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CHAPTER 2 LITERATURE REVIEW

LITERATURE REVIEW

SPTM, SVKM’ S, NMIMS, MUMBAI 11

2.1 Reported methods for enhancing solubility and dissolution of the drug

The emergence of high-throughput screening (i.e., a method for screening thousands

of potential drug candidates) has led to an increase in the number of poorly water-

soluble drugs. The delivery of such drugs into the body in a sufficiently bioavailable

form has been challenging for formulation researchers, especially if a drug also is

insoluble in an organic medium.

Although several approaches can enhance a drug's solubility and dissolution such as:

2.1.1 Physical modifications

This often aim to increase the surface area, solubility and/or wettability of the powder

particles and are therefore focused on particle size reduction, generation of amorphous

states or salt formation 14-15

2.1.2 Micronization

The increase in bioavailability after micronization of drugs, e.g., by jet or ball milling

has been well documented 16-18

2.1.3 Solubilization

Solubilising the drug by using solubilising agent and any suitable method or

combination of methods.

In one study solubilization of a potential anti-human immunodeficiency virus agent

[PG-300995 or 2-(2-thiophenyl)-4-azabenzoimidazole], having intrinsic solubility 51

g/mL,was solubilized using multiple approaches including combinations of pH

control and cosolvency, micellization, or complexation. The combined techniques

increased the solubility of both the unionized and ionized species. The solubility of

the drug increased from 20 to 200 times depending on the pH and concentration of

solubilization agents. These formulations are stable for at least 6 months after storing

at room temperature and 37°C.19

Solubility of valsartan was also increased by solubilisation. 20

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Combined effects of cosolvency and inclusion complexation on drug solubility were

studied using a model hydrophobic compound (carbamazepine) and a model

hydrophilic compound (Compound S). Propylene glycol (PG) was used as the

nonaqueous solvent, and deionized water was employed for the aqueous systems.

Hydroxypropyl beta-cyclodextrin (HPBCD) was chosen as the complexing agent and

studied at concentrations up to 28% (w/v). Complex formation constants (Kc) and

solubility enhancement ratios were determined for the respective compounds in

various water/PG vehicles. The data suggested that the inclusion of the compounds

was most favorable when water alone was used as the vehicle. However, the

combined approach of cosolvency and complexation resulted in a significant increase

in the total apparent solubility of carbamazepine (the hydrophobic compound). The

same was not observed with Compound S (the hydrophilic model), since PG

weakened the interactions between the molecule and HPBCD, and thus, no synergistic

or additive effects were observed with the combined approach of complexation and

cosolvency.21

2.1.4 Cosolvency

Organic solvents are amongst the most powerful solubilization agents for a large

number of water-insoluble drugs.

Biphenyl dimethyl dicarboxylate (BDD) is a synthetic analogue of schizandrin C, one

of the components isolated from Fructus schizandrae, and has been widely prescribed

for improvement of liver functions and symptoms of patients with liver disease.

However, its oral preparations have been known to have limited bioavailability due to

its extremely low solubility in water, and its solubility problem also limits preparation

of its parenteral dosage forms. In this research, solvent systems were searched to

solubilize BDD to overcome these problems. The ternary solvent systems of N,N'-

dimethylacetamide (DMA)/alcohol/water and Cremophor EL/DMA/alcohol were

studied intensively for this purpose. BDD was solubilized effectively in these

cosolvents, and the results showed that the cosolvent systems were effective for

solubilizing BDD up to the concentration that might be employed for preparation of

parenteral dosage forms. Formulation of a BDD concentrate for intravenous infusion

was proposed employing the cosolvent system of Cremophor EL/DMA/alcohol. 22

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2.1.5 Complexation with beta-cyclodextrin

Cyclodextrins (CDs) are cyclic oligosaccharides, containing six (α-CD), seven (β-CD)

or eight (γ-CD) α-1,4-linked -glucose units, with a hydrophilic outer surface and a

hydrophobic cavity, in which may be included a great variety of ‘guest’ molecules of

suitable size and shape, resulting in a stable association without formation of covalent

bonds .In the pharmaceutical field this phenomenon has been extensively applied to

enhance the solubility, dissolution rate and bioavailability of slightly soluble drugs in

gastrointestinal fluids .

Among the cyclodextrins, β-CD is the most useful compound for drug complexation.

However, the relatively low aqueous solubility of β-CD (about 1.8% w/v, at 25°C)

suggested the use of chemically-modified CDs with different physical properties and

inclusion behaviour. In particular, hydroxypropyl-β-cyclodextrin (HP-β-CD) is widely

used, because of its amorphous nature, high water solubility and solubilising power

and low toxicity .

R. Stancanelli, A. Mazzaglia, S. Tommasini et al. found improvement in

bioavailabilityof isoflavones by complexation with modified cyclodextrins23

Study done by Stéphane Gibaud, Siham Ben Zirar and co workers demonstrate that

the very poorly soluble drug melarsoprol forms 1:1 inclusion complexes with βCD

and its derivatives, especially RAMEβCD and HPβCD. The solubilization

enhancement factor by βCD is limited but could be multiplied by a factor of about

7.2 × 103 using RAMEβCD and HPβCD. The stability constants determined by the

solubility method and the UV spectrophotometer are high and in good agreement for

both methods, suggesting that inclusion was the essential mode of complexation.

When compared to the pure drug, the dissolution profile of the Mel/RAMEβCD

complex is dramatically improved, which proved its suitability to develop an oral

form. 24

2.1.6 Spray drying

One of the most common approaches used to reduce particle size is milling, a

mechanical micronization process. Milling is a well-established technique which is

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relatively cheap, fast and easy to scale-up. However, milling has several

disadvantages, the main one being the limited opportunity to control important

characteristics of the final particle such as size, shape, morphology, surface properties

and electrostatic charge. In addition, milling is a high energy process which causes

disruptions in the drug's crystal lattice, resulting in the presence of disordered or

amorphous regions in the final product. These amorphous regions are

thermodynamically unstable and are therefore susceptible to recrystallization upon

storage, particularly in hot and humid conditions. The alteration of the surface

properties also changes the milled product's saturation solubility as well as blending

and flow properties, which in turn, have an impact on the formulation process.

