Rayat Bahra Institute of Pharmacy, Hoshiarpur
Oral mucous membrane drug delivery is seen to offer a possible substitute for oral administration. When a quick onset of action is required and higher patient compliance is sought than with oral medications, the sublingual route can be helpful. The sublingual region of the oral cavity has a higher permeability than the buccal region, which is higher than the roof of the mouth region. By avoiding hepatic first-pass metabolic processes, the portion of the drug absorbed through the sublingual blood vessels has good bioavailability. For patients with dysphagia, elderly people, and children, sublingual technology requires improved lifecycle management to enable simple dosage. The sublingual route is the most often used method for systemic effects due to its painlessness, avoidance, adaptability, and—above all—patient compliance. The sublingual region is the most drug-permeable location in the oral cavity. Onset of action is needed in the case of some acute diseases. Hence the Sublingual drug delivery can be best promising route of administration for a faster and direct absorption of drug into systemic circulation. The most permeable region for a drug absorption in buccal cavity is the Sublingual region. Emerging trends in the field include personalized medicine, which tailors treatments based on individual patient needs, and the integration of digital health technologies for dose monitoring and adherence tracking. Additionally, innovations in bioenhancers and permeation enhancers aim to overcome challenges related to drug solubility and absorption. Despite these advancements, challenges such as drug stability, taste masking, and patient compliance persist. Future research focuses on addressing these limitations through enhanced formulation techniques, improved patient education, and streamlined regulatory processes. Overall, sublingual drug delivery continues to evolve, offering significant benefits for therapeutic efficacy and patient care while paving the way for future developments in pharmacotherapy.
Sublingual drug delivery offers systemic drug delivery for a prompt start to the healing process. When swallowing becomes problematic, sublingual drug administration All age groups can benefit from the system, but it is especially beneficial for elderly and paediatric patients, as well as those who are mentally challenged or even nauseous the reticulated vein of the sublingual region, which is located beneath the oral mucosa, is where drug particles are passively absorbed in the sublingual drug delivery system (1,2). From there, they are transported by the internal jugular vein and facial veins before reaching the systemic circulation. Compared to the oral route, the sublingual route has absorption that is three to ten times higher. Such formulations typically result in tablet disintegration in the oral cavity due to the extremely small volume of saliva. Sublingual absorption causes a quick commencement of activity, which is reflected in a brief acting time. Sublingual drug delivery products have been created for a variety of purposes, including migraines and mental health disorders (3,4).
Fig 1 Sublingual drug delivery system overview
Mucosal anatomy and physiology (5,6):
The mucosa is about 100 and 200 µm thick. Mucosa is made up of polar yet neutral lipids, such as cholesterol. Glucosyl ceramide and sulphate. Water, proteins, glycoprotein, high potassium (7X plasma), bicarbonate (3X plasma), calcium, phosphorus, chloride, and low sodium (1/10X plasma) make up 99.5% of saliva. Five percent of saliva is found in the sublingual gland. Saliva has a pH between 5.6 and 7.0.
Figure 2- Enviroment at sublingual region and buccal region
Sublingual absorption mechanism (7,8)
Three separate layers make up the mucosal lining. The epithelial membrane, which is made up of stratified squamous epithelial cells and serves as a protective barrier, is the outermost layer. The basement membrane, which resupplies the epithelium, is the innermost layer of the epithelial membrane. The submucosa and lamina propria are located beneath the epithelium. Collagen and elastic fibres are found in the lamina propria, a moist and less thick layer of connective tissue. Additionally, the oral submucosa has a substantial blood artery supply.
Drug solutes administered sublingually are quickly absorbed into the reticulated vein, which is located beneath the oral mucosa. From there, they are carried by the internal jugular vein and facial veins before being emptied into the systemic circulation. The medicine enters the bloodstream straight through the floor of the mouth and the ventral surface of the tongue when administered sublingually. The medication enters the oral mucosa mostly through passive diffusion into the pilonidal membrane.
Figure 3 – Schematics of oral mucosa
Figure 4- Advantage and Disadvantage of sublingual drug delivery system (8,9)
The drug selection for preparation of sublingual tablets (10,11,12)
The following criteria shall be followed by the drug to be formulated into sublingual drug delivery are as below
The drugs those are unstable in parenteral preparation are suitable for sublingual dosage form.
Factors Affecting the Sublingual Absorption
1.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.
