BUCCAL MUCOADHESIVE DRUG DELIVERY

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BUCCAL MUCOADHESIVE DRUG DELIVERY

• Dr. Ranendra N Saha
• Professor of Pharmacy
• Dean, Faculty Division III Educational
  Development Division
• BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE,
  PILANI, INDIA

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Introduction

• Oral route is the most preferred for systemic
  delivery of drugs
• Disadvantages
• Degradation of sensitive drugs in GI tract
• Gastric irritation
• Poor and erratic absorption of biopharmaceutically
  compromised drugs
• Hepatic first pass metabolism
• Alternative absorptive mucosae like oral, nasal,
  rectal are need of hour for systemic delivery of
  such drugs especially proteins and peptides

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Advantages of Transmucosal Routes

• Better patient acceptability compared to
  parenteral route
• Avoidance of degradation of sensitive drugs in GI
  tract
• Better and quicker drug absorption
• Avoidance of gastric irritation
• Possible bypass of first pass metabolism

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Oral Mucosal Drug Delivery

• Buccal or sublingual regions within oral cavity
  can be used for systemic delivery of drugs
• Sublingual mucosa lacks expanse of smooth muscle
  or immobile mucosa, so unsuitable for retentive
  modified release dosage forms
• Buccal mucosa is robust and mucosa is immobile so
  ideal for retentive dosage forms
• Highly vascularized, so rapid drug absorption
• Venous blood reaches the heart directly via
  internal jugular vein
• So buccal mucoadhesive dosage forms like tablets,
  patches, gels have been extensively reported in
  literature

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Disadvantages of Buccal Route

• Low permeability sometimes results in low flux
• Total surface area available for absorption is
  less ( 170 cm2)
• Size limitation of dosage form, so more
  appropriate for drugs with low dose
• Swallowing of saliva may lead to loss exposure of
  drug to GI tract
• Sometimes inconvenient and voluntary removal is
  possible

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Buccal Mucoadhesive Dosage Forms

• General Considerations
• Dosage form size (Appropriate for drugs with low
  dose)
• Excipients with multiple functions need to be
  used
• Taste masking is essential
• Reported mucin turnover rate is 12 -14 h, so
  maximum duration of delivery should be less than
  this
• Physiology of mucus membrane under disease
  condition need to be accounted for (e.g. Cancer
  patients suffer from oral candidosis)
• Permeation enhancers are sometime needed if drug
  is poorly permeable

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Buccal Mucoadhesive Dosage Forms

• Three types of buccal mucoadhesive
• dosage forms are extensively reported
• Tablets
• Patches
• Gels
• Delivery systems are sometimes
• classified based upon mode of drug
• release
• Multidirectional
• Unidirectional

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Routes of Drug Transport

• Permeability of buccal mucosa is greater than
  skin but less than intestine and sublingual
  mucosa
• Approximate thickness of 500-800 µm
• Keratin layer and membrane coating granules are
  reported for barrier properties of buccal mucosa
• Paracellular (between cells)
• Transcellular (across cell)

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Permeation Enhancers
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Marketed Buccal Formulations/ Advanced
Developmental Stage
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Buccal Mucoadhesive Tablets
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Buccal Mucoadhesive Patches/Gels
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Buccal Mucoadhesive Tablets ofLercanidipine

• Objectives
• Preparation of buccal mucoadhesive controlled
  drug delivery systems of Lercanidipine
  hydrochloride using various mucoadhesive and rate
  controlling polymers either alone or in
  combination
• Selection of appropriate formulation additives on
  the basis of preformulation studies
• Optimization of physical characteristics of
  formulations such as size, shape, thickness,
  hardness, friability and surface pH
• Evaluation and optimization of designed
  formulations for in vitro release character and
  in vitro mucoadhesive property
• Assessment of acceptability of drug free
  formulations in human volunteers
• In vivo pharmacokinetic and bioavailability
  studies in rabbits

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Lercanidipine Hydrochloride

• Calcium channel antagonist
• Highly lipophilic
• Erratic oral absorption
• Slow onset of action
• Long duration of action
• Oral availability 20-30
• Extensive first pass metabolism P 450 (CYP) 3A4
• Metabolites are inactive
• Plasma concentration vs. Dose curve not linear
• Food causes variable increase in absorption
• Accumulation into the phospholipid bilayer of the
  cell membrane, resulting in longer duration of
  action
• Mostly excreted as metabolites approx. 50 in
  faeces 44 in urine
• Half Life 2-6 Hrs
• Dose 10 40 mg OD

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Buccoadhesive Tablets of Lercanidipine

• Compatibility of drug and excipients was studied
  using techniques like DSC, FTIR and HPLC
• Compatible polymers were selected for formulating
  tablets
• Tablets were prepared using direct compression
  technique
• Drug (100 ) and excipients (80 ) were mixed
  geometrically and compressed using 10mm flat
  faced punches
• Physical characterization of prepared
  formulations were carried out by determining
  weight variation, hardness, thickness and
  friability
• Developed formulations were evaluated for content
  uniformity
• In vitro mucoadhesive strength of developed
  formulations was evaluated using Texture Analyzer
  and porcine buccal mucosa

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Composition of Developed Tablets of Lercanidipine
Apart from these ingredients each formulation
contained mannitol (80 mg/tablet), lactose (80
mg/ tablet), talc (2 mg/tablet) , magnesium
stearate (2 mg/tablet) and drug (10 mg/tablet)
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In vitro Release Studies

