Current Status In Buccal Drug Delivery System

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Mr. Manish S. Wani

Mr. Manish S. Wani

Transmucosal routes of drug delivery involves the delivery of the drug through the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity 3 Amongst these oral cavity is a novel site for drug delivery. The oral mucosa has been investigated in several studies as a means to give both local and systemic amounts of drug. Drug delivery across the oral mucosa, can be divided into three different types 3,4

  1. Sublingual delivery, consisting of administration through the membrane of the ventral surface of the tongue and the floor of the mouth.
  2. Buccal delivery , consisting of administration through the buccal mucosa, mainly composed of the lining of the cheeks and
  3. Local delivery , consisting of administration through all areas other than former two region.

These sites differ anatomically in their permeability to drugs, rate of drug delivery, and ability to maintain a delivery system for the time required for drug release out of the delivery apparatus and into the mucosa.

Buccal Drug Delivery 4

The buccal mucosa lines the inner cheek, and buccal formulations are placed in the mouth between the upper gingivae (gums) and cheek to treat local and systemic conditions. The buccal route provides one of the potential route for typically large, hydrophilic and unstable proteins, oligonucleotides and polysaccharides, as well as conventional small drug molecules. The oral cavity has been used as a site for local and systemic drug delivery.

Advantages Of Drug Delivery Via The Buccal Lining : 2, 5  

  1. Bypass of the gastrointestinal tract and hepatic portal system, increasing the bioavailability of orally administered drugs that otherwise undergo hepatic first-pass metabolism . In addition the drug is protected from degradation due to pH and digestive enzymes of the middle gastrointestinal tract
  2. Improved patient compliance due to the elimination of associated pain with injections; administration of drugs in unconscious or incapacitated patients; convenience of administration as compared to injections or oral medications.
  3. Sustained drug delivery.
  4. A relatively rapid onset of action can be achieved relative to the oral route, and the formulation can be removed if therapy is required to be discontinued.
  5. Increased ease of drug administration
  6. Though less permeable than the sublingual area, the buccal mucosa is well vascularized , and drugs can be rapidly absorbed into the venous system underneath the oral mucosa.
  7. In comparison to TDDS, mucosal surfaces do not have a stratum corneum. Thus, the major barrier layer to transdermal drug delivery is not a factor in transmucosal routes of administration. Hence transmucosal systems exhibit a faster initiation and decline of delivery than do transdermal patches.
  8. Transmucosal delivery occurs is less variable between patients, resulting in lower intersubject variability as compaired to transdermal patches.
  9. The large contact surface of the oral cavity contributes to rapid and extensive drug absorption

Limitations Of Buccal Drug Delivery 2, 5  

Depending on whether local or systemic action is required the challenges faced while delivering drug via buccal drug delivery can be enumerated as follows.

  1. For local action the rapid elimination of drugs due to the flushing action of saliva or the ingestion of foods stuffs may lead to the requirement for frequent dosing.
  2. The non-uniform distribution of drugs within saliva on release from a solid or semisolid delivery system could mean that some areas of the oral cavity may not receive effective levels.
  3. For both local and systemic action, patient acceptability in terms of taste, irritancy and ‘mouth feel’ is an issue.

For systemic delivery the relative impermeability of oral cavity mucosa with regard to drug absorption, especially for large hydrophilic biopharmaceuticals, is a major concern.

Structure And Design Of Buccal Dosage Form  5

Buccal Dosage form can be of

1. Matrix type: The buccal patch designed in a matrix configuration contains drug, adhesive, and additives mixed together

2. Reserviour type: The buccal patch designed in a reservoir system contains a cavity for the drug and additives separate from the adhesive. An impermeable backing is applied to control the direction of drug delivery; to reduce patch deformation and disintegration while in the mouth; and to prevent drug loss.

Additionally, the patch can be constructed to undergo minimal degradation in the mouth, or can be designed to dissolve almost immediately.

Transmucosal drug delivery systems can be bi-directional or unidirectional. Bi-directional (Figure 1) patches release drug in both the mucosa and the mouth while, Unidirectional (Figure 2) patches release the drug only into the mucosa.

