EP-4739335-A1 - INTRANASAL DELIVERY

EP4739335A1EP 4739335 A1EP4739335 A1EP 4739335A1EP-4739335-A1

Abstract

The present invention relates to formulations, devices and delivery of leucine-5-enkephalin (LENK) formulated with N-palmitoyl-N-acetyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQor Molecular Envelope Technology - MET). In particular, the present invention relates to delivering leucine-5-enkephalin encapsulated in GCPQ. intranasally via a drug or medicine dispersion and delivery system. The dispersion methods employ curved surfaces to impart rotational motions to one or more fluid flows from a pressurized container to create turbulence and improve mixing of medicament with fluid.

Inventors

UCHEGBU, IJEOMA
SCHATZLEIN, ANDREAS
MACK, ANTHONY
MATHIAS, Sheila

Assignees

Virpax Pharmaceuticals Inc.

Dates

Publication Date: 20260513
Application Date: 20240701

Claims (1)

Claims 1. An intranasal nanoparticle suspension comprising leucine enkephalin and quaternary ammonium palmitoyl glycol chitosan (GCPQ), wherein the ratio of the concentration in w/v of GCPQ to leucine enkephalin is from about 1:1 to about 2:1, and wherein GCPQ has a palmitoylation level between 10 mole % and 20 mole % and a quaternization level between 8 mole % and 12 mole %, wherein the formulation has a pH from 5.5 to 6.5. 2. The intranasal suspension of claim 1 wherein the size of the liposomes comprise a bimodal size distribution of nanoparticles from 10-40nm in diameter and nanoparticles of greater than 50nm. 3. The intranasal nanoparticle suspension of claim 2 wherein the nanoparticles having a diameter of 10- 40nm contain no leucine enkephalin and the nanoparticles having a diameter of greater than 50nm contain leucine enkephalin. 4. A powdered intranasal formulation comprising leucine enkephalin and quaternary ammonium palmitoyl glycol chitosan (GCPQ), wherein the ratio of the concentration in w/v of GCPQ to leucine enkephalin is from about 1:1 to about 2:1, and wherein GCPQ has a palmitoylation level between 10 mole % and 20 mole % and a quaternization level between 8 mole % and 12 mole %, wherein the formulation has a moisture content of below 5%. 5. The powdered intranasal nanoparticle formulation of claim 4 wherein the leucine enkephalin comprises 0.45 to 0.55 mg per mg of the powdered intranasal liposomal formulation. 6. A method for treating pain, comprising intranasally administering to a human or animal in need thereof a composition comprising a therapeutically effective amount of leucine enkephalin and an amphiphilic quaternary ammonium palmitoyl glycol chitosan (GCPQ); wherein the amphiphilic GCPQ is capable of self-assembly in aqueous media into particles having a mean particle size between 20-500 nm; wherein intranasally administering the composition delivers the hydrophilic neuroactive peptide to the brain of the human or animal. 7. The method of claim 6 wherein the particle size of the particles has a bimodal distribution. 8. The method of claim 7 wherein the bimodal distribution has particles having a diameter of 10-40nm which contain no leucine enkephalin and the particles having a diameter of greater than 50nm contain leucine enkephalin. 9.The method of claim 6 wherein the composition is in the form of a suspension. 10.The method of claim 9 wherein the amount of leucine enkephalin administered is from 150 to 180 mg per kg weight of the animal or human per day. 11.The method of claim 6 wherein the composition is in the form of a powder. 12.The method of claim 11 wherein the amount of leucine enkephalin administered is from 100 to 120 mg per kg weight of the animal or human per day. 13. A device for delivering a composition intranasally to a mammal comprising: a therapeutically effective amount of a leucine enkephalin and an amphiphilic compound N-palmitoyl-N- acetyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan as dried powder microparticles with a mean particle size greater than 5µm and has a moisture content of less than 5%; wherein the amphiphilic molecule self-assembles in aqueous media into nanoparticles having a mean particle size between 3-500 nm and wherein the composition is contained with a capsule comprising a pressurized container for a fluid, a chamber for containing the particles, at least one channel running between the container and the chamber to provide fluidic communication between the container and chamber in use, and at least two distinct concave surfaces on or integral with at least part of an internal wall or internal walls of the chamber, the concave surfaces so arranged that once fluidic communication between the chamber and container is established to create a fluid flow from the container to the chamber through the at least one channel and toward the concave surfaces, each concave surface imparts a rotational motion to a fluid flow or portion of fluid flow that impinges upon it, so that within the chamber a rotationally turbulent flow of fluid is produced in order to engage with the particles and to produce a mobile fluid comprising the particulate. 