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SUBLINGUAL TABLET-NOVEL DRUG DELIVERY SYSTEM

Authors:

Abstract

Drug delivery via the oral mucous membrane is considered to be a promising alternative to the oral route and promising method of systemic drug delivery which offers several advantages. Sublingual literally meaning "under the tongue", administrating substance via mouth in such a way that the substance is rapidly absorbed via blood vessels under tongue. Sublingual route is a useful when rapid onset of action is desired with better patient compliance than orally ingested tablets. In terms of permeability, the sublingual area of the oral cavity (i.e. the floor of the mouth) is more permeable than the buccal (cheek) area, which in turn is more permeable than the palatal (roof of the mouth) area. The portion of drug absorbed through the sublingual blood vessels bypasses the hepatic first-pass metabolic processes giving more acceptable bioavailability , rapid onset of action, patient compliance, self-medicated. Dysphagia (difficulty in swallowing) is common among all ages of people and more in pediatric, geriatric, psychiatric patients. Various techniques can be used to formulate sublingual tablets. New sublingual technologies address many pharmaceutical and patient needs, ranging from enhanced life-cycle management to convenient dosing for pediatric, geriatric, and psychiatric patients with dysphagia. This review highlights the different sublingual dosage forms, factors affecting the sublingual absorption, advantages, different sublingual formulation such as tablets and films, evaluation various in vitro and in vivo evaluation parameters and commercially available sublingual dosage forms.
SUBLINGUAL TABLET-NOVEL DRUG DELIVERY SYSTEM
Mr.Vishan Singh Sain, Dr.Ghanshyam Patel, Dr.Divyakant Patel, Dr.Yogesh
Patel, Ms.Jaini Patel, Ms.Tora Shah, Dr.Vijay Patel, Ms.Priyanka Yadav
Department of Pharmaceutics: Sharda School of Pharmacy, Pethapur,
Gandhinagar.
ABSTRACT:
Drug delivery via the oral mucous membrane is considered to be a promising alternative to the
oral route and promising method of systemic drug delivery which offers several advantages.
Sublingual literally meaning “under the tongue”, administrating substance via mouth in such a
way that the substance is rapidly absorbed via blood vessels under tongue. Sublingual route is a
useful when rapid onset of action is desired with better patient compliance than orally ingested
tablets. In terms of permeability, the sublingual area of the oral cavity (i.e. the floor of the
mouth) is more permeable than the buccal (cheek) area, which in turn is more permeable than the
palatal (roof of the mouth) area. The portion of drug absorbed through the sublingual blood
vessels bypasses the hepatic first‐pass metabolic processes giving more acceptable
bioavailability , rapid onset of action, patient compliance, self-medicated. Dysphagia (difficulty
in swallowing) is common among all ages of people and more in pediatric, geriatric, psychiatric
patients. Various techniques can be used to formulate sublingual tablets. New sublingual
technologies address many pharmaceutical and patient needs, ranging from enhanced life‐cycle
management to convenient dosing for pediatric, geriatric, and psychiatric patients with
dysphagia. This review highlights the different sublingual dosage forms, factors affecting
the sublingual absorption, advantages, different sublingual formulation such as tablets and
films, evaluation various in vitro and in vivo evaluation parameters and commercially available
sublingual dosage forms.
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INTRODUCTION
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 liquid‐intake/diets have difficulties in
swallowing these dosage forms. 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. 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. In terms of permeability, the
sublingual area of the oral cavity is more permeable than the buccal (cheek) area, which in
turn is more permeable than the palatal (roof of the mouth) area. The differences in
permeability are generally based on the relative thickness, the blood supply, and degree
of keratinization of these membranes. In addition to the differences in the permeability of the
various mucous membranes, the extent of drug delivery is also affected by the
physicochemical properties of the drug to be delivered. Sublingual products have been developed
for numerous indications ranging from migraines (for which rapid onset of action is
important) to mental illness (for which patient compliance is important for treating
chronic indications such as depression and schizophrenia) .