Buccal Patch  designed for Bidirectional drug release                                                                                         

Figure 2 : Buccal Patch  designed for Bidirectional drug release

Buccal Patch designed for Unidirectional drug release

Figure 3: Buccal Patch designed for Unidirectional drug release

Structure Of Oral Mucosa 4, 6

The oral mucosa is comprised of squamous stratified (layered) epithelium, basement membrane , the lamina propria and submucosa. It also contains many sensory receptors including the taste receptors of the tongue.

Cross section of  Oral Mucosa

Figure 1: Cross section of  Oral Mucosa

Buccal Mucosa: Environment 7

The oral cavity is marked by the presence of saliva produced by the salivary glands and mucus which is secreted by the major and minor salivary glands as part of saliva.

Role of Saliva

  • Protective fluid for all tissues of the oral cavity.
  • Continuous mineralization / demineralization of the tooth enamel .
  • To hydrate oral mucosal dosage forms.

Role of Mucus

  • Made up of proteins and carbohydrates.
  • Cell-cell adhesion
  • Lubrication
  • Bioadhesion of mucoadhesive drug delivery systems

Permeability Of Drugs Through Buccal Mucosa 4

There are two possible routes of drug absorption through the squamous stratified epithelium of the oral mucosa:

i.Transcellular (intracellular, passing through the cell) and

ii.Paracellular (intercellular, passing around the cell).

Permeation across the buccal mucosa has been reported to be mainly by the paracellular route through the intercellular lipids produced by membrane-coating granules.

Although passive diffusion is the main mechanism of drug absorption, specialised transport mechanisms have been reported to exist in other oral mucosa (that of the tongue) for a few drugs and nutrients; glucose and cefadroxil were shown to be absorbed in this way.

The buccal mucosa is a potential site for the controlled delivery of hydrophilic macromolecular therapeutic agents (biopharmaceuticals) such as peptides, oligonucleotides and polysaccharides. However, these high molecular weight drugs usually have low permeability leading to a low bioavailability, and absorption enhancers may be required to overcome this.

The buccal mucosa also contains proteases that may degrade peptide-based drugs. In addition, the salivary enzymes may also reduce stability.

Disease states where the mucosa is damaged would also be expected to increase permeability. This would be particularly true in conditions that result in erosion of the mucosa such as lichen planus, pemphigus, viral infections and allergic reactions.

Buccal Drug Delivery And Mucoadhesivity 8

In the development of these Buccal drug delivery systems, mucoadhesion of the device is a key element. The term ‘mucoadhesive’ is commonly used for materials that bind to the mucin layer of a biological membrane. Mucoadhesive polymers have been utilized in many different dosage forms in efforts to achieve systemic delivery of drugs through the different mucosae. These dosage forms include tablets, patches, tapes, films, semisolids and powders. To serve as mucoadhesive polymers, the polymers should possess some general physiochemical features such as

i Predominantly anionic hydrophilicity with numerous hydrogen bond-forming groups

ii Suitable surface property for wetting mucus/mucosal tissue surfaces and

iii Sufficient flexibility to penetrate the mucus network or tissue crevices.

The polymers which have been tried and tested over the years include 9 Carboxymethyl cellulose, Carbopol, Polycarbophil, Poly(acrylicacid/ divinyl benzene), Sodium Alginate, Hydroxyethyl cellulose, Hydroxypropyl methylcellulose, Hyaluronic acid, Gelatin, Guar Gum, Thermally modified Starch, Pectin, Polyvinyl pyrrolidone, Acacia, Polyethylene glycol, Psyllium

Amberlite-200 resin, Hydroxypropyl cellulose, Chitosan, Hydroxyethyl methacrylate.

There are some Novel Mucoadhesive Polymers 4 under development , these include 9 Copolymer of PAA and PEG monoethylether monomethacrylate, PAA complexed with PEGylated drug conjugate, Hydrophilic pressure-sensitive adhesives (PSAs), AB block copolymer of oligo(methyl methacrylate) and PAA , Polymers with thiol groups (cysteine was attached covalently to polycarbophil by using carbodiimide as a mediator.

