INTRODUCTION:

Oral administration is a route of administration where a substance is taken through the mouth. Many medications are taken orally because they are intended to have a systemic effect, reaching different parts of the body via the blood stream. Tablet is defined as a compressed solid dosage form containing medicaments with or without excipients. According to the Indian Pharmacopoeia Pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drugs or a mixture of drugs, with or without diluents.

They vary in shape and differ greatly in size and weight, depending on amount of medicinal substances and the intended mode of administration. It is the most popular dosage form and 70% of the total medicines are dispensed in the form of Tablet¹. Solid medicaments may be administered orally as powders, pills, cachets, capsules or tablets. These dosage forms contain a quantity of drug which is given as a single unit and they are known collectively as solid unit dosage forms, even in the case of sustained action preparations which, technically, contain the equivalent of several normal doses of drug². Tablet that disintegrates or dissolve rapidly in the patients mouth are convenient for young children, elderly patients, mentally retarded and bedridden patients who used to suffer most probably with the problem of dysphasia and hand tremors. A fast dissolving sublingual tablet when placed in the mouth, rapidly get dispersed or dissolved and swallowed in the form of liquid. When sublingual tablets placed under the tongue, it produces immediate systemic effect by enabling the drug absorbed quickly or directly through mucosal lining of the mouth beneath the tongue. The drug absorbed from stomach goes to mesenteric circulation which connects through portal vein. Thus absorption through oral cavity avoid first pass metabolism. The sublingual tablets are usually small and flat, compressed lightly to keep them soft. The tablets must dissolve quickly allowing the drug to be absorbed. 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. Systemic drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological action³. Sublingual products have been designed for numerous indications ranging from migraine (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). Sublingual route provides time’s greater absorption of the drug than oral route and is only surpassed by hypodermic injection^3-10. Sublingual route is very much appropriate for short-acting drugs. Most of the drugs which are administered through the sublingual route are absorbed by simple diffusion; here the sublingual area acts like a litmus paper readily soaking up the substances; however not all the substances are permeable and accessible to oral mucosa. Majority of drugs which are administered through sublingual route falls in the category of antianginal drug. Systemic drug delivery through the sublingual route had emerged from the desire to provide immediate onset of pharmacological effect. Sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first pass metabolic processes⁴. Because of underdeveloped muscular and nervous system swallowing problems is common in children, and this could be easily overcome with the help of fast disintegrating sublingual tablets. Oral route of drug administration has been considered as the most popular one because it holds an edge over other routes such as it is the most natural, uncomplicated, convenient, safe means to administer drugs, greater flexibility in dosage form design, ease of production and low cost. By selecting the appropriate pharmaceutical excipients in the correct proportion, in combination with optimal manufacturing techniques the sublingual tablets could be prepared effectively⁵.

OVERVIEW OF THE ORAL CAVITY:

The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the sub mucosa as the innermost layer. The oral mucosa in general is intermediate between that of the epidermis and intestinal mucosa in terms of permeability. There are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa¹¹.

SUBLINGUAL GLANDS:

Salivary glands 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 fluid which is produced by the glands gets mix with the food, so the food gets easily chewed. 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 to 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 frequent¹².

PERMEABILITY:

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. The permeability’s of the oral mucosa decrease in the order of sublingual greater than buccal and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and non-keratinized, the buccal thicker and nonkeratinized¹³. The diagram of sublingual glands and sublingual artery is shown in Fig.1.

Fig.1. Diagram of sublingual glands and sublingual artery

Sublingual drug absorption mechanism:

The absorption is affected by the lipid solubility and hence the permeability of the solution which commonly known as osmosis, the ionization, and the molecular weight of the drug. The cells of oral epithelium adsorb the drug by the process of endocytocis. It is unlikely that the same mechanism is observed throughout the stratified epithelium. However, it is believed that acidic stimulation of the salivary glands, with the accompanying vasodilatation, 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.^14,15The 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 acidic the taste is, greater the stimulation of salivary output; serving to avoid potential harm to acid‐sensitive tooth enamel by bathing the mouth in copious 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 sub mental 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.^16,
17

FACTORS AFFECTING THE SUBLINGUAL ABSORPTION¹⁸:

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.