The target sites for local drug delivery in the oral cavity include the following: Buccal,
Sublingual, Periodontal region, Tongue, Gum. Other desirable targeting sites adjacent to oral
cavity include pharynx, larynx, adenoids and tonsils. Within the oral cavity, delivery of drugs via
the membranes of the oral cavity is classified into three categories:
i. Sublingual delivery which is systemic delivery of drugs through the mucosal membranes
lining the floor of the mouth to the systemic circulation;
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ii. Buccal delivery which is drug administration through the mucosal membranes lining the
cheeks and the area between the gums and upper and lower lips to the systemic circulation.
iii Local delivery which is drug delivery to periodontal, gingival, delivery for the local treatment
of ulcers, bacterial and fungal infections and periodontal disease.
Sublingual glands
Sublingual glands are also known as the salivary glands which are present in the floor of
mouth underneath the tongue. These glands produce mucin and help to promote the
production of saliva. Because of the secretions of the glands, the interior area of the
mouth is kept lubricated, which is necessary for chewing and swallowing food. The
lubrication and binding functions of the sublingual glands cannot be underestimated. A
secretion from the glands mix with food as it is chewed, making the material slippery
and easily swallowed. Because of the saliva content of the masticated food, it can move
without difficulty into the throat and on to the digestive tract. Low levels of saliva
production can make the process of swallowing much more difficult and will increase the
potential for food to lodge in the throat. Along with providing lubrication, these glands also
aid in the promotion of good oral hygiene. Absorption means transfer of drug from its site of
administration to the systemic circulation, so it is obvious that absorption is directly
proportional to the membrane layer thickness. Sublingual > Buccal > Gingival > Palatal having
mucosa thickness of 100‐200, 200, 250, 500‐600 micrometer respectively. Because of the high
permeability and the rich blood supply, the sublingual route is capable of producing a
rapid onset of action which makes it an appropriate route for drugs with short delivery
period and in frequent dosing regimen. The drug is released in to saliva and its subsequent
spreading may cause the drug to be absorbed across the oral cavity
Sublingual absorption
Salivary glands which are present in the floor of the mouth underneath the tongue. They are also
known as sublingual glands. They produce mucin in turn produces saliva. The interior area of the
mouth remains lubricated due to production of the saliva by the glands, which is necessary for
chewing and food swallowing. The fluid which is produced by the glands gets mixed with the
food, so the food gets easily chewed. Due to low secretion of the saliva it can create problem in
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swallowing the food and potential for food lodge in the throat increases. The absorption is
transfer of the drug from its site of administration into systemic circulation, so it can be said that
absorption is directly proportional layer thickness. The absorption of the drug follows in this way
Sublingual > Buccal > Gingival > Palatal. Due to high permeability and rich blood supply, the
sublingual route can produce rapid onset of action so the drug with short delivery period can be
delivered and dose regimen is frequent. The drug gets diluted in the saliva and from there the
drug is adsorbed across the oral cavity. 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. There is considerable evidence that most sublingual substances are absorbed by
simple diffusion; the sublingual area acting rather likes litmus paper, readily soaking up
the substances. However, not all substances are permeable and accessible to oral mucosa.
Mechanics of sublingual absorption
The absorption potential of oral mucosa is influenced by the lipid solubility and therefore
the permeability of the solution (osmosis); the ionization (pH); and the molecular weight of the
substances. For example, absorption of some drugs via oral mucosa is shown to increase
when carrier pH is lowering (more acidic) and decrease with a lowering of pH (more alkaline).
The cells of the oral epithelium and epidermis are also capable of absorbing by
endocytosis (the uptake of particles by a cell as if by hollowly wrapping itself around it.