Factors Affecting Drug Delivery Via Buccal Route 10

The rate of absorption of hydrophilic compounds is a function of the molecular size. Smaller molecules (75-100 Da) generally exhibit rapid transport across the mucosa, with permeability decreasing as molecular size increases. For hydrophilic macromolecules such as peptides, absorption enhancers have been used to successfully alter the permeability of the buccal epithelium, causing this route to be more suitable for the delivery of larger molecules.

Only the nonionized forms of molecules have the ability to cross-lipoidal membranes in significant amounts. The more lipid soluble a compound is, the higher its permeability. The permeabilities for these compounds are direct functions of their oil-water partition coefficients.  The partition coefficient is a useful tool to determine the absorption potential of a drug. In general, increasing a drug’s polarity by ionization or the addition of hydroxyl, carboxyl, or amino groups, will increase the water solubility of any particular drug and cause a decrease in the lipid-water partition coefficient. Conversely, decreasing the polarity of a drug (e.g. adding methyl or methylene groups) results in an increased partition coefficient and decreased water solubility. The partition coefficient is also affected by pH at the site of drug absorption. With increasing pH, the partition coefficient of acidic drugs decreases, while that of basic drugs increases. The partition coefficient is also an important indicator of drug storage in fat deposits. Obese individuals can store large amounts of lipid-soluble drug in fat stores. These drugs are dissolved in the lipid and are a reservoir of slow release from these fat deposits.

The ionization of a drug is directly related to both its pKa and pH at the mucosal surface. Only the nonionized form of many weak acids and weak bases exhibit appreciable lipid solubility, and thus the ability to cross lipoidal membranes. As a result, maximal absorption of these compounds has been shown to occur at the pH at which they are unionized, with absorbability diminishing as ionization increases.

In short one can say that the lipid solubility of drugs is an important factor in Transmucosal Drug Delivery system. Along with lipid solubility, drugs selected for Transmucosal Drug Delivery system must have physiochemical properties, including size and pKa that facilitate drug movement through the mucosa at a rate capable of producing therapeutic blood concentrations. The drug must resist, or be protected by salivary and tissue enzymes that could cause inactivation. Additionally, the drug and adhesive materials must not damage the teeth, oral cavity, or surrounding tissues (e.g. by keratinolysis, discoloration, and irritation).

Methods To Increase Drug Delivery Via Buccal Route

Absorption enhancers 10

Absorption enhancers have demonstrated their effectiveness in delivering high molecular weight compounds, such as peptides, that generally exhibit low buccal absorption rates. These may act by a number of mechanisms, such as increasing the fluidity of the cell membrane, extracting inter/intracellular lipids, altering cellular proteins or altering surface mucin. The most common absorption enhancers are azone, fatty acids, bile salts and surfactants such as sodium dodecyl sulfate. Solutions/gels of chitosan were also found to promote the transport of mannitol and fluorescent-labelled dextrans across a tissue culture model of the buccal epithelium while Glyceryl monooleates were reported to enhance peptide absorption by a co-transport mechanism.

Table 1: List of Permeation Enhancers 4

Sr. no

Permeation Enhancers

Sr. no

Permeation Enhancers

1

2,3-Lauryl ether

14

Phosphatidylcholine

2

Aprotinin

15

Polyoxyethylene

3

Azone

16

Polysorbate 80

4

Benzalkonium chloride

17

Polyoxyethylene

5

Cetylpyridinium chloride

18

Phosphatidylcholine

6

Cetyltrimethyl ammonium bromide

19

Sodium EDTA

7

Cyclodextrin

20

Sodium glycocholate

8

Dextran sulfate

21

Sodium glycodeoxycholate

9

Glycol

22

Sodium lauryl sulfate

10

Lauric acid               

23

Sodium salicylate

11

Lauric acid/Propylene

24

Sodium taurocholate

12

Lysophosphatidylcholine

25

Sodium taurodeoxycholate

13

Menthol

26

Sulfoxides

Prodrugs 10

Hussain et al delivered opioid agonists and antagonists in bitterless prodrug forms and found that the drug exhibited low bioavailability as prodrug.

