WO2020077284A1 - Macrocyclic lactone formulations ...

Macrocyclic Lactone Formulations, Methods of Their Preparation and Use of the Formulations in Treating Pathologies Secondary to Ophthalmic Parasites

Want more information on Ivermectin Api Manufacturers? Feel free to contact us.

Technical Field of the Invention

This invention pertains to the utilization of macrocyclic lactone parasiticides, particularly ivermectin and other avermectins like doramectin and selamectin, and milbemycins such as moxidectin and milbemycin oxime, as antiparasitic agents for preparing formulations used to treat conditions typically induced by ophthalmic parasites. Conditions include parasitic infections of the eye caused by Demodex mites in both humans and animals. The invention also provides a method for preparing an amorphous or crystalline solid dispersion using ivermectin and a polymer, as well as the use of such formulations for treating Demodex mite-induced conditions.

Background of the Invention

Ocular demodicosis is identified by a pathological overgrowth of the Demodex family of parasites, which can shift from a commensal to a parasitic relationship, particularly Demodex folliculorum and brevis. These mites, which can inhabit diverse regions such as the eyelashes, eyelash root, follicles, anterior eyelid, meibomian glands, and surrounding cutaneous periocular tissue, may cause inflammation and various ocular symptoms. This may lead to conditions like evaporative dry eye, eyelash loss, meibomian gland destruction, chalazion formation, and ocular rosacea.

Among the two, Demodex folliculorum measures around 0.3-0.4 mm and is typically found at the root of the eyelash. When infesting these areas, it disrupts the host epithelium, leading to hyperkeratinization, eyelash loss, and inflammation. Disruption may result in symptoms of inflammation (blepharitis and keratitis), which can cause subsequent conditions like evaporative dry eye disease, meibomian gland dysfunction, and ocular rosacea.

Demodex brevis, being smaller at 0.2-0.3 mm, usually burrows within sebaceous glands and specifically within the meibomian gland around the eyelid. This can lead to mechanical obstruction, gland architecture loss, and hypersensitivity within the gland, resulting in inflammation, chalazion formation, and ocular surface inflammation.

Demodex mites show resistance to many treatments, but methods involving either topical tea tree oil or oral anti-parasitic agents have been effective in reducing signs of eyelid inflammation. Studies with oral ivermectin and topical tea tree oil have demonstrated eradication of Demodex mites and symptomatic improvement in subjects. The mechanism behind tea tree oil’s effectiveness likely involves clean-up of epidermal debris and its anti-inflammatory, antibacterial, and antifungal properties. Despite its efficiency, FDA-approved treatments for ocular demodicosis are still lacking.

One aspect of this invention is a topical formulation of ivermectin applied to the anterior eyelid, eyelashes, and meibomian gland, possibly with an applicator to allow precision dosages and simultaneous cleansing of the area.

Although ivermectin is effective, systemic side effects from oral administration present significant drawbacks. A topical ivermectin formulation would localize treatment, minimize systemic exposure, and reduce risks of side effects and drug interactions. This localized treatment also ensures high antibiotic concentration at the infestation site, potentially reducing local resistance.

Delivering ivermectin directly to the eyelid and eyelashes minimizes systemic exposure, reducing the risk of drug-related side effects and interactions. It also ensures higher localized concentrations of the antiparasitic agent, thereby decreasing the risk of local resistance. Moreover, the applicator aids in cleaning keratin debris while treating the infestation.

Research points out that topical ivermectin can significantly improve treatment for ocular demodex infestations by administering directly to the conjunctiva and cornea, avoiding unnecessary exposure of the eye to high levels of the drug.

Using a precision applicator to target ivermectin directly to infested areas maximizes its efficacy and minimizes exposure. The solid amorphous dispersion formulation, combined with a particle size distribution below 4μm, enhances penetration to the site of infestation without causing mechanical irritation.

Ivermectin amorphous solid dispersions studied include: (a) Ivermectin-loaded microparticles for parenteral sustained release: in vitro characterization and effect of some formulation variables (J Microencapsul. 2010; 27(7): 609-17); (b) Sustained-release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: in vitro and in vivo evaluation (Drug Deliv., 2017; 24(1): 622-631); and (c) WO2016016665A1 where dispersions are prepared by co-precipitation in a microfluidizator/microreactor with a stabilizing agent.