These engulfed particles are usually too large to diffuse through its wall). It is unlikely that this
mechanism is used across the entire stratified epithelium. It is also unlikely that active
transport processes operate within the oral mucosa. However, it is believed that acidic
stimulation of the salivary glands, with the accompanying vasodilation, facilitates
absorption and uptake into the circulatory system. The mouth is lined with a mucous
membrane which is covered with squamous epithelium and contains mucous glands. The
sublingual mucosal tissue is similar to that of buccal mucosa. The salivary glands consist of
lobules of cells which secrete saliva through the salivary ducts into the mouth. The three pairs of
salivary glands are the parotid, the submandibular and the sublingual which lies on the floor of
the mouth. The more acid the taste, the greater the stimulation of salivary output; serving to
avoid potential harm to acid‐sensitive tooth enamel by bathing the mouth in copious
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neutralizing fluid. The sublingual artery travels forward to the sublingual gland, it
supplies the gland and branches to the neighboring muscles and to the mucous membranes of the
mouth, tongue and gums. Two symmetrical branches travel behind the jawbone under the tongue
to meet and join at its tip. Another branch meets and anastomoses with the submental branches
of the facial artery. The sublingual artery stems from the lingual artery the body's main blood
supply to the tongue and the floor of the mouth which arises from the external carotid artery. The
proximity with the internal carotid artery allows fast access to its route supplying the greater part
of the cerebral hemisphere.
Osmosis
In order for a drug to be effectively absorbed sublingually, it needs to be able to travel across the
buccal mucous membranes; by a process of diffusion known as osmosis which applies to all
forms of absorption by the body; governing both intestinal and sublingual absorption. The
distribution of water across cell walls depends on the osmotic difference in the blood
between the intracellular and extracellular fluid. Small particles that readily dissolve in
water, rarely present a problem in permeation and diffusion, and so are able to move freely
between the tissues of the body. Active transportation into cells leads to rapid metabolisation of
the substances. Molecules such as glucose (fructose) and amino acids are essential for cell
metabolism and special mechanisms have evolved to facilitate their rapid diffusion and
permeation across cell membranes
Drugs for sublingual administration
Sublingual drug administration is applied in the field of cardiovascular drugs, steroids, some
barbiturates and enzymes. It has been a developing field in the administration of many vitamins
and minerals which are found to be readily and thoroughly absorbed by this method.
Sublingually absorbed nutrition, which avoids exposure to the gastric system and liver, means
direct nutritional benefits, particularly important for sufferers of gastro‐intestinal difficulties such
as ulcers, hyperactive gut, coeliac disease, those with compromised digestion, the elderly and
invalids the nutritional benefit is independent of gastro intestinal influences. Examples of drugs
administered by this route include antianginal like nitrites and nitrates, anti hypertensive like
nifedipine, analgesics like morphine and bronchodilators like fenoterol. Certain steroids like
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estradiol and peptides like oxytocin can also be administered e.g. fentanyl citrate, apomorphine,
prochlorperazine dimaleate, and hydrazine HCl.
1.Sublingual formulation Sublingual tablets
They are to be placed under the tongue and produce immediate systemic effect by enabling the
drug absorbed directly through mucosal lining of the mouth beneath the tongue. The drug
absorbed from stomach goes to mesenteric circulation which connects to stomach via portal vein.
Thus absorption through oral cavity avoids first pass metabolism. The tablets are usually small
and flat, compressed lightly to keep them soft. The tablet must dissolve quickly allowing the API
to be absorbed quickly. It is designed to dissolve in small quantity of saliva. After the tablet is
placed in the mouth below the tongue, the patient should avoid eating, drinking, smoking and
possibly talking in order to keep the tablet in place. Swallowing of saliva should also be avoided
since the saliva may contain dissolved drug. Bland excipients are used to avoid salivary
stimulation. Various techniques can be used to formulate rapidly disintegrating or dissolving
tablets. Direct compression is one of these techniques which require incorporation of a
superdisintegrant into the formulation, or the use of highly water-soluble excipients to achieve
fast tablet disintegration. Direct compression does not require the use of water or heat during the
formulation procedure and is the ideal method for moisture and heat-labile medications.
