The Benefits and Challenges of PEGylating Small Molecules - Pharmaceutical Technology

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The Benefits and Challenges of PEGylating Small Molecules
Polyethylene glycol (PEG) conjugation is a highly effective technical and commercial strategy to develop macromolecules. The authors explain the benefits and process of PEGylation and how it may be applied to small molecules.

Pharmaceutical Technology

An example of the use of this technology is the "retasking" of the opiate antagonist naloxol to treat opioid-induced constipation and bowel dysfunction. Opioids exert their effect by binding mu receptors in the CNS to provide analgesia. Mu receptors are also present in the gastrointestinal (GI) tract. Opioid binding in the GI tract can cause severe constipation and bowel dysfunction, which is a significant problem for patients who require continuous use of opioids to control intractable pain. It is estimated that 200 million opioid prescriptions are filled each year in the US and that more than 40% of patients will experience opioid-induced constipation and bowel dysfunction.

Figure 4: Permeation of PEG–naloxol, naloxone, and reference standards in rats. (FIGURES ARE COURTESY OF THE AUTHORS.)
Naloxol and naloxone are well known antagonists of opioids and are used to treat drug overdose. Conjugating naloxol to a small-molecular-weight PEG such as PEG–naloxol prevents the drug molecule from crossing the blood–brain barrier and interfering with analgesia. Yet the technique allows naloxol to bind to the mu receptors in the GI tract to mitigate the undesirable effects of opioids. PEGylation has the additional benefit of increasing the oral availability of the molecule.

Figure 5: The effect of PEG–naloxol on gastrointestinal (GI) transit time and central morphine efficacy. (FIGURES ARE COURTESY OF THE AUTHORS.)
Preclinical studies of PEG–naloxol in rats demonstrate reduced permeation of the rat brain, compared with naloxone, improved GI transit, and maintenance of pain relief (see Figures 4–5). Phase I clinical-trial data of PEG–naloxol indicate that the compound provided a 10-fold increase in oral bioavailability over that of naloxone, was rapidly absorbed in plasma, provided a clinically relevant improvement in transit time through the gut (as measured by the hydrogen breath test), and demonstrated minimal reversal of CNS efficacy (as measured by pupillometry) (see Figure 6). Moreover, the data show an extended half life of 10 h. PEG–naloxol is currently in Phase II development.

Figure 6: Concentration of PEG–naloxol in plasma over time. (FIGURES ARE COURTESY OF THE AUTHORS.)
Another application of PEGylated CNS-exclusion technology involves using small-molecular-weight PEGs on diphenyhydramine to treat allergic rhinitis. The allergic-rhinitis market is a $6.7-billion segment with a large unmet market need. The most effective antihistamines make patients drowsy, and those that are nonsedating are not strong enough to meet the needs of all patients. Preclinical data show that PEGylating diphenyhydramine dramatically reduces the concentration of the drug in the CNS compared with the native molecule, while retaining the antihistamine activity. The molecule is currently in preclinical studies.


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