ORAVESCENT: A NOVEL TECHNOLOGY FOR THE TRANSMUCOSAL DELIVERYOF DRUGS

Guided by :

Mr. Raghukiran,

Head of the Department of Pharmaceutics,

Teegala Krishna Reddy College Of Pharmacy.

R.VenkateshTKR College Of Pharmacy

INTRODUCTION

The OraVescent SL and BL drug delivery systems have been designed to promote drug absorption through the oral mucosa (sublingual and buccal delivery, respectively).

This may enable more rapid absorption of drugs that have a long Tmax.

In other instances, this route of administration may be desirable to avoid the first-pass effect and so improve the bioavailability of the drug.

HISTORICAL DEVELOPMENT

The effervescence reaction has been known and utilized in pharmaceutical dosage forms for a long time, a patent having been issued in 1872.

Carbon dioxide is released as a result of the interaction of an acid with a carbonate or a bicarbonate salt.

More recently, Eichmann and Robinson explored the potential for CO2 to promote the transport of a drug across a biological membrane.

The mechanisms by means of which CO2 acts as an absorption promoter were summarized as follows:

1. A solvent drag effect.2. Opening of tight junctions.3. Increase in the hydrophobicity of the cell membrane, thus promotingthe absorption of hydrophobic drugs.

DESCRIPTION OF THE TECHNOLOGY

From a consideration of the Henderson-Hasselbach equation, it is known that pH values lower than the pKa of a weak base, promote its ionization in aqueous solution.

On the other hand, when the pH of the solution is above the pKa, the ionization of the weak base is repressed and the non-ionized form predominates.

The ionized form of the drug is much more water soluble than the nonionized form, whereas the latter is usually much more permeable to biological tissues.

Therefore, conventional wisdom directs that, a pH lower than the pKa of the drug, be used when the solubility of the drug is limited.

Where absorption of the weakly basic drug into a biological system is slow or incomplete, a pH somewhat higher than the pKa of the drug may be chosen.

Often, the pH that is chosen is a compromise between that which is desirable for optimizing the solubility of the drug and that which promotes absorption.

If we could have a system that develops a low pH initially, the solubility of the weak base would be enhanced.

If the pH of this system could then be made to slowly rise, the ionized form of the drug in solution would slowly change to the un-ionized form and hence, absorption would be promoted.

When the effervescence reaction occurs, CO2 is liberated. The CO2 that is released, will dissolve in the saliva. The saliva becomes more acidic owing to the formation of carbonic acid.

Later, owing to the loss of CO2 from solution, the pH of the solution gradually rises.

(The liberated CO2 is either absorbed by the mucosal tissues where it might promote drug absorption, or it is lost to the air space in the oral cavity.)

The overall pH variation with approximately equimolar amounts of citric acid and sodium bicarbonate is from about 6 to about 8.4, i.e., a variation of about 1 pH unit in either direction from normal salivary pH.

1)NaHCO3 + C3H5O(COOH)3 + H2O → CO2 +2H20 + NaC3H5O(COOH)2COO-

2)CO2 + H2O → H2CO3

RESEARCH AND DEVELOPMENT

The hypothesis that effervescence and the resulting pH transition can be utilized to enhance the delivery of poorly soluble weak bases, was tested in human subjects with Fentanyl as the model drug.

Fentanyl was selected for the present study because its pKa is 7.3 and its un-ionized form is highly lipophilic and poorly water soluble.

Absorption of Fentanyl from the gastrointestinal tract is slow and the drug also undergoes gut wall, and extensive hepatic metabolism.

The study was conducted in Belfast, Northern Ireland and the protocol was approved by the Ethics Committee of Queen’s University of Belfast.

Twelve normal, healthy male volunteers aged 18–55 years participated in the study. Each subject’s body weight was not more than 15% above or 15% below the ideal weight for his height and estimated frame, adapted from the 1983 Metropolitan Life Table.

After an overnight fast, the subjects were given one of three dosing regimens according to a randomization schedule:

1. An OraVescent Fentanyl buccal tablet.

2. A tablet that was similar to (1) in size, shape, and drug content but contained lactose in place of the absorption-enhancing components.