a. Fast disintegrating sublingual tablets (FDT)
FDT is defined as a solid dosage form that contains medicinal substances and disintegrates
rapidly (within few seconds) without water when kept on the tongue. The drug is released,
dissolved, or dispersed in the saliva, and then swallowed and absorbed across the GIT. FDTs also
are also called as Orodispersible tablet, mouth-dissolving, quick-dissolving, fast-melt, and
freeze-dried wafers. Tablets that disintegrate or dissolve rapidly in the patient’s mouth are
convenient for young children, the elderly and patients with swallowing difficulties and in
situations where potable liquids are not available. Direct compression is one of the techniques
which require the incorporation of a superdisintegrant into the formulation, or the use of highly
water soluble excipients to achieve fast tablet disintegration. Compared to conventional dosage
form the drug dissolution, its absorption as well as onset of clinical action and its bioavailability
may be significantly greater. Though chewable tablets are available in the market, they are not
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same as the new FDTs. Patients for whom chewing is difficult or painful can use these FDTs. It
can be used easily in infants and in children who have lost their primary teeth and who do not
have full use of their permanent teeth.
Recent market studies indicate that more than half of the patients prefers FDTs than other
conventional dosage forms and most patients would ask their doctors for FDTs (70%), purchase
FDTs (70%), or prefer FDTs than regular tablets or liquids (>80%). The US Food and Drug
Administration Center for Drug Evaluation and Research (CDER) defines, in the, Orange Book,
an FDT as “a solid dosage form containing medicinal substances, which disintegrates rapidly in
saliva, usually within a few seconds, when placed upon the tongue”. The implication of these
dosage forms is emphasized by the term “Orodispersible Tablet”, by the European
Pharmacopoeia which defines it as a tablet that can be placed in oral cavity where it disperses
rapidly before swallowing. FDTs has been developed for numerous indications ranging from
migraines (in which quick onset of action is necessary) to mental illness (in which patient
compliance is necessary for treating chronic indications such as mental depression and
schizophrenia).
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b. Bioadhesive sublingual tablets
The new sublingual tablet concept presented is based on interactive mixtures consisting of a
water soluble carrier covered with fine drug particles and a bioadhesive component. With this
approach, it is possible to maintain rapid dissolution in combination with bioadhesive retention
of the drug in the oral cavity. Bioadhesion is usually defined as the bond formed between two
biological surfaces or between a biological and a synthetic surface. Problem associated with
sublingual tablet formulation is that there is always a risk that the patient will swallow part of the
dose before the active substance has been released and absorbed locally into systemic circulation.
This could result an unwanted prolongation of the pharmacological effect. Addition of a
bioadhesive component is a well-known method of increasing the possibility of a more site-
specific release. However, this concept is normally applied to non-disintegrating tablets or disc
to achieve extended release of the active substance and, consequently, such a system will not be
suitable for a fast acting formulation. Therefore, it would be of interest to study a disintegrating
tablet which releases the drug quickly, but which also has bioadhesive properties which could
prevent the drug from being swallowed.
Bioadhesion mechanisms
The mucus layer is often involved in the adhesion of a bioadhesive polymer and is present as
either a gel layer adhering to the mucosal surface or a solution or suspension of various
substances. The mucus layer mainly consists of mucin glycoprotein, inorganic salts, proteins,
lipids and water with the composition varying depending on its source. The between the two
materials causing a double layer of electric charge, which results in attraction forces. The
adsorption theory involves adhesion between the mucosa and the adhesive material by van der
waals interaction, hydrogen bonds and related forces. The wetting theory involves interfacial
tensions between the two materials. Penetration of the polymer chains into the mucus network
and vice versa, causing a mechanical bond, is referred to as the diffusion theory. The importance
of water content and movement of water into the adhesive material from the mucosa, i.e.
dehydration of the mucosa, has also been suggested as a mechanical for adhesion.
