chapter 3 review of literature - information and...

CHAPTER 3

REVIEW OF LITERATURE

Porecha S K

K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 45 of 210

CHAPTER 3. REVIEW OF LITERATURE

3.1 Review of literature for intranasal delivery for Brain Targeting

Many drugs are not being effectively and efficiently delivered using conventional drug delivery

approach to brain or central nervous system due to its complexicity. Many advanced and

effective approaches to brain delivery of drugs have emerged in recent years Intranasal drug

delivery is one of the focused delivery option for brain targeting as the brain and nose are

connected with olfactory route and peripheral circulation. Realization of nose to brain transport

and therapeutic viability of this route can be traced from ancient times and has been

investigated for rapid and effective transport in the last few decades. Various approaches and

delivery systems are developed for brain targeting through nasal route. A great deal of interest

has been recently focused for the exploration of the intranasal route for the delivery of drugs to

the brain due to its high permeability of the nasal epithelium. Even though a number of

challenges are still to be overcome, especially with respect to toxicity, the potential of nasal

drug delivery (NDD), including the ability to target drugs across the BBB, are very high.

Considerable efforts have been made by the scientists in exploring the prospects for brain

targeting following intranasal administration. Table 3 describes list of some research work done

on nose to brain delivery.


Porecha S K


Table 3 Research work done on Nose to brain delivery

Sr.

No

Drug Delivery system Parameters studied Ref

Major Inference

1 Sumatriptan Thermoreversible

gel

Viscosity, mucoadhesive strength, Brain

targeting Index

69

Improvement in nasal residence time and absorption of drug

2 Ropinirole In situ Ion sensitive

gel

Gel strength, viscosity, pH, Drug diffusion,

Pharmacokinetic study

70

AUC 0-480 minutes obtained after intranasal administration was 8.5 times higher than

obtained with intravenous administration

3 Estradiol Nanoparticles Size, Entrapment efficiency, loading capcity,

Drug targeting Index

71

Higher CSF concentration after intranasal administration in comparision to IV

administration

4 Olnazepine Nanoparticles Entrapment efficiency, particle size, zeta

potential, MTDSC, X-ray diffraction

72

Higher drug concentration obtained in brain after intranasal administration

5 Olnazepine Liposomes DSC, particle size, packing arrangement,

Brain targeting efficiency

73

Significant efficient brain targeting obtained after intranasal administration

6 Tremadol HCl Microspheres Yield, incorporation efficiency, particle size,

in vitro drug release, Histopathological

study, radiolabelling, DSC, XRD

74

The radio imaging study indicated localization of drug in brain

7 Venlafaxine Nanoparticles particle size, size distribution, zeta potential,

encapsulation efficiency and in vitro drug

release, confocal laser scanning microscopy,

pharmacodynamic study, brain/plasma ratio

75


Porecha S K

K.B.I.P.E.R Kadi Sarva Vishwavidyalaya 7 of 210

The brain/blood ratios of VLF for VLF (i.v.), VLF (i.n.), VLF chitosan NPs (i.n.) were 0.0293,

0.0700 and 0.1612, respectively, at 0.5 h, indicative of better brain uptake of VLF chitosan

NPs.

Many products are already on the market and many more drugs are under investigation for

intranasal delivery. Table 4 and 5 enlists the nasal drug products for brain drug delivery on the

market and under development respectively [76-79].

Table 4 Marketed nasal product for brain targeting

Product Drug Indication Manufacturer

Stadol NS® Butorphanol tartarate

Management of pain

& migraine Roxane Labs.

AscoTop® Nasal Zolmitriptan Migraine & cluster

headache Astrazeneca

Imigran® Nasal Sumatriptan Migraine & cluster

headache Glaxosmith Kline

Migranal® Nasal Spray Dihydroergotamine Migraine Novartis Pharma

Nicotrol® NS Nicotine Smoking Cessation Pfizer

DDAVP® Nasal spray Desmopressin acetate

Prevention polydipsia

and polyurea Ferring Pharm.


Porecha S K


Table 5 Nasal products for brain targeting under development

Drug substance Indication Dosage form Status Manufacturer

Butorphanol Migrane Solution

(spray) Phase III

ITI Intranasal

Therapeutics, Inc.