14. The device of claim 13 wherein the moisture content of the particles is less than 10% after storage at 25°C and 60% relative humidity for at least 6 months. 15. The device of claim 13 wherein the moisture content of the particles is less than 10% after storage at 30°C and 65% relative humidity for at least 6 months. 16. The device of claim 13 wherein the change in leucine enkephalin content relative to the powder is less than 10% after storage at 25°C and 60% relative humidity for at least 6 months. 17. The device of claim 13 wherein the change in leucine enkephalin content relative to the powder is less than 10% after storage at 30°C and 65% relative humidity for at least 6 months. 18. The device of claim 13 wherein the change in leucine enkephalin content relative to the powder is less than 5% after storage at 30°C and 65% relative humidity for at least 6 months. 19. The device of claim 13 wherein the microparticles have a mean particle diameter of 10 – 50 micrometers. 20. The device of claim 13 wherein the microparticles have a mean particle diameter of about 20 micrometers 22. The device of claim 13 wherein the microparticles when dispersed in aqueous media provide nanoparticles which exhibit a bimodal size distribution in which the particle size of the nanoparticles is between 10-20 nm for the first mode and between 80 to 650 nm for second mode. 23 The device of claim 13 containing microparticles where the microparticles may be changed on contact with aqueous media to nanoparticles with a size distribution of the particles is greater than 60% for mode 2 and greater than 30% for mode 1. 24 The device of claim 13 wherein the mass of particles delivered by the device is from 19 to 25 mg per kg mammal mass per day. 25. A composition comprising leucine enkephalin and an amphiphilic compound N-palmitoyl-N-acetyl-N- monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan as dried powder microparticles with a mean particle size greater than 5µm and has a moisture content of less than 5%; wherein the amphiphilic molecule self-assembles in aqueous media into nanoparticles having a mean particle size between 3-500 nm. 26. The composition of claim 25 wherein the ratio of amphiphilic compound to leucine enkephalin is from 1:10 to 10:1. 27. The composition of claim 25 wherein the ratio of amphiphilic compound to leucine enkephalin is from 1:3 to 3:1. 28. The composition of claim 25 wherein the ratio of amphiphilic compound to leucine enkephalin is from 1:2 to 2:1. 29. The composition of claim 25 wherein the ratio of amphiphilic compound to leucine enkephalin is 1:1. 30. The composition of claim 25 wherein the ratio of amphiphilic compound to leucine enkephalin is 2:1. 31. The composition of claim 25 further comprising a pharmaceutically acceptable carrier. 32. The composition of claim 31 wherein the ratio of amphiphilic compound to leucine enkephalin to pharmaceutically acceptable carrier is from 1:0.1:10 to 10:10:1. 33. The composition of claim 31 wherein the ratio of amphiphilic compound to leucine enkephalin to pharmaceutically acceptable carrier is from 2:0.1:10 to 10:5:1. 34. A method for treating pain, comprising intranasally administering to a human or animal in need thereof a composition comprising a therapeutically effective amount of leucine enkephalin and an amphiphilic quaternary ammonium palmitoyl glycol chitosan (N-palmitoyl-N-acetyl-N-monomethyl-N,N- dimethyl-N,N,N-trimethyl-6-O-glycolchitosan); wherein the amphiphilic GCPQ is capable of self-assembly in aqueous media into particles having a mean particle size between 3-500 nm and wherein the particles are dried and loaded into a capsule which when activated intranasally delivers the particles to the brain of the human or animal. 35. The method of claim 34 wherein the ratio of amphiphilic compound to leucine enkephalin is from 1:10 to 10:1. 36. The method of claim 34 wherein the ratio of amphiphilic compound to leucine enkephalin is from 1:3 to 3:1. 37. The method of claim 34 wherein the ratio of amphiphilic compound to leucine enkephalin is from 1:2 to 2:1. 38. The method of claim 34 wherein the ratio of amphiphilic compound to leucine enkephalin is 1:1. 39. The method of claim 34 wherein the ratio of amphiphilic compound to leucine enkephalin is 2:1. 40. The method of claim 34 further comprising a pharmaceutically acceptable carrier. 41. The method of claim 40 wherein the ratio of amphiphilic compound to leucine enkephalin to pharmaceutically acceptable carrier is from 1:1:10 to 10:10:1. 42. The method of claim 40 wherein the ratio of amphiphilic compound to leucine enkephalin to pharmaceutically acceptable carrier is from 2:1:10 to 10:5:1.

