Ivermectin

Associated long-acting platforms

Oral solid form, Polymer-based particles

Administration route

Oral, Subcutaneous

Therapeutic area(s)

Use case(s)

Use of drug

Drug information

Delivery device(s)

Lyndra’s proprietary LYNX™ drug delivery platform is a novel approach to oral drug delivery that enables once-a-week or even once-a-month dosing. Key proprietary features include: (1) A flexible core that allows the dosage form to maintain its desired shape in the stomach, preventing premature passage into the small intestine. (2) Linkers connecting dosage form arms to the core. These linkers are designed to soften and disintegrate, allowing the dosage form to safely exit the body. (3) A proprietary coating that makes the capsule easy to swallow and ensures it remains intact in the oesophagus.

Scale-up prospects

Compound is commercially manufactured.

Tentative equipment list for manufacturing

(1) Fermentation & Extraction tanks: Bacterial fermentation vessels to produce avermectin and its subsequent extraction from the fermentation broth. (2) Hydrogenation reactors: Allows the conversion of avermectin to ivermectin by selective hydrogenation. (3) Filtration systems: Removes impurities from the ivermectin solution. (4) Crystallizers: Vessels used to crystallize ivermectin from the solution. (5) Dryers: Required to remove solvent from the crystallized ivermectin. (6) Packaging equipment: Machinery to package the final drug product.

Manufacturing

Avermectin derivatives such as ivermectin are unstable in acidic and alkaline conditions, in addition to being sensitive to strong light. Product formulations containing avermectins usually include antioxidant excipients as they susceptible to chemical oxidation processes.

Specific analytical instrument required for characterization of formulation

(1) Identification of residual impurities: High-performance liquid chromatography (HPLC), gas chromatography (GC), mass spectrometry (MS). (2) Determine concentration: Ultraviolet-visible spectrophotometry. (3) Elucidate melting point and identify polymorphic forms: Differential scanning calorimetry. (4) Analyse crystal structure and determine polymorphic forms: X-ray powder diffraction (XRPD). (5) Drug solubility: Dissolution testing apparatus.

LYN-163-C-101

Identifier

ACTRN12621001218886

Link

https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621001218886

Phase

Phase I

Status

Recruiting

Sponsor

Lyndra®Therapeutics, Inc. (Lyndra)

More details

Not provided

Purpose

Evaluate the safety and tolerability of long-acting oral capsules (LYN-163) containing 28mg ivermectin in a drug-releasing formulation.

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2022-05-26

Anticipated Date of Last Follow-up
Not provided

Estimated Primary Completion Date
2023-04-15

Estimated Completion Date
2023-04-15

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults

Genders

• Male
• Female

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
Yes

Comments about the studied populations

Participants are healthy male and female individuals aged between 18-49 years, with a body weight greater than or equal to 56 kg. Participants are excluded if they have a history of X-ray, computed tomography scan, or angiogram of the abdomen within one year of Screening.

Health status

Study type

Interventional (clinical trial)

Enrollment

25

Allocation

Non-randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

Not provided

Residual solvents used

Not provided

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

Andrew M. Bellinger et al. Oral, ultra–long-lasting drug delivery: Application toward malaria elimination goals.Sci. Transl. Med.8,365ra157-365ra157(2016).DOI:10.1126/scitranslmed.aag2374

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra–long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra–long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.

Bellinger AM, Jafari M, Grant TM, Zhang S, Slater HC, Wenger EA, Mo S, Lee YL, Mazdiyasni H, Kogan L, Barman R, Cleveland C, Booth L, Bensel T, Minahan D, Hurowitz HM, Tai T, Daily J, Nikolic B, Wood L, Eckhoff PA, Langer R, Traverso G. Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals. Sci Transl Med. 2016 Nov 16;8(365):365ra157. DOI: 10.1126/scitranslmed.aag2374. PMID: 27856796; PMCID: PMC5264553.

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra–long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra–long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.

Awasthi A, Razzak M, Al-Kassas R, Harvey J, Garg S. An overview on chemical derivatization and stability aspects of selected avermectin derivatives. Chem Pharm Bull (Tokyo). 2012;60(8):931-44. DOI: 10.1248/cpb.c12-00258. PMID: 22863694.

Naturally occurring avermectins (AVMs) and its derivatives are potent endectocide compounds, well-known for their novel mode of action against a broad range of nematode and anthropod animal parasites. In this review, chemical and pharmaceutical aspects of AVM derivatives are described including stability, synthetic and purification processes, impurities and degradation pathways, and subsequent suggestions are made to improve the chemical stability. It has been found out that unique structure of AVM molecules and presence of labile groups facilitated the derivatization of AVM into various compounds showing strong anthelmintic activity. However, the same unique structure is also responsible for labile nature related to sensitive stability profile of molecules. AVMs are found to be unstable in acidic and alkaline conditions. In addition, these compounds are sensitive to strong light, and subsequently presence of photo-isomer in animals treated topically with AVM product is well known. The pharmacoepial recommendations for addition of antioxidant into drug substance, as well as its products, arises from the fact that AVM are very sensitive to oxidation. Formations of solvates, salts, epoxides, reduction of double bonds and developing liquid formulation around pH 6.2, were some chemical approaches used to retard the degradation in AVM. This coherent review will contribute towards the better understanding of the correlation of chemical processes, stability profile and biological activity; therefore, it will help to design the shelf-life stable formulations containing AVMs.

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