Patent Application
20230355898
The present invention relates to nebulized anti-viral medications and nebulizers for delivering medication, and more particularly disposable nebulizers having onboard compressed gas to aerosolize the medication and to provide continuously variable droplet size of the medications.
A nebulizer is a drug delivery device that is used to deliver medication in the form of an aerosolized mist into the lungs of a patient. Nebulizers use oxygen, compressed air, ultrasonic power, and the like to break up solutions and suspensions into small aerosol droplets that are inhaled from the mouthpiece of the device. Nebulizers are commonly used for the treatment of respiratory diseases, such as asthma, cystic fibrosis, and COPD. Due to the Covid-19 pandemic, there is increased interest in and need for improvements to nebulizers.
The most commonly used nebulizers are jet nebulizers. Jet nebulizers are connected by tubing to a supply of a propellant, such as compressed gas, such as air or oxygen. Upon release into the nebulizer, the compressed gas flows at high velocity through a liquid medicine to turn it into an aerosol that is inhaled by the patient.
Conventional nebulizers, while effective in delivering medical treatment to the lungs, suffer from drawbacks. A nebulizer is expensive. Nebulizers are also bulky and are generally used at a single location, such as in a hospital room or a home. While some nebulizers are smaller and can be carried by hand, the units are not suitable for convenient everyday use or for distribution to remote areas. It would be advantageous to have a device that matches the functionality of a conventional nebulizer, but which can be carried in a pocket, a purse, or the like.
Conventional nebulizers operate from 13 psi all the way up to 50 psi. A jet nebulizer with a lower flow or pressure will increase particle size and a higher flow or pressure will decrease particle size. Therefore, using higher air flow rate in nebulizer therapy could decrease the amount of treatment time needed to deliver the set amount of medication as well as a decrease in particle size.
Aerosolized drugs can also be delivered by hand-held devices known as metered dose inhalers. Metered dose inhalers are typically used to deliver multiple metered doses on an as-needed basis, such as for asthma. Metered dose inhalers operate differently from the present invention.
Potential pulmonary delivery of antiviral drugs is mentioned in the art. Pulmonary delivery of hydroxychloroquine has been described in US Pub 2008/0138397 A1 to Schuster et al., which describes the use of a sustained release formulation of hydroxychloroquine that minimizes the bitter or otherwise unpleasant taste of a drug or its potential to stimulate the cough reflex when administered by the pulmonary/inhalation route. A liposomal formulation of hydroxychloroquine is specified. Liposomal formulations are sensitive to shear and may be compromised by the process of aerosolization required for the targeted delivery. U.S. Pat. No. 5,384,128 to Meezan, et al. generally discloses increasing the permeability of epithelial cells to chloride ion as means of treating cystic fibrosis.
Despite advances in the art, there remains a desire and a need to improve nebulizers and the bioavailability of drugs administered at the respiratory tract of an animal/human.
It is an object of the inventions to provide disposable nebulizers.
It is an object of the inventions to provide to disposable nebulizers that can be pre-loaded with medicine.
Another object of the inventions is to provide disposable nebulizers that are configured for one-time use by individual users prior to disposal.
The foregoing objectives are achieved by providing a disposable nebulizer having the features described herein.
According to one approach, a nebulizer is provided suitable for medication delivery to the lungs, having a compressed air chamber in communication with a medication chamber, the communication sealed by a spring valve in a rested state, the spring valve being openable in an actuated state, a nebulizer chamber in communication with the medication chamber, the nebulizer chamber having a pressure release orifice, a facemask integral or in direct communication with the nebulizer chamber, wherein the nebulizer chamber is configured to deliver a stream the nebulized particle stream to the facemask, wherein the compressed air chamber is configured to have the volume and pressure of air needed to nebulize the medication through the pressure release orifice, wherein the nebulizer chamber has a continuously variable nebulizing pressure feed at the pressure release orifice; and wherein the spring valve is released by a pair of levers that when actuated, force the medication chamber and the gas chamber together to open the spring valve.