Furthermore, milled particles often show aggregation and agglomeration which results

in poor wettability and thus poor dissolution.

An alternative to milling involves growing the particle from a solution to the desired

size range under controlled conditions, for example by spray drying.

Spray drying was used to produce particles of the model drug griseofulvin in an

attempt to improve the drug's dissolution rate and oral bioavailability. Small amounts

of hydrophilic surfactant, Poloxamer 407, were also incorporated into the particles in

an attempt to enhance particle wetting. Dissolution studies showed the spray dried

particles with Poloxamer 407 had the highest dissolution rate, followed by spray dried

particles without surfactant, followed by the control. This indicated that both the spray

drying process and the inclusion of the hydrophilic surfactant contributed to enhanced

dissolution rates. 25

2.1.7 Solid dispersion

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. 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

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problems with solid dispersion systems may be overcome by using surface active and

self-emulsifying carriers. The carriers are melted at elevated temperatures.

Solid dispersion systems in which the drug is dispersed in solid water-soluble

matrices either molecularly or as fine particles have also shown promising results in

increasing bioavailability of poorly water-soluble drugs.

Solid dispersion systems of water-insoluble piroxicam in polyethylene glycol (PEG)

4000 and in urea were prepared by fusion and solvent methods .The in vitro

dissolution studies showed that the dispersion systems containing piroxicam and

PEG4000 or urea gave faster dissolution than the corresponding simple mixtures. The

storage testings showed that all dispersions were stable, except that uptake of water

during storage may occur in the PEG system. A single-dose study with rabbits showed

that the dispersion systems provided statistically significant to a higher extent and rate

of bioavailability than the corresponding physical mixture. 26

In another study,oral bioavailability of a poorly water-soluble drug was greatly

enhanced by using its solid dispersion in a surface-active carrier. The weakly basic

drug (pKa 5.5) had the highest solubility of 0.1 mg/ml at pH 1.5, <1 μg/ml aqueous

solubility between pH 3.5 and 5.5 at 24±1 °C, and no detectable solubility

(<0.02 μg/ml) at pH greater than 5.5. Solid dispersion formulations of the drug were

prepared by dissolving the drug in the molten carrier (65 °C) and filling the melt in

hard gelatin capsules. The oral bioavailability of this formulation in dogs was

compared with that of a capsule containing micronized drug blended with lactose and

microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate

80 and water. Absolute oral bioavailability values from the capsule containing

micronized drug, the capsule containing solid dispersion and the oral liquid were

1.7±1.0%, 35.8±5.2% and 59.6±21.4%, respectively. Thus, the solid dispersion

provided a 21-fold increase in bioavailability of the drug as compared to the capsule

containing micronized drug. 27

2.1.8 Nanoparticle technology

In the recent years, nanoparticle technology has emerged as a strategy to tackle such

formulation problems associated with poorly water-soluble and poorly water- and

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lipid-soluble drugs. 28-30

Nanoparticles are solid colloidal particles ranging in size

from 1 to 1000 nm that are used as drug delivery agents 31

. The reduction of drug

particles to the nano-scale increases dissolution velocity and saturation solubility,

which leads to improved in vivo drug performance. 32-33

Various processes such as wet milling, high-pressure homogenization, emulsification,

precipitation, rapid expansion, and spray freezing can be used to produce drug

nanoparticles.

Wet milling

In a study conducted by Liversidge and Cundy, the bioavailability of danazol, a

poorly bioavailable gonadotropin inhibitor, improved when administered to subjects

as a nanocrystal suspension prepared by wet milling compared with a danazol

macrosuspension. By formulating danazol as a nanocrystal suspension, the absolute

bioavailabilty increased to 82.3%, compared with 5.2% of a commercial danazol

suspension. 34

High-pressure homogenization

In a recent study, the dissolution characteristics of nifedipine were significantly

increased with regard to the commercial product by preparating nanoparticles using

high-pressure homogenization. After 60 min, 95% of drug nanoparticles were

dissolved ~5% of the unmilled drug was dissolved. 35

Precipitation with a compressed fluid antisolvent (PCA)

In the PCA process (patented by RTP Pharmaceuticals and licensed to SkyePharma

Plc [London, UK]), supercritical carbon dioxide is mixed with organic solvents

containing drug compounds. The solvent expands into supercritical carbon dioxide,

thus increasing the concentration of the solute in the solution, making it

supersaturated, and causing the solute to precipitate or crystallize out of solution.

Microparticles and nanoparticles are formed after drug precipitation by mass transfer

because of organic solvent extraction into carbon dioxide and the diffusion of carbon

dioxide into the droplets. High mass-transfer rate is important to minimize particle

agglomeration and reduce drying time. 36-37

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Rapid expansion from a liquefied-gas solution (RESS)

This process was used by Young et al. to prepare nanoparticles of cyclosporine in the

size range of 500–700 nm 38

. Tween-80 solution was used as a surfactant to prevent

flocculation and agglomeration of nanoparticles. Researchers reported that the

cyclosporine particles formed by this process could be stabilized for drug

concentrations as high as 6.2 and 37.5 mg/mL in 1.0 and 5% (w/w) tween 80

solutions.

Spray freezing into liquid (SFL)

Highly potent danazol nanoparticles contained in larger structured aggregates were

produced by the SFL process 39

. The SFL powders exhibited significantly enhanced

dissolution rates. The micronized bulk danazol exhibited a slow dissolution rate; only

30% of the danazol was dissolved in 2 min. Nonetheless, 95% of the danazol was

dissolved in only 2 min for the SFL highly potent powders. In a recent study, SFL

danazol/PVP K-15 powders with high surface areas and high glass transition

temperatures remained amorphous and exhibited rapid dissolution rates after 6 months

in storage. 40

Evaporative precipitation into aqueous solution (EPAS)

Evaporative precipitation into aqueous solution (EPAS) is a particle engineering

technology reported to produce submicron to micron-sized drug particles stabilized by

surfactants or polymers and dispersed in an aqueous medium During processing, drug

dissolved in an organic solvent is sprayed through an atomizing nozzle into an

aqueous solution containing a hydrophilic stabilizer to produce an aqueous dispersion

Rapid evaporation of the organic solvent at elevated temperature produces very high

supersaturation and rapid precipitation of the drug in the form of suspended particles.