• In vitro drug release studies were carried out
  using USP Type I dissolution apparatus with minor
  modifications
• Media Phosphate Buffer (pH 6.8) with 2.5v/v
  Polysorbate 80
• Temperature 37 1 oC
• RPM 25
• Volume Withdrawn 5 mL

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In vivo Human Acceptability Studies

• Acceptability of developed formulations was
  studied in healthy male human volunteers between
  age of 20-25 years
• Freshly prepared placebo formulations were used
• Volunteers were asked to wash the oral cavity
  with around 100 mL of distilled water
• Developed formulations were pressed against the
  mucosal lining of cheek for 1 min
• Water and food were not allowed only for first 30
  and 60 min of study repectively
• Volunteers were asked to record time of tablet
  placement and time and circumstances at end of
  adhesion (erosion or dislodgement of tablets)
• Volunteers were given a questionnaire to assess
  the acceptability of the designed tablets

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In vivo Bioavailability Study in Rabbits

• New Zealand white male rabbits were used
• The mean weight of the animals selected for the
  study was 1.79 0.24 kg
• Food was stopped to all animals 8-10 h prior to
  the actual start of experimentation
• Food and water was not given to animals till 2 h
  after the start of the study
• To study the oral pharmacokinetics, 2 ml of 5
  mg/ml solution of drug in 40 v/v PEG 400 in
  water was administered to rabbits using an oral
  catheter
• For buccal dosing, the mouth of rabbit was
  opened using specially designed mouth restrainers
• The tablet was pressed gently against mucosal
  lining of cheek for 1 min to ensure adhesion
• Blood samples (1 ml) were withdrawn from the
  marginal ear vein at different time points and
  serum drug concentration was determined using
  in-house developed and validated HPLC method

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Results and Discussion
Table Results of quality control tests carried
out on designed buccal mucoadhesive tablets
a For each batch 20 tablets were taken b Mean of
three batches with duplicate determination per
batch
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In vitro Release Studies
(a)
(b)
Figure Comparative in vitro release profiles of
drug from tablet formulations prepared using
different polymers at varying
proportions (a) Chitosan (b) Carbopol
(Each point represents mean and SD of three
batches with duplicate determination per batch)
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In vitro Release Studies
(c)
(d)
Figure Comparative in vitro release profiles of
drug from tablet formulations prepared using
different polymers at varying
proportions (c) HPMC K4M and HPMC K 15M (d) HPMC
K100 M (Each point represents
mean and SD of three batches with duplicate
determination per batch)
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Table Model fitting of in vitro drug release
data for determination of mechanism and kinetics
of release
a Diffusion exponent indicative of release
mechanism b Time for 50 drug release
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In vitro Mucoadhesion Studies
Figure Results of in vitro mucoadhesion studies
of designed tablet formulations (Each point
represents mean and SD of three batches with
duplicate determination per batch)
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Human Acceptability Studies
Table Scoring system followed for evaluating
acceptability of formulations in humans
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Human Acceptability Studies
Table Results of human acceptability studies of
the designed formulations
Figure Results of mucoadhesion studies of tablet
formulations in healthy human male volunteers
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In vivo Bioavailability Studies
Figure In vivo profiles following administration
of single dose of drug (10 mg) in rabbits by oral
and buccal route (Each value represents mean of 3
independent determinations with standard
deviation)
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In vivo Bioavailability Studies
Table Summary of pharmacokinetic parameters of
drug following administration of single dose of
10 mg by oral and buccal route (Mean
SD for 3 rabbits)
a Maximum serum concentration b Time to reach
Cmax c Calculated using terminal portion of
profile d Area under the serum
concentration-time curve e Mean residence time f
Relative bioavailability
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Conclusions

• The drug was found to be compatible with
  excipients selected for the study using
  techniques like DSC, FTIR and HPLC
• Polymers reported for both mucoadhesive and
  release retardation properties were used
• Designed tablets were found to possess good
  physical characteristics indicating suitability
  of the manufacturing method
• A series of formulations retarding in vitro drug
  release from 4-10 h were designed
• Most of the formulations showed anomalous
  non-Fickian drug release pattern
• Drug release rate was found to be inversely
  proportional to the amount of retarding polymer
  in the formulations
• In vitro mucoadhesive strength was dependent upon
  type of polymer and polymer proportion in the
  tablets
• Tablets prepared using carbopol showed maximum
  mucoadhesion

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Conclusions

• All the formulations were found to be acceptable
  in human acceptability studies with no apparent
  discomfort to volunteers
• Formulation prepared using carbopol adhered for
  longest duration in human volunteers
• In vivo bioavailability studies in rabbits,
  showed significantly higher plasma
• Chitosan used in designed formulations is also
  reported as a permeation enhancer
• Designed buccal mucoadhesive controlled release
  formulations overcome the disadvantage of poor
  and erratic oral bioavailability associated with
  currently marketed formulations
• This increased and predictable availability of
  drug may result in substantial dose reduction of
  Lercanidipine Hydrochloride

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References

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Acknowledgements

• Authors are thankful to
• University Grants Commission, New Delhi, India
  for financial support
• Glenmark Pharmaceuticals, Mumbai, India for
  generous gift sample of Lercanidipine
  Hydrochloride
• IPCA Laboratories, Mumbai, India and Noveon,
  Mumbai, India for generous gift samples of
  polymers