Buccal and Sublingual Tablets

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Buccal and Sublingual Tablets:

Buccal and Sublingual Tablets Guided by: Dr. Rishad Jivani Prepared By: Zeel Shah M Pharm sem II Roll no: 08 Year : 2012 Department of Pharmaceutics C. U. Shah College of Pharmacy & research, Wadhwan

Contents::

Contents: BUCCAL TABLETS: Introduction Physiology of oral cavity Oral mucosa as site for drug delivery Mechanism Factors affecting Bioavaibility of Buccal Delivery System Types of buccal dosage form Evaluation Advantages of buccal drug delivery system Disadvantages of buccal drug delivery system

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B. SUB LINGUAL TABLETS: Introduction Types of Sublingual tablets Fast Disintegrating Sub lingual Tablets Bioadhesive Sublingual Tablets Thin film Drug delivery system Lipid Matrix Sublingual Tablets Sublingual Immunotherapy Sublingual Vitamin Tablets Evaluation of Sublingual Tablets Mechanism of Sublingual Tablets Factors affecting Absorption of Sublingual Tablets Advantages of Sublingual Tablets Disadvantages of sublingual Tablets

Introduction[1]:

Introduction [1] Oromucosal delivery, especially that utilising the buccal and sublingual mucosa as the absorption site, is a promising drug delivery route which promotes rapid absorption and high bioavailability , with subseqent almost immediate onset of pharmacological effect. Mucoadhesion is the relatively new and emerging concept in drug delivery. Mucoadhesion is the special case of bioadhesion where the biological tissue is an epithelium covered by mucus . Mucoadhesive drug delivery system prolong the residence time of the dosage form at the site of application or absorption and facilitate an intimate contact of the dosage form with the underline absorption surface and thus contribute to improved and / or better therapeutic performance of the drug.

Physiology of oral cavity[2]:

Physiology of oral cavity [2]

Structure of Oral mucosa[3]:

Structure of Oral mucosa [3] 1: Stratum basale 2: Stratum spinosum 3: Stratum granulosum 4: Stratum corneum Schematic illustration of the layers in normal oral mucosa.

Permeability:[6] :

Permeability: [6] The oral mucosa in general is somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin. As indicative by the wide range in this reported value, there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa. In general, the permeability of the oral mucosa decrease in the order of sublingual greater than buccal , and buccal greater than palatal.

Permeability Barrier:[6]:

Permeability Barrier: [6] It is currently believed that the permeability barrier in the oral mucosa is a result of intercellular material derived from the so-called ‘membrane coating granules’ (MCG). When cells go through differentiation, MCGs start forming and at the apical cell surfaces they fuse with the plasma membrane and their contents are discharged into the intercellular spaces at the upper one third of the epithelium. This barrier exists in the outermost 200µm of the superficial layer. Permeation studies have been performed using a number of very large molecular weight tracers , such as horseradish peroxidase and lanthanum nitrate. When applied to the outer surface of the epithelium, these tracers penetrate only through outermost layer or two of cells. When applied to the submucosal surface , they permeate up to, but not into, the outermost cell layers of the epithelium.

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Another barrier to drug permeability across buccal epithelium is enzymatic degradation. Saliva contains no proteases, but does contain moderate levels of esterases , carbohydrases , and phosphatases . However, several proteolytic enzymes have been found in the buccal epithelium. Endopeptidases and carboxypeptidases were not present on the surface of porcine buccal mucosa, whereas aminopeptidases appeared to be the major enzymatic barrier to the buccal delivery of peptide drugs.