The EPAS process was used to produce a nanoparticle suspensions of cyclosporine A

and danazol, which showed high dissolution rates. Nanoparticle suspensions produced

by the EPAS process can be incorporated into a parenteral dosage form or can be

dried to produce solid oral dosage forms. 41-43

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Multiple emulsion method

Nanoparticles are also produced by multiple emulsion method .44

Nonoencapsulation technique

Nanoencapsulation techniques are reported to enhance release of many drugs.45

Ion gelation Technique

Nanoparticles of chitosan can be prepared with ionic gelation with polyanions such as

tripolyphosphate. 46

2.1.9 Cogrinding

Cogrinding processes are comparatively seldom described in the literature and have

often employed large quantities of water-soluble polymers as dispersion carriers. 47-48

Vogt,Vertzoni,et al studied oral bioavailability of EMD 57033, a calcium sensitizing

agent with poor solubility, in dogs using four solid dosage form formulation

approaches: a physical blend of the drug with excipients, micronization of the drug,

preparation of coground mixtures and spray-drying of the drug from a nanocrystalline

suspension. Drug micronization and cogrinding was realized by a jet-milling

technique. Nanoparticles were created by media milling using a bead mill. All

formulations were administered orally as dry powders in hard gelatine capsules.

While micronization increased the absolute bioavailability of the solid drug

significantly compared to crude material (from nondetectable to 20%), cogrinding

with specific excipients was able to almost double this improvement (up to 39%).

With an absolute bioavailability of 26%, spray-dried nanoparticular EMD 57033

failed to show the superior bioavailability that had been anticipated from in vitro

data.49

2.1.10 Self emulsifying drug delivery systems

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants,

ideally isotropic, sometimes including cosolvents, which emulsify under conditions of

gentle agitation, similar to those which would be encountered in the gastro-intestinal

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tract. Hydrophobic drugs can often be dissolved in SEDDS allowing them to be

encapsulated as unit dosage forms for peroral administration. When such a

formulation is released into the lumen of the gut it disperses to form a fine emulsion,

so that the drug remains in solution in the gut, avoiding the dissolution step which

frequently limits the rate of absorption of hydrophobic drugs from the crystalline

state. Generally this can lead to improved bioavailability, and/or a more consistent

temporal profile of absorption from the gut.50

Wu,Wang and Que prepared self-microemulsifying drug delivery system

(SMEDDS) to improve peroral bioavailability of silymarin. SMEDDS was a system

consisting of silymarin, Tween 80, ethyl alcohol, and ethyl linoleate. Particle size

change of the microemulsion was evaluated upon dilution with aqueous media and

loading with incremental amount of silymarin. In vitro release was investigated by a

dialysis or an ultrafiltration method. Pharmacokinetics and bioavailability of silymarin

suspension, solution, and SMEDDS were evaluated and compared in rabbits. Plasma

silybin, which was treated as the representing component of silymarin, was

determined by high-performance liquid chromatography. After gavage administration

of silymarin suspension, plasma silybin level was very low and fell below limit of

detection 4 h after. As for silymarin solution and SMEDDS, double peak of maximum

concentrations were observed, which was characteristic of enterohepatic circulation.

Relative bioavailability of SMEDDS was dramatically enhanced in an average of 1.88

and 48.82-fold that of silymarin PEG 400 solution and suspension, respectively. 51

2.1.11 Solid solution

The term ‘solid dispersion’ is applied to those systems in which drug particles are

homogeneously distributed throughout a solid matrix. This system provides the

possibility of reducing the particle size of drugs to nearly molecular level, to

transform the drug from the crystalline to partially amorphous. Where as in solid

solution the drug is completely molecularly dispersed and drug has no crystal

structure in the solid solution.

Solid solutions can be classified as either continuous or discontinuous solid solutions

based on their miscibility. They can also be classified as substitutional, interstitial and

amorphous solid solutions based on the way in which the solvate molecules are

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distributed in solvendum .In continuous solid solution, the components are miscible in

all proportions, where as in discontinuous solid solution the components solubility in

each is limited. That is, in discontinuous solid solution, one of the solid components is

completely dissolved only in a certain region of the phase diagram Various techniques

have been used to differentiate solid solutions from solid dispersions. These include

thermoanalytical (MDSC/DSC), XRD, IR and drug dissolution rate from the

formulation. Absence of crystallinity of drug or complete absence of drug peak (either

in DSC or XRD) indicates formulation to be a solid solution .

In a study Kapsi and Ayres investigated solid solutions of itraconazole, a water

insoluble antifungal, for improved dissolution and improved bioavailability

Polyethylene glycol (PEG) and drug were made into a solid solution at 120 °C. The

cooled, solid solution was then ground into granules of different sizes. Solid solutions

of lower drug concentration dissolved at a faster rate, and drug dissolution improved

considerably with increasing molecular weight of PEG. Initial treatment of

itraconazole with the wetting agent/cosolvent glycerol prior to making itraconazole

into a solid solution improved drug dissolution, and also reduced the PEG amount

required to dissolve drug to form solid solution. Addition of a polymer such as HPMC

to the solid solution eliminated precipitation of drug following dissolution. 52

The present work is based on enhancing the bioavailability of a poorly soluble

antihypertensive agent by a suitable approach which will overcome all above stated

problems.

2.2 Selection of drug

Classes of antihypertensive drugs53-54

1. Angiotensin converting enzyme(ACE) inhibitors

ACE inhibitors or angiotensin converting enzyme inhibitors, are a group of

pharmaceuticals that are used primarily in treatment of hypertension and

congestive heart failure Primarily angiotensin converting enzyme inhibitors

reduce the activity of the renin-angiotensin-aldosterone system.

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2. Angiotensin – II receptor antagonist(ARB)

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers

(ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which

modulate the renin angiotensin aldosteron system. Their main use is in hypertensive

(high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and

congestive heart failure .These substances are AT1-receptor antagonists – that is, they

block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors

directly causes vasodilation, reduces secretion of vasopressin, reduces production and

secretion of aldosterone, amongst other actions – the combined effect of which is

reduction of blood pressure.