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Measurement of bio-adhesive strength
Bio-adhesion strength of the tablets was measured on a modified physical balance. The method
used bovine cheek pouch as the method mucosal and IPB ph 6.6 as the moistening fluid. The
surface of the mucosal membrane was first blotted with a filter paper and then moistened with
25/L 1 of IPB pH 6.6. the weight in grams is required to detach the tablets from the mucosal
surface gave the measure of bio-adhesive strength.
c. Lipid matrix sublingual tablets
Such tablets are 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 neutraceuticals that are often taken orally. For e.g. Glutathione
MB12(methylcobalamin) melatonin.
2. Thin film drug delivery
Thin film drug delivery is a process of delivering drugs of the systemic circulation via thin film
that dissolves when in contact with liquid, often referred to a dissolving films or strips and
dissolve within 1min when placed in the mouth without drinking or chewing. Such dissolving
film or strip are typically designed for oral administration, with the user placing the strip on or
under the tongue or along the inside of the cheek. Thin film’s ability to dissolve rapidly without
the need for water provides an alternative to patients with swallowing disorders and to patients
suffering from nausea, such as those patients receiving chemotherapy. The first developed fast-
dissolving dosage form consisted in tablet form, and the rapid disintegrating properties were
obtained through a special process or formulation modifications. More recently, fast-dissolving
films are gaining interest as an alternative to fast-dissolving tablets to definitely eliminate
patients’ fear of chocking and overcome patent impediments. Fast dissolving films are generally
constituted of plasticized hydrocolloids. Problems are caused by foaming during the film
formation due to the heating of the material or solvent evaporation, the flaking during the slitting
and the cracking in the cutting phase. The films should be stable to moisture, facilitate the
handling, have to be flexible and exhibit a suitable tensile stress and do not stick to the packaging
materials and fingers.
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Film can be prepared by five methods:
1. Solvent casting.
2. Semisolid casting.
3. Hot melt extrusion.
4. Solid dispersion extrusion.
5. Rolling.
1. Solvent casting method
Film is formulated using the solvent casting method, whereby the water-soluble ingredients are
dissolved to form a clear viscous solution. The API and other agents are dissolved in smaller
amounts of the solution and combined with the bulk. This mixture is then added to the aqueous
viscous solution. The entrapped air is removed by vacuum. The resulting solution is cast as a
film and allowed to dry, which is then cut into pieces of the desired size.
2. Semisolid casting
Solution of water soluble film forming polymer is mixed with solution of acid insoluble polymer
which forms homogenous viscous solution. The ratio should be 1:4. For e.g. cellulose acetate
phthalate, cellulose acetate butyrate. It is then sonicated which is coated on non-treated casting
film.
3. Hot melt extrusion
In present method the mass is prepared first under the control of temperature and steering speed.
Afterwards, the film is coated and dried in a drying tunnel, once again the temperature, air
circulation and line speed are controlled. Then follows a slitting and in the last step the films are
punched, pouched and sealed.
4. Solid dispersion extrusion
Solid dispersions are prepared by immiscible components and drug. Finally the solid dispersions
are shaped in to films by means of dies.
5. Rolling
Solution or suspension drug is rolled on the carrier. The solvent is mainly water and mixture of
water and alcohol. The film is dried on the rollers and gives desired shape and size.
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Evaluation
Hardness and thickness
The test is done as per the standard methods. The hardness of three randomly selected tablets
from each formulation is determined by placing each tablet diagonally between the two plungers
of tablet hardness tester (with the nozzle) and applying pressure until the tablet broke down into
two parts completely and the reading on the scale is noted down.The thickness of three randomly
selected tablets from each formulation is determined in mm using a vernier caliper (Pico India).
The average values is calculated.
Drug Content
Randomly ten tablets are selected from formulation, finely powdered and powder equivalent mg
of drug is accurately weighed and transferred to 100ml volumetric flasks containing solution of
desired pH. The flask is shaken to mix the contents thoroughly. The volume is made up to the
mark with solution and filtered. One ml of the filtrate is suitably diluted and drug content is
estimated using a double beam UV-visible spectrophotometer. This procedure is repeated thrice
and the average value is calculated.
Wetting time (WT)
It is useful for quality control and provides supportive evaluation of these sublingual tablets.