Description

Intranasal Delivery FIELD OF THE INVENTION The present invention relates to formulations, devices and delivery of leucine-5-enkephalin (LENK) formulated with N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan or N- palmitoyl-N-acetyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ or Molecular Envelope Technology, MET). In particular, the present invention relates to delivering leucine-5-enkephalin encapsulated in GCPQ intranasally via a drug or medicine dispersion and delivery system. The delivery methods employ curved surfaces to impart rotational motions to one or more fluid flows from a pressurized container to create turbulence and improve mixing of medicament with fluid. BACKGROUND TO THE INVENTION The treatment of diseases of the brain is significantly limited by the blood brain barrier. Over the last decade intranasal administration of drugs has gained increasing interest as a non-parenteral therapy. Originally seen as a route of administration for the local treatment of congestion, infection, rhinitis or nasal polyposis, in recent years a variety of products have entered the market for the systemic treatment of a variety of ailments. Nasal delivery of drugs has many advantages, including avoidance of first pass metabolism, avoidance of degradation in the gut, rapid onset with quick diffusion into the systemic system that parallels with intravenous administration and patient compliance due to the non-invasive nature and ease of self-medication. Within the nasal passage there are two main areas of absorption: the respiratory zone, which has the largest surface area and is highly vascularized, where active principles can cross the epithelium via para- or-transcellular routes, and the olfactory epithelium. The latter comprises only 3-5% of the total surface area of the nasal cavity and therefore is not largely involved in systemic absorption, but can allow direct access to the CNS, bypassing the blood brain barrier via the processes of olfactory neurons, through to the synaptic junctions with neurons of the olfactory bulb. There are physical disadvantages associated with administration via the nasal route that must be overcome. These include mucociliary clearance, enzymatic activity of the nasal mucosa, peptidases and drug metabolizing enzymes. In addition, molecular weight and lipophilicity play a part in absorption—low molecular weight molecules having a molecular weight less than 300 Da tend to be rapidly absorbed whereas for molecules between 300-1000 Da, lipid solubility is an important property. Lipophilic molecules diffuse freely, whereas it is thought that hydrophilic molecules must pass through the paracellular route. Molecules with a molecular weight above 1 kDa absorb very slowly and have a low bioavailability. These barriers can be addressed by altering the physiochemical properties of the molecule, increasing permeability by coadministration of an absorption promoter or reducing excretion/degradation by co-administering inhibitors. Absorption promoters currently under development include alkylsaccharides (Intravail®), chitosan (ChiSys™), low methylated pectin (PecSys™) and polyethylene glycol. Chitosan and its derivatives are commonly used as absorption enhancers due to chisosan's well documented ability to facilitate paracellular transport by opening the tight junctions or by interacting with extra-cellular matrix components. Chitosan increases the bioavailability of verapamil when administered nasally to rabbits in comparison to nasal verapamil solution (Abdel Mouez et al; Eur J Pharm Sci 2013, 30, 59-66). In addition, polylactic acid nanoparticles modified with chitosan have been used to encapsulate the analgesic peptide Neurotoxin. Rats intranasally administered with these chitosan modified nanoparticles had an increased concentration of neurotoxin in the periaqueductal gray in comparison to polylactic acid alone loaded nanoparticles (Zhang et al; Drug Development and Industrial Pharmacy 2013, 39, (11), 1618-24). Endogenous opioid peptides Leucine5-enkephalin (LENK) and Methionine5-enkephalin (MENK) are mainly degraded by cleavage of the N-terminal tyrosine. In the presence of polycarbophil-cysteine (0.25%) and glutathione (1%) LENK has shown reduced degradation and enhanced transportation across freshly excised bovine nasal mucosa. The absorption enhancer sodium glycocholate and protease inhibiter puromycin co-administered with LENK reduced degradation in nasal washings. However, this combination of excipients can lead to cell leakage and therefore toxicity. Chitosan formulations can also reduce the degradation of peptides. For instance, a chitosan-EDTA conjugate has been shown to reduce the degradation of LENK (Bernkop-Schnürch et al; 1997, Pharm Res 14, 917-22). LENK has also been nasally administered with trimethyl chitosan nanoparticles and shown enhanced antinociception in two mouse pain models in comparison to LENK alone (Kumar et al; I