In one approach, the continuously variable nebulizing pressure feed has a retractable and extendable needle to retract and extend into the pressure release orifice.
The present nebulizer can have the retractable needle attached to a threaded shaft disposed within a threaded bore, which is rotatable by a control knob to retract and extend into the pressure release orifice. The nebulizer chamber can be configured to produce a nebulized particle stream in the range of 1-10 μm.
In one approach, the medication can be an antiviral with a carrier, which is nebulizable to a particle stream in the range of 3-5 μm.
The nebulizer can be configured so that the force required to open the spring valve to an actuated state is less than 3 nM of force.
The nebulizer can be configured so that the actuation levers remain aligned along its travel path by a guide track on one of the levers and a paul, which is guided within the track, on the other lever and that the compressed air chamber is configured to hold up to 120 PSI of air, preferably in the range of 20-60 PSI.
The nebulizer has a pressure release orifice and can be configured to produce aerosolized fluid of varying droplet/particle sizes ranging from 1-10 micrometers in diameter, preferably 3-5 micrometers. The pressure release orifice can be 0.35-2.0 mm in diameter.
Accordingly, to advance at least the aforementioned deficiencies in the art, described herein are compositions and methods related to site-specific delivery of a pharmaceutically active compound to the respiratory tract of an animal/human, and in particular compositions and methods related to delivery of an approved pharmaceutically active compound (“drug”) with antiviral activity to a viral infection site of the respiratory tract which synergistically maximizes interaction of the drug with extracellular virus particles, inhibits/reduces viral epithelial cell entry through potential interaction with sites of extracellular viral binding to epithelial cell membranes, and potentiates drug partitioning into epithelial cells.
According to one approach, an inhalation formulation is provided having an aerosolizable formulation (such as an aqueous aerosolizable formulation) and may have a pharmaceutically active anti-viral compound present as a neutral compound (free acid or free base, or water insoluble salt or ion pair); an excipient capable of forming a liquid complex with the pharmaceutically active anti-viral compound; and a polymeric surfactant suitable for pulmonary administration. In one approach the pharmaceutically active anti-viral compound is an aminoquinoline. In another approach, the pharmaceutically active anti-viral compound is at least one of chloroquine (CQ), hydroxychloroquine (HCQ) and amodiaquine.
The excipient forming a liquid complex with the pharmaceutically active anti-viral compound can be present in a 0.2:1 to a 5:1 excipient to drug mass ratio. The excipient forming a liquid complex with the pharmaceutically active anti-viral compound may be present in a 1:1 excipient to drug mass ratio. The excipient may be propylene glycol, USP.
The polymeric surfactant suitable for administration to the respiratory tract may be capable of producing a micellar solution with the drug liquid complex at mass ratios to the drug liquid complex of 8:1 or lower.
The polymeric surfactant suitable for administration to the respiratory tract is capable of producing a micellar solution with the drug liquid complex at mass ratios to the drug liquid complex of 4:1. The polymeric surfactant suitable for administration to the respiratory tract is capable of producing a micellar solution with the drug liquid complex is tocopheryl polyglycerol succinate. The aerosolized formulation may comprise micelle sizes less than 100 nm. According to another approach aerosolized aqueous formulation may comprise micelle sizes less than 50 nm.
The aerosolized droplets may be less than 5 μm and lipoidal particles containing approved drugs are less than 100 nm.
The pharmaceutically active anti-viral compound may be a non-charged chloroquine in a 1:1 ratio with the excipient that is lipophilic and liquid at body temperature.
In other various embodiments, the eutectic excipient may be USP propylene glycol; the formulation may be an isotonic micellar solution; the aerosolized droplets may be 1-10 μm, 1-5 μm, 5-10 μm, 3-5 μm; the formulation eutectic excipient has a lower melting point than the drug.