Unlike the disintegration test, the wetting test uses minimal water, which may be more
representative of the quantity of moisture available sublingually. Using this test, the time
required for moisture to penetrate the tablet completely is measured and possibly represents the
time required to release drug in the presence of minute volumes of saliva. The tablet was placed
above absorbent paper fitted into a petri dish. After the paper is thoroughly wetted with distilled
water, excess water is completely drained out of the dish. The time required for the water to
diffuse from the wetted absorbent paper throughout the entire tablet is then recorded using a
stopwatch.
Disintegration test
A relatively simple method with rigorous conditions is developed. Each individual tablet is
dropped into 10ml glass test tube (1.5cm diameter) containing 2ml distilled water, and the time
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required for complete tablet disintegration is observed visually and recorded using a stopwatch.
The visual inspection is enhanced by gently rotating the test tube at a 45° angle, without
agitation, to distribute any tablet particles that might mask any remaining undisintegrated portion
of the tablets. In the USP disintegration test for sublingual tablets, the disintegration apparatus
for oral tablets is used without the covering plastic disks, and 2 minutes is specified as the
acceptable time limit for tablet disintegration.
Water absorption ratio
A piece of tissue paper folded twice is placed in a small Petri dish Containing 6ml of water. A
tablet is put on the tissue paper and allowed to completely wet. The wetted tablet is then
weighted. Water absorption ratio, R was determined using following equation.
R = 100 × Wa Wb/Wa
where, Wa = Weight of tablet after water absorption
Wb = Weight of tablet before water absorption.
In vitro disintegrating test
Disintegration times for sublingual tablets is determined using USP tablet disintegration
apparatus with desired medium. The volume of medium was 900ml and temp was 37± 2°C. The
time in seconds taken for complete disintegration of the tablets with no palatable mass remaining
in the apparatus is measured.
In vitro dissolution test
In-vitro release rate of sublingual tablets will be carried out using United State Pharmacopoeia
(USP) XXIV dissolution testing apparatus (Paddle method). A aliquot sample of the solution is
withdrawn from the dissolution apparatus. The samples are replaced with fresh dissolution
medium of same quantity. The samples are filtered through Whatman filter paper No 40 and
analysed in UV spectrophotometer. The percentage drug release is calculated using an equation
obtained from the calibration curve.
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Test for film Tensile Strength
Tensile strength is the maximum stress applied to a point at which the film specimen breaks. It is
calculated by the applied load at rupture divided by the cross-sectional area of the film as given
below:
Tensile strength = Load at failure × 100
Film thickness × film width
Percent Elongation
A film sample stretches when stress is applied and it is referred to as strain. Strain is basically the
deformation of film divided by original dimension of the sample. Elongation of film increases as
the plasticiser content increases.
Percent elongation -L * 100
Lo
where, L = Increase in length of film
Lo = Initial length of film.
Young’s Modulus
Young’s modulus or elastic modulus is the measure of stiffness of film. It is represented as the
ratio of applied stress over strain in the region of elastic deformation as follows:
Young’s Modulus = Slope * 100
Film thickness *Cross-head speed
Folding Endurance
Folding endurance is determined by drying process repeated folding of the film at the same place
till the breaks. The number of times the film is folded without dry breaking is computed as the
folding endurance value
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Diagram of sublingual gland and sublingual artery.
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Thickness
The thickness of the polymer films was measured by using screw gauge. The thickness of each
strip at six different areas was determined and standard deviation was calculated.
In vitro disintegration time
In vitro disintegration time is determined visually in a glass dish of 25ml distilled water with
swirling every 10sec. The disintegration time is the time when the film starts to break or
disintegrates. The disintegration time of prepared films was measured in triplicate.
Uniformity of drug content
The film of area 1x1cm2 was cut and dissolved in 6.8 phosphate buffer solution and made up to
100mL in a volumetric flask. Then 1mL was withdrawn from the solution and diluted to
10mL.The absorbance of the solution was taken at 276nm and concentration was calculated. By
correcting dilution factor, the drug content was calculated. The test was performed in triplicate.