Hydromorphone Pain Solution

(spray) Phase II

ITI Intranasal

Therapeutics, Inc.

Morphine Pain n.i Phase II NastechWest

PH284 Eating disorder n.i Phase II Pherin Pharmaceuticals

Triptan Migrane n.i Phase II West Pharmaceutical

Services;

Somatropin Growth Failure n.i Phase I Nastech

PH94B Acute anxiety

Disorders n.i Phase I

Pherin

Pharmaceuticals

Midazolam

Anxiety,

Sedation,

Amnesia

Solution

(spray) Phase I

ITI Intranasal

Therapeutics, Inc.

Lorazepam Seizure and

anxiety

Solution

(spray) Phase I

ITI Intranasal

Therapeutics, Inc.

Morphine Acute Pain

Relief

Solution

(spray) Phase II Javelin Pharmaceuticals

Alprazolam Panic disorder n.i Phase II

Fabre Kramer

Pharmaceutical

Inc.

Triazolam Insomnia n.i Phase II

Fabre Kramer

Pharmaceutical

Inc.

n.i= Information not available


Porecha S K


Various patents have been filed in this area disclosing the recent trends in the formulation

compositions for intranasal delivery to brain. Table 6 enlists various patents on nose to brain

delivery [80-95].

Table 6 Patents on intranasal delivery for Brain Targeting

Sr.

No

Patent No Inventor Company

Claim

1 WO07947A1 Frey II, W. H NA

This invention disclosed a method for delivering neutrotrophic agents as GM-1,

ganglioside, FGF, bFGF, IGF, IGF-I, NGF, Insulin, Phosphatidylserine, a plasmid or vector

and an antisense oligonucleotide to the CNS by way of a tissue innervated by the

trigeminal nerve that is outside the nasal cavity and or sinuses.

2 US20026342478 Frey II, W. H NA

This patent described a method for transporting neurologic therapeutic agents to the

brain by means of the olfactory neural pathway and a pharmaceutical composition

useful in the treatment of brain disorders inside the nasal cavity

3 US20006121289 Houdi, A.A et al Thermax

This patent describes a method for intranasal administration of bupropion to prevent or

treat nicotine withdrawal symptoms and depression. The invention claimed improved

bupropion bioavailability and higher brain concentration after nasal administration

4 US20026369058 Hussain, A.A et al New Millennium Pharmaceutical

Research Inc.

This patent disclosed a method for enhancing the rate of delivery and to reduce the

dose, of folic acid and its derivatives alone or in combination with other drugs as

cholinesterase inhibitors and acetylcholinesterase inhibitor to the CNS by nasal

administration to provide rapid response for prevention or treatment of Alzheimer's

disease or stroke. The method also provides for direct absorption of folic acid into the

CNS and a pharmaceutical composition consisting of folic acid, or its salt, and an

aqueous carrier.


Porecha S K


5 US20030225031A1 Quay, S.C et. al. Nastech Pharmaceutical Company

A patent claiming a pharmaceutical composition for treatment of dementia, Alzheimer's

disease, learning disorders, nicotine withdrawal syndrome by acetylcholinesterase

inhibitor, comprising a liquid or gel solution for nasal administration of the drug and a

permeation enhancer for transmucosal drug uptake into the cerebral spinal fluid by

transnasal administration.

6 US20060003989A1

Quay, S.C. et al

Nastech Pharmaceutical Company

This patent disclosed methods and compositions comprising intranasal targeted delivery

to the CNS of acetylcholinesterase (ACE) inhibitors as galantamine and its carboxylate

salts to prevent and treat Alzheimer's disease.The patent indicated higher permeation

of drug in brain

7 US20060141029A1 Heller, J et. al. Erimos Pharmaceuticals LLC

The compositions contain a substantially pure preparation of catecholic butane, as

NDGA compounds in a pharmaceutically acceptable carrier or excipient by various

routes of administration including intranasal administration.

8 US20036380175

Hussain A. A. et al New Millennium Pharmaceutical

Research, Inc

This patent disclosed a method for enhancement of delivery of water insoluble delta-9-

Tetrahydyocannabiol (THC) by the administration of its water soluble ester prodrugs via

the nasal route to the brain for treatment of nausea and vomiting.

