Oral transmucosal delivery

Details Oral transmucosal delivery Oral transmucosal delivery

2001-06-01

2002-12-03

Azpuru, Carlos (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S435000

Reexamination Certificate

active

06488953

ABSTRACT:

The present invention relates to an autoadhesive oral transmucosal delivery device for delivering a pharmaceutically active agent via mucosal tissues in the mouth. The invention also relates to the use of a hydrogel body in preparation of a medicament for oral transmucosal delivery.
The transmucosal delivery of pharmaceutically active agents to a patient is known. In particular, the buccal region of the mouth in the upper gum and inside cheek region provides a barrier to delivery that is more permeable than the skin itself and tends to be less variable between individuals. The buccal mucosa also has a significantly lower depot effect than skin. The use of steroid mucoadhesive gels for the treatment of mouth ulcers is common, and is now a significant consumer market.
There are also technologies available which rely on the adhesion of a solid sustained delivery device to the mucosal membranes to allow sustained delivery of active agent. Such systems generally comprise an adhesive layer and a delivery matrix including the active agent, typically in the form of a small tablet or patch. In the Cydot (trademark) system the patch is non-degradable and must be removed after use. In the Theratech (trademark) system the tablet dissolves after a number of hours in situ. Advantages of transmucosal delivery are said to include rapid onset of drug delivery, sustained drug delivery levels and rapid decline of drug delivery at the end of the desired treatment time. The transmucosal route also delivers active agent directly into the system and avoids the first-pass through the liver metabolism process which is characteristic of oral delivery. The transmucosal membranes also appear to allow the passage of relatively high molecular weight drugs, including peptides.
Hydrogels are known sustained release delivery vehicles and a typical hydrogel having well documented pharmacological acceptability is disclosed in patent specifications GB2047093 and GB2047094 which describe cross-linked polyurethane materials having the ability to swell and absorb several times their own weight of water. The hydrogel polymer has been used as a pessary to deliver dinoprostone (a prostaglandin) to the cervix to ripen it prior to the induction of labour and is available under the trademarks Propess and Cervidil. The pessary is enclosed in a net pouch and usually remains in place for up to 24 hours.
The use of the hydrogel polymer for localised application for the treatment of maladies of the mouth has been disclosed in passing in the GB patent specifications mentioned above.
The immobilisation of transmucosal delivery devices in the buccal region is clearly desirable in order to prevent the device being accidentally swallowed by the patient. However, mucosal tissues have a high moisture content and it is correspondingly difficult to adhere solid devices to them in an effective manner. Moreover, any suitable adhesive must not only be effective but also pharmacologically acceptable, and the presence of a further component imposes undesirable complexities on the development of a suitable product.
The present invention is based on the surprising discovery of autoadhesive properties of the hydrogel to moist mucosal surfaces, allowing the device to remain in place over a time which is sufficiently extended to allow effective delivery of active agent.
In particular, the present invention provides an autoadhesive oral transmucosal delivery device which comprises:
a body formed of a hydrogel capable of absorbing water to achieve a water-content whereat the device autoadheres to an oral mucosal surface;
the hydrogel body comprising a pharmaceutically active agent which is released while the body is adhered to the mucosal surface.
The term “autoadhesive” in the present specification is taken to mean that the device itself adheres to the mucosal tissue by virtue of its own properties and without the need to employ any other adhesive material.
The invention also extends to the use of the hydrogel in an autoadhesive medicament for oral transmucosal delivery of active agent.
The hydrogel body as supplied will usually contain little or no water (e.g. less than 1 or 2 wt %) and will absorb water from the surroundings after administration. It is found that autoadhesion occurs at hydrogel water contents below 50% by weight, particularly less than 45% and especially less than 35% by weight. It is found that there is also generally a lower limit above which autoadhesion occurs of around 25% by weight. Autoadhesion typically requires a water content in the range 35 to 45% by weight. Generally, hydrogel polymer will be chosen such that the water uptake is sufficient to allow the device to firmly adhere to the mucosal membranes in less than 15 minutes (e.g. in 10 to 15 minutes). During this time, the patient may need to hold the device in place using his cheek muscles, and so this period should generally speaking not be longer than 10 to 15 minutes. Thereafter, the device should remain in place until the active agent has been substantially released. Generally, the device should remain adhered whilst it absorbs further water for a period of at least one hour, particularly at least 2 hours and preferably at least 4 hours. A preferred adherence period is in the range 2-3 hours before the device becomes detached. At this point, the patient knows that the treatment is complete and can spit out the spent device.
Generally, the hydrogel is a polyurethane hydrogel of the type disclosed in patent specifications GB2047093 and GB2047094. These patent specifications disclose cross-linked polyurethane hydrogels. Typically, the polyurethane is prepared from a long chain polyethylene glycol (e.g. PEG 2000, 4000, 6000 and 8,000 which has been extensively dried), a triol (for example hexanetriol) as cross-linking agent and a diisocyanate (such as dicyclohexyl isocyanate). The mixture is cured at elevated temperatures in a mould.
Other polymers such as polyhydroxyethylmethacrylates, polyvinylpyrrolidones and celluloses may be used provided they show the required autoadhesion properties.
The delivery device is generally in the form of a conformable unit, which is flexible enough (particularly when swollen) to be accommodated within the buccal cavity in intimate contact with the mucosal membrane. Preferred shapes include sheets, discs, ovals, kidney shapes, strips and cylinders. Generally, the smallest dimension is in the range 5-15 mm and the longest dimension in the range 10-25 mm. Preferred thicknesses are in the range 0.5-5 mm, especially 0.5 to 2.5 mm and particularly 1-2.5 mm.
Generally, the hydrogel is loaded with active agent by soaking the hydrogel in a solution of active agent of required concentration for a time sufficient for absorption to occur, followed by drying the hydrogel down to the required water content. Uptake of active agent may be improved by the use of low molecular weight cosolutes such as sodium chloride, potassium chloride, sodium saccharin and benzoic acid.
The objective of the device of the invention is to provide a controlled release of the active agent to the mucosal membrane during its period of adhesion. Preferably, the release rate is substantially constant through this period. The active agent may be absorbed systemically or may exert a local action on adjacent tissue structures.
If necessary, penetration enhancers, as known in the art, may be employed to assist the rate of transmucosal delivery, depending on the nature of the active agent, for example its lipophilic or hydrophilic characteristics, size and molecular weight. Generally, the more lipophilic the compound, the better the absorption. The nonionised form of the active agent appears to be best for absorption. The pH of the buccal tissue mucosa is around 6.8 and both acidic and basic active agents are suitable candidates. In view of the rapid and effective delivery through mucosal tissues, penetration enhancers may not be required. Such penetration enhancers are known from topical application to skin tissue which constitutes a more significant barrier to absorption.

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