In-vitro dissolution studies
Dissolution study was carried out in USP paddle type apparatus using 300mL of stimulated
salivary fluid (pH 6.8) as a dissolution medium at 50rpm. Temperature of the dissolution
medium was maintained at 37±0.5ºC. Samples of 5ml were withdrawn at every 4 minute
interval, filtered (through 0.45μ) and replaced with 5ml of fresh dissolution medium. The
samples were suitably diluted and estimated spectrophotometrically at 276nm by using ELICO-
164 double beam UV-Visible spectrophotometer. The dissolution experiments were conducted in
triplicate. Dissolution rate was studied for all designed formulations and dissolution parameters
were calculated.
Factors affecting the sublingual absorption
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,
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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. 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 oil‐ to‐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.
Advantages
A relatively rapid onset of action can be achieved compared to the oral route, and the
formulation can be removed if therapy is required to be discontinued.
Liver is bypassed and also drug is protected from degradation due to pH and digestive enzymes
of the middle gastrointestinal tract.
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.
Low dosage gives high efficacy as hepatic first pass metabolism is avoided and also reduces the
risk of side effects.
The large contact surface of the oral cavity contributes to rapid and extensive drug absorption.
Due to rapidity in action these sublingual dosage forms are widely used in emergency
conditions e.g. asthma.
Rapid absorption and higher blood levels due to high vascularization of the region and
therefore particularly useful for administration of antianginal drugs.
They also present the advantage of providing fast dissolution or disintegration in the oral
cavity, without the need for water or chewing.
Ease of administration to patients who refuse to swallow a tablet, such as pediatric, geriatric
patients and psychiatric patients.
Convenience in administration of drug and accurate dosing as compared to liquid formulations.
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Water is not required for swallowing the dosage form, which is convenient feature for patients
who are traveling and do not have immediate access to water.
•Good mouth feels property helps to change the basic view of medication as “bitter pill”,
particularly for pediatric patients.
Fast dissolution of medicament and absorption which will leads to rapid, onset of action.
Some drugs are absorbed from the mouth pharynx and esophagus as the saliva passes down into
the stomach, in such cases bioavailability of drugs is increased.
It provides advantages of liquid formulations in the form of solid dosage form.
Pregastric absorption can result in improved bioavailability and as a result of reduced dosage,
improved clinical performance through a reduction of unwanted effects.
Disadvantages
Since sublingual administration of drugs interferes with eating, drinking, and talking, this
route is generally considered unsuitable for prolonged administration.
•Although this site is not well suited to sustained‐delivery systems.
Sublingual medication cannot be used when a 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. Various types of sublingual dosage forms are available but tablets, films and
sprays are in trends these days. For the preparation of these dosage forms different
methods are described depends upon the feasibility and advantages over the others.
Since sublingual administration of drugs interferes with eating, drinking, and talking, this route
is generally considered unsuitable for prolonged administration.
•Although this site is not well suited to sustained‐delivery systems.
Sublingual medication cannot be used when a 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.
Mukt Shabd Journal
Volume XII, Issue V, MAY/2023
ISSN NO : 2347-3150
Page No :474
CONCLUSION
Sublingual drug delivery have been used for formulation of many drugs with view point of rapid
drug release and quick onset of action. Sublingual products were developed to overcome the
difficulty in swallowing conventional tablet, among pediatric, geriatric and psychiatric patients
with dysphagia. The target population has expanded to those who want convenient dosing
without water anywhere, anytime. The potential for such dosage forms is promising because
strong market acceptance and patient demand. Recently many drugs have been formulated
for sublingual drug delivery with an objective of rapid drug release and restricting the
region of drug release to mouth. Compared to commonly used tablets, capsules and other oral
dosage forms, sublingual absorption is generally much faster and more efficient. Sublingual
dosages are convenient for young children, the elderly and patients with swallowing
difficulties, and in situations where potable liquids are not available. Peak blood levels of
most products administered sublingually are achieved within 10‐15 minutes, which is
generally much faster than when those same drugs are ingested orally. Sublingual absorption is
efficient. The percent of each dose absorbed is generally higher than that achieved by means of
oral ingestion. Various types of sublinguual dosage forms are available in market like tablets,
films and sprays.
