Saliva is also produced in the minor salivary glands (also called accessory and intrinsic glands). These are found beneath the epithelium throughout the mouth except for the anterior part of the hard palate and the alveolar ridges supporting the teeth. Most of the mucous present in the oral cavity is derived from the minor salivary glands; however minor glands do not produce the same composition of the saliva.
Table 5: Composition of saliva by minor salivary glands
Glands on buccal mucosa
Labile glands of lips
Glossopalatine glands in isthmus of glossopalative fold/sometimes on the soft palate
Palatine glands found in the posterolateral areas of the hard palate/ the submosa of hard palate/uvula
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Anterior lingual glands of Blandin and Nuhn
Posterior lingual glands associated with the ventral surface of tongue
Lingual glands which open on to the
Dorsal surface of the tongue
The flow rate of individual minor salivary glands is difficult to determine. The saliva produced in the minor salivary glands may play an important role in drug delivery as this is the saliva which may be most directly in contact with the drug or delivery system. If drugs are delivered from a patch with an outer surface impermeable to saliva the low buffering capacity of the saliva from these glands may permit easy modification of the local microenvironment by appropriate delivery system excepients.
From the point of view of drug absorption from adhesive patches the minor salivary glands and their contents are probably of the most significant. A retensive oro- mucosal drug delivery system is likely to be located over these minor salivary glands. Whether these ducts will become blocked or infected during the administration of these systems has yet to be reported. However, their low flow rates would almost certainly not resulted in the formation of a mucous layer forming between the membrane surface and the delivery system. It has been reported that the flow of saliva from minor salivary glands is continuous thus it does not appear possible to choose a time of day when the salivary flow may be lower from the point of view of application. It may be significant to distinguish which saliva (mucous or serous) best aids/ hinders the adhesion of patches since this may also determine the most appropriate site for application.
Thus far we have considered the mucous film as a asset to aid retention of the delivery system. A additional consideration is that the mucous film of saliva produced on the tissues may prevent to some degree absorption of materials from the mouth therefore acts as a barrier to drug absorption.
Movement of oral tissues:
Here we considered the effect of swallowing, talking and eating on the movement of tissues in the oral cavity. If oro- mucosal drug delivery systems are to remain in place for a period of time some idea over the movement of the tissues at the site of attachment, and on their movement over other tissues and of the movement of other tissues against the delivery systems would be required. The least movement of any of the tissues in the oral cavity has been observed during sleeping and this period may be the most suitable period for drug administration, if dislodgement of delivery system proves to be a problem; however, swallowing and mouth movement do continue while sleeping. If delivery needs to be continued for prolonged periods, some research would need to be performed on the role of the tongue during oral mucosal drug delivery which, at various stages of mastication and swallowing, and may compress against the palate, induce suction pressures and wipe across tissues and delivery systems. It necessary to prove and determine the exact movement of the tongue during mastication and talking and to measure which pressures are exerted on the various regions of the oral cavity during these activities. Such information may dictate site selection and help optimize retention of the delivery system at a specific site.
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LIST OF MARKETED SUBLINGUAL TABLETS:
ISORDIL 2.5 mg SUBLINGUAL TABLET
ISORDIL 5.0 mg SUBLINGUAL TABLET
ISORDIL 7.5 mg SUBLINGUAL TABLET
ISORDIL 10.0 mg SUBLINGUAL TABLET
ATIVAN® 1 mg SUBLINGUAL TABLETS ATIVAN® 2 mg SUBLINGUAL TABLETS
Fentanyl (as citrate)
100 mg SUBLINGUAL TABLET
200 mg SUBLINGUAL TABLET
300 mg SUBLINGUAL TABLET
400 mg SUBLINGUAL TABLET
600 mg SUBLINGUAL TABLET
Subutex 2mg and 8mg SUBLINGUAL TABLETS
Suboxone 2mg and 8mg SUBLINGUAL TABLETS
Edluar 5mg or 10mg SUBLINGUAL TABLETS
SAPHRIS 5mg or 10mg SUBLINGUAL TABLETS
IN VITRO AND IN VIVO STUDY METHODS
ANIMAL MODELS FOR STUDIES
Due to the limited tissue area in the human buccal cavity has encouraged the use of animal models that may imitate human oral mucosal absorption. Each and every animal
model have their advantages and disadvantages. Rats, hamsters, dogs, rabbits, guinea
pigs, and rhesus monkeys have all been used in buccal studies [Ritschel, W.A., et al. 1985]. Almost all animals have a completely keratinized epithelium. The hamster cheek pouch has a large surface area but is not flushed with the saliva. The oral mucosa of the monkey, has been widely used but the high cost of procurement as well as difficult to handle are disadvantages when it comes to select
these animals. Human mucosa is similar to rabbit mucosa since it has regions of nonkeratinized
tissue. However, the small surface area and difficulty in accessing the required tissue make it
unusable. The animal of primary choice remains the pig because of comparable permeability to
human buccal mucosa and a large surface area enabling reduced changeability in the data [Song, Y., et al. 2004].