3. Beta blockers

Beta blockers (sometimes written as β-blocker) is a class of drugs used for various

indications, but particularly for the management of cardiac arrhythmias,

cardioprotection after myocardial infarction (heart attack), andhypertension. Asbeta

adrenergic receptor antagonist, they diminish the effects of epinephrine (adrenaline)

and other stress hormones. Beta blockers may also be referred to as beta-adrenergic

blocking agents, beta-adrenergic antagonists, or beta antagonists.

Beta blockers block the action of endogenous catecholamines (epinephrine

(adrenaline) and norepinephrine (noradrenaline) in particular), on β-adrenergic

receptors, part of the sympathetic nervous system which mediates the "fight or flight "

response. There are three known types of beta receptor, designated β1, β2 and β3. β1-

Adrenergic receptors are located mainly in the heart and in the kidneys. β2-Adrenergic

receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular

smooth muscle, and skeletal muscle. β3-receptors are located in fat cells.

4. Calcium channel blockers

Calcium channel blockers (CCBs) are a class of drugs and natural substances that

disrupt the calcium (Ca2+

) conduction ofcalcium chanels. It has effects on many

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Table 2.1 List of antihypertensive agents with their solubility and

bioavailability55

Sr.No. Name Class Solubility in

water

Bioavailability

1 Benazepril ACE Inhibitor Soluble 34%

2 Captopril ACE Inhibitor soluble 75%

3 Enalapril ACE Inhibitor Sparingly 60%

4 Fosinopril ACE Inhibitor soluble 36%

5 Lisinopril ACE Inhibitor Soluble 25%

6 Moexipril ACE Inhibitor Soluble 13%

7 Perindopril ACE Inhibitor Soluble 75%

8 Quinapril ACE Inhibitor Soluble 60%

9 Ramipril ACE Inhibitor Insoluble 50-60%

10 trandolapril ACE Inhibitor Insoluble 10%

11 Candesartan ARA Insoluble 15%

12 Eposartan

mesylate

ARA Insoluble 13%

13 Irbesartan ARA Insoluble 60-80%

14 losartan ARA Freely soluble 33%

15 Olmesartan ARA Insoluble 26%

16 Telmisartan ARA Insoluble 42-58%

17 Valsartan ARA Slightly 25%

18 Atenolol Beta blocker Soluble 50%

19 betaxolol Beta blocker Soluble 89%

20 Bisoprolol Beta blocker Soluble 80%

21 Carvedilol Beta blocker Insoluble 25-35%

22 Esmolol Beta blocker Soluble -

23 labetalol Beta blocker Soluble 25%

24 metoprolol Beta blocker Soluble 50%

25 Nadolol Beta blocker Slightly

soluble

30%

26 Pindolol Beta blocker Insoluble 95%

27 Propranolol Beta blocker Soluble 25%

28 Sotalol Beta blocker Soluble 90-100%

29 Timolol Beta blocker Soluble 90%

30 Amlodipine CCB Soluble 64-90%

31 Bepridil CCB Slightly

soluble

60%

32 Diltiazem CCB Soluble 40%

33 Felodipine CCB Insoluble 20%

34 Isradipine CCB Insoluble 15-24%

35 Nicardipine CCB Slightly

soluble

35%

36 Nifedipine CCB Insoluble -

37 Nisoldipine CCB insoluble 5%

38 Verapamil CCB Soluble 35%

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excitable cells of the body, such as cardiac muscle, i.e.heart , smooth muscles of

blood vessels, or neurons.

Calcium channel blockers work by blocking voltage-gated calcium channels

(VGCCs) in cardiac muscle and blood vessels. This decreases intracellular calcium

leading to a reduction in muscle contraction. In the heart, a decrease in calcium

available for each beat results in a decrease in cardiac contractility. In blood vessels, a

decrease in calcium results in less contraction of the vascular smooth muscle and

therefore an increase in arterial diameter (CCB's do not work on venous smooth

muscle), a phenomenon called vasodilation.Vasodilation decreases total peripheral

resistance, while a decrease in cardiac contractility decreases cardiac output. Since

blood pressure is determined by cardiac output and peripheral resistance, blood

pressure drops

Drugs which were shortlisted were Eposartan, Trandolapril,Candesartan and

Nisoldipine because of the low solubility and low bioavailability but amongst them

Eposartan is having a high melting point(250˚ C) which can be a limiting factor while

developing drug delivery systems, Trandolapril gets convert after metabolism into its

metabolite trandolaprilate which is 300 times more active than parent compound.

Biovailability of nisoldipine was low due to pre systemic metabolism in the gut wall

so enhancing the solubility was not the solution to enhance biovailability of the drug.

Finally Candesartan was selected as the drug of choice which is available in the form

of a prodrug Candesartan cilexetil .

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2.3 Drug profile

Candesartan cilexetil is not official in any of the pharmacopoeia.

Drug Description56

Candesartan cilexetil is a prodrug which is hydrolyzed to candesartan during

absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype

angiotensin II receptor antagonist.

Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-

ethoxy-1-[p-(o-1Htetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate,

cyclohexyl carbonate (ester).

Its empirical formula is C33H34N6O6, and its structural formula is

Figure 2.1 Chemical structure of Candesartan cilexetil

Candesartan cilexetil is a white to off-white powder with a molecular weight of

610.67. It is practically insoluble in water and sparingly soluble in methanol.

Candesartan cilexetil is a racemic mixture containing one chiral center at the

cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration,

candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug,

candesartan, which is achiral.

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Indications

Hypertension

CC is indicated for the treatment of hypertension in adults and children 1 to < 17

years of age. It may be used alone or in combination with other antihypertensive

agents.

Heart Failure

CC is indicated for the treatment of heart failure (NYHA class II-IV) in adults with

left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular

death and to reduce heart failure hospitalizations.

Dosage and administration

Adult Hypertension

Dosage must be individualized. Blood pressure response is dose related over the range

of 2 to 32 mg. The usual recommended starting dose of CC is 16 mg once daily when

it is used as monotherapy in patients who are not volume depleted. CC can be

administered once or twice daily with total daily doses ranging from 8 mg to 32 mg.

Larger doses do not appear to have a greater effect, and there is relatively little

experience with such doses. Most of the antihypertensive effect is present within 2

weeks, and maximal blood pressure reduction is generally obtained within 4 to 6

weeks of treatment with CC.