 Substances Used to Increase Permeability: [9] :

Substances Used to Increase Permeability: [9] Permeation Enhancers 23-lauryl ether Aprotinin Azone Benzalkonium chloride Cetylpyridinium chloride Cetyltrimethylammonium bromide Cyclodextrin Dextran sulfate Lauric acid Lauric acid/propylene glycol Lysophosphatidylcholine Menthol Methoxysalicylate Methyl oleate

The mucus layer: [7]:

The mucus layer: [7] Mucus is a translucent and viscid secretion which forms a thin, continuous gel blanket adherent to the mucosal epithelial surface. The mean thickness of this layer varies from about 50 to 450 micrometers in humans. It is secreted by the goblet cells lining the epithelia or by special exocrine glands with mucus cells acini . The exact composition of the mucus layer varies substantially depending on the species, the anatomical location and the Pathophysiological state. However, it has the following general composition 1. Water - 95% 2. Glycoproteins and Lipids - 0.5 to 5% 3. Mineral salts - 0.5 to 1% 4. Free Proteins - 0.5 to 1%

Functions of mucus layer: [7]  :

Functions of mucus layer: [7] The Primary functions of the mucus layer are: Adhesion: Mucus has strong cohesional properties and firmly binds to the epithelial cell surface as a continuous gel layer. 2. Barrier: The role of the mucus layer as a barrier in tissue absorption of drugs and other substrates is well known as it influences the bioavailability of drug. 3. Lubrication : An important role of the mucus layer is to keep the mucosal membrane moist. Continuous secretion of mucus from the goblet cell is necessary to compensate for the removal of the mucus layer due to digestion, bacterial degradation and volatilization of mucin molecules.

Mechanism of Buccal Drug Delivery System: [7]:

Mechanism of Buccal Drug Delivery System: [7] There are two permeation pathways for passive drug transport across the oral mucosa: 1. Paracellular routes. 2. Transcellular routes. Permeants can use these two routes simultaneously, but one route is usually preferred over the other depending on the physicochemical properties of the diffusant . Since the intercellular spaces and cytoplasm are hydrophilic in character, lipophilic compounds would have low solubilities in this environment. The cell membrane , however, is rather lipophilic in nature and hydrophilic solutes will have difficulty permeating through the cell membrane due to a low partition coefficient.

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Therefore, the intercellular spaces pose as the major barrier to permeation of lipophilic compounds and the cell membrane acts as the major transport barrier for hydrophilic compounds. Since the oral epithelium is stratified, solute permeation may involve a combination of these two routes. The route that predominates, however, is generally the one that provides the least amount of hindrance to passage. Dearden and Tomlison (1971) pointed out that salivery secretion alters the buccal absoption kinetics from drug solution by changing the concentration of drug in the mouth. [10] The linear relationship between salivery secretion and time is given as follows: [10] Where, M= Mass of drug in mouth at time t K= Proportionality Constant C= Concentratio of the drug at time Vi= Volume of solution put into the mouth cavity Vt = Salivery secretion rate

Factors affecting Bioavaibility of Buccal Delivery System: [7] :

Factors affecting Bioavaibility of Buccal Delivery System: [7] Inherent permeability of the epithelium: The permeability of the oral mucosal epithelium is intermediate between that of the skin epithelium, which is highly specialized for barrier function and the gut, which is highly specialized for an adsorptive function. Within the oral cavity, the buccal mucosa is less permeable that the sublingual mucosa. Thickness of epithelium: The thickness of the oral epithelium varies considerably between sites in the oral cavity. The buccal mucosa measures approximately 500-800 micrometers in thickness.

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Blood supply: A rich blood supply and lymphatic network in the lamina propria serve the oral cavity, thus drug moieties which traverse the oral epithelium are readily absorbed into the systemic circulation. The blood flow in the buccal mucosa is 2.4mL min-1 cm. Metabolic activity: Drug moieties adsorbed via the oral epithelium are delivered directly into the blood, avoiding first-pass metabolism effects of the liver and gut wall. Thus oral mucosal delivery may be particularly attractive for the delivery of enzymatically labile drugs such as therapeutic peptides and proteins. Saliva and mucus: The activity of the salivary gland means that the oral mucosal surfaces are constantly washed by a stream of saliva, approximately 0.5-2L per day. The sublingual area, in particular, is exposed to a lot of saliva which can enhance drug dissolution and therefore increase bioavailability.

