Buccal drug delivery system

A SEMINAR ON BUCCAL DRUG DELIVERY SYSTEM

Prepared by: Guided by:

Shivam Thakore Mrs Shital Acharya

Vishal Gajipara Mr Jaymin Patel

04/08/2023 1Department of Pharmaceutical Technology,

LJ Institute of Pharmacy, Ahmedabad

What is BDDS??? Delivery of drug through Buccal mucosa of oral

cavity is called BDDS. Buccal mucosa lines the inner region of cheeks.

In biological term, the product is placed between upper gingiva (gums) & cheek to treat local & systemic conditions.



Advantages Avoids 1st pass metabolism Avoids acid/Enzyme metabolism Permeation is faster with respect to Skin & TDDS (4-

4000) Large surface area with respect to sub-lingual mucosa Good patient compliance with respect to parental Easy administration & removal in case of toxicity. For unconscious or comatose patients



Disadvantages Drugs with bitter taste or irritant to mucosa or having

noxious smell Not for children Eating & drinking difficulty Salivary erosion & it may enter GIT & choke esophagus Less surface area than skin Drugs unstable at Buccal pH(6.5 to 7)



Anatomy/Physiology of Buccal Cavity



Buccal Environment

It has four parts & is 500-800um thick & 150Cm^2 approx

Epithelium: 40-50 cell thick & is major barrier for lipophilic drug. It has initially square shaped cells which further grows in the elliptical cells which are permeable for hydrophilic drugs. It may be Keratinized (having High MW) or non-keratinized (Low MW).

Mostly, non-keratinized epithelium is permeable to drug very easily due to absence of acylceramides & only small amounts of ceramides. Also they contain small amounts of neutral but polar lipids (Cholesterol Sulfate& Glucosyl ceramides). Hence more permeable to formulation



Cont… Lamina propria: Barrier for hydrophilic drug Hence highly hydrophilic & highly lipophilic drug

are not suitable for BDDS.

Salivary Secretions: It is secreted by Parotid, Sub-maxillary & Sub-lingual glands

99 % Aq liquid

1% Solute {Na, K, Ca, Mg, Mucin, Albumin,

Enzymes(Amylase, lipase) }



Mucin Biochemistry The pH of saliva is due to Mucin (6.2-7.4). Mucins are synthesized by the goblet cells and

special exocrine glands & secreted by sialic cells & Mucus cells

It is gylcorylated glycoprotein having large peptide backbone & oligosaccharides side chains & 14 side chains made up of oligosaccharide.

End part of side chains has negative charge due to sialic acid, sulphonic grp & fructoic grp which attract cationic polymers.



Factors affecting…FACTORS…

Polymer related factors MW of polymerFlexibilityH-bond capacity Cross-linking density Charge Concentration

Drug related factors Mw of Drug,Lipophilicity

Patient Related factors Salivary secretion ratepH of Buccal CavityEating/Drinking habit



POLYMER RELATED FACTORS

MW of polymer MW increases, chain & ultimately adhesion increases Eg PEG4000

Flexibility Should be high

H-bond Capacity HPMC, Carbopol, PVA, PMA

Cross-linking density Should be low as possible

Charge Charged molecule will be highly adhere

Concentration 0.5-2 % optimum, because it will directly increase the cross linking & hence binding decreases

DRUG RELATED FACTORS

MW of Drug Mw of drug increases, the Absorption decreases

Lipophilicity Should be high

PATIENT RELATED FACTORS

Salivary secretion rate

pH of Buccal Cavity

Eating/Drinking habit



Mechanism of Adhesion The term bioadhesion is commonly defined as adhesion

between two materials where at least one of the material is of biological origin.

When adhesion is restricted to mucus layer lining of the mucosal surface, then it is known as Mucoadhesion.