Binding to the oral mucosa:

systemic availability of drugs that bind to oral mucosa is poor.

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.

Lipophilicity of the 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 the passive permeation.

Thickness of the 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.

ADVANTAGES^19-21:

· Rapid onset of action is achieved as compared to the oral route.

· Liver is bypassed and also drug is protected from metabolism due to digestive enzymes of the middle gastro intestinal 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.

DISADVANTAGES²²:

· 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.

· The patient should not smoke while taking sublingual medication, because smoking causes vasoconstriction of the 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.

· One disadvantage, in any case, is tooth staining and brought about by long term utilization of this technique with acidic or generally burning medications and fillers.

Physicochemical Criteria of drug for Sublingual Drug Delivery:

The essential physico chemical characteristics of a drug for suitable candidate. The formulation of SLTs are summarized in Table 1^23-29.

Commonly used list of Superdisintegrants for SLTs:

The commonly used superdisintegrantsin the formulation of SLTs and their characteristics were summarized in Table 2³⁰

Table 1. Physicochemical Criteria of drug for Sublingual Drug Delivery

Physicochemical Properties of Drug	Accepted Range
Dose	< 20 mg
Taste	Not intensely bitter
Stability	Good stability in water & saliva
Molecular weight	Small to moderate (163.3-342.3g/mol)
pKa	>2 for acidic Drug; < 10 for basic Drug
Log p	1.6 to 3.3
Lipophilicity	Lipophilic

A.4. Hot melt Extrusion:

Dissolution rate and bioavailability of poorly-water soluble drug formulations can be improved by the homogeneous and consistent mixing of ingredients, in a twin screw extruder. This provides better mixing to produce a homogeneous solid containing finely dispersed drug^42-47

B. Patented techniques:

Rapid-dissolving characteristic of ODTs is generally attributed to fast penetration of water into tablet matrix resulting in to fast disintegration. Several technologies have been developed on the basis of formulation aspects and different processes and resulting dosage forms vary on several parameters like mechanical strength, porosity, dose, stability, taste, mouth feel, dissolution rate and overall bioavailability. Table 4, represents the list of unique patented technologies, with their advantages and disadvantages⁴⁸.

EVALUATION PARAMETERS:

Evaluation parameters of tablets mentioned in the pharmacopoeias need to be assessed, along with some special tests. The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blend.

Pre-compression Studies:

The directly compressible tablet blends were evaluated for pre-compression studies to determine their flow and compressibility⁴⁹.

Angle of Repose (θ):

Was determined by funneling method, the blend was poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2 cm above hard surface. The blend was poured till the time when the upper tip of the pile surface touched the lower tip of the funnel. The θ is calculated by the equation below⁴⁹.

θ = Tan ^–1h / r (1)

Where, θ = angle of repose, h = height of heap and

r = radius of base of heap circle.

Bulk density (BD):

A quantity of 2 g of blend from each formulation, previously lightly shaken to break any agglomerates formed, was introduced into a 10 mL measuring cylinder and the volume is noted as bulk volume. The BD was calculated by the equation below⁴⁹.

BD = weight of powder/ Bulk volume (2)

Tapped density (TD):

After the determination of BD, the measuring cylinder was fitted with a tapped density apparatus. The tapped volume was measured by tapping the powder for 500 times. Later the tapping was done for another 750 times and the tapped volume was noted (the difference between these two volumes should be less than 2%). If it is more than 2%, tapping is continued for another 1250 times and the constant tapped volume was noted. The TD was calculated by the following equation⁴⁹.

TD = Wt. of powder / Tapped volume (3)

Carr’s Index (CI):

The percentage of CI is calculated by the equation below⁴⁹.

CI= (TD-BD) ×100 / TD (4)

Hausner’s Ratio (HR):

Is a number that correlates to the flow ability of a powder. It is calculated by the equation⁴⁹.

