Reformulating Injectables for Oral Delivery - Pharmaceutical Technology

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Reformulating Injectables for Oral Delivery
Could oral absorption-enhancing technologies change the shape of protein delivery?


Pharmaceutical Technology
Volume 35, Issue 10, pp. 48-56

Other commercial approaches

Various other companies have developed their own approaches to delivering large molecules orally. Merrion Pharmaceuticals's GIPET technology platform uses small- and large-molecule surface-active materials to enhance drug absorption in the small intestine. The surface-active agents used in GIPET are generally regarded as safe (GRAS) materials, including fatty acids and derivatives, surfactants (e.g., mono- or diglycerides), and lecithin.

GIPET materials form mixed-micelle vesicular structures and liquid crystals that entrap the active compound through physical or physical–chemical interactions, according to the company. Mixing the enhancer and drug sometimes increases the latter's lipophilic properties, thus enabling large molecules to cross the gastrointestinal membrane. The micelles and liquid crystals also protect drug molecules from enzymatic degradation.

By acting as mild surfactants, GIPET enhancers increase the fluidity of the apical membrane and aid the transcellular transport of drug molecules. The agents also can increase the paracellular transport of drugs by contracting cytoskeletal actin filaments, which open the tight junctions and permit increased permeation of hydrophilic compounds. This function is not considered a significant component of the activity of GIPET, however.

The technology can be used to create three types of dosage forms. GIPET I yields enteric-coated tablets that contain the surface-active materials in powder form, along with the drug. GIPET II creates microemulsions of oil, surfactant, and drug in an enteric-coated gel capsule. GIPET III produces a mixture of fatty-acid derivatives in an enteric-coated gel capsule. All three GIPETs can deliver peptide or protein drugs. GIPET dosage forms can be created using conventional solid oral dosage manufacturing equipment.

In Phase I clinical studies, GIPET successfully delivered acyline, a decapeptide that can be used to treat prostate and breast cancer, by the oral route and achieved pharmacological activity. GIPET also delivered a peptide of a similar size, desmopressin, in the clinic. Merrion currently is collaborating with a partner to deliver larger peptides with GIPET. No products created through this technology have been marketed, however (2).

Intravail technology from Aegis Therapeutics uses transmucosal absorption enhancers for the oral delivery of potent peptides and proteins. The Intravail absorption enhancers comprise a group of alkylsaccharides related to mild surfactants common in personal care and food products. The GRAS enhancers do not irritate mucosal membranes.

Studies conducted at Albany Medical College have shown that the Intravail excipients can promote the oral absorption of certain peptides, such as octreotide and the antiobesity–antidiabetic leptin fragment D-Leu-OB3. The technology provides bioavailability comparable to or exceeding that achieved by subcutaneous injection. In one study, Intravail increased the oral absorption of an antibreast-cancer peptide by a factor of 10 and reduced the projected daily oral human dose from 2 mg/day to 200 μg/day. In addition to increasing bioavailability, the Intravail excipients have been shown to prevent peptide and protein aggregation and reduce resulting immunogenicity.

The Intravail technology delivers protein therapeutics as large as 30,000 Da, including GLP-1 analogs, calcitonin, growth hormone, leptin, insulin, erythropoietin, and low molecular weight heparins. Intravail formulations are compatible with conventional manufacturing processes for flash-dissolve wafers, tablets, and gelcaps.

In August 2011, Aegis received a patent for its Intravail-based oral formulations of several GLP-1 analogs. In April 2011, Aegis and scientists at Albany Medical College found that an Intravail-based oral formulation of the peptide octreotide achieved systemic bioavailability that exceeded that achieved by subcutaneous injection.

The NanoCrystal technology from Alkermes (formerly Elan Drug Technologies) is designed to increase drugs' solubility and can be used to deliver proteins and peptides (3). First, nanosized drug particles are created through methods such as wet milling, homogenization, precipitation, and supercritical-fluid techniques. This step increases the drug's surface area and enhances its dissolution profile. Proprietary stabilizers, such as F68 and sodium deoxycholate, are then surface adsorbed onto the drug particles to prevent agglomeration. This process yields an aqueous dispersion that behaves like a solution and can be sprayed onto a substrate, such as lactose, and compressed into a tablet (4).

Scientists have used the NanoCrystal technology to deliver zinc insulin orally. By altering peptides' particle size and surface properties, NanoCrystal technology can improve bioavailability by as much as 600%, according to the company. The technology also enabled sirolimus, an injectable cancer compound sold by Pfizer, to be formulated as an oral tablet. The technology can boost the drug's rate of absorption and reduce the size of the required dose.


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