In another approach, an aminoquinoline eutectic formulation is provided having the drug free base, a physiologically compatible eutectic excipient, in a 1:1 mass ratio, that is liquid at body, and/or ambient temperature, a polymeric surfactant suitable for administration to the respiratory tract of an animal/human that is capable of producing a micellar solution of the aminoquinoline eutectic system at surfactant:eutectic system mass ratio of 4:1 or lower and having micelle sizes less than 100 nm and ideally less than 50 nm, and an isotonic aqueous vehicle at physiological pH. In this approach, the excipient is hydrophilic and selected from the group of: tetraethylene glycol, propylene glycol USP, 1,3-propanediol, 1,3-butylene glycol, pentylene glycol, and combinations thereof. The polymeric surfactant may be D-a-tocopheryl polyethylene glycol 1000 succinate NF (TPGS). The aerosolizable formulation may have a viscosity of +/−0.10 cP of 1.92 cP. The aerosolizable formulation may be configured for presence of the antiviral's active ingredients in optimized quality and minimal quantity in vivo for a duration in those regions of 1 day to 30 days.
The aerosolizable formulations herein can be shelf stable at ambient temperatures between 60 and 75 degrees Fahrenheit (15 and 25 degrees Celsius) for up to 6 months.
A nebulizer is provided to aerosolize the present formulations having a mechanism to continuously adjust aerosolized droplets size in the range of 1-10 μm.
Other features will become more apparent to persons having ordinary skill in the art to which the assemblies pertain and from the following description and claims. While the features described herein may be susceptible to various modifications and alternative forms, specific embodiments thereof are herein described in detail. It should be understood, however, that the detailed description thereto are not intended to be limiting to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the subject matter as defined by at least the appended claims.
Notwithstanding any other forms which may fall within the scope of the present invention, preferred embodiments of the disclosure will now be described, by way of example only, with reference to the accompanying drawings in which:
While the features described herein may be susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the drawings and detailed description thereto are not intended to be limiting to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the subject matter as defined by at least the appended claims.
In the following detailed description of the preferred embodiments, reference is made to the accompanying drawings which form a part hereof, and in which are shown by way of illustration specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention.
A jet apparatus 32 may be provided above and in communication with the pressure relief valve 44. The jet apparatus is configured to aerosolize the medications when they are released from the medication storage chamber 28 into the nebulization chamber 30. When the preloaded delivery member 40 (shown as a spring as an example) is released by a user, using the lock lever/sear 42 for example, the air 46 in the air chamber 36 is compressed and evacuated through the pressure relief valve 44, which opens at a certain pressure. The compressed air 46 is further compressed by the jet apparatus 32 prior to being expelled into the nebulizer chamber 30, where it aerosolizes or nebulizes the medicine 23 to form the aerosolized/medication 27.
In the embodiment of
A handle, such as the side handle 34 shown in
In embodiments, the disposable nebulizer 20 is a single use nebulizer unit that does not require a power source. In the embodiment of
In the embodiment of
It is theorized that the use of higher air flow will improve the efficacy of the device for nebulizer therapy. Using higher air flow rate may decrease the amount of treatment time needed to deliver the set amount of medication as well as a decrease in particle size.
The circumference and/or length of the air chamber can be adjusted to allow the necessary ambient air pressure volume needed before compression begins.
The spring 40 pressure and the jet apparatus/regulator 32 can be adjusted for specific PSI requirements.
The flow line diameter after the pressure relief value 44 can be adjusted to achieve the required CFM (cubic feet of air moved).
The piston assembly can be substituted with a pre-charged pneumatic cylinder connected to the pressure relief valve 44 or the cylinder itself can be made of sufficient material to allow it to serve as its own pre-charged pneumatic chamber which would discharge through the pressure relief value.
The storage chamber 28 for the pre-filled medication 23 can be outfitted with a mechanical fill slot designed for high speed or automated filling machines.