Generally such adhesion occurs in four different steps… Wetting & Swelling Interpenetration of polymer chains in mucin chains Formation of chemical bonds between Entangled

chains



1. Wetting and swelling of polymer to permit intimate contact with biological tissue.

2. Inter-penetration of bioadhesive polymer(BP) chains and entanglement of polymer and mucin chains.







3. Formation of chemical bonds between Entangled chains.

Chemical bonds may be primary(covalent) or secondary(ionic, van dervaals, H-bonds)



Theories of AdhesionAdsorption theory: Polymer/groups form covalent/non-covalent bonds which will bind very strongly (also H-bonds, vanderwaal’s bonds).

Wetting theory: Polymer with positive spreading co-efficient will have good binding.

Diffusion theory: Permeability is good in mucin due to chain flexibility.

Fracture Theory: Irregular surface of polymer & mucin give good physical entanglement.

Electronic theory: Electric bilayer between polymer & mucin is responsible.



Formulation of BDDSS

olid

Dos

age

form

s • Tablets• Patches/films• Wafers• Lozenges• Powders

Sem

i-Sol

id D

asag

e fo

rms • Gels

• Ointments

Liqu

id D

osag

e fo

rms • Sprays



Basic Formulation components

Muco-adhesive Polymers Permeation enhancers

Diluents Plasticizer

Preferred Drug Candidate



Selection of DRUG for BDDSI. MW should be less than 1000da

II. It should be having both nature i.e. hydro-lipophilic type

III. Should be potent {low dose so that formulation is not bulky}

IV. Non-irritant to mucosa

V. Drugs that degrades in GIT.



List of API’s delivered via Buccal routeAPI

Acyclovir Metronidazole

Buprenorpine Metoprolol tartrate

Carbamazepine Morphine sulphate

Chlorpheniramine maleate Nifedipine

Danazol Omeprazole

Diclofenac sodium Pentazocine

Diltiazem Pindolol

Flurbiprofen Piroxicam

Hydrocortisone acetate Rh EFG

Insulin Testosterone

Lignocaine Terbutaline sulphate

LHRH Theophyline

Zinc sulphate Triamcinolone acetate



Mucoadhesive Polymers These are the main component for adhesion. They attract water from the biological surrounding, get

swells & adhere to the membrane. Normally they should be having hydrophilicity, numerous

H-bonding groups, flexibility, interpenetration with mucus & tissues



Ideal features… Non-toxic, non-irritant & pure. Good spreadibility, wetting, swelling, solubility &

biodegradable if possible. Adhesion should be quick & with sufficient mechanical

strength. Should have peel,tensile,shear strength. Should easily incorporate drug in formulation & it should

not be obstacle in drug release. Cost effective.



Examples Hydrogels:

Polyacrylates, carbopol, polycarbophils

PVA, Ethylene Vinyl alcohol, cellulose derivatives, alginates

Thiolated Polymers

Hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone.

Eg: Thiomers of chitosan and polyacrylic acid etc

04/08/2023 23Department of Pharmaceutical Technology, LJ

Institute of Pharmacy, Ahmedabad

Permeation Enhancers Permeation is very limiting factor in BDDS. Substances that facilates permeation through Buccal

mucosa are called PE. Epithelium & Lamina Propria are very effective barrier to

absorption. They should be used with very care & in optimum

concentration(<1%), above this concentration toxicity due to membrane damage may occur & histopathological study should be done.



Mechanisms of PE’s Increasing fluidity & integrity of cell membrane. Extracting inter/intra cellular lipids. Altering cellular proteins. Altering mucus rheology. Acting at the tight junctions. Increasing thermodynamic activity of drugs. Surface tension decreasing.



Permeation EnhancersTypes ExamplesChelators EDTA, Citric acid, Sodium salicylate,

methoxy salicylates

Surfactants SLS, Polyoxyethylene,Benzalkonium chloride, Cetylpyridinium chloride,Cetyltrimethyl ammonium bromide.

Bile salts sodium glycocholate, sodium deoxycholate,sodium taurocholate, sodium glycodeoxycholate,sodium taurodeoxycholate

Fatty acids Oleic acid, Capric acid, Lauric acid, PG, methyloleate,Phosphatidylcholine.