HR = TD / BD (5)

The Limits for powder flow characteristics were mentioned in Table 5.

Table 5. Limits for powder flow characteristics

Flow Character	Angle of Repose (degrees)	Carr's Index (%)	Hausner’s Ratio
Excellent	25–30	≤ 10	1.00-1.11
Good	31–35	11-15	1.12-1.18
Fair	36–40	16-20	1.19-1.25
Passable	41–45	21-25	1.26-1.34
Poor	46–55	26-31	1.35-1.45
Very Poor	56–65	32-37	1.46-1.59
Very, very Poor	>66	> 38	> 1.60

Post-compression Studies:

Wt. variation test:

An electronic balance was used to accurately weigh the individual wt. of twenty tablets which were randomly selected from each formulation and checked for the acceptability of wt. variation⁵⁰. The Acceptable limit of weight variation test as per U.S.P. was mentioned in Table 6.

Table 6. Acceptable limits of weight variation test as per U.S.P.

Average weight of the tablet	Acceptable % deviation
80 mg or less	10
More than 80 mg but less than 250 mg	7.5
250 mg or more	5

Friability test:

The friability of the 20 tablets from each batch was tested by a friabilator at a speed of 25 RPM for 4 min. The tablets were then de-dusted, re-weighed, and percentage weight loss was calculated by the equation below⁵⁰.The limit for % friability is NMT 1%.

(Initial wt. – wt. after friability)

% Friability = ------------------------------------ x 100 (6)

Initial wt.

Hardness test:

Is used to evaluate the diametrical crushing strength of tablets from each formulation using a hardness tester⁵¹.

Thickness:

Thickness of tablets from each formulation was determined using a verniercalipers⁴².

Wetting Time (WT) and Swelling Index (SI):

A piece of tissue paper folded twice was placed in petri dish having an internal diameter of 5.5 cm, containing 6 mL of water. A tablet was placed on the paper and the time required for complete wetting was measured as wetting time, using a stopwatch. The wetted tablet was then reweighed and water absorption ratio (R) was determined using following equation⁵¹.

SI = [(W_a – W_b) / W_b] × 100 (7)

Where, W_b and W_a were the weights of the tablet before and after water absorption.

In vitro disintegration time and fineness of dispersion:

It is specified in the European Pharmacopeia (EP 6.0) that disintegration time determination procedure for ODT is same as that of conventional uncoated tablets and that the tablets should be dispersed within less than 3 min. The obtained tablet’s dispersion was passed through a sieve screen with a nominal mesh aperture of 710 mm to confirm the fineness of dispersion⁵².

Assay:

To evaluate the drug content, 3 tablets from each formulation were powdered in motor and pestle. Blend equivalent to 1 mg of drug was accurately weighed and transferred into a 100 mL volumetric flask. Then, the volume was made up to 100 mL with pH 6.8 phosphate buffer and ultra-sonicated for 2 min to extract the drug from the tablet blend and filtered through 0.45 μm Poly Tetra Fluoro Ethylene (PTFE) filter disc, the filtrate was suitably diluted if necessary and its absorbance was measured by a suitable spectrophotometric method⁵³.

In vitro dissolution studies:

Were performed on 6 tablets (n=6) form each batch using the dissolution apparatus with USP-II / Paddle apparatus. Each dissolution flask is filled with 900 mL of pH 6.8 Phosphate buffer; speed of the paddle was maintained at 50 RPM; the temperature was kept stable at 37°C ± 0.5°C. At required time intervals, 5 mL of dissolution media was withdrawn with a pipette containing 0.45 μ (PTFE) filter disc, suitably diluted if necessary and its absorbance was measured by a suitable spectrophotometric method. Furthermore, 5 mL of fresh pH 6.8 phosphate buffer was replaced to the dissolution flask to keep the volume of dissolution medium constant⁵³.

Mouth Feel Evaluation:

A panel of 6 volunteers was employed to assess the mouth feel of the prepared SLTs. The human test was performed according to the guidelines of WMA Helsinki declaration. The comments of the panel volunteers were recorded⁵³.