No initial dosage adjustment is necessary for elderly patients, for patients with mildly

impaired renal function, or for patients with mildly impaired hepatic function. In

patients with moderate hepatic impairment, consideration should be given to initiation

of CC at a lower dose. For patients with possible depletion of intravascular volume

(eg, patients treated with diuretics, particularly those with impaired renal function),

CC should be initiated under close medical supervision and consideration should be

given to administration of a lower dose .CC may be administered with or without

food.

If blood pressure is not controlled by CC alone, a diuretic may be added. CC may be

administered with other antihypertensive agents.

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Pediatric Hypertension 1 to < 17 Years of age

CC may be administered once daily or divided into two equal doses. Dosage should

be adjusted according to blood pressure response. For patients with possible depletion

of intravascular volume (e.g., patients treated with diuretics, particularly those with

impaired renal function), CC should be used under medical supervision .

Children 1 to < 6 years of age

The dose range is 0.05 to 0.4 mg/kg per day. The recommended starting dose is 0.20

mg/kg (oral suspension).

Children 6 to < 17 years of age

For those less than 50 kg, the dose range is 2 to 16 mg per day. The recommended

starting dose is 4 to 8 mg.

For those greater than 50 kg, the dose range is 4 to 32 mg per day. The recommended

starting dose is 8 to 16 mg.

Doses above 0.4 mg/kg (1 to < 6 year olds) or 32 mg (6 to < 17 year olds) have not

been studied in pediatric patients.

An antihypertensive effect is usually present within 2 weeks, with full effect generally

obtained within 4 weeks of treatment with CC.

CC should not be given to children < 1 year of age for hypertension.

Adult Heart Failure

The recommended initial dose for treating heart failure is 4 mg once daily. The target

dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-

week intervals, as tolerated by the patient.

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Side Effects

Clinical Studies Experience

Adult Hypertension

Fatigue, peripheral edema, chest pain, headache, branchitis, coughing, sinusitis,

nausea, abdominal pain, diarrhea, vomiting, arthralgia,albuminuria.

Body as a Whole:asthenia,fever;

Central and Peripheral Nervous System:paresthesia,vertigo;

Gastrointestinal System Disorder:dyspepsis,gastroenteritis;

Heart Rate and Rhythm Disorders:tachycardia, palpitation;

Metabolic and Nutritional Disorders: creatine phosphokinase increased,

hyperglycemia, hypertriglyceridemia,hyperurecemia;

Musculoskeletal System Disorders:myalgia;

Platelet/Bleeding-Clotting Disorders:epistaxis;

Psychiatric Disorders:anxiety, depression,somnolence;

Respiratory System Disorders:dyspnea;

Skin and Appendages Disorders:rash, sweating increased;

Urinary System Disorders:heamaturia.

Other reported events seen less frequently included angina pectoris, myocardial

infarction, andangioedema.

Pediatric Hypertension

Worsening of renal disease.

Postmarketing Experience

The following have been very rarely reported in post-marketing experience:

Digestive: Abnormal hepatic function and hepatitis.

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Hematologic:Neutropenia , leukopenia, and agranulocytosis.

Metabolic and Nutritional Disorders:hyperkalemia,hyponatremia.

Renal: renal impairment, renal failure.

Skin and Appendages Disorders: Pruritus and urticaria.

Drug interactions

No significant drug interactions have been reported in studies of candesartan cilexetil

given with other drugs such as glyburide, nifedipine, digoxin, warfarin,

hydrochlorothiazide, and oral contraceptives in healthy volunteers, or given with

enalapril to patients with heart failure (NYHA class II and III). Because candesartan is

not significantly metabolized by the cytochrome P450 system and at therapeutic

concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or

are metabolized by those enzymes would not be expected.

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported

during concomitant administration of lithium with ACE inhibitors, and with some

angiotensin II receptor antagonists. An increase in serum lithium concentration has

been reported during concomitant administration of lithium with CC, so careful

monitoring of serum lithium levels is recommended during concomitant use.

Precautions

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal

morbidity and death when administered to pregnant women. Several dozen cases have

been reported in the world literature in patients who were taking angiotensin-

converting enzyme inhibitors. Post-marketing experience has identified reports of

fetal and neonatal toxicity in babies born to women treated with Candesartan cilexetil

during pregnancy.

LITERATURE REVIEW


Morbidity in Infants

Children < 1 year of age must not receive CC for hypertension. The consequences of

administering drugs that act directly on the renin-angiotensin system (RAS) can have

effects on the development of immature kidneys.

Hypotension

In adult or children patients with an activated renin-angiotensin system, such as

volume- and/or salt-depleted patients (eg, those being treated with diuretics),

symptomatic hypotension may occur. These conditions should be corrected prior to

administration of CC, or the treatment should start under close medical supervision .

Major Surgery/Anesthesia

Hypotension may occur during major surgery and anesthesia in patients treated with

angiotensin II receptor antagonists, including CC, due to blockade of the renin-

angiotensin system. Very rarely, hypotension may be severe such that it may warrant

the use of intravenous fluids and/or vasopressors.

Impaired Hepatic Function

Based on pharmacokinetic data which demonstrate significant increases in

candesartan AUC and Cmax in patients with moderate hepatic impairment, a lower

initiating dose should be considered for patients with moderate hepatic impairment.

Renal Function Deterioration

As a consequence of inhibiting the renin-angiotensinaldosterone system, changes in

renal function may be anticipated in some individuals treated with CC. In patients

whose renal function may depend upon the activity of the renin-angiotensin-

aldosterone system (eg, patients with severe heart failure), treatment with angiotensin-

converting enzyme inhibitors and angiotensin receptor antagonists has been

associated with oliguria and/or progressive azotemia and (rarely) with acute renal

failure and/or death.

LITERATURE REVIEW


Hyperkalemia

In heart failure patients treated with CC, hyperkalemia may occur, especially when

taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as

spironolactone

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity when candesartan cilexetil was orally

administered to mice and rats for up to 104 weeks at doses up to 100 and 1000

mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the

drug by dietary administration. These (maximally-tolerated) doses of candesartan

cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice,

approximately 7 times and, in rats, more than 70 times the exposure in man at the

maximum recommended daily human dose (32 mg).