9 US20036506801 Yee K. K. et. al. Monell Chemical Senses Center

Disclosed the methods of treating anosmia, methods of enhancing the rate of olfactory

nerve recovery and methods of enhancing nerve regeneration by administering an

effective amount of a retinoid compound as retinoic acid, administered orally,

intranasally or by injection

10 US20060229233A1 Frenkel D. et.al. ID Biomedical Corporation

Invention disclosed the composition and methods for treating neurodegenerative

disorders associated with deleterious protein aggregation aberrant protein folding


Porecha S K


Such as brain amylogenic diseases.

11 US20050002987A1 Choi, Y.M et. al. NA

An invention comprising transnasal microemulsions containing diazepam for epilepsy

treatment was disclosed. Nasal administration of these microemulsions produces a high

plasma concentration of diazepam comparable to intravenous administration. These

microemulsions were found to be particularly suitable for a prompt and timely

treatment of patients in the acute and/or emergency treatment of status epilepticus

and other fever induced seizures

12 1124/MUM/2004 Ambikanandan, M. et. al. NA

Disclosed sedatives loaded intranasal nasoadhesive microemulsions for brain targeted

delivery in insomnia. The microemulsion comprised of benzodiazepines, zaleplon,

xolpidem and its pharmaceutically acceptable salts, analogs or derivatives and

surfactant/s, cosurfactant/s, dispersed phase/s, oil phase/s, antioxidant/s,

inorganic/organic salt/s, mucoadhesive or reactive polymer/s

13 1125/MUM/2004 Ambikanandan, M. et. al. NA

Patent described composition of drug loaded intranasal nasoadhesive microemulsions

for brain targeted delivery in migraine, comprising triptans as zolmitriptan, sumatriptan,

almotriptan, rizatriptan, dihydroergotamine, caffeine and its pharmaceutically

acceptable salts, analogs or derivative, surfactant/s, cosurfactant/s, dispersed phase/s,

oil phase/s, antioxidant/s inorganic/organic salt/s, mucoadhesive or reactive polymer/s.

14 WO00044350A1 Cevc, G et. al. NA

Invention disclosed transnasal transport/ immunization with highly adaptable carriers as

conventional vesicles liposomes, lipid suspensions comprising soya phosphatidylcholine

and ultradeformable vesicles/transferosomes comprising a mixture of

Phosphatidylcholine and (bio) surfactants (cholate or polysorbate (Tween 80)). The

invention further claimed the transport of preferably large molecules across nasal

mucosa by means of these specially designed, highly adaptable carriers loaded with

therapeutic polypeptides, proteins and other macromolecules by overcoming the BBB

for achieving successful protective or tolerogenic immunisation via nasal antigen or


Porecha S K


allergen administration

15 US20016610271 Wermeling, D.P. NA

Disclosed a therapeutic composition of lorazepam and its derivatives for intranasal

administration of a predetermined volumetric unit dose in the form of a spray. The

composition for intranasal administration producing a sedative-anxiolytic physiological

response in patient essentially consists of lorazepam; polyethylene glycol and propylene

glycol as a solvent-carrier for the lorazepam; and a sweetener.

16 US20070140981A1 Castile J.D et. al. NA

An invention by Castile Jonathan claimed compositions for the intranasal administration

of zolpidem or a pharmaceutically acceptable salt thereof in the form of aqueous

solutions containing a cyclodextrin and/or chitosan, and their derivatives for the

treatment or prevention insomnia and neurological disorders.


Porecha S K


3.2 Review of Literature for microemulsion based intransal delivery for brain

targeting:

Several nasal formulations have been used for brain targeting. The formulations include liquid,

semisolid and solid dosage forms. Liquid dosage forms include Nasal drops, nasal sprays,

emulsion and microemulsions. Semisolid dosage forms include ointments, nasal gel and insitu

gel while solid dosage forms include nasal powder, liposomes, and nanoparticles.

Microemulsions has been recently explored as an alternative drug delivery system through

nasal route to demonstrate a possible alternative to IV administration and a promising

approach for rapid delivery of CNS medications. Since microemulsion is optical isotropic,

thermodynamically stable system and imparts relatively more lipophilicity to the formulation,

poorly water soluble drugs and drugs, prone to hydrolysis can be successfully formulated and

administered by microemulsion. Microemulsion also improves absorption across mucosal

membranes due to its lipophilic nature and smaller globule size, which allow the reduction of

dose and systemic side effects and may also be effective to achieve faster onset of action.

