Tuesday, April 21, 2015

Insulin Therapy for Diabetics (4)

Continuation Of Insulin Therapy for Diabetics

Oral-lynTM: Generex Biotechnology Corporation (Toronto, Canada) is developing a buccal insulin formulation based on RapidMistTM, an advanced buccal drug delivery technology. Oral-lynTM is a liquid formulation of human regular insulin with a spray propellant for prandial insulin therapy. The formulation results in an aerosol with relatively large micelles where the majority of the particles have a mean size >10 μm and therefore cannot go into the lungs. Each puff is claimed to deliver 10 U of insulin. The absorption rate of administered insulin as a puff is 10%, and that corresponds to 1 U when 1 puff of 10 U is delivered, which means 10 puffs will deliver 10 U insulin for a meal. Clinical studies in healthy volunteers and subjects with type 1 and type 2 diabetes have shown that the oral insulin spray was absorbed in direct relation to the amount given, and it had a rapid onset and a shorter duration compared with regular insulin given subcutaneously. In all of the studies conducted, the oral insulin spray was generally well tolerated. The only side effects included mild episodes of transient dizziness in some healthy volunteers and subjects with type 1 diabetes. The product is on the market in a number of countries (e.g., Ecuador and India). Without appropriately designed and performed phase 3 trials at hand, it is not possible to make any clear statement about the benefits/risk ratio of the different buccal insulins.



Oral insulin: Oral insulin has benefits in terms of compliance among patients, as well as physiological advantages because oral insulin can mimic the physiological fate of insulin through first pass to the liver, directly and effectively inhibiting hepatic glucose production. Since the initial discovery of insulin by Banting and Best in 1922, the oral form of insulin has been the elusive goal. Difficulties encountered for oral insulin delivery, since it is a protein, include degradation by the low pH of the stomach and the digestive enzymes in the stomach and small intestine. The major barrier for insulin absorption is the intestinal epithelium. All these factors lead to low bioavailability, and that leads to significant inter- and intra-subject
variability.

Nanotechnologies have brought some hope for improved delivery of insulin. Nanotechnology applications for delivery of hydrophilic drugs such as insulin might be achieved using biodegradable polymers such as chitosan, which has been extensively exploited for the preparation of nanoparticles for oral controlled delivery of several therapeutic agents. In recent years, chitosan cross-linked to various hydrophobic polymers has been utilized for the preparation of orally delivered drugs because of improved permeation and sustained release characteristics.

The newer products that are being tried include water-soluble, long-acting insulin derivative, [(2-sulfo)-9-fluorenylmethoxycarbonyl]3-insulin, vitamin B12-dextran nano particles, lipid nanoparticles, and PEGylated calcium phosphate nanoparticles as oral carriers for insulin. Protection of insulin from the gastric environment has been achieved by coating the nanoparticles with a pH-sensitive polymer that dissolves in the intestine at mild alkaline pH. In rats, oral insulin nanoformulation significantly (P<0.05) reduced blood glucose in normal and diabetic rats. Biocon (Bangalore, India) is manufacturing IN-105, which is in late phase 3. IN-105 is a human recombinant insulin conjugated with polyethylene glycol via an acetyl chain. It is orally bioavailable and stable at ambient conditions. Preclinical studies in different species have shown acceptable efficacy and safety. Its maximal circulating insulin levels after oral administration of 5 mg were observed after 20 minutes, and the maximum drop in glucose occurred at 40 minutes after oral administration. Phase 1 and phase 2 trials demonstrated that the absorption of IN-105 and the reduction in blood glucose levels were proportional to the dose administered.

Inhaled insulin: The inhaled products fall into two main groups: the dry powder formulations and solution, which are delivered through different inhaler systems. Exubera®, containing rapid-acting insulin in powder form, was studied in patients with type 1 and type 2 diabetes mellitus. The results of a patient preference study, using a comparison of utility scores, showed a greater preference for the inhaled route over insulin injection. However, issues like cost, the bulkiness of the device, and the small number of studies in subjects with underlying respiratory disease prevented widespread use of this new mode of delivery. Exubera® was available for less than one year, and then Pfizer took it off the market in 2007 because the drug failed to gain market acceptance.

Afrezza®: (MannKind Corporation, Valencia, CA, USA) is recombinant human insulin, using the Technosphere® concept and administered using a next-generation inhaler called Dreamboat ®. Technosphere® is a drug delivery system created by micro particles (2-3 μm) that form microspheres, which are then lyophilized into a dry powder for inhalation. Transdermal insulin: Transdermal insulin delivery is a needle-free alternative and avoids the disadvantages associated with other alternative routes such as the pulmonary and nasal routes. Permeation of compounds is limited to small, lipophilic molecules. The stratum corneum, the outermost layer of the skin, constitutes the major barrier for insulin permeation to reach useful levels. Several chemical and physical enhancement techniques such as iontophoresis, ultrasound/ sonophoresis, micro-needles, electroporation, laser ablation, and chemical enhancers have been explored to overcome the stratum corneum barrier to increase skin permeability.

Methods to improve transdermal delivery:
1. Chemical enhancers, which alter the lipid structure of the stratum.
2. Iontophoresis, which enhances the transdermal delivery of compounds via the use of a
small electric current.
3. Micro-needle technology, which involves the creation of micron-sized channels in the
skin, thereby disrupting the stratum corneum barrier and delivering the drug into the
epidermis without disruption of nerve endings.
4. Sonophoresis, which uses ultrasound and has been shown to increase skin permeability
of insulin. It is still being evaluated

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