The methods used for measuring the amount of drug absorbed have to be designed in such
a way as to account for local delivery of the drug to the mucosa as well as systemic delivery
through the mucosa into the circulation. A selection of in vivo and in vitro techniques has been
developed and tested over the years.
IN VIVO METHODS
Both human and animal models have been used for in vivo testing of oro- mucosal drug
delivery. The animal models which reflects with the structure and properties of the human mucosa has been selected. An important in vivo technique has implemented using human test
volunteers, the ''buccal absorption test'' was developed and established by [Beckett and Triggs
et.al., 1967]. They adjusted solutions of several basic drugs to various pH values with buffer, and
placed the solution in the subject's mouth. The basic drug solution of varying pH was circulated about 300-400 times by the movement of the cheeks and tongue for a contact time of 5 min. The solution was then expelled, and the volunteer's mouth was rinsed with 10 ml distilled water for 10 s. The rinsed distilled water was collected, and combined with the earlier expelled solution, and the fraction of the drug remaining in this solution was measured by gas-liquid chromatography. Finally observed that the absorption of drug from the oral cavity dependent on pH.
These methods have been used to examine different types of dosage forms (composite films, patches, and bioadhesive tablets) and their mucosal drug absorption and have been used to evaluate both buccal and sublingual absorptions across the respective mucosa [Aungst, B.J., et al. 1988].
Yamahara et al.,1990 developed and used glass perfusion cell for the measurement
of drug absorption through mucosal membranes of anesthetized male beagle dogs. The cell
enclosed a biocompatible bioadhesive polymer O-ring that adhered the cell to the oral
mucosal membrane. This type of cell can be used to measure buccal and sublingual absorption
as well as perfusion through the surface of the tongue
IN VITRO METHODS
The in vivo studies does not provide information regarding the varying permeabilities of different regions in the oral cavity, and also information on the actual systemic absorption of the drugs. Also, the continuous flow of saliva affects the pH of the applied solution as well as the overall volume. So, several methods have been used as tools in invitro assessing of such drawbacks, mainly Disk method, Perfusion cell method were used as tools.
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These methods have been proved to be important tools in the study of transmucosal absorption,
Since they can make easy studies of drug permeation under controlled experimental conditions.
Oral mucosal tissue can be surgically removed from the oral cavity of the selected animal and the connective tissue held over on it is removed by applying heat at 60oc or chemically by using various enzymes or EDTA, [de Vries, M.E., et al. 1991] and [Garren, K.W., and A.J. Repta. 1989] if not removed it may acts as a permeation barrier. Tissues are stored in buffer solution
( usually in kreb's). Storage step is the important in preserving the integrity and viability of the tissue. The separated tissue is placed in between donar and receptor compartment of side by side diffusion cell. The donor contains the drug solution, whereas the receptor usually contains a buffer solution to emulate the body fluids. The chambers can be stirred continuously to ensure even distribution of the drug and are maintained at a desired temperature. The epithelial side of the tissue faces the donor chamber, allowing the drug to pass from the donor chamber through the tissue into the receptor chamber from where samples can be withdrawn at specific time intervals and replaced with fresh receptor solution.
Different kinds of diffusion cell apparatus have been used in such in vitro experiments.
Some of these are small volume diffusion cells as described by Grass and Sweetana [Grass, G.M., and S.A. Sweetana. 1988], Using chambers [Artusi, M., et al. 2003] and Franz diffusion cells [Senel, S., et al. 1998].
The in vitro methods, though relatively simple have various disadvantages:
(a) The conditions of tissue separation, preparation, and storage may affect the viability, integrity, and therefore their barrier function. Tests assessing the ATP levels have been used to analyze the viability and integrity of tissue. A method for ATP extraction using perchloric acid and subsequent analysis of ATP in nanomoles per gram of tissue has been described by Dowty
et al. [Dowty, M.E., et al. 1992].
(b) Human oral mucosa is relatively expensive and available in limited amounts.
Therefore, animal mucosae which have to be chosen carefully in order to resemble the human
mucosa as closely as possible are used.
(c) A specific complication occurs in cases of sublingual mucosa. Various ducts from the submandibular and the sublingual salivary glands open into the mucosal surface, and thus a sufficiently large piece of mucosa that is not perforated by these ducts is difficult to obtain [Harris, D., and J.R. Robinson. 1992] . Also, the presence of enzymes in the tissue indicates that there is a high probability of the drugs being metabolized during transport across the mucosa and therefore appropriate metabolism studies and drug-stabilizing efforts should be undertaken, these Studies were performed and measured the extent of metabolism of TRH in rabbit buccal mucosa in vitro and reported by [Dowty, M.E., et al. 1992].