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Ability to retain delivery system: The buccal mucosa comprises an expense of smooth and relatively immobile surface and thus is ideally suited to the use of retentive delivery systems. Species differences: Rodents contain a highly keratinized epithelium and thus are not very suitable as animal models when studying buccal drug delivery. Transport routes and mechanisms: Drug permeation across the epithelia barrier is via two main routes: A. The paracellular route: between adjacent epithelial cells; B. The transcellular route: across the epithelial cells, which can occur by any of the following mechanism: 1. passive diffusion, 2. carrier mediated transport and 3. Via endocytic processes.

Types of Buccal Dosage Forms::

Types of Buccal Dosage Forms: Buccal Dosage form can be of two types: 1. Matrix Type 2. Buccal patches Matrix Type: [8] Prerequisites of such delivery systems are adhesion to mucosa for retention and extension of drug delivery. Variety of polymers are available for such type of delivery system like Chitosan , gelatin , cellulose and its derivatives from natural origin, Carbopol , HPMC, HPC, PVP , Polycarbophil , Polyoxyethylene and thiolated polymers from semisynthetic and synthetic origin.

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Evaluation of buccal drug delivery system: Evaluation of mucoadhesive buccal tablets: [11] Weight variation Hardness Friability Thickness Content uniformity Microenvironment pH Bioadhesion studies Swelling study In-vitro dissolution studies

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Advantages of Buccal Drug Delivery System: [1] A prolonged residence time at the site of drug action or absorption. A localization of drug action of the delivery system at a given target site. An increase in the drug concentration gradient due to the intense contact of particles with the mucosal. Ease of administration. Termination of therapy is easy.{except gastrointestinal} Permits localization of drug to the oral cavity for a prolonged period of time. It offers a passive system of drug absorption and does not require any activation. The presence of saliva ensures relatively large amount of water for drug dissolution.

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Systemic absorption is rapid. Can be administered to unconscious patients. {except gastrointestinal} A significant reduction in dose can be achieved there by reducing dose related side effects. Drugs which are unstable in the acidic environment are destroyed by enzymatic or alkaline environment of intestine can be administered by this route. Drugs which show poor bioavailability via the oral route can be administered conveniently. It offers a passive system of drug absorption and does not require any activation.

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This route provides an alternative for the administration of various hormones, narcotic analgesic, steroids, enzymes, cardiovascular agents etc. The buccal mucosa is highly perfused with blood vessels and offers a greater permeability than the skin. Less dosing frequency. Shorter treatment period. Increased safety margin of high potency drugs due to better control of plasma levels. Maximum utilization of drug enabling reduction in total amount of drug administered.

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Reduction in fluctuation in steady state levels and therefore better control of disease condition and reduced intensity of local or systemic side effects. The presence of saliva ensures relatively large amount of water for drug dissolution. Systemic absorption is rapid. Zero-order controlled release. [7] Robust. [7] Low metabolic activity [7]

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Demerits of Buccal drug Delivery system: [1] Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste, odour, cannot be administered by this route. Drugs, which are unstable at buccal pH cannot be administered by this route. Only drugs with small dose requirements can be administered. Drugs may swallow with saliva and loses the advantages of buccal route. Eating and drinking may become restricted. Swallowing of the formulation by the patient may be possible. Over hydration may lead to the formation of slippery surface and structural integrity of the formulation may get disrupted by the swelling and hydration of the bioadhesive polymers.

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SUBLINGUAL TABLETS: Introduction: [14] Sublingual, meaning literally 'under the tongue' refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. Systemic drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological effect. Dysphagia (difficulty in swallowing) is a common problem of all age groups, especially elderly, children, and patients who are mentally retarted , uncooperative, nauseated or on reduced liquidintake / diets have difficulties in swallowing these dosage forms.