Non-surfactants Unsaturated cyclic ureas.

Inclusion complexes: Cyclodextrins



Important formulation Tablets Is small, flat, generally oval shape with 5-8mm diameter. It is directly placed onto mucosal surface & adheres to it. DC/WG may be used to formulate.



We can get Unidirectional Release Multidirectional release (as with conventional product)

Generally for unidirectional release, a backing membrane is applied, which is impermeable to liquid, to one side so that no drug release is observed form that side & non-coated surface adheres to the Buccal mucosa. Ethyl Cellulose is used as backing membrane.



Different marketed Buccal tablets…

Prochlorperazine maleate tab (BuccastemR M) Glycerl trinitrite Buccal tab (Suscord) Fentanyl Buccal tab (Fentora) Miconazole Buccal tab (Oravig) Testosterone (Striant) patented product





Buccal Patches/films They are long, flat, thin thickness, transparent with high

surface area. They can be prepared by two methods

Solvent casting method Direct milling method



Solvent Casting Method Here drug & all excipients are weighed and dispersed in

the suitable organic solvent & coated on the release liner.

The organic solvent is allowed to evaporate & after evaporation the thin layer of the backing material is laminated on to the sheet of coated release liner to form laminate.

After that the whole patch is ready to cut into required size (almost 2*2 cm2 )



Direct Milling Method Here, drug & excipients are mixed mechanically

by milling or kneading. After mixing the resultant material is rolled on the

release liner till desired thickness is achieved. Finally as the previous method, backing material

is laminated. Though there is no difference in the patch

performance manufactured by either of the method but with the SOLVENT method there are chance of residual solvent.

Hence this Solvent free method is highly used



What does backing layer does…Control the direction of drug releaseAlso prevent drug lossesMinimize deformation during handling &

transportationReduces the disintegration of device during the

application

Examples

Nitroglycerin patches

Fentanyl patches (Onsolis)



Evaluating the BDDSDosage forms Tablets Patches Semi-solids Sprays

In-vitro test

Weight Variation Y Y

Assay Y Y Y Y

Thickness Y Y

Friability Y

Disintegration time Y Y

Residence time Y Y Y

Tensile strength Y

Folding endurance Y

Viscosity Y

Droplets size Y

Dissolution Y Y Y

Mucoadhesion Strength

Y Y Y

Permeability test Y Y Y Y



Some important in-vitro test Disintegration time:

Slide frame method: film on slide + drop of water in it. Note the time when hole is observed in the film.

Petri dish method: film in Petri plate + 2 ml of water in it. Check time till film dissolves.

Residence time:

Take a slide, stick a mucosa on it with gum. Place our dosage form on it with few droplets of PBS 6.8, allow it to stick on it. Now make it inclined at 30 C & at constant rate add PBS 6.8 drop wise on it without moving the slide. Note the time till dosage form detaches from mucosa.

Permeation Study: Franz diffusion cell



Residence time Locally modified USP disintegration apparatus was

used. DT media: 800 mL PBS pH 6.8 at 37 °C. The buccal tissue was glued to the surface of a glass slab, vertically attached to the apparatus. The buccal tablet was hydrated from one surface using 0.5 mL of PBS pH 6.8, and then the hydrated surface was brought into contact with the mucosal membrane. The glass slab was vertically fixed to the apparatus and allowed to run in such a way that the tablet was completely immersed in the buffer solution at the lowest point and was out at the highest point. The time necessary for complete erosion or detachment of the tablet from the mucosal surface was recorded.





Muco-adhesive strength



Shear Force (for various polymers)

The shear test measures the force required to separate two polymer-coated glass slides joined by a thin film of natural or synthetic mucus. The results of this technique often correlate well with in vivo testresults.