2.Binding to Oral Mucosa
Systemic availability of drugs that bind to oral mucosa is poor
3.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.
4.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.
5.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.
Sublingual Formulation (17,18,19,20)
Sublingual Tablets
Sublingual tablets dissolve under the tongue, allowing active ingredients to absorb directly into the bloodstream through the mucosal tissues. This contrasts with traditional oral tablets, which must be swallowed and passed through the digestive system before the drug is absorbed into the bloodstream.
Mechanism of Action:
When patients place a sublingual tablet under the tongue, it dissolves quickly due to the rich blood supply in the sublingual area. This rapid dissolution facilitates faster therapeutic effects compared to oral tablets which undergo a slower digestive process.
There are two primary types of sublingual tablets:
Bioadhesive sublingual tablets:
This new sublingual tablet concept is based on a combination of bioadhesive polymer and a water-soluble carrier coated with tiny particles of substances. These drugs may make it simple to improve dissolution rate.
Sublingual mouthwash
formulation that contains a drug that has been dispersed or dissolved in a solvent, is filled into a container with a metered valve, and, upon deposition, delivers an appropriate dosage of the drug through the valve into the sublingual region.
Sublingual spray
The sublingual spray (SL Spray) is an unprecedented pharmaceutical administration technology in which the drug can be atomized under the tongue which in-turn facilitate drug diffusion into the capillary network and often acts faster than the other oral administrations, with better bioavailability and so there may be a proven improvement in the onset of therapeutic activity. General sublingual dosage form consists of tablet, film, mini pills, etc., and the advanced formulations include micro particulate spray, atomized liquid etc. The advanced formulation has a better penetrating ability than the conventional sublingual dosage forms. The capillary network absorbs the medication/drug, forwarding them directly into the bloodstream without entering the Gastro-intestinal system.
Sublingual Films
Mouth dissolving films or strip, a new drug delivery system for the oral delivery of the drugs, was developed based on the technology of the transdermal patch. The delivery system consists of a very thin oral strip, which is simply placed on the patient’s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the medication for oromucosal absorption or with formula modifications, will maintain the quick-dissolving aspects allow for gastrointestinal absorption to be achieved when swallowed. Sublingual strips are similar to tablets in that they easily melt in the mouth and dissolve rapidly. Suboxone is an example of medication that comes in a sublingual strip.
Sublingual Drops
Concentrated solutions to be dropped under the tongue, as with some nicocodeine cough preparatations.
Sublingual Spray
Spray for the tongue; certain human and veterinary drugs are dispensed as such.
Lozenge
Effects a metred and patient-controlled-rate combination of sublingual, buccal, and oral administration, as with the Actiq fentanyl lozenge-on-a-stick (lollipop).
Effervescent Sublingual Tablets
This method drives the drug through the mucous membranes much faster (this is the case in the stomach with carbonated or effervescent liquids as well) and is used in the Fentora fentanyl tablet.
Sublingual and buccal formulations marketed and in clinical trials
Table no.1 Sublingual formulations marketed and in clinical trials
|
Sublingual and buccal formulations marketed and in clinical trials |
|||
|
Drug |
Dosage form |
Indication |
Status |
|
Lorazepam |
Tablet |
Sedation |
Marketed (Ativan) |
|
Zolpidem |
Tablet |
Insomnia |
Marketed (Edluar) |
|
Melatonin |
Tablet |
Insomnia |
Marketed (Melatonin Sublingual) |
|
Allergen extract |
Tablet |
Allergic rhinitis |
Marketed (Grastek, Oralair, Odactra, Ragwitek) |
|
Polyvalent mechanical bacterial lysate (biological) |