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Sublingual administration of the drug means placement of the drug under the tongue and drug reaches directly in to the blood stream through the ventral surface of the tongue and floor of the mouth. The drug solutes are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein and then drained in to systemic circulation. For these formulations, the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. Many pharmaceuticals are designed for sublingual administration, including cardiovascular drugs, steroids, barbiturates, enzymes, and increasingly, vitamins and minerals.

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Types of Sublingual tablets: [15] Fast Disintegrating Sublingual Tablets Bioadhesive Sublingual Tablets Thin film Drug delivery system Lipid Matrix Sublingual Tablets Sublingual Immunotherapy Sublingual Vitamin Tablets

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Fast Disintegrating Sublingual Tablets: [16] A fast dissolving tablet system can be defined as a dosage form for oral administration, which when placed in mouth, rapidly dispersed or dissolved and can be swallowed in form of liquid. Recently fast dissolving formulation is popular as NDDS because they are easy to administer and lead to better patient compliance. Paediatric and geriatric patient have difficulty in swallowing the conventional dosage forms these dosage forms dissolve or disintegrate in the oral cavity within a minute without the need of water or chewing.

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For these formulations, the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. The medication can then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa, or it can be swallowed as a solution to be absorbed from the gastrointestinal tract.

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Bioadhesive sublingual tablets: Bioadhesive sublingual tablet Consisting of a water-soluble carrier covered with fine drug particles and a bioadhesive component. This concept is normally applied to non-disintegrating tablets or extended release tablets. Thin film Drug delivery system: [14] Solvent casting is a process which comprises of casting a dope from a casting die onto a casting support, drying the cast dope on the casting support form film, stripping off the film from the casting support, and further drying the film while conveying the film with carrying it at both side edges of the film by a pin tenter , wherein residual volatile component content of both side edges of the film being carried by the pin tenter . Solvent Evaporation technique can also be used instead of solvent casting for the preparation of sublingual films.

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Lipid Matrix Sublingual Tablets: [17] Lipid Matrix Sublingual Tablet is formulated using advances in sublingual and liposomal technology to create a dosage form that offers a faster and more complete absorption than traditional oral routes of administration. The Lipid Matrix Sublingual Tablet is a bioavailable , quick, convenient, and consistent dosage form for many specialty nutraceuticals that are often taken orally. Examples Include: Glutathione MB12 ( Methylcobalamin ) Melatonin.

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Sublingual Immunotherapy: Allergic rhinitis, a common condition, affects between 10% and 40% of people worldwide. The typical clinical features include sneezing, watery rhinorrhoea , nasal blockage, itchy, watery eyes and itchy throat. Avoiding the cause, i.e. the allergen, is the first-line treatment recommended by guidelines. This is followed by prescriptions of drugs called antihistamines and topical nasal corticosteroids. In severe cases and when usual therapy fails specific immunotherapy is recommended.

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Immunotherapy involves the administration of gradually increasing doses of the allergen over a period of time to desensitise the patient. It modifies the immune response and treats the cause rather than the symptoms. Sublingual immunotherapy is taken as drops or tablets, placed under the tongue 3 or more times/week, containing a specific allergen which interacts with the immune system to decrease allergic sensitivity. Commonly the allergen is taken once a day. The antigen persists on the mucosal surface and is taken up by dendritic cells which interact with T lymphocytes (T-cells).

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As a safe and effective method of treating the underlying disease, sublingual immunotherapy is capable of modifying the natural progression of allergic disease which can begin with allergic food sensitivities and eczema in young children and progress through allergic rhinitis and asthma in older children and adults. How does the process work? The first step is to confirm a patient’s allergies through allergy testing. Then, a custom-mixed vial of drops is prepared for the patient. The patient takes drops under the tongue daily. During the first four months, called the “ escalation phase ,” the dosage is gradually increased. After that, in the “ maintenance phase ,” the patient takes the same dose of drops each day.

