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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.
CHAPTER 3. REVIEW OF LITERATURE
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 46 of 210
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
CHAPTER 3. REVIEW OF LITERATURE
Porecha S K
K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 47 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.
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 48 of 210
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
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 49 of 210
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.
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Porecha S K
K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 50 of 210
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
CHAPTER 3. REVIEW OF LITERATURE
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 51 of 210
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
CHAPTER 3. REVIEW OF LITERATURE
Porecha S K
K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 52 of 210
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.
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Porecha S K
K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 53 of 210
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).
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 54 of 210
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,
Physicochemical characterization
Biodistribution study, Gamma
100
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 55 of 210
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
Physicochemical characterization
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
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 56 of 210
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
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 57 of 210
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
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 58 of 210
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.
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 59 of 210
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
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 60 of 210
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].
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 61 of 210
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
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K.B.I.P.E.R Kadi Sarva Vishwavidyalaya Page 62 of 210
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
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