Use in Specific Populations

Nursing Mothers

It is not known whether candesartan is excreted in human milk, but candesartan has

been shown to be present in rat milk. Because of the potential for adverse effects on

the nursing infant, a decision should be made whether to discontinue nursing or

discontinue CC, taking into account the importance of the drug to the mother.

Pediatric Use

The antihypertensive effects of CC were evaluated in hypertensive children 1 to < 17

years of age in randomized, double-blind clinical studies .

Geriatric Use

Hypertension

No overall differences in safety or effectiveness were observed between these

subjects and younger adult subjects, and other reported clinical experience has not

identified differences in responses between the elderly and younger patients, but

greater sensitivity of some older individuals cannot be ruled out.

LITERATURE REVIEW


Heart Failure

abnormal renal function , hypotension and hyperkalemia.

Overdose

No lethality was observed in acute toxicity studies in mice, rats, and dogs given single

oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral

doses of the primary metabolite, candesartan, the minimum lethal dose was greater

than 1000 mg/kg but less than 2000 mg/kg.

Clinical Pharmacology

Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-

converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of

the renin-angiotensin system, with effects that include vasoconstriction, stimulation of

synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of

sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of

angiotensin II by selectively blocking the binding of angiotensin II to the AT1

receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its

action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT2 receptor found in many tissues, but AT2 is not known to be

associated with cardiovascular homeostasis. Candesartan has much greater affinity ( >

10,000-fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the

biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment

ofhypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction

also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it

does not affect the response to bradykinin. Whether this difference has clinical

relevance is not yet known. Candesartan does not bind to or block other hormone

receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of

angiotensin II on renin secretion, but the resulting increased plasma renin activity and

LITERATURE REVIEW


angiotensin II circulating levels do not overcome the effect of candesartan on blood

pressure.

Pharmacodynamics

Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent

manner. After 1 week of once daily dosing with 8 mg of candesartan cilexetil, the

pressor effect was inhibited by approximately 90% at peak with approximately 50%

inhibition persisting for 24 hours.

Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity

(PRA), increased in a dose-dependent manner after single and repeated administration

of candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients.

ACE activity was not altered in healthy subjects after repeated candesartan cilexetil

administration. The once-daily administration of up to 16 mg of candesartan cilexetil

to healthy subjects did not influence plasma aldosterone concentrations, but a

decrease in the plasma concentration of aldosterone was observed when 32 mg of

candesartan cilexetil was administered to hypertensive patients. In spite of the effect

of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium

was observed.

Hypertension

Adults

In multiple-dose studies with hypertensive patients, there were no clinically

significant changes in metabolic function, including serum levels of total cholesterol,

triglycerides, glucose, or uric acid.

Heart Failure

In heart failure patients, candesartan ≥ 8 mg resulted in decreases in systemic vascular

resistance and pulmonary capillary wedge pressure.

Pharmacokinetics

Distribution

The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound

to plasma proteins ( > 99%) and does not penetratered blood cells. The protein

LITERATURE REVIEW


binding is constant at candesartan plasma concentrations well above the range

achieved with recommended doses. In rats, it has been demonstrated that candesartan

crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats

that candesartan passes across the placental barrier and is distributed in the fetus.

Metabolism and Excretion

Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of

0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is

excreted unchanged in urine. Following an oral dose of 14

C-labeled candesartan

cilexetil, approximately 33% of radioactivity is recovered in urine and approximately

67% in feces. Following an intravenous dose of 14

C-labeled candesartan,

approximately 59% of radioactivity is recovered in urine and approximately 36% in

feces. Biliary excretion contributes to the elimination of candesartan.

Adults

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during

absorption from the gatsrointestinal tract to candesartan, a selective AT1 subtype

angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine

and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an

inactive metabolite. The elimination half-life of candesartan is approximately 9 hours.

After single and repeated administration, the pharmacokinetics of candesartan are

linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive

metabolite do not accumulate in serum upon repeated once-daily dosing.

Following administration of candesartan cilexetil, the absolute bioavailability of

candesartan was estimated to be 15%. After tablet ingestion, the peak serum

concentration (Cmax) is reached after 3 to 4 hours. Food with a high fat content does

not affect the bioavailability of candesartan after candesartan cilexetil administration.

Pediatrics

In children 1 to 17 years of age, plasma levels are greater than 10-fold higher at peak

(approximately 4 hours) than 24 hours after a single dose.

Children 1 to < 6 years of age, given 0.2 mg/kg had exposure similar to adults given 8

mg.

http://www.rxlist.com/script/main/art.asp?articlekey=2484

LITERATURE REVIEW


Children > 6 years of age had exposure similar to adults given the same dose.

The pharmacokinetics (Cmax and AUC) were not modified by age, sex or body

weight.

Candesartan cilexetil pharmacokinetics have not been investigated in pediatric

patients less than 1 year of age.

From the dose-ranging studies of candesartan cilexetil, there was a dose related

increase in plasma candesartan concentrations.

The renin-angiotensin system (RAS) plays a critical role in kidney development. RAS

blockade has been shown to lead to abnormal kidney development in very young

mice. Children < 1 year of age must not receive ATACAND. Administering drugs

that act directly on the renin-angiotensin system (RAS) can alter normal renal

development.

Geriatric and Sex

The pharmacokinetics of candesartan have been studied in the elderly ( ≥ 65 years)

and in both sexes. The plasma concentration of candesartan was higher in the elderly

(Cmax was approximately 50% higher, and AUC was approximately 80% higher)

compared to younger subjects administered the same dose. The pharmacokinetics of

candesartan were linear in the elderly, and candesartan and its inactive metabolite did

not accumulate in the serum of these subjects upon repeated, once-daily

administration. No initial dosage adjustment is necessary. There is no difference in the

pharmacokinetics of candesartan between male and female subjects.

Renal Insufficiency

In hypertensive patients with renal insufficiency, serum concentrations of candesartan

were elevated. After repeated dosing, the AUC and Cmax were approximately

doubled in patients with severe renal impairment (creatinine clearance < 30

mL/min/1.73m²) compared to patients with normal kidney function. The

pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis

are similar to those in hypertensive patients with severe renal impairment.