Various researchers have demonstrated the advantages of intranasal microemulsion based

drug delivery system (Table 7).


Porecha S K


Table 7 Research work on Transnasal microemulsion for brain targeting

Sr.

No

Drug Excipients used Parameters evaluated Ref.

Major Inference

1 Diazepam Capmul MCM, Captex

200 P, Tween 80,

Alcohol

Globule size, viscosity, pH, zeta

potential, Invitro drug diffusion,

Histopathological study,

Pharmacodynamic parameters

96

Onset of action was rapid and duration of sleep was higher in comparison to control and

showed no toxicity on sheep nasal mucosa

2 Sildenafil

Citrate

Oleic acid, Labrasol,

Transcutol

Physicochemical characterization, Nasal

cilotoxicity study, Pharmacokinetic

parameters

97

Higher relative bioavailability (112%) and shorter Tmax (0.75 hrs) for intransal

microemulsion delivery of silenafil citrate obtained. The safe and viable microemulsion

contained oleic acid (8.33%), Labrasol (33.33%) and Transcutol (16.33%)

3 Fexofenadine Lauroglycol 90,

Labrasol, Plurol Olique

CC49, PEG 400

Physicochemical characterization In vivo

toxicity study, Pharmacokinetic

parameters

98

In vivo method for nasal cytotoxicity study showed the developed formulation temporary

damage to epithelium. Tmax was observed within 5 minutes after intransal administration

at 1 mg/kg dose of the formulation

4 Nimodipine Labrafil M 1944 CS,

Cremophor RH 40,

Ethanol

Physicochemical characterization

Pharmacokinetic parameters

99

The formulation showed no nasal ciliotoxicity and nimodipine uptake in olfactory bulb

was three fold in comparision to intravenous injection

5 Risperidone Capmul MCM, Tween

80, Transcutol,


Biodistribution study, Gamma

100


Porecha S K


Propylene glycol scientigraphy study

Higher drug transport efficiency & Direct nose to brain drug transport efficiency. Gamma

scientigraphy image indicated localization of drug in brain.

6 Rivastigmine Capmul MCM, labrasol,

Transcutol, Chitosan

Physicochemical characterization Nasal

ciliotoxicity

101

No nasal toxicity and higher diffusion coeffiecient

7 Mitrazepine Capmul MCM, Tween

80, PEG 400


pharmacodynamic study, Brain/plasma

uptake ratio

102

The formulation indicated improvement in pharmacodynamic parameters and higher

brain/plasma ratio obtained in comparision to oral tablet

8 Clonazepam Isopropyl myristate,

Tween 80, Cremophor

EL, lecithin, PEG 200,

PG, Ethanol

Polarized light microscopy, globule size,

viscosity, drug release, In-vivo study

103

Rapid tmax of 10 minutes was obtained

9 Clonazepam Medium chain

triglyceride,

polyoxyethylene 35

ricinoleate and

polysorbate 80

Physicochemical characterization, Nasal

ciliotoxicity, pharmacodynamic study,

Brain/plasma uptake ratio

104

The researcher reported unaltered tight junction presence in human nasal mucosa

treated with prepared microemulsion. Localization of drug in brain was also confirmed

with gamma scientigraphy study and higher brain/plasma (0.67) ratio at 0.5 hr following

intranasal administration incomparision to intanasal solution administration and

intravenous administration

10 Ziprasidone Isopropyl myristate,

cremophor EL,

cremophor RH 40

Viscosity, pH, drug content, refractive

index, conductivity, zeta potential, in

vitro drug release

105


Porecha S K


Faster drug permeation was obtained

11 Sumatriptan

succinate

Isopropyl myristate,

Tween 80, Span 80

pH, viscosity, globule size, zeta

potential, Exvivo permeation,

Histopathological study

106

No toxicity and higher drug release was obtained

12 Zolmitriptan Egg lecithin, medium

chain triglyceride,

poloxamer 188,

glycerol, EDTA, sodium

oleate

Physicochemical characterization and

pharmacokinetic study

107

Higher AUCCSF/plasma was obtained

13 Diazepam Ethyl laurate, Tween

80, propylene glycol,

ethanol

Phase behavior, solubilization capacity,

pharmacokinetic parameters

108

Maximum drug plasma concentration was arrived within 2-3 minutes. Also reported that

the nasal liquid formulation that contains more than 10% water, less surfactant and free

of alcohol shows less nasal irritation.