Tablet |
Chronic obstructive pulmonary disease |
Marketed (Ismigen) |
|
Isosorbide dinitrate |
Tablet |
Angina |
Marketed (Isordil) |
|
Sufentanil |
Tablet |
Pain |
Marketed (Dsuvia, Zalviso) |
|
Glyceryl trinitrate (nitroglycerin) |
Tablet, spray |
Angina |
Marketed (Anginine, |
|
Lycinate, Nitrolingual Pump Spray) |
|||
|
Fentanyl |
Tablet, spray, film, lozenge |
Pain |
Marketed (Abstral, Actiq, Subsys, Fentora, Onsolis) |
|
Buprenorphine |
Tablet, film |
Pain |
Marketed (Temgesic, Belbuca) |
|
Nicotine |
Tablet, film, gum, lozenge, spray |
Smoking cessation |
Marketed (Nicabate, Nicotinell, Nicorette, QuitX, Nicaway, Nicabate Oral Strips, Nicorette QuickMist) |
|
Vitamin B12 |
Tablet, spray, oral liquid |
Vitamin deficiency |
Marketed (Sublingual Vitamin B12) |
|
Desmopressin |
Tablet, wafer |
Nocturia |
Marketed (Minirin Melt, Nocdurna) |
|
Buprenorphine + naloxone |
Film |
Opioid dependence |
Marketed (Suboxone) |
|
Asenapine |
Wafer |
Schizophrenia |
Marketed (Saphris) |
|
Midazolam |
Oral liquid |
Epilepsy |
Marketed (Buccolam, Epistatus) |
|
(prefilled oral syringes) |
|||
|
Nystatin |
Oral liquid |
Oral candidiasis |
Marketed (Nilstat, Mycostatin) |
|
Miconazole |
Gel |
Oral candidiasis |
Marketed (Daktarin, Decozol) |
|
Triamcinolone |
Paste |
Oral ulceration |
Marketed (Kenalog in Orabase) |
|
Zolmitriptan |
Tablet |
Cluster headache |
Phase IV |
|
Misoprostol |
Tablet |
Induction of labor, blood loss in myomectomy, abortion |
Phase III/IV |
|
Y-2 (adaravone and borneol) |
Tablet |
Healthy |
Phase I |
|
Alprazolam |
Tablet |
Anxiety disorder, sedation for endoscopy |
Phase I/II/III completed |
|
Riluzole |
Tablet |
Social anxiety disorder, amyotrophic lateral sclerosis |
Phase I/II/III |
|
Lobeline |
Tablet |
Methamphetamine dependence, Attention deficit disorder |
Phase I/II |
|
Cyclobenzaprine |
Tablet |
PTSD, fibromyalgia |
Phase III |
|
Olanzapine |
Tablet |
Schizophrenia |
Phase IV completed |
|
Agomelatine |
Tablet |
Major depressive disorder |
Phase III completed |
|
ALKS 5461 |
Tablet |
Major depressive disorder |
Phase III completed |
|
Sildenafil |
Tablet, wafer |
Erectile dysfunction |
Phase III completed |
|
Cannabidiol |
Tablet, oral liquid |
Diabetic neuropathies, chronic pain, anxiety, inflammatory bowel disease |
Phase I/II |
|
Allergen extract (mite, artemisia annua, apple, birch pollen, grass pollen, blatella germanica, milk, peanuts, ragweed) |
Oral liquid |
Atopic dermatitis, allergic rhinitis, allergic conjunctivitis, food hypersensitivity |
Phase I/II/III/IV |
|
Influenza vaccine |
Oral liquid |
Healthy |
Phase I completed |
|
Naloxone |
Oral liquid |
Chronic pruritus |
Phase I/II completed |
|
Ketorolac |
Oral liquid |
Postoperative pain |
Phase IV |
|
Oral enterotoxigenic Escherichia coli vaccine (biological) |
Oral liquid |
Gastroenteritis Escherichia coli |
Phase I |
|
Cholera toxin B subunit (biological) |
Oral liquid |
Healthy |
Phase I completed |
|
UISH001 |
Oral liquid |
Urinary incontinence |
Phase I/II completed |
|
Methadone |
Oral liquid |
Cancer Pain |
Phase I completed |
|
Cyclobenzaprine |
Oral liquid |
Healthy |
Phase I completed |
|
Tacrolimus |
Oral liquid, powder |
Bone marrow transplant, organ transplant, chronic renal failure |
Phase IV |
|
Ticagrelor |
Powder, tablet |
Acute coronary syndrome, percutaneous coronary intervention |
Phase IV |
|
Tizanidine |
Powder |
Muscle spasticity |
Phase I/II completed |
|
Polyoxidonium |
Spray |
Acute respiratory infection |
Phase III |
|
Flumazenil |
Spray |
Healthy |
Phase I/II completed |
|
Artemether |
Spray |
Plasmodium falciparum malaria |
Phase III completed |
|
Insulin |
Film, spray |
Healthy, type 1 diabetes, Type 2 diabetes |
Phase I/III |
|
Ketamine |
Film, wafer |
Healthy, pain |
Phase I/II completed |
|
Dexmedetomidine |
Film |
Schizophrenia |
Phase I |
|
Apomorphine |
Film |
Parkinson’s disease |
Phase II/III |
|
Montelukast |
Film |
Alzheimer disease |
Phase II |
|
Diazepam |
Film |
Epilepsy |
Phase III |
|
NTG1523 (nitroglycerin) |
Rapid absorbable capsule |
Angina pectoris |
|
(Ref: clinicaltrials.gov; ema.europa.eu; fda.gov; tga.gov.au; drugs.com).
