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Absorption of therapeutic agents across mucosal membranes or the skin

a technology of mucosal membranes and therapeutic agents, applied in the direction of aerosol delivery, immunological disorders, drug compositions, etc., can solve the problems of poor absorption of therapeutic agents of large molecular weight and/or high hydrophilicity, and poor absorption of therapeutic agents across mucosal membranes. , to achieve the effect of improving the absorption of therapeutic agents, avoiding degradation by stomach acid, and improving absorption ra

Inactive Publication Date: 2014-03-13
CRITICAL PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a way to deliver therapeutic agents to the respiratory tract and nasal or buccal cavities through mucosal membranes. This mode of delivery has several advantages, including the ability to avoid degradation from stomach acid, bile, and other first-pass effects. It allows for quicker onset of action, lower dosing, and more accurate dosing. The invention also includes a pharmaceutical composition containing a therapeutic agent and an absorption enhancer, which can be in the form of a spray, powder, or tablet for nasal, buccal, or oral delivery. The invention improves the delivery of oral drugs by allowing them to be better transported across the gastrointestinal tract.

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.

Method used

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  • Absorption of therapeutic agents across mucosal membranes or the skin
  • Absorption of therapeutic agents across mucosal membranes or the skin
  • Absorption of therapeutic agents across mucosal membranes or the skin

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0124]Insulin (available from Sigma-Aldrich) was dissolved in varying concentrations of Solutol® HS15 solutions ranging from 1 to 40% w / v in 0.063M phosphate buffered saline (PBS). The formulations were then administered intranasally to Sprague Dawley rats at 4 IU / kg and blood samples taken at frequent intervals up to 2 hours after administration. Blood glucose was measured using a standard glucose meter and insulin determined in the plasma by an enzyme linked immunosorbant assay (ELISA).

[0125]A group of rats was also administered with insulin dissolved in PBS via subcutaneous injection as comparison to the intranasal doses.

[0126]The results are shown in FIG. 1.

[0127]Solutol® HS15 formulations at 7.5% and 10% w / v in PBS were most effective at promoting the transport of insulin across the nasal mucosa showing a decrease in plasma glucose levels of 70%, as compared to control insulin solutions which showed a decrease of 15%.

example 2

[0128]Human growth hormone (hGH) (obtained from Bioker (Sardinia)) was dissolved in a 5% w / v Solutol® HS15 solution in PBS. The solution was then administered to Sprague Dawley rats intranasally at a dose rate of 5 mg / kg and compared to a subcutaneous administration of 5 mg / kg hGH. hGH levels in the serum were determined by enzyme linked immunosorbant assay (ELISA) up to 24 hours after administration.

[0129]The results are shown in FIG. 2.

[0130]The 5% w / v Solutol® HS15 formulation was effective at enhancing the transport of hGH across the nasal mucosa with a bioavailability of 17% compared to subcutaneous administration. The bioavailability of hGH administered nasally without an absorption enhancer is less than 1%.

example 3

[0131]To prepare hGH loaded microparticles, micronised hGH, PLGA, PLA and Solutol® HS15 was added to a pressure vessel. The vessel was sealed and CO2 was introduced. The temperature was raised to above 32° C., and the pressure increased above 76 bar. Under these conditions CO2 becomes supercritical and dissolves into the polymer, which becomes liquefied. The liquefied polymer, hGH and Solutol® HS15 were then mixed and microparticles of a suitable size for injection were formed by solidification after the drug / polymer mixture was atomized and depressurised. hGH loaded microparticle formulations containing PLGA, PLA and PEG 600 were also prepared using the same method. The microparticles were administered to Sprague Dawley rats intranasally at a dose rate of 5 mg / kg hGH and compared to a subcutaneous administration of hGH. Blood samples were taken up to 24 hours after administration and hGH levels in the serum were determined by enzyme linked immunosorbant assay (ELISA).

[0132]The resu...

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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. ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/14A61K31/7088A61K31/519A61K39/00A61K38/28A61K38/27
CPCA61K47/14A61K38/28A61K31/7088A61K31/519A61K39/00A61K38/27A61K9/0031A61K9/0034A61K9/0043A61K9/0056A61K9/0073A61K9/02A61K9/12A61K9/1641A61K9/1647A61K9/19A61K31/00A61K47/10A61P1/08A61P11/00A61P29/00A61P37/04
Inventor ILLUM, LISBETHJORDAN, FARON MICHAELLEWIS, ANDREW LESTER
Owner CRITICAL PHARMA LTD
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