3. An Actiq oral transmucosal delivery system, which is marketed by Anesta Corporation in the United States.

Water was allowed ad lib except for the period from dosing to 4 h postdose. Subjects followed a menu and meal schedule as determined by the clinic with the first meal approximately 5 h after dosing.

Subjects taking treatments (1) and (2) were asked to place the tablet between the upper gum and inside of the cheek, above the premolar tooth.

The tablets were left in place for 10 min. If, at that time, a subject felt that a portion of the tablet remained undissolved, he was requested to gently massage the area of the outer cheek, corresponding to the tablet’s placement, for a maximum of 5 min.

A member of the clinic staff checked the subject’s mouth at 15 min, to see if any portion of the tablet remained. The residue, if any, was allowed to dissolve on its own without further manipulation.

Administration of treatment (3) was according to the directions on the package insert of the product.

After dosing, blood samples were withdrawn at predetermined time points for 36 h.

The blood samples were centrifuged and the separated serum was frozen until assayed by an LC/MS/MS method.

The assay method was sufficiently sensitive to allow a limit of quantitation of 0.05 ng/mL.

The serum level versus time plots are shown in Figure:

Fentanyl bioavailability after buccal administration.

The OraVescent enhanced delivery system displayed superior pharmacokinetics when compared to either the nonenhanced tablet (2) or the commercial dosage form (3).

A comparison of the enhanced and nonenhanced formulations (1 versus 2) indicates that the enhanced delivery system functioned as intended; i.e., effervescence promoted absorption.

The following comparisons can be made of fentanyl pharmacokinetics after OraVescent versus Actiq administration:

OraVescent buccal(1)

Nonenhanced buccal (2)

Actiq (3)

Cmax (ng/mL)

0.6412 (0.2804)

0.3986 (0.0744) 0.4073 (0.1537)

AUC (0-t) (ng/hr/mL)

2.656 (0.6729) 2.041 (0.8690) 1.809 (0.9358)

Median Tmax (h)

0.501 2 2

1. Fentanyl peak serum levels are higher (0.6 ng/mL compared to 0.4 ng/mL).

2. Systemic fentanyl bioavailability is more complete (the AUC is approximately 1.47 times as high).

3. Fentanyl is more rapidly absorbed (Tmax is 0.5 h compared to 2 h).

In above Figure, the serum levels obtained during the first 30 min are plotted on an expanded scale.

These graphs clearly reveal the faster absorption of fentanyl from the OraVescent formulation during the initial stages.

The rapid initial rise in fentanyl serum levels indicates that the delivery system has the potential to provide quicker onset of pain relief.

Fentanyl is an anaesthetic agent that may be used for induction of anaesthesia and, in combination with other anaesthetic agents, in the post induction phase.

It is also used for the treatment of moderate to severe chronic pain, such as that experienced by cancer patients. For this purpose, it is often administered as a transdermal drug delivery system.

This system provides continuous delivery of the medication for 72 hours and its efficacy and safety have been established.

An example of such a system is Duragesic transdermal system (Jansen Pharmaceutical Products, L.P).

Cancer patients often experience severe pain of short duration while on an otherwise adequate dose of fentanyl, or other long acting formulation. For relief of this “breakthrough” pain, an additional low-dose, quick-acting medication is needed.

Rapidity of onset of action of the supplementary medication is essential.

The OraVescent fentanyl drug delivery system(DDS) is designed to fulfil this requirement.

The results of this study show that the OraVescent DDS functioned as intended; i.e., the system promoted the absorption of a weak base.

A rapid initial rise in serum levels and a faster and more complete absorption, relative to the commercial product, was observed.

OraVescent fentanyl, therefore, has the potential for a quicker onset of action and may be useful for the relief of breakthrough cancer pain.

REFERENCES

1. Michael J. Rathbone. Modified-Release Drug Delivery Technology.

2. WT Cooper. Improvements in preparing or making up medicated and other effervescing mixtures. British patent 3160, 1872.

3. JD Eichmann, JR Robinson. Mechanistic studies on effervescent-induced permeability enhancement. Pharm Res 15:925–930, 1998.

4. A Martin. Physical Pharmacy. 4th ed. Philadelphia: Lea & Febiger, 1993.

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