Muco/bio adhesion test Modified physical balance. Here lighter pan had replaced the

right pan and the left pan had been replaced by a glass slide. The height of the total set-up was adjusted to accommodate a glass container of 6.6 cm height. Buccal tablet was stacked to the glass slide with the help of the knob, which was situated at the base of the physical balance. Five grams weight from the right pan was then removed. This lowered the glass slide along with the tablet over the membrane with a weight of 5.0 g. This was kept undisturbed for 5 min. Then, the weights on the right-hand side were slowly added in increments of 0.1 g till the tablet just separated from the membrane surface. By using this weight calculate the bio-adhesive force using following equation

Bio adhesive force (N) = weight in grams × G/1000



Modified Balance Method



04/08/2023

Block Diagram of Modified Balance Method

43Department of Pharmaceutical Technology,


TEXTURE ANALYZER: Here the force required to remove the formulation from

a model membrane is measured, which can be a disc composed of mucin , a piece of animal mucous



In-vivo test Buccal Absorption study: Assay of drug solution,

after mouth gargles. Perfusion study Kinetic study



Chien Diffusion Cell



Recent Innovations Gel Forming Liquids: This type of a formulation is liquid upon instillation

and undergoes a phase transition to form a viscoelastic gel in response to stimulus such as temperature, ionic strength or ph

Carbomers become more viscous upon increased pH.

Gellan gum and alginate both form gel in response to increased ionic strength (particularly with Ca+2 ions).

Poloxamers and smart hydrogel®( Advanced medical solution) gel at approximately body temperature.



Slowly disintegrating buccal mucoadhesive plain tablet (SDBMPT)• Prepared by incorporating large amount of HPC.

e.g. tablet having 20mg drug, 20mg HPC, 20mg CMC & 60mg lactose – mixed & compressed with a flat faced die that is 8mm in diameter.

• Limitation: softens on extended period and lose its shape which hinders the control of

disintegration over long time periods



BCTS (Buccal Covered Tablet System)

• Sandwiched S-DBMP-T system between two polyethylene sheets

• Upper sheet contains hole to absorb water and lower sheet is made of adhesives



OraVescent technology

• System which transports drug through across the mucosal membrane.

• Based on effervescent technology and administered buccally or sublingually by Cima labs Inc

• Principle: pH < pKa of weak base –

ionization and solubilization



Marketed products Striant®, developed by Columbia Labs, is a testosterone

extended-release buccal tablet that delivers testosterone systemically for hormone replacement in hypogonadal men.

Asftach® is a buccal tablet containing triamcinolone acetonide for treatment of apththous ulcers, and contains a bioadhesive layer and a dissolvable lactose nonadhesive backing layer

DentiPatch® has been developed by Noven, which is a lidocaine extended-release buccal patch that adheres to the gingival tissue to provide for local analgesia, and was approved in the United States in May 1996.



Cydot® is an example of a patch technology where the patch adheres to the buccal mucosa for a period of up to 24 hours to slowly release melatonin for normalizing circadian rhythms.

Buccal Methyltestosterone

Brand name-Metandren, Ciba;

Avoids first-pass hepatic metabolism

Prochlorperazine

Brand name -Oreton ,Schering Buccastem,

Alternative to enteral tablet







MARKETED FORMULATIONS

PRODUCT COMPANY BIOADHESIVE AGENT

PHARMACEUTICAL FORM

Buccastem® Reckitt Benckiser PVP, Xanthum gum

Buccal tablet

Corlan pellets® Celltech Acacia gum Oromucosal pellets

Suscard® Forest HPMC Buccal tablet

Gaviscon liquid® Reckitt Benckiser Sodium alginate Oral liquid

Orabase® Convatech Pectin, Gelatin Oral paste

Corsodyl gel® GlaxoSmithKline HPMC Oromucosal gel



SUB-LINGUAL DRUG DELIVERY SYSTEM



Administering the drug via membrane located below the tongue is called Sublingual DDS(SLDDS) generally called floor of mouth.

The SLDDS is almost similar to the BDDS having some more advantages than Buccal drug delivery system.

Generally factors affecting the SLDDS are almost similar to factors related with the BDDS.