Nalbuphine and naloxone bitter drugs when administered to dogs via the buccal mucosa, the caused excess salivation and swallowing. As a result, the drug exhibited low bioavailability. Administration of nalbuphine and naloxone in prodrug form caused no adverse effects, with bioavailability ranging from 35 to 50% showing  marked improvement over the oral bioavailability of these compounds, which is generally 5% or less

pH 10

Shojaei et al evaluated permeability of acyclovir at pH ranges of 3.3 to 8.8, and in the presence of the absorption enhancer, sodium glycocholate. The in vitro permeability of acyclovir was found to be pH dependent with an increase in flux and permeability coefficient at both pH extremes (pH 3.3 and 8.8), as compared to the mid-range values (pH 4.1, 5.8, and 7.0).

Patch design 10

Several in vitro studies have been conducted regarding on the type and amount of backing materials and the drug release profile and it showed that both are interrelated. Also, the drug release pattern was different between single-layered and multi-layered patches.

Toxicity And Irritancy Associated With Buccal Drug Delivery: 11

Formulations that produce local damage at the site of application, such as ulceration of the mucosa, would preclude their widespread usage as a result of the associated pain and discomfort. This is articularly important in buccal drug delivery where the formulation is in contact with the mucosa for extended periods. Toxic effects can arise from the drug itself, the bioadhesive or from other components of the formulation. For example, carbomers have been reported to produce mucosal irritation believed to result from a localised low pH, whereas lectins have been shown to be cytotoxic. Excipients such as absorption enhancers (e.g., sodium dodecyl sulfate) have also been reported to be irritant.

List Of Drugs Delivered Via Buccal Route 6

In an effort to determine the feasibility of buccal ROUTE as a novel route of drug delivery, several drugs (Table 2) have been studied. The variation in class of compounds illustrates that the pharmaceutical industries have an alternative and novel routes of administration for existing drugs.

Table 2 : List of Active Ingredients delivered via a buccal route 6

Sr. No.

Active Ingredients

Sr. No.

Active Ingredients

1.

Acitretin

26

Metronidazole

Acyclovir

26

Melatonin

Arecoline

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28

Metoprolol tartrate

Buprenorpine

29

Morphine sulphate

Carbamazepine

30

Nalbuphine

Cetyl Pyridinium chloride

31

Nicotine

Chlorhexidine diacetate

32

Nifedipine

Chitosan

33

Omeprazole

Chlorpheniramine maleate

34

Oxytocin

Cyanocobalamin

35

Pentazocine

Danazol

36

Protirelin

Denbufylline

37

Pindolol

Diclofenac sodium

38

Piroxicam

Diltiazem Hydrochloride

39

Propranolol

Ergotamine tartrate

40

Propolis

Fluride

41

Recombinant human epidermal growth factor (Rh EFG)

Flurbiprofen

42

Salmon calcitonin

Glucagon-like peptide (GLP)-1

43

Sodium fluoride

Hydrocortisone acetate

44

Testosterone

Insulin

45

Terbutaline  sulphate

Lactoferrin

46

Theophylline

Lignocaine

47

Thyotropin releasing hormone

Leu-enkephalin

48

Triamcinolone acetate

Luteinizing hormone releasing

Hormone (LHRH)

 

Zinc sulphate

References :

1. Pramodkumar T.M., Shivakumar H.G., Desai K.G., Oral Transmucosal Drug Delivery Systems, Indian Drugs, 2004, 41(2).

2. Lalla J.K. and Gurnancy R.A., Polymers for mucosal Delivery-Swelling and Mucoadhesive Evaluation, Indian Drugs, 2002, 39(5).

3. Sevda Senel, Mary Kremer, Katalin Nagy and Christopher Squier,  Delivery of Bioactive Peptides and Proteins Across Oral (Buccal) Mucosa, Current Pharmaceutical Biotechnology, 2001, 2, 175-186.