Candesartan cannot be removed by hemodialysis. No initial dosage adjustment is

necessary in patients with renal insufficiency.

LITERATURE REVIEW


In heart failure patients with renal impairment, AUC0-72h was 36% and 65% higher

in mild and moderate renal impairment, respectively. Cmax was 15% and 55% higher

in mild and moderate renal impairment, respectively.

Hepatic Insufficiency

The pharmacokinetics of candesartan were compared in patients with mild and

moderate hepatic impairment to matched healthy volunteers following a single oral

dose of 16 mg candesartan cilexetil. The increase in AUC for candesartan was 30% in

patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with

moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan

was 56% in patients with mild hepatic impairment and 73% in patients with moderate

hepatic impairment. The pharmacokinetics after candesartan cilexetil administration

have not been investigated in patients with severe hepatic impairment. No initial

dosage adjustment is necessary in patients with mild hepatic impairment.

Heart Failure

The pharmacokinetics of candesartan were linear in patients with heart failure

(NYHA class II and III) after candesartan cilexetil doses of 4, 8, and 16 mg. After

repeated dosing, the AUC was approximately doubled in these patients compared with

healthy, younger patients. The pharmacokinetics in heart failure patients is similar to

that in healthy elderly volunteers

Dosage form and strengths Tablets for oral use available in the strengths of 2mg, 4

mg, 8 mg, 16 mg and 32 mg.

Brand names Atacand, Candesar

LITERATURE REVIEW


2.4 Drug characterization57

TCV-116( Candesartan )

Figure 2.2 Schematic diagram of solid forms of Candesartan cilexetil

Table 2.2 Characterization of solid forms of Candesartan cilexetil

Property Form I Form II Amorphous

Melting point 163˚ C 120˚ Not specified

DSC Endothermal

peak169 ˚C

Endothermal peak

120˚ C

Endothermal peaks

could not be clearly

seen

XRD (2θ˚) 9.82˚ 7.28˚

IR Absorption band at

1717 cm-1

1736cm

-1 1728cm

-1

Figure 2.3 Reported DSC spectra of different forms of Candesartan Cilexetil.

LITERATURE REVIEW


Figure 2.4 Reported XRD spectra of different forms of Candesartan Cilexetil.

Table 2.3 Crystal properties of Form I and Form II of candesartan cilexetil

Figure 2.5 Reported

13C CP/MAS spectra of Form I and Form II of candesartan

cilexetil

LITERATURE REVIEW


Figure 2.6 Reported 13

C CP/MAS spectra of amorphous form of candesartan

cilexetil

Figure 2.7 Reported IR spectra of different forms of candesartan cilexetil

LITERATURE REVIEW


2.5 Formulation patents related to drug

Table no. 2.4 Formulation patents related to drug 58-60

Sr.

No

.

Patent No. Title Description

Publi

shing

date

1

US2006/016580

6A1

WO2006/07421

8A2

AU2006/20408

3A1

Nanoparticulate

candesartan

formulations

Elan pharma international

limited

Candesartan +stabilizer by

grinding , homoginising ,

precipitating and supercritical

processing

July

27

2006

2 WO2009/01323

7A2

Stable solid

pharmaceutical

composition

comprising

candesartan or

pharmaceutically

active forms thereof

KRKA,D.D.NOVO

MESTO,Smarjeska Cesta

Candesartan+plasticizer(trieth

yl citrate)

Jan

29

2009

3 WO2008/10917

0 A1

Pharmaceutical

composition

comprising

candesartan cilexetil

Teva Pharmaceutical

Industries LTD

Candesartan+ amino

acid(Leucine)

Sep

12

2008

4 US2009/004831

7 A1

Formulations of

candesartan

KENYON & KENYON

LLP,NY,US

Candesartan+non ionic

surfactant + wet granulation

Feb

19

2009

5 US2009/004831

6A1

Pharmaceutical

composition

comprising


KENYON & KENYON

LLP,NY,US

Candesartan+amino acid

Feb

19

2009

6 WO2009/01781

2A2

Improved formulations

of candesartan

Teva Pharmaceutical

Industries LTD

Candesartan+ Non ionic

surfactant

Feb

5,

2009

7 WO2009/13564

6 A2

Stable pharmaceutical

compositions and their

processes for

preparation sutaible

for industrial scale

Farmaprojects,santa Eulalia

Candesartan +PEG 100-400

Nov

12

2009

8 WO2009/12187

1A1

Pharmaceutical

compositions

comprising

candesartan

KRKA,D.D.NOVO

MESTO,Smarjeska Cesta

Candesartan+grafted

copolymer

Oct

8

2009

9 WO2008/07782

3A1

Self microemulsifying

drug delivery systems

LEK Pharmaceuticals

SMEDDS of candesartan

July

3

2008

10 WO2005/07039 Pharmaceutical Ranbaxy laboratories,India Aug

LITERATURE REVIEW


8A2 compositions of


stabilized with co

solvents

Candesartan+cosolvents 4

2005

11 AU2007/26335

1A2

Tablets comprising

Candesartan cilexetil

SIEGFRIED Generics

International

Candesartan +HCZ

JUN

14

2007

12 US2009/001817

5A1

Pharmaceutica

excipient complex

KENYON & KENYON

LLP,NY,US

Candesartan+poloxamer

Jan

15

2009

13 US2009/020858

3A1

Tablets comprising


SIEGFRIED Generics

International

Candesartan +HCZ

Aug

20

2009

14

US2008/011856

4A1

WO2006/07949

6A1

Pharmaceutical

composition

containing candesartan

cilexetil as lipophilic

crystalline substance

LEK Pharmaceuticals

Candesartan+Carrageenan

May

22

2008

Aug

3

2006

15

WO2008/06509

7A2

US2010/004164

4A1

Stabilized solid

pharmaceutical

composition of


Laboratorios

Liconsa,Barcelona

Candesartan +stabilizer(ester

of hydroxycarboxylic acid and

monohydroxy alcohol)