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Sublingual Vitamin Tablets: [17] The only Sublingual vitamin that all doctors recommend is vitamin B12 ( Cyanocobalamin ). you must have enough of it for your bodies metabolism. Recommended to be taken once a day.

Evaluation: [15]:

Evaluation: [15] General Appearance Size and Shape Tablet thickness Uniformity of weight Tablet hardness Friability Wetting time Surface pH In-vitro dispersion time In-vitro Disintegration test Stability testing of drug (temperature dependent stability studies)

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Mechanism of Sublingual Tablets: [16] Upon sublingual administration drug reaches directly in to the blood stream through the ventral surface of the tongue and floor of the mouth. The drug solutes are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein and then drained in to systemic circulation.

PowerPoint Presentation:

The main mechanism for the absorption of the drug in to oral mucosa is via passive diffusion into the lipoidal membrane. The absorption of the drug through the sublingual route is 3 to 10 times greater than oral route and is only surpassed by hypodermic injection. For these formulations, the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity.

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Sublingual absorption is mostly rapid in action, but also short acting in duration. For example, Nitroglycerine is an effective antianginal drug but is extensively metabolized when taken orally (>90%). It is rapidly absorbed through the sublingual mucosa, and its peak plasma level is reached within 1 ‐ 2 min. Because of its short biological half life (3 ‐ 5 min.), however the blood concentration of nitroglycerine declines rapidly to a level below the therapeutic concentration within 10 ‐ 15 min.

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Factors affecting Sublingual Drug Delivery System: [15] Lipophilicity of drug: For a drug to be absorbed completely through sublingual route, the drug must have slightly higher lipid solubility than that required for GI absorption is necessary for passive permeation. Solubility in salivary secretion: In addition to high lipid solubility, the drug should be soluble in aqueous buccal fluids i.e. biphasic solubility of drug is necessary for absorption. pH and pKa of the saliva: As the mean pH of the saliva is 6.0, this pH favors the absorption of drugs which remain unionized. Also, the absorption of the drugs through the oral mucosa occurs if the pKa is greater than 2 for an acid and less than 10 for a base

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Binding to oral mucosa: Systemic availability of drugs that bind to oral mucosa is poor. Thickness of oral epithelium: As the thickness of sublingual epithelium is 100‐200 μm which is less as compared to buccal thickness. So the absorption of drugs is faster due to thinner epithelium and also the immersion of drug in smaller volume of saliva. Oil to water partition coefficient: Compounds with favorable oilto ‐ water partition coefficients are readily absorbed through the oral mucosa. An oil‐water partition coefficient range of 40‐2000 is considered optimal for the drugs to be absorbed sublingually.

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Advantages of Sublingual Tablets: [15] Mesenteric circulation is by-passed so there is no loss of drug by first pass effect. Higher bioavailability and onset of action compare to oral route. Rapid absorption due to high vascularisation beneath the tongue. Reduce the side effect due to low dose and high efficacy. Provide fast dissolution or disintegration in oral cavity without water or chewing action. pH in the mouth is relatively neutral so drug will be more stable. Improved patient compliance. Relatively large contact surface area provides rapid and extensive absorption.

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Disadvantages of Sublingual Drug Delivery System: [15] Sublingual administration of drugs interferes with eating, drinking, and talking; this route is generally considered unsuitable for prolonged administration. Holding the dose in mouth is inconvenient, if any is swallowed that portion must be treated as an oral dose and subjected to first pass metabolism. Only small doses can be accommodated easily.

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Not suitable for sustain release formulations. It cannot be used when patient is uncooperative or unconscious. The patient should not smoke while taking sublingual medication, because smoking causes vasoconstriction of the blood vessels. This will decrease the absorption of the medication.