SLDDS vs BDDSSLDDS BDDS

The absorption via sub lingual route is faster than buccal mucosa due to the thickness of the sublingual mucosa.It is 100-200 µm thick

Here, in BDDS, the thickness of buccal mucosa is 500um approximately, hence permeation is slow in compare to sublingual route

Hence, in emergency conditions, like angina pectoris/asthmatic attack, SLDDS in preferred than BDDS due to faster permeation of drug

Sub lingual mucosa has rapid absorption and has higher blood levels due to very high vascularization of the region than Buccal mucosa

It has less vascularization than sublingual mucosa.



Drug administered Antianginal like nitrites and nitrates Anti hypertensive like nifedipine Analgesics like morphine Bronchodilators like fenoterol Certain steroids like estradiol Peptides like Oxytocin can also be administered



Various formulations Sublingual tablets Fast-disintegrating sublingual tablets Bioadhesive sublingual tablet Thin film drug delivery Lipid matrix sublingual tablet Sublingual immunotherapy Sublingual vitamin tablet



Evaluating SLDDS Surface pH of the tablet Uniformity of weight Content uniformity Hardness Thickness Diameter Disintegration time Wetting time Friability Dissolution test Folding endurance Bioadhesion strength Permeation studies % Elongation



Marketed Products



References Katsumi Iga, “Modified-Release Drug Delivery Technology”,

Edited by Michael, J Rathbone , Jonathan Hadgraft and Michael S . Roberts, Informa Healthcare 2002, New York, USA

Jaiswal S B, Brahmankar DM, “Biopharmaceutics & Pharmacokinetics, A treatise” 2nd edition, Vallabh Prakashan, New Delhi

Jain N K, “Controlled and Novel Drug Delivery Systems”, 1st edi, 2009 reprint, CBS publishers, New Delhi

Chien Yie W, “Novel Drug Delivery system”, 2nd edition, revised & Expanded, volume 50, Informa healthcare, New York, USA

K. Patel Nibha1 and SS. Pancholi, “An Overview on: Sublingual Route for Systemic Drug Delivery”, International Journal of Research in Pharmaceutical and Biomedical Sciences, Vol. 3 (2) Apr – Jun2012



Neha narang, Jyoti sharma, “Sublingual mucosa as a route for systemic drug delivery”, International Journal of Pharmacy and Pharmaceutical Sciences, Vol 3, Supply 2, 2011.

Pharmaquest.weebly.com/uploads/9/9/4/2/9942916/3.sublingual_dds.pdf/accessed at 24/2/2013

Smart D John, “Drug delivery using buccal-adhesive systems”, Advanced drug delivery reviews, Elsevier Science Publishers, Volume 11, Issue 3, September 1993, Pages 253-270

Miller Nazila Salamat miller, Chittchang Montakarn, Johnston Thomas P, “The use of mucoadhesive polymers in buccal drug delivery Advanced Drug Delivery Reviews, Elsevier Science Publishers, Volume 57, Issue 11, 3 November 2005, Pages 1666-1691”



Questions to CRAACK GTU… Discuss the merits and demerits of sublingual

dosage forms. How are they evaluated? Discuss the in-vitro evaluation models for oral drug

delivery systems. Explain evaluation methods for mucoadhesive

drug delivery. Write applications of buccal & sublingual drug

delivery systems. Explain the structure of buccal mucosa. Give a

brief account of mucoadhesive polymers for buccal delivery.



Discuss the merits and demerits of mucoadhesive buccal drug delivery. How one can evaluate mucoadhesive buccal formulation?

Describe methods to determine muco-adhesion property of formulations.

Discuss in brief delivery systems for oral mucosa. What are the objectives of sublingual drug delivery

system? Discuss evaluation parameters of sublingual drug delivery system.

Enlist various method used for bio adhesive property measurement. Discuss any one.

Explain significance of sublingual drug delivery system. How they are evaluated?



THANKS FOR ATTENTIONLJIP, AHMEDABAD



Health & Medicine

Buccal drug delivery system