The storage chamber 28 can alternatively be outfitted with a cap intended to allow manual or mechanical filling with the cap installed after the storage chamber has been filled.
The onboard compressed air provides the force required to aerosolize a suitable fluid, including fluid-based pharmaceuticals, thus eliminating the need for user access to electrical or other power sources. The adjustable nozzle diameter allows the nebulizer to produce aerosolized fluid of varying droplet/particle sizes, ranging from, for example, 1-10 micrometers in diameter (preferably about 3-5 micrometers, and most preferred at about 3 micrometers).
These two features can allow the nebulizer device to achieve longer treatment durations, by increasing the pressure in the compressed air chamber and/or by decreasing the droplet size by decreasing the nozzle diameter using the adjustable nozzle. The targeted delivering of more precise size droplets is advantageous to target and treat specific areas of tissues within the respiratory tract of a user. For example, this feature allows medication to target the upper or lower respiratory tract with custom dosing levels that can be specified based on the stage of exposure Additionally, the lever geometry of the actuation arms minimizes the force required for actuation to less than 3 nM of force; a force that has been shown to be achievable by the 95th percentile of human subjects.
This embodiment may be manufactured using additive manufacturing methodologies such as 3D printing and crimping technologies. Limiting the complexity to additive materials and a small number of generally available valve components reduces supply chain vulnerabilities. Ease of manufacture of the present embodiments can be realized because: it can be 90 percent 3D printed, design changes are easier than injection molded devices, uniform materials are used, low work op count (about 3 work operations), low effort to integrate with other equipment, shipping and drug design (modify jet for different fluid specifications), easy modeling and design advancement, and easy to prepackage.
The device uses a small number of components/parts, which renders the manufacture and sourcing less vulnerable to disruption and has less failure modes. There are reduced key components in the present embodiment compared to 50 or more parts in nebulizers known in the art. Since most of the components of the present embodiment can be 3D printed, this provides 2 critical pandemic solutions: (a) the design can be modified and improved with changes to a software model and easily distributed, thus allowing access to a vast pool of intellectual capital worldwide and rapid sharing and testing of prototypes, and (b) the potential to utilize a vast network of micro-manufacturing facilities worldwide. This is a significant step forward in eliminating supply chain disruptions when it is critical to produce and deliver lifesaving medications in a timely manner anywhere in the world. Another advantage is that the present embodiments are small in size from the perspective of manufacture, logistics and useability.
In this embodiment, no external power is needed (e.g., neither electrical grid connectivity nor battery are required) and no fuels delivered to a site of use. This embodiment is propelled only by elastic or potential energy (spring piston or pre-charged pneumatic compression). It therefore does not require external delivery of fuel or electricity, thus not dependent on variations in the local specification for electoral current or its availability. This allows simple administration to a common design, which can access more points of manufacturing and provide a more rapid response chain for the ultimate delivery of potentially life-saving medications anywhere in the world.
Thus, the present embodiment provides a disposable—one-time use—unit dose delivery system. The device provides a valuable clinical application and a key advancement in allowing the preferred results of direct supply to the pulmonary tract of micronized particles via nebulization, while avoiding the risk of traditional nebulizers. For example, there is no recirculated air risk. The unit can be used by the patient without requiring close-in assistance or exposure to exhaled droplets. The unit is disposable and poses no need to clean between applications. In total this provides both key solutions to enable nebulized delivery of medications and a more sanitary environment to help reduce the transmission and spread of respiratory infections during and after treatment. The present embodiments ensure that ambient/‘fresh’ air can be drawn into the atomized medication flued on inhale and that ‘used’ or ‘exhaust’ air can escape from the mask.
The functional and ergonomic design of the present embodiments is engineered to use readily available medical grade polymers with most of the parts made from a single material. This helps ensure drug efficacy and enhanced sterility for extended periods of time. It also promotes supply chain integrity by avoiding multiple materials sourcing for final manufacture and assembly.
