Phospholipid depot

Abstract

The present invention is directed to compositions and methods of preparation of phospholipid depots that are injectable through a fine needle.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 13 / 523,860 filed Jun. 14, 2012, issued on Dec. 13, 2016 under U.S. Pat. No. 9,517,202 B2, which application is a continuation of PCT / US2010 / 060964, filed Dec. 17, 2010, which application claims priority to U.S. Provisional Patent Application No. 61 / 288,220, filed Dec. 18, 2009, the teachings of all of which are hereby incorporated by reference in their entireties for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to phospholipid depot compositions for insulin and other drugs and methods for preparation.BACKGROUND OF THE INVENTION[0003]An injectable depot is designed to prolong the duration of action and reduced the frequency of injection for a drug. Such depots are generally administered by subcutaneous or intramuscular injection or by injection or instillation into body tissues, vessels or cavities. A depot prolongs the action of a pharmacolog...

AI Technical Summary

Benefits of technology

The compositions achieve improved injectability and stability, enabling a peak-less pharmacokinetic profile for insulin, enhancing glycemic control and patient compliance by providing a prolonged and controlled release of insulin, reducing injection force, and allowing for the use of heat-sensitive drugs without terminal sterilization.

Problems solved by technology

A major disadvantage of the polymer depots is that they require large diameter needles for injection or implantation due to the physical size of the microcapsules / microspheres and / or the high viscosity of the polymer gel.

However, in common medical practice, needles of size greater than 21 G are generally not used for injection because they cause significant pain and psychological trauma for patients.

Unfortunately, most biological molecules such as protein drugs are incompatible with strong solvents.

Over time, this mass diffuses slowly into a surrounding tissue and / or is degraded by phospholipase, which is an enzyme distributed throughout the body that slowly hydrolyzes phospholipids, resulting in a slow release of the trapped drug.

However, to date, there has been few successful depot drug product based on phospholipids.

One primary problem is the poor injectability associated with phospholipid-based compositions.

However, once the phospholipid concentration exceeds about 20% in a composition, the composition becomes thick, viscous and difficult to inject through fine needles without using an excessively high force.

With their honey-like consistency, the Phosal compositions are very difficult to inject using a conventional hypodermic needle and syringe.

Thus, it will take 2-5 minutes or more to manually extrude 1 mL of the Phosal-based depot through a 26 G needle even using a very high force—which is impractical for general medical use and definitely not suitable for self-administration.

Another difficulty working with phospholipids is that phospholipids are only soluble in certain organic solvents (e.g., ethanol) or oil (e.g., vegetable oil) and many drugs (such as insulin or other protein drugs) are only soluble and stable in water, but not soluble or stable in solvents or oils that can dissolve phospholipids.

Therefore, it has been impossible to manufacture phospholipid-based depots using conventional solvent methods or other methods disclosed in prior art without having the solvent-sensitive drugs precipitate or degrade (See WO 2006 / 002050, U.S. Pat. No. 5,807,573, WO / 1994 / 008623, U.S. Pat. No. 5,004,611 and Harry Tiemesseen, et al.

Another hurdle in the production of phospholipid depots relates to difficulty in preparing a depot suitable for injection under sterile conditions.

Many drugs are heat-sensitive and cannot survive heat sterilization (e.g., autoclaving) or radiation sterilization.

Glucose level fluctuations, especially the high peaks and valleys resulting from poor glycemic control, are high risk factors for diabetes-associated complications that can lead to morbidity and mortality.

Despite its long history of use (over 70 years), NPH is not an ideal depot formulation for basal insulin therapy.

However, if the patient were to awaken in the middle of the night and get out of bed, the hypoglycemic episode could lead to fainting.Short duration of action: NPH releases a substantial amount of its insulin within the first few hours and is depleted in about 14-16 hours, making it suitable only as a twice-a-day (BID) formulation.

The resulting sub-optimal glycemic control increases the risk for diabetic complications.Poor dose uniformity: For suspensions like NPH, an intrinsic problem is the inability to achieve uniform injection-to-injection dosing in a small volumes—even with strict adherence to the rigorous pre-injection mixing / shaking instructions.

For NPH this difficulty is further compounded because it is typically injected in very small volumes (<1 mL).

Thus, the variability with respect to the amount of insulin injected dose-to-dose for NPH can be as high as 10-20%, which also contributes to poor glycemic control.

LANTUS® is also associated with a high incidence of injection site pain possibly due to its low pH formulation (pH 4).

Images