New technique and device for controlled and continuous drug delivery into the brain: a proof-of-concept study

Background: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that plays an important role in glucose homeostasis and food intake. In people, GLP-1 receptor agonists (GLP-1RAs) are commonly used for the treatment of type 2 diabetes mellitus (DM) and obesity; however, non-adherence to injectable medications is common. OKV-119 is an investigational drug delivery system intended for subdermal implantation and delivery of the GLP-1RA exenatide for up to 6 months.Hypothesis/Objectives: Develop protocols for the subcutaneous (SC) insertion and removal of OKV-119 and to evaluate its tolerability, in vivo drug-releasing characteristics, and weight-loss effects in cats.Animals: Two cadaveric and 19 purpose-bred cats.Methods: In cadavers, OKV-119 insertion protocol and imaging were performed at three SC locations. The safety and tolerability of OKV-119 implants were assessed in a small (n = 4 cats) 62-day study. Weekly plasma exenatide concentrations and body weight were measured in a 42-day proof-of-concept study designed to evaluate OKV-119 prototypes implanted in cats (n = 15).Results: In anesthetized cats, the duration of insertion and removal procedures was 1–2 min. OKV-119 was easily identified on radiographs, and well-tolerated without any apparent implant site reactions. Following implantation, exanatide plasma concentrations were observed for up to 35 days. Plasma exenatide concentrations were correlated to weight loss.Conclusion and clinical importance: Our findings suggest that OKV-119 could be easily inserted and removed during a routine clinic visit and can be used to safely and effectively deliver exenatide. Future studies of OKV-119, configured to release exenatide for a longer extended months-long duration, are warranted to determine whether the combination of metabolic improvements and beneficial weight-loss, coupled with minimal impact on pet-owner's lifestyle, lead to improved outcomes for obese cats and feline DM patients.

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A New Technique and Device for Controlled and Continuous Drug Delivery into the Brain – A Proof of Concept Study

10.1101/746966 ◽

2019 ◽

Author(s):

U.R. Anoop ◽

Kavita Verma

Keyword(s):

Drug Delivery ◽

Optic Nerve ◽

Blood Brain Barrier ◽

Ex Vivo ◽

Brain Barrier ◽

Continuous Drug Delivery ◽

A New Technique ◽

Invasive Techniques ◽

The Brain

AbstractBackgroundDrug delivery into the brain has been a challenge for the past 100 years because of the blood brain barrier. The existing non-invasive techniques cannot provide controlled and continuous drug delivery into the brain and the invasive techniques make the brain prone to infection from external agents. Hence a new technique which can provide controlled and continuous drug delivery without the need for any surgical intervention in the brain holds immense potential.ObjectiveThe objective of this study is to deliver drugs into the brain using a novel oral and maxillofacial technique and device.MethodDrug delivery into the brain from the oral and maxillofacial region was tested using a novel technique and device in an in vivo rabbit model and an ex vivo goat head model. A control animal and an experimental animal were used in each study. Drugs which do not cross the blood brain barrier normally were tested. Dopamine was delivered in vivo from the maxillo-facial region. Anti-glial fibrillary acidic protein antibody was delivered ex vivo from the oral region. Samples were collected from different sites including the brain and the optic nerve.ResultsThe in vivo model showed a significant increase of dopamine at the pons (51.89%), midbrain (27%), medulla (48.5%) and cortex (72.637%). On including samples from other regions in the t-test, the increase was not statistically significant (p=0.538), suggestive of a central feedback mechanism for brain and peripheral dopamine. A decrease in plasma dopamine during drug delivery further supported a central control for dopamine. In the ex vivo model, a statistically significant (p=0.047) delivery of antibodies occurred at multiple sites including pons (86.7%), cortex (256.5%), and the optic nerve (128.8%).ConclusionThis technique and device can deliver drugs into the brain without detectable increase in systemic circulation. Therefore it may be used for delivering drugs in Parkinson’s disease, Alzheimer’s disease, Pain management, Brain tumors especially pontine tumors, infections like neuro-AIDS, Basal meningitis etc. Retinal drug delivery may also be possible.

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