4. Amir H Shojaei, Buccal Mucosa As A Route For Systemic Drug Delivery, Journal of Pharmacy and Pharmaceutical Sciences, 1998,1(1), 15-30.

5. Mitra A. K, Alur H. H., Johnston, Peptides and Protein- Buccal Absorption, Encyclopedia of Pharmaceutical technology, Marcel Dekker Inc., 2002, Edition 2081-2093.

6. Salamat-Miller N, Chittchang M, Johnston TP, The use of mucoadhesive polymers in buccal drug delivery, Advance DrugDelivery Review, Nov 2005, 57(11), 1666-1691.

7. Marcos Luciano Bruschi and Osvaldo de Freitas, Oral Bioadhesive Drug Delivery Systems,  Drug Development and Industrial Pharmacy, 2005, 31(3), 293-310.

8. Bhaskara Jasti, Xiaoling Li, Gary Cleary, Recent Advances in Mucoadhesive Drug Delivery Systems, Bussiness Briefing : Pharmtech, 2004, 194-196

9. K.P.R. Chowdhary and L.Shrinivas, Mucoadhesive Drug Delivery Systems: A review of Current Status, Indian Drugs, Sep 2000, 37(9), 400-406.

10. Deirdre Faye Vaughan, Pharmacokinetics of Albuterol and Butorphanol Administered Intravenously and via a Buccal Patch, A Thesis Submitted to the office of Graduate Studies of Texas A&M University In Partial Fulfillment of the requirements for the Degree of  Master of Science, May 2003.

11. Smart JD, Buccal drug delivery, Expert OpinionDrug Delivery,  May 2005, 2(3), 507-17.

About Authors:

M.S. Wani*, Dr. S.R. Parakh, Dr. M.H. Dehghan, S.A. Polshettiwar, V.V. Chopade, V.V. Pande

Mr. Manish S. Wani

Mr. Manish S. Wani

Working as Lecturer at MAEER’s, Maharastra Institute of Pharmacy, MIT campus, Pune. He has done his M.Pharm in Pharmaceutics from Pune University . He has also done his MBA from Pune University.
Email : manishswani@yahoo.co.in, Phone no. (020) 25381755 (R), 9823531755(M)

Dr. S. R. Parakh

Dr. S. R. Parakh

Working as Principal and Professor in Pharmaceutics at MAEER’s, Maharastra Institute of Pharmacy, MIT Campus, Pune-411038.  Email:srparakh@rediffmail.com.

Dr. M.H. Dehghan

Dr. M.H. Dehghan

Working as Principal and Professor in Pharmaceutics at Y.B. Chavan’s, College of Pharmacy , Dr. Rafiq Zakaria Campus, Aurangabad . Email: mhdehghan@hotmail.com

Mr. Satish A. Polshettiwar

Mr. Satish A. Polshettiwar

Working as Lecturer at MAEER’s, Maharashtra Institute of Pharmacy, MIT Campus, Pune. He has done his M.Pharm in Quality Assurance from Nagpur University .
Email : contact_psatish@yahoo.co.in

Pande V. V.

Pande V. V.

Lecturer, Department of Pharmacology, MAEER’s, Maharashtra Institute of Pharmacy, MIT Campus, Pune. .     E-mail: vishalpande1376@gmail.com

Vitthal V. Chopade

Vitthal V. Chopade M. Pharm In Quality Assurance Lecturer in Pharmaceutics at Siddhant College of Pharmacy Pune. E-mail: vi_research@rediffmail.com

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velluri.prasad's picture

sir, Im currently doing an project on Buccal adhesive tablets of Diltiazem HCl. I formulated and evaluated with 90mg of the drug and the best formulation released the drug uptp 7hrs. But text books suggrsting that the maximum dose allowable is 30 ng throug buccal mucosa. I think that those limit for dast dissolving buccal tablets. whats your opinion regarding adhesive tablets. Please reply me at madhupharma@gmail.com thaks