Marketed Preparations of Sublingual Tablets: [22,23,24] :

Marketed Preparations of Sublingual Tablets: [22,23,24] Fentanyl Buccal Tablets (marketed as Fentora ) Nicorette sublingual Tablets Sublingual Nitroglycerin Tablets Oravig ( miconazole ) Buccal Tablets Striant SR 30 mg Mucoadhesive Buccal Tablets.

GTU asked QUESTIONS:

GTU asked QUESTIONS Discuss the merits and demerits of sublingual dosage forms. How are they evaluated? [ July 2011] [05] Explain significance of sublingual drug delivery system. How they are evaluated?[Dec 2011] [05] Write applications of buccal & sublingual drug delivery systems. [Dec. 2010] [06] Explain the structure of buccal mucosa. Give a brief account of mucoadhesive polymers for buccal delivery. [ July 2010] [05]

References:

References International Journal of Applied Biology and Pharmaceutical technology; Volume: 2: Issue-1: Jan-Mar -2011; Pg 434,435 http://www.google.co.in/imgres?imgurl=http://2.bp.blogspot.com/_hL0QrZsPcvY/SaP_tYAvpqI/AAAAAAAAAYE/L_KFCUR_lSU/s400/or1.jpg&imgrefurl=http://www.learn-free-medical-transcription.blogspot.com/2009/02/lesson-56-oral-cavity-anatomy-and.html&h=325&w=400&sz=20&tbnid=U11zP-w90bsc5M:&tbnh=90&tbnw=111&prev=/search%3Fq%3Danatomy%2Bof%2Bbuccal%2Bcavity%26tbm%3Disch%26tbo%3Du&zoom=1&q=anatomy+of+buccal+cavity&docid=gAwv5RlwVRnigM&hl=en&sa=X&ei=elN1T7aDO5GrrAfvmNyuDQ&ved=0CEIQ9QEwBQ &dur=2240 Radiologic Clinics Of North America, Volume 36, Number 5, September 1998 Basic Human Anatomy- O’rahilly , Muller, Carpenter & Swenson, Chapter-51 http://en.wikipedia.org/wiki/Oral_mucosa_tissue_engineering J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 1 (1):15-30, 1998

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Asian Journal of Biochemical and Pharmaceutical Research, Issue 2 (Vol. 1) 2011, page no:-105-108 International Journal of Drug Delivery 2 (2010), page no. 37-48 http://www.pharmtech.com/pharmtech/data/articlestandard/pharmtech/252002/22629/article.pdf http://www.pharmatutor.org/articles/review-on-buccal-patches www.pharmscidirect.com , Int J Pharm Biomed Res 2010, 1 (4), 129-134. International Journal of Pharma and Bio Sciences V1(2)2010, page no-3-5 International Journal of PharmTech Research, CODEN (USA): IJPRIF ISSN : 0974-4304, Vol.1, No.4, pp 978-981, Oct-Dec 2009 International Journal of Pharmacy and Pharmaceutical Sciences, ISSN- 0975-1491 Vol 3, Suppl 2, 2011, page no- 18-22

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International Journal of Drug Development & Research,October -December 2011, Vol. 3, Issue 4, ISSN 0975-9344, page No.36-44. International Journal of Pharmacy and Pharmaceutical Sciences, ISSN- 0975-1491 Vol 2, Issue 3, 2010,page no.-86-92 www.pharmainfo.net New Concepts of Administration of Drugs in Dosage Form By Susanne Brideneberg , pg. 19. http://www.medindia.net/news/healthinfocus/Allergic-Rhinitis-Sublingual-Immunotherapy-Offers-Efficient-and-Low-Risk-Treatment-79729-1.htm http://en.wikipedia.org/wiki/Sublingual_immunotherapy http://www.hopkinsmedicine.org/sinus/allergy/sublingual_immunotherapy.html http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126082.htm

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http://www.drugs.com/newdrugs/fda-approves-oravig-miconazole-buccal-oropharyngeal-candidiasis-2114.html http://www.medicines.org.uk/emc/medicine/24144/SPC/

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