Summary of the Invention

The invention broadly focuses on treating ophthalmic pathologies resulting from parasitic infestations in the eyelash, eyelid, or surrounding cutaneous tissue by topically applying a formulation containing a solution, semi-solid, suspension, or gel comprising particles of solid dispersions of ivermectin and a polymer.

The method may include formulations with particles having a D90 particle size below 10 microns, ideally between 800 nm and 4 microns. The polymer could be an extended or immediate release polymer, either natural or synthetic biodegradable types.

Natural biodegradable polymers may include polysaccharides, cyclodextrin, chitosan, alginate and derivatives, sodium hyaluronate, xanthan gum, gellan gum, starch, proteins, albumin, gelatin, fibrins, and collagen.

Synthetic biodegradable polymers comprise polyesters, polyethers, poly(anhydrides), poly(urethanes), poly(alkyl cyanoacrylates) (PACA), poly(orthoesters), cellulose and derivatives, poly(N-vinylpyrrolidones) (PVP), poly(vinyl alcohols) (PVA), and poly(acrylamides).

The polyesters may include poly(glycolic acid) (PLA), poly(l-lactic acid) (PLA), and poly(lactide-co-glycolide) (PLGA), the polyether may include poly(ethylene glycol) and poly(propylene glycol), and cellulose and derivatives may include hydroxyl propyl methyl cellulose, hydroxy ethyl cellulose, hydroxy ethyl methyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, cellulose acetate, cellulose acetate phthalate, methylcellulose, ethyl cellulose, carboxymethylcellulose, microcrystalline cellulose, and silicified microcrystalline cellulose.

Particles of ivermectin and polymer may include amorphous or crystalline ivermectin or a co-crystal involving ivermectin.

The formulation could also include a liquid or semi-solid carrier, such as a polymeric gelling agent and other excipients, to stabilize the dispersion without dissolving ivermectin and polymer particles. Excipients might include mineral oil, poloxamer 407, carbomer, methylcellulose, and sodium carboxymethyl cellulose.

The formulation might have a viscosity between about 30,000 cP and 100,000 cP, preferably within 30,000 to 90,000 cP.

When applying, care should be taken to avoid contact with the conjunctiva or cornea.

In another aspect, the invention includes a solid dispersion composed essentially of ivermectin and a polymer. This protects ivermectin from terminal sterilization processes (gamma irradiation, heat sterilization, e-beam irradiation), increases the drug's bioavailability, and regulates the release of ivermectin. The formulation can contain ivermectin in amorphous or crystalline form with particle sizes below 10 microns, ideally within 800 nm to 4 microns. The ratio of ivermectin to polymer ranges from about 10:1 to about 1:10, preferably 1:3 to 4:1.

Potential features of the solid dispersion include PVP VA-64 at a ratio of 1:1 or PVP K-30 at a 1:3 ratio. The polymer HPMC-E4M might be present at a 4:1 ratio.

The particles in the solid dispersion could also contain mixed ratios, with one population having a faster ivermectin release than another.

Particle size and composition can explicitly vary between different polymer types to achieve desired release rates.

Another formulation aspect involves using a gel, ointment, or solution containing a solid dispersion suspended in oil and a polymeric hydrocarbon gelling agent. This formulation aims for a viscosity between 30,000 and 100,000 cP, ideally 40,000 to 90,000 cP.

Embodiments might feature polymeric hydrocarbon gels, poloxamer 407, carbomer, methylcellulose, and sodium carboxymethyl cellulose. The hydrocarbon gels may include oils and gelling polymers.

The pharmaceutical formulation could release ivermectin over twelve hours using standard dissolution testing methods.

It might also be part of a kit comprising the formulation and a precision applicator.

Additionally, the invention includes a method of killing Demodex by applying the pharmaceutical formulation to the eyelash, eyelid, or surrounding cutaneous tissue, ensuring contact with the conjunctiva or cornea is avoided.

Description of the Drawings

Figure 1: Scanning electron microscope image of ASD (ivermectin and PVP-VA-64) - Example 1.