Evaluation Parameters (21,22,23,24,25,26)
General Appearance The general appearance of a tablet, its visual identity and over all "elegance" is essential for consumer acceptance. Include in are tablet's size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws and consistency and legibility of any identifying marking.
Size and Shape The size and shape of the tablet can be dimensionally described, monitored and controlled.
Tablet Thickness Tablet thickness is an important characteristic in reproducing appearance and also in counting by using filling equipment. Some filling equipment utilizes the uniform thickness of the tablets as accounting mechanism.
Wetting Time 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. A piece of tissue paper (12 cm X 10.75 cm) folded twice was placed in a small Petri dish (ID = 6.5 cm) containing 6 ml of Sorenson's buffer pH 6.8. A tablet was put on the paper, and the time for complete wetting was measured. Three trials for each batch and the standard deviation were also determined.
Uniformity of Weight I.P. procedure for uniformity of weight was followed, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight.
Table no.-2 I.P weight variation limits
|
IP limit for weight variation Avg. Weight of Tablet |
% Variation Allowed |
|
80mg or less |
10 |
|
60mg but < 250mg |
7.5 |
|
250mg or more |
5 |
Friability It is measured of mechanical strength of tablets. Roche friabilator can be used to determine the friability by following procedure. A preweighed tablet was placed in the friabilator. Friabilator consist of a plastic-chamber that revolves at 25 rpm, dropping those tablets at a distance of 6 inches with each revolution. The tablets were rotated in the friabilator for at least 4 minutes. At the end of test tablets were dusted and reweighed, the loss in the weight of tablet is the measure of friability and is expressed in percentage as %Friability = loss in weight / Initial weight x 100. (27,28.29,30)
Tablet Hardness Hardness of tablet is defined as the force applied across the diameter of the tablet in the order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. Hardness of the tablet of each formulation was determined using Monsanto Hardness tester.
In-Vitro Dispersion Time In-vitro dispersion time can be measured by dropping a tablet in a beaker containing 50 ml of Sorenson's buffer pH 6.8.
In-Vitro Disintegration Test The test can be carry out on 6 tablets using the apparatus specified in I.P. 1996 distilled water at 37ºC ± 2ºC was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass remaining in the apparatus measure in seconds. (31,32)
CONCLUSION
The sublingual and buccal routes of administration have significant advantages for systemic drug delivery. They have shown to be an effective alternative to the traditional oral route, especially when fast onset of action is required. In addition, they are useful for drugs that undergo high hepatic clearance or degradation in the gastrointestinal tract, and for patients that have swallowing difficulties. Although significant advances in drug formulation have been reported in the literature, particularly to improve retention and absorption in the buccal and sublingual regions, very few of them have translated to the clinical phase. For clinical translation to be justified, there needs to be a clear benefit of efficacy and/or safety with any new drug formulation compared to clinically available dosage forms. In addition, comprehensive evaluations of the pharmacokinetics, stability, efficacy, and safety of the formulations are required in appropriate animal models as well as in clinical studies, based on regulatory standards and protocols. For innovative platforms, such as nanoparticles, mechanism of action and safety of the different carriers following mucosal interaction and/or uptake need to be explored further. Complexity in drug formulation is also a key factor that can be a barrier to clinical translation, irrespective of its therapeutic efficacy. Therefore, simplification in formulation design is required to allow efficient and reproducible large-scale manufacturing. The availability of standardized testing methods can also be a limitation to reliably assess the quality of more complex or innovative formulations for regulatory standards.
REFERENCES
Maninder Pal Singh*, Ashita Pawaiya, Gurpreet Kaur, A Review on Sublingual Drug Delivery System for Better Bioavalibility, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 1879-1890. https://doi.org/10.5281/zenodo.15222571
10.5281/zenodo.15222571
