wherein the composition is coated with coating
composition comprising a film forming polymer and polyethylene glycol.
2. The stable tablet according to claim 1 wherein the cosolvent is selected from the group
consisting of propylene glycol, polyethylene alcohol, ethanol, glycerin, propylene glycol
esters, polyethylene glycol esters and mixtures thereof.
3. The stable tablet according to claim 2 wherein the cosolvent is propylene glycol.
4. The stable tablet according to claim 1 wherein the concentration of cosolvent is in the
range of 1 % to 10%w/w of the total weight of the composition.
5. The stable tablet according to claim 1 wherein tablet further comprises a fatty acid ester,
surfactant and other pharmaceutically acceptable excipients.
6. The stable tablet according to claim 5 wherein fatty acid ester is selected from glycerol
stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glycerol oleate, glycerol
linoleate, glyceryl lauropalmitoleate or mixtures thereof.
7. The stable tablet according to claim 6 wherein fatty acid ester is glyceryl caprate.
8. The stable tablet according to claim 6 wherein fatty acid ester is glyceryl caprylate.
9. The stable tablet according to claim 5 wherein the surfactants are selected from sodium
lauryl sulphate, poloxamer, Polysorbate 80.
10. The stable tablet according to claim 9 wherein the surfactant is Polysorbate 80.
11. The stable tablet according to claim 5 wherein other pharmaceutically acceptable
excipients are selected from a group consisting of filler, binder, disintegrant, lubricant,
coloring and flavoring agent.
12. The stable tablet according to claim 1 wherein film forming polymer is selected from the
group consisting of ethyl cellulose, Hydroxypropyl methylcellulose, Hydroxypropyl cellulose,
methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose
acetate phthalate; Waxes such as polyethylene glycol; methacrylic acid polymers or mixtures thereof.
13. The stable tablet according to claim 12 wherein film forming polymer is Hydroxypropyl
methylcellulose.
14. The stable tablet according to claim 12 wherein film forming agent is present in the
concentration 25-90% by weight of coating composition.
15. The stable tablet according to claim 1 wherein polyethylene glycol is present in the
concentration 10-75% by weight of coating composition.

16. The stable tablet according to claim 1 wherein coating composition further comprises other
coating additives such as plasticizers, coloring agents, gloss producer and
lubricants/glidants.
17. The stable tablet according to claim 1 wherein the tablet is further coated with one or more
functional and/or non-functional layers.
18. A process for preparation of a stable tablet of Candesartan Cilexetil wherein the process
comprises the steps of
a) dispersing Candesartan Cilexetil in a solution of cosolvent in water
b) granulating the blend of diluents and disintegrant with above dispersion,
c) optionally further granulating with binder solution
d) lubricating the granules of step b) or step c), and
e) compressing into suitable size tablet,
f) coating the above tablet with a coating composition comprising a film forming polymer
and polyethylene glycol.
19. The process for preparation according to claim 18 wherein coating composition is applied
over the tablet as a solution or dispersion.
20. The process for preparation according to claim 19 wherein solution or dispersion is
prepared in a solvent.
21. The process for preparation according to claim 20 wherein solvent is selected from a group
comprising of water, ethanol, methanol, isopropyl alcohol, chloroform, acetone, ether or
mixtures thereof.
22. The process for preparation according to claim 21 wherein solvent is water.
23. The process according to claim 18 wherein the tablet is coated using coating techniques
such as spray coating, fluidized bed processing or dip coating.
24. The process according to claim 23 wherein the tablet is coated using spray coating.
25. A stable tablet for oral administration for the treatment of hypertension comprising a
therapeutically effective amount of Candesartan Cilexetil and a cosolvent, wherein the tablet
is coated with a coating composition comprising a film forming polymer and polyethylene
glycol.
26. A stable tablet for oral administration comprising a therapeutically effective amount of
Candesartan Cilexetil with fatty acid ester, surfactant and propylene glycol wherein the
tablet is coated with a coating composition comprising a film forming polymer and
polyethylene glycol.
27. The stable tablet according to claim 26 wherein the concentration of fatty acid ester is in
the range of 0.5% to 5%w/w, surfactant is in the range of 0.1% to 2%w/w and propylene
glycol is in the range of 1% to 10%w/w of the total weight of the composition.
28. The stable tablet according to claim 26 wherein fatty acid ester is selected from selected
from glycerol stearate, glycerol palmitate, glyceryl caprate, glyceryl caprylate, glyceryl
caprylate/caprate, glycerol oleate, glycerol linoleate, glyceryl lauropalmitoleate or mixtures
thereof.
29. The stable tablet according to claim 28 wherein fatty acid ester is glyceryl caprate.
30. The stable tablet according to claim 28 wherein fatty acid ester is glyceryl caprylate.
31. The stable tablet according to claim 26 wherein the surfactants are selected from sodium
lauryl sulphate, poloxamer, Polysorbate 80 or mixtures thereof.
32. The stable tablet according to claim 31 wherein the surfactant is Polysorbate 80.
33. A stable tablet comprising an effective amount of Candesartan Cilexetil and cosolvent wherein the tablet is coated with a coating composition comprising a film forming polymer and polyethylene glycol as described and illustrated herein.