Figure 2: Scanning electron microscope image of ASD (ivermectin and PVP K-30) - Example 2.

Figure 3: Scanning electron microscope image of ASD (ivermectin and HPMC E4M) - Example 3.

Figure 4: Thermogram of ASD (ivermectin and PVP-VA-64) - Example 1.

Figure 5: Thermogram of ASD (ivermectin and PVP K-30) - Example 2.

Figure 6: Thermogram of ASD (ivermectin and HPMC E4M) - Example 3.

Figure 7: Diffractogram of ASD (ivermectin and PVP-VA-64) - Example 1.

Figure 8: Diffractogram of ASD (ivermectin and PVP K-30) - Example 2.

Figure 9: Diffractogram of ASD (ivermectin and HPMC E4M) - Example 3.

Figure 10: Raman spectrum for ivermectin, PVP VA-64, and mixtures of both.

Figure 11: Raman spectrum for ivermectin, PVP K-30, and mixtures of both.

Figure 12: XRPD diffractogram of ASD (ivermectin and PVP-VA-64).

Figure 13: XRPD diffractogram of ASD (ivermectin and PVP K-30).

Figure 14: XRPD diffractogram of ASD (ivermectin and HPMC E4M).

Figure 15: Results of solubility trials on artificial sebum.

Description of the Invention

The invention includes a solid dispersion of avermectin, like ivermectin, or milbemycin and a polymer. Dispersions may include amorphous or crystalline ivermectin.

The method for producing ASD with ivermectin and a polymer involves spray drying a solution of these two components dissolved in a solvent such as ethanol or methanol. The polymer can prevent the ivermectin from degrading during sterilization and prolonged storage.

Polymers for ASD may be biodegradable, natural or synthetic. Examples include polysaccharides like cyclodextrin and chitosan, or synthetic types such as polyesters like poly(glycolic acid) and poly(lactic acid).

Below are the structures for poly(vinylpyrrolidone) (PVP) and hydroxypropyl methylcellulose (HPMC).

The solvent can be water, organic, or a mixture. The spray drying process involves preparing a solution, spraying via a nozzle, drying with nitrogen, and collecting the particles. Parameters such as drying temperature and gas flow rate can vary based on equipment and desired particle size.

1. Prepare the spray solution with ivermectin and polymer in solvent

2. Form solid dispersion by spraying through a nozzle

3. Collect solid dispersion particles

Adjustments to parameters like nozzle type, atomization gas flow, and solution flow rate allow obtaining consistent ASD.

Example: Nozzle orifice (0.7mm), drying temperature range (20°C to 100°C), and drying gas flow rate (20 kg/h to 120 kg/h).

Small scale spray dryers produce ASD with a d90 particle size less than 10 micrometers, commonly under 4 micrometers, ideal for ophthalmic use without causing irritation.

The ASD is incorporated into a gel vehicle to increase bioavailability, stability, and control release of the ivermectin.

Sterilization methods include Gamma irradiation, e-beam, or heat. The polymer prevents ivermectin degradation. The sterile ASD formulation can be applied with an applicator directly to the infestation site.

Examples of ASD formulations with different polymers are summarized in Table 1.

First, prepare a feed solution. In examples, ivermectin was dissolved in ethanol or an ethanol/water mixture.

Following ivermectin dissolution, polymer is added. Example 1: PVP VA-64 (1:1 ratio). Example 2: PVP K-30 (1:3). Example 3: HPMC-E4M (4:1).

Table 1: Feed Solution Composition Summary

Spray drying forms the ASD. Table 2 details operating conditions for the spray dryer used.

Characterizations of the ASDs (Examples 1-3) include Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Laser diffraction, X-Ray Powder Diffraction (XRPD), Raman Spectroscopy, and High Performance Liquid Chromatography (HPLC).

Polymer use in ASD protects ivermectin during sterilization. ASDs were tested with Gamma irradiation at 25 kGy for 22 hours. XRPD and HPLC confirmed the stabilization and integrity of ivermectin.

Figures 12-14 illustrate ASD remaining amorphous after 1 month post-irradiation, confirming the form’s stability for medicinal use.

Table 3 shows HPLC results indicating polymer protection during Gamma irradiation, with PVP K-