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Article
Full-text available
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Chapter
Over the last three decades, intraoral dosage forms (IODFs) have been evolving as an acceptable, and in some cases as the preferred, alternative to conventional tablets (CTs) and capsules. Quick-dissolving intraoral dosage forms (QODs) are a type of IODFs that have gained much attention recently due to improved patient compliance and ease of administration compared to conventional oral dosage forms (e.g., tablets and capsules). QODs include orally disintegrating tablets (ODTs), the only dosage form of this nature recognized by the FDA listed in Approved Drug Products with Therapeutic Equivalence Evaluations (i.e., the Orange Book)1 [e.g., Claritin® RediTabs® 24 Hour Non-Drowsy Orally Disintegrating Tablets (loratadine orally disintegrating tablets)].2 The European Pharmacopoeia, however, defines a similar term, “orodisperse,” as a tablet that can be placed in the mouth where it disperses rapidly before swallowing.3 The simplest definition of an ODT is a unit dose that disintegrates in the oral cavity. The Center for Drug Evaluation and Research (CDER) defines an ODT to be “a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.”4 As the majority of the QODs on the market or in different stages of development are in the category of ODTs, the discussion in this chapter primarily focuses on this particular type of dosage form.
Article
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Article
Tablets of glyceryl trinitrate were prepared by direct compression employing microcrystalline cellulose. These tablets were nonfriable and exhibited sublingual availability comparable to commercially available hypodermic tablets. Compressed tablets of microcrystalline cellulose showed only slight loss of glyceryl trinitrate at 50° when compared to commercial hypodermic tablets which lost up to 95 per cent. Glyceryl trinitrate formulated in a directly compressed sublingual tablet of microcrystalline cellulose presents an aesthetic stable dosage form which is a marked improvement over presently available glyceryl trinitrate dosage forms.
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Asthma management is changing, and there are many potential new drugs undergoing early and late phase trials. Nonetheless, it is unlikely that any dramatic alterations in therapy will occur within the next 3 years. The asthma treatment paradigm has altered over the past 10 or so years, with the emphasis on symptom relief from short acting beta agonists giving way to preventive treatment of underlying airway inflammation with inhaled corticosteroids. More recently, long acting beta agonists have been demonstrated to reduce the need for increasing doses of inhaled steroids in patients with poorly controlled asthma. This article reviews these trends.
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1. The pharmacokinetics and pharmacodynamics of verapamil administered via the oral and sublingual routes were compared in a randomised, two-way cross-over study involving six healthy male volunteers. 2. Administered sublingually, a verapamil 40 mg (Securon) crushed tablet produced a significantly higher peak plasma concentration (P less than 0.05), a greater rate of absorption (P less than 0.05), and greater bioavailability (P less than 0.05) when compared with orally administered verapamil 40 mg (Securon). 3. In comparison with oral dosing, PR intervals were significantly (P less than 0.05) prolonged between 30 and 90 min after sublingual verapamil dosing. 4. Correlations between log plasma verapamil concentration and percentage increase in PR interval were greater after sublingual compared with oral dosing in all volunteers.
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The regional permeability of oral mucosa to salicylic acid was investigated in vivo in hamsters along with histological variations, especially the degree of keratinization. Histological sections from six regions, i.e., sublingual mucosa, buccal mucosa, dorsum of tongue, ventral surface of tongue, labial mucosa, and cheek pouch mucosa, were prepared to assess the degree of keratinization. The area under the plasma concentration-time curve of salicylic acid following the administration of salicylic acid to the oral mucosa with a film dosage form and the thickness of stratum corneum of each site were in inverse proportion to each other, suggesting that the stratum corneum layer represents the principle barrier to drug absorption.
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