14 Insulin Fluorescein

isothiocyanate,

Labrasol, glycerol

oleate, isopropyl

palmitate, propylene

carbonate

Globule size, measurement of

fluroscence intensity

109

Two fold higher fluroscence intensity was obtained with intranasal microemulsion in

comparison to aqueous drug solution

15 Lorazepam Cremophor EL 35,

Transcutol P,

lauroglycol, labrafil M

1944 CS

Solubilization capacity, particle size, In

vivo absorption efficiency

110


Porecha S K


Larger AUC, Mean bioavailability of 80.84% in comparison to intramuscular injection

16 Sumatriptan

succinate

Labrafil M 1944CS,

cremophor RH 40,

Transcutol

Clarity, pH, globule size, viscosity,

stability, In vitro diffusion study

111

Controlled in vitro release obtained for 4 hrs

17 Paliperidone Oleic acid, labrasol,

Transcutol, cremophor

RH 40,

TEM, polarizing microscopy, Clarity, pH,

globule size, viscosity, stability, In vitro

diffusion study, Nasal toxicity

112

The composition did not show any nasal toxicity on sheep nasal mucosa and higher

diffusion coefficient in comparison to drug solution

18 Paliperidone Oleic acid, labrasol,

Transcutol, cremophor

RH 40,

TEM, polarizing microscopy, Clarity, pH,

globule size, viscosity, stability, In vitro

diffusion study, Nasal toxicity

113

The composition did not show any nasal toxicity on sheep nasal mucosa and higher

diffusion coefficient in comparison to drug solution

19 Cabergoline Capmul MCM, Tween

80, PEG 400,

Transcutol

Globule size, conductivity, viscosity, pH,

zeta potential, Invitro drug diffusion,

Pharmacodynamic parameters,

pharmacokinetic study

114

The formulation did not show any toxicity and significant improvement in

pharmacodynamic parameters. Brain/plasma ratio at 0.25 hrs after intranasal

administration of microemulsion was 10 times in comparison to intravenous

administration

20 Buspirone IPM, Tween 80 ,

propylene

Glycol, chitosan, HPMC

Droplet size, PDI, zeta potential,

viscosity , TEM, pharmacokinetic study

115

They indicated higher relative bioavailability of Buspirone in comparision to intranasal

solution administration

21 Nitrendipine Caproyl 90, Tween 80, Physicochemical parameters, Nasal 116


Porecha S K


Transcutol toxicity study, pharmacodynamic study

Daily nasal administration of formulation for four consecutive weeks has no effect on

histopathology of nasal mucosa. Peak plasma concentration obtained with nasal

microemulsion was considerably higher than obtained with conventional oral tablet. The

tmax obtained with nasal microemulsion was 1 hr while tmax obtained with oral tablet was

3 hrs.


Porecha S K


3.3 Review of Literature for Carbamazepine:

Carbamazepine has been used as mainstream therapy for the treatment of epilepsy since

decades. However, its administration by oral route has certain side effects like gastric

disturbances, liver failure, and severe skin reaction. Carbamazepine is widely available as oral

dosage form which showed poor absorption and prolonged tmax. Scientists have tried to

develop novel formulations of carbamazepine to minimize above stated limitations (Table 8).

Table 8 Research work done on carbamazepine

Sr. No Dosage form Major Implications Ref.

1 Self microemulsifying

drug delivery system for

oral administration

5 fold increase in bioavailabilty in comparision to

commercial tablet

117

2 Parenteral formulations

comprising

carbamazepine or its

derivatives (US6316417

B1)

A parenteral formulation consisting essentially of

5H-dibenazepine-5-carboxamide, water, and

glucose. The patent claims reduction of dose (65-

70%) required in comparison to stated oral dose.

118

3 Oral controlled release

matrix tablet with

cyclodextrin complex

The marketed product released the drug and 44% in

acidic medium and 83% in 12 hours whereas the

optimized formulation F13 released the drug 88 %

in 12hrs.