Accelerated stability studies of the optimized formulation:

Were carried according to an international conference on harmonization (ICH) guidelines. Tablets were packed in final pack and maintained at 45 °C ± 2 °C and 75 % ± 5 % RH. Up to 6 months, at the end of 1^st, 2^nd, 3^rd, and 6^th M the respective samples were withdrawn and evaluated for post compression studies⁵⁴.

CONCLUSION:

The study revealed that the sublingual tablets have proved to be better patient compliance and better way of drug delivery for pediatric and geriatric patients. Sublingual drug deliveries have been used for formulation of many drugs; especially for the drugs that require the rapid onset of action. These tablets overcome the difficulty in swallowing. The target population has extended to those who want convenient tablets without water. The drug content of the tablets enters the systemic circulation through capillaries present in sub lingual cavity; thus rapid onset of action is achieved.

ACKOWLEDGMENT:

The authors are thankful to Padmasree Dr. M. Mohan Babu, Chairman, Sree Vidyanikethan Educational Institutions, Tirupati-517 102; A.P.; India; Dr. C. K. Ashok Kumar, and Dr. S. Mohana Lakshmi; Principal and Vice-Principal, Sree Vidyanikethan College of Pharmacy, Tirupati -517 102; A.P.; India; for providing us the required facilities and being a constant support to bring out this review article.

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Received on 30.01.2019 Accepted on 30.03.2019

Asian J. Pharm. Res. 2019; 9(2): 97-103.

DOI: 10.5958/2231-5691.2019.00016.9

Superdisintegrant	Commercial Brands	Mechanism of action	Special comment
Cross linked Cellulose	Crosscarmellose® Ac-Di-Sol®, Vivasol® Primellose®, Solutab®	Swells 4-8 folds in < 10 sec. Swelling and wicking both	Swells in two dimensions. Direct compression or Granulation Starch free
Cross linked PVP	crosspCovidone M® Kollidon® Polyplasdone®	Swells very little and returns to original size after compression but act by capillary action	Water insoluble and spongy in nature so get porous tablet
Crosslinked starch (Sodium Starch Glycolate)	Explotab® Primogel®	Swells 7-12 folds in < 30 sec	Swells in three dimensions and high level serve as sustain release matrix
Crosslinked alginic Acid	Alginic acid NF	Rapid swelling in aqueous medium or wicking action	Promote disintegration in both dry or wet granulation

Active ingredient	Brand name	Manufacturer
Asenapine	Saphris	Merck
Buprenorphine HCl	Subutex	Sun pharma
Ergoloid mesylates	Ergomes	Cipla
Ergotamine tartrate	Ergomar	Rosedale pharmaceuticals
Fentanyl citrate	Abstral	Galena Biopharmaceuticals
Isosorbide dinitrate	Imdur	Astrazeneca
Nitroglycerin	Nitrostat	pfizer
Zolpidem tartrate	Intermezzo	Purdue Pharma

S. No.	Technique	Advantages	Disadvantages
1	Zydis	Quick dissolution, Self preserving and increased bioavailability.	Expensive process, poor stability at higher Temperature & humidity.
2	Orasolv	Taste-masking is twofold, quick Dissolution	Low mechanical strength
3	Durasolv	Higher mechanical strength than Orasolv, Good rigidity.	Inappropriate with larger dose
4	Flashtab	Only conventional table ting technology	--
5	Wow tab	Adequate dissolution rate and hardness.	No significant change in Bioavailability
6	Oraquick	Faster and efficient production, appropriate for heat-sensitive drugs	--
7	Ziplet	Good mechanical strength, satisfactory properties can be obtained at high dose (450 mg) and high weight (850 mg).	As soluble component dissolves, rate of water diffusion in to tablet is decreased because of formation of viscous concentrated solution.
8	FlashDose	High surface area for Dissolution	High temperature required to melt the matrix can limit the use of heat-sensitive drugs, sensitive to moisture and humidity.