Absorption of therapeutic agents across mucosal membranes or the skin

Abstract

Absorption of a therapeutic agent across a mucosal membrane or the skin can be enhanced using an absorption enhancer comprising a hydroxy fatty acid ester of polyethylene glycol.

Description

[0001]This application is a division of U.S. patent application Ser. No. 13 / 063,411, which is a U.S. national stage entry under 35 U.S.C. §371 of International Patent Application No. PCT / GB2009 / 051188, filed Sep. 14, 2009, which claims priority from Great Britain Patent Application No. 0816642.3, filed Sep. 12, 2008 and Great Britain Patent Application No. 0820799.5, filed Nov. 13, 2008.FIELD OF THE INVENTION[0002]This invention relates to the enhancement of absorption of therapeutic agents across mucosal membranes or the skin. In particular, the invention concerns the use of a hydroxy fatty acid ester of polyethylene glycol for enhancing transmucosal or transdermal delivery of a pharmaceutically active therapeutic agent. The invention also relates to compositions and methods for administration of a pharmaceutically active therapeutic agent to a mucosal membrane or the skin.BACKGROUND OF THE INVENTION[0003]Administration of therapeutic agents to the mucosa is well known in the art. ...

AI Technical Summary

Benefits of technology

[0048]A particular advantage of the present invention is that it allows and / or improves the delivery of therapeutic agents to the respiratory tract, in particular pulmonary delivery, and to the nasal or buccal cavities. Delivery via these mucosal membranes is particularly convenient, and the therapeutic agent may be transported directly into the systemic circulation, thus avoiding degradation from stomach acid, bile, digestive enzymes and other first-pass effects. As a result, these routes of delivery provide the potential for an improved onset of action, lower dosing and more accurate dosing, and may thus enhance the efficacy and safety profile of the therapeutic agent. As an alternative to oral administration, these alternative routes would benefit patients with swallowing disorders and patients suffering from nausea.

[0049]Thus, according to a second aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutic agent and an absorption enhancer comprising a hydroxy fatty acid ester of polyethylene glycol, which composition is in a form suitable for administration to the mucosal membranes of the nasal cavity, buccal cavity and / or respiratory tract.

[0050]The rapid onset of the therapeutic effect of a therapeutic agent contained in a composition according to the invention may be evaluated by determining the time after administration of the therapeutic agent when the maximum plasma concentration is reached (Tmax). The Tmax when the composition is nasally administered with the absorption enhancer is relatively short, compared to the Tmax of a similar composition that does not contain the absorption enhancer. Also, experiments have shown that the nasal absorption of growth hormone and insulin may be increased by a factor of at least 2 compared with the absorption obtained after administration of a similar composition that does not contain a hydroxy fatty acid ester of polyethylene glycol.

[0051]Compositions administered to the mucosal membranes of the nasal cavity, buccal cavity and / or respiratory tract may preferably be in the form of a spray, aerosol or dry powder, including spray-dried or freeze-dried particles, microspheres or nanoparticles. Additional compositions that are preferred for buccal delivery are buccal or sublingual tablets, pastilles or lozenges, or compositions in the form of a thin film. Thin film drug delivery (also known as orally dissolving thin film) refers to a thin film strip similar in size, shape and thickness to a postage stamp, which is typically placed on or under the tongue or along the inside of the cheek and allowed to dissolve.

[0052]Despite the problems associated with delivery involving the gastrointestinal tract, oral delivery remains a popular and acceptable route for the administration of therapeutic agents. The present invention is beneficial in the oral delivery of therapeutic agents because it allows the improved transport of drugs across the gastrointestinal tract. Absorption of drugs takes place in the small intestines and the colon. Compositions for oral delivery are typically produced as tablets or capsules, or in liquid form.

[0053]Compositions in a particulate form are particularly useful for the delivery of therapeutic agents to mucosal membranes. In particular, dry powders are used for nasal delivery (nasal insufflation) and pulmonary delivery (dry powder inhalers). Solid dosage forms such as tablets, for buccal, oral and vaginal delivery, and also capsules for oral delivery, may be produced by incorporating the therapeutic agent in a particulate form.

Problems solved by technology

Despite the advantages of mucosal routes of delivery, many therapeutic agents, such as peptides and proteins and hydrophilic small molecular weight drugs, are poorly absorbed across a mucosal membrane due to their physicochemical characteristics (eg large molecular weight, hydrophilicity, lability), and must therefore be administered by injection or infusion.

For some of these drugs, such as insulin administered to type 1 diabetics, a multiple daily dosing by injection is necessary and results in non-compliance, especially among younger patients (Drug Discovery Today, 7, 2002, 1184-1189; J Control Rel, 87, 2003, 187-198).

In particular, agents of large molecular weight and / or high hydrophilicity are poorly absorbed across mucosal membranes.

This is a particular problem for biologic drugs or “biologics”, such as peptides and proteins, polynucleic acids, SiRNA, RNA and antigens, since these are mostly large molecular weight molecules of a polar nature.

A further problem regarding the delivery of biologics, is that biologics are prone to degradation by enzymes such as peptidases and proteases, especially when administered via the gastrointestinal tract.

However, absorption enhancers employed previously in nasal studies, such as salicylates, bile salts and bile salt derivatives, phospholipids and lysophospholipids, sodium lauryl sulphate and cyclodextrins and chitosan derivatives, have in some cases been shown to result in irritation or damage to the mucosal membrane.

A variety of other mucosal absorption enhancer systems have been developed to deliver therapeutic agents across a mucosal membrane, but problems reported have included irritation, malabsorption and clearance of the therapeutic agent preventing successful absorption into the systemic circulation.

Many excipients such as polyethylene glycol and glycofurolum (U.S. Pat. No. 5,397,771) can be highly viscous and therefore unsuitable for intranasal and mucosal delivery.

The high solubility of colchicines means that the increase in oral absorption is unlikely to be due to increased drug solubility in the intestinal fluids due to Solutol.

Such uses have, however, been restricted to the solubilisation of poorly soluble drugs and / or inhibition of P-Gp and CYP450.

However, transdermal delivery is also hampered by the problems mentioned above for drug delivery across mucosal membranes.

The skin's low permeability limits the number of drugs that can be delivered in this manner, with the result that many hydrophilic compounds and / or compounds of high molecular weight are not currently deliverable by the transdermal route.

Without the use of absorption enhancers, many drugs will not diffuse into the skin at a sufficient rate to obtain therapeutic concentrations.

A particular concern for transdermal delivery is the possibility that a local irritation will develop at the site of application.

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