119

4 Solid lipid nanoparticles Improvement in dissolution and invitro diffusion

coefficient

120

5 Fast disintegrating tablet The optimized formulation showed 90%

Drug release in 3.9 minute.

121

6 Floating tablet Floating leg time of 3 minutes and t80 of 540-600

minutes.

122

7 Unidirectional buccal

patch

Optimized formulation released 99.01% of drug in

140 min

123


Porecha S K


8 Solid dispersion by hot

melt extrusion

Higher dissolution rate 124

9 Intranasal microemulsion Drug release in 8 hours from optimized formulation

was 64.6%.

125

10 Mucoadhesive

nonoemulgel

The prepared formulation was characterized with

respect to oil droplet size, mucoadhesion, in-vitro

release of the drug and CBZ uptake by

phosphatidylcoline liposomes as an in-vitro model

for olfactory cells. The in-vitro release of CBZ from

MNEG was very low, however CBZ uptake via

liposomal membrane reached 65% within 1 hr.

Treatment of animals with MNEG significantly

prolonged the onset times for convulsion of

chemically convulsive mice and protected the

animals from two electric shocks.

126

A. owen et al developed HPLC method for the determination carbamazepine in the brain of

mice by using Acetonitrile: water as mobile phase with UV detection at 285 nm. The reported

method was selective selective, reproducible and precise with a detection limit 45 ng/ml[127].


Porecha S K


3.4 Review of Literature for Phenytoin:

Phenytoin (PHE) is a hydantoin compound related to the barbiturates that are used for the

treatment of seizures. It is an effective anticonvulsant for the chronic treatment of tonic-clonic

(grand mal) or partial seizures and the acute treatment of generalized status epilepticus. Very

little of an orally administered dose of phenytoin is absorbed from the stomach because

phenytoin is poorly soluble. The oral formulation of PHN results into slower onset of action and

thus a novel formulation of PHN to overcome the stated limitations are required. Scientists

have tried to develop novel formulations of Phenytoin to overcome stated limitations (Table 9).

Table 9 Research work done on Phenytoin

Sr.

No

Dosage form Major Inference Ref

1 Patent

US6245917 B1:

For the process

patent of

manufacturing of

crystalline sodium

phenytoin.

reported crystalline sodium phenytoin of this invention is

biologically effective to control generalized tonic-clonic (grand

mal) and complex partial (psychomotor, temporal lobe)

seizures in a daily dosage of from about 30 mg to about 3000

mg, and preferably about 100 mg to about 1000 mg per day

for a typical adult patient.

128

2 Phenytoin

emulsion using

sesame oil.

The study demonstrated the absorption of phenytoin by the

digestive tract was better when it was given as a sesame oil

suspension or emulsion than as a powder in beagle dogs.

129

3 Solid dispersions

with urea, PEG

and PVP

The results revealed a marked increase of dissolution rate and

solubility of phenytoin contained in solid dispersion in

comparison with the corresponding physical mixtures and

pure phenytoin.

130

4 Solid dispersion They reported Drug solubility and dissolution rate 131


Porecha S K


using PEG 6000

and PVPK30.

improvement by these formulations. They also reported that

that the intraperitoneal administration in mice of the solid

dispersion system of phenytoin exhibited anticonvulsant

activity similar to diphenylhydantoin sodium salt.

5 Cyclodextrin

inclusion complex

CD-based formulations of phenytoin increased peak plasma

concentration of phenytoin about 1.6-fold and bioavailability

(AUC0–24 h) of phenytoin about 2-fold compared to plain

phenytoin. The researcher indicated that increased

bioavailability of phenytoin in the presence of CDs was due to

an increased extent of drug dissolution.

132

6 Mouth dissolving

tablet

Optimized formulation showed less wetting time (14 sec.) and

99.12% drug release than other formulation

133

7 Microemulsion

using corn oil

The phenytoin plasma concentrations from the emulsion at

each observed time were about 1.5-2 times higher than those

from the suspension, significantly at time of 5, 6 and 7 hr after

administration. The AUC increased from 65.6 to 106.7

mug.hr/ml after phenytoin suspension or emulsion oral

administration, respectively

134


chapter 3 review of literature - information and...

Documents