June

5

2008

Feb

18

2010

16 WO2005/12372

0A1

Fine particles of

angiotensin II

antagonist candesartan

cilexetil and process

for production thereof

Ranbaxy laboratories,India

Candesartan+organic

solvent+crystallization

Dec

29

2005

17 WO2005/08464

8A1

Pharmaceutical

compositions

comprising



Candesartan+water soluble

polymer(Poly vinyl

alcohol/maltodextrin/xanthan

gum)

Sept

15

2005

18 WO2005/07975

1A2

Oral pharmaceutical

compositions of



Candesartan+fatty

substance(Lipids/phospholipid

s)

Sept

1

2005

19 WO2008/06872

7A2

Pharmaceutical

composition

comprising



Candesartan+Buffering agent

June

12

2008

20 WO2008/11803

1A1

Pharmaceutical

composition

comprising


and method of

manufacturing thereof

ZAKLADY

FARMACEUTYCZNE

POLPHARMA

Candesartan+graft copolymer

Oct 2

2008

LITERATURE REVIEW


21 US2004/001824

0A1

Method of producing

preparation Containing

bioactive substance

WENDEROTH,LIND and

PONACK

Candesartan + Copolymer

Jan

29

2004

22 WO2008/04500

6A1

Formulations of

candesartan

FAKO ILAClARI

Candesartan+antioxidant

APR

17

2008

23 EP1346722 B1

Method of producing

preparation Containing

bioactive substance

Takeda Pharmaceuticals

company,Japan

Candesartan+biodegradable

polymer

Dec

10

2008

24 WO2006/11363

1A1

Bioenhanced

compositions

Rubicon research PVT

LTD,India

ARB+solubility enhancing

agent

OCT

26

2006

25 AU

2003/242895A1 Novel combination

Pfizer Inc

Phosphodiesterase type

5+Angiotensin II receptor

antagonist

Mar

4

2004

26 EP2165702A1

Stable and readily

dissolved

compositions of


prepared with wet

granulation

HELM AG, BLUEPHARMA

IND FARMACEUTICA

Cnadesartan +sodium

docusate+wet granulation

Mar

24

2010

27 CN 101669940

A

Candesartan

cilexetil/hydrochloroth

iazide capsule and

preparation method

thereof

BEIJING RUIYIREN

TECHNOLOGY

Candesartan +

Hydrochlorothiazide+

Capsule

Mar

3

2010

28 CN 101623275

A

Capsule containing


and preparation

method thereof

JIANGSU TIANYISHI

PHARMACEUTIC

Jan

13

2010

29

CN 101612151

A

Solid Oral

administration


cilexetil or

candesartan

hydrocholorothiazide

and method for

preparing solid oral

administration

preparation

Zhehjiang Huahai

Pharmaceutical

Candesartan pellets

Dec

30

2009

30 CN 101584700

A

Pharmaceutical

composition

Suyun Wang

Candesartn+hydrochlorothiazi

de+Amlodipine

Nov

25

2009

31 CN 101554381

A


hydrochlorothiazide

double layer tablets

and method of

Qingdao Huanghai

Pharmaceutica

Candesartan+Hydrochlorothia

zide+slow and fast releasing

Oct

14

2009

LITERATURE REVIEW


preparation thereof layer

32

WO

2009134086

A2

Pharmaceutical

formulation for

treatment of

cardiovascular disease

Hanall Pharmacutical Co LTD

Simvastatin early release

+candesartan retarded release

Nov

5

2009

33

KR

20090049089

A

Pharmaceutical

composition


cilexetil

Astrazeneca

Candesartan cilexetil tab with

AUC more than 1.5

May

15

2009

34

KR

20080039303

A

Controlled relwase

composition

comprising

candesartan and HMG

–CoA reductase

inhibitors

Hanall Pharmacutical Co LTD

Controlled release candesartan

May

7

2008

35 JP 2009107944

A

Medicinal

Composition

Takeda chemical industries

Ltd

Candesartan core tab+

Covering with

polymer+pioglitazone layer

May

21

2009

36 SI 22572 A


composition which

comprises candesartan

or its pharmaceutically

active forms

KRKA Tovarna Zdravil

Candesartan/its

pharmaceutically active form

+ at least one plasticizer

Feb

28

2009

37 SI 22571 A


composition which

comprises candesartan

or its pharmaceutically

active forms

KRKA Tovarna Zdravil

Granulation in high speed

granulator without dispersion

in solvent

Feb

28.

2009

38 EP 1997479

A1

Stabilized amorphous


compositions for oral

administration

HELM AG

Candesartan+methacrylate

polymer+organic solvent

Dec

3

2008

39

KR

20070062500

A

Stable micronized


and methods for

preparing thereof

TEVA PHARMA

Micronizing candesartan by

slurrying in alcohol

June

15

2007

40 EP 1952806 A

Process for the

preparation of

adsorbates of

candesartan

HELM AG

Adsorbates of candesartan in

amorphous form

Aug

6

2008

41 CN 101062038

A

Candesartan

hydrochlorothiazide

dispersible tablets and

the preparing method

thereof

Liu Fenming

Fast dispersible candesartan

Oct 3

2007

42 CZ 16311 U1 Novel pharmaceutical ZENTIVA Apr

12

LITERATURE REVIEW


composition for oral

administration


cilexetil

2006

43 WO 9956734

A2

Transdermal

therapeutic system for

the administration of

candesartan

HEXAL AG,

STRUENGMANN THOMAS

Nov

11

1999

2.6 Selection of techniques for solubility enhancement

Above metioned list is a list of patents till date but at the time of selection of

technologies patents till end of 2007 were considered.

As mentioned in the table present above formulations which were patented were

transdermal systems, dispersible tablets, micronised candesartan, combinations with

solubility enhancing agents, stabilizers, fatty acids, polymers, grafted polymers,other

drugs, and nanoparticulate drug delivery system.

Although patent WO2006/113631A1 covers combination of solubility enhancing

agents and ARB’s ,formulation of given specifically for candesartan in this patent was

a not combination of candesartan with cyclodextrins.

Based on the information available in the patents and exempting the approaches

which were patended the techniques for solubility and dissolution rate enhancement

of candesartan cilexetil selected for present research work were-

1. Complexation with cyclodextrins and modified cyclodextrins

2. Liquisolid technology

3. Self microemulsifying drug delivery systems

4. Nanoparticulate drug delivery system

chapter 2 literature review - information and...

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