The present embodiments are easy to use in the absence of any assistance thus reducing exposing others to infection. The device is reliable since no independent of energy source is needed resulting in less failure modes.
The present embodiments use “green” and socio-economically positive technology. By-products of manufacturing process are fully re-useable; power independence means reduction of producing toxic materials associated with compressor or batteries; manufacturing power and pollution footprint minimum; and an ability to penetrate into underserved markets with limited resources.
As shown in the figures, a portable nebulizer 50 of the present embodiments has a facemask 52 having an aerosol chamber 54 sized to mount to a face mask/housing interface 72. As a guide, alignment arrows 111 (
Medication chamber 79 and compressed air/gas chamber 98 are connected by a lower medication chamber compressed air chamber interface 85. Medication chamber 79 is held in place not only by interface 85, but also by the nebulizer frame 76 having living hinge/frame interlaces 74 and a latch arm lock 70 attached to the living hinge/frame interlaces 74 and a stop 78. Interface 85 has a spring-loaded valve 118 having a hollow stem 102 to insert to a medication chamber 79 bore 126 configured to receive stem 102. Valve spring 118 is tensioned to seal compressed air chamber 98 in its rested state and to release the compressed air in its actuated state. As shown, medication chamber 79 has a compressed air channel 86 to receive the compressed air in the actuated state from stem 102. Air channel 86 may be configured to extend above the medication 104 already present in medication chamber 79, though not required. As air is forced into the medication chamber 79 in the activated state, pressure is placed on medication 104 to force it through aerosol channel 88 and into the nebulizer. In one embodiment, 3 ml of medication can be placed in a medication chamber 79 having a volume of 5 ml. The compressed air chamber 98 is configured per application to deliver enough pressure to deliver the medication through the pressure release orifice.
Actuation arms 92 are also mounted as a living hinge at hinge points 99 and 100. Hinge point 100 is mounted to nebulizer frame 76 and hinge 99 is mounted to a living hinge/nebulizer frame interface 56. Pivot points 99 and 100 are configured to allow activation of the release of air from the air chamber 98 using less than 3 nM of force. As shown, in the at rest state, actuation arms 92 extend away from the device. To keep the activation arms from extending too far or to move out of alignment when activating the air chamber, an actuation arm lock 6 may be provided having wings 96 and 97 held in place by a paul 110 guided along a predetermined length of travel by track 116. Thus, the present embodiments ensure that the ‘wings’ 96 and 97 on the bottom of the two nebulizer handles 92 remain aligned along the path of actuation motion and that they not be able to disengage due to paul 110 guided in a track 116 (
As the actuation arms 92 are squeezed to rotate them toward the device the compressed air chamber 98 and nebulizer frame 76 are forced against the living hinge/nebulizer frame interface 56. Once they meet, the user needs to add the additional force needed to continue travel of the actuation arms 92 to squeeze the interface of the air chamber 98 and nebulizer frame 76 forcing spring valve 118 downward, thus opening valve 118 and forcing air into the medication chamber 79 (See,
Compressed air chamber 98 may in some embodiments also be charged (or even recharged) using an access port 106 (See
Accordingly, a bicycle pump or other available compressed air generator could be used to charge the chamber. Compressed air chamber 98 is also sized to allow for the desired amount pressure to force the desired amount of medication 104 through the jet housing. As shown in
To provide nebulization, disposed within nebulizer housing orifice 94 is a retractable nebulizer jet needle 62. Droplet size control variation ‘knob’ 58 holds the nebulizer jet needle 62 and is threaded 60 into the nebulizer housing 66 causing the forward and backward motion of the nebulizer jet needle 62 in the housing (See,
Presented herein are compositions and methods related to site-specific delivery of a pharmaceutically active compound to the respiratory tract of an animal/human, and in particular compositions and methods related to delivery of an approved pharmaceutically active compound (“drug”) with antiviral activity to a viral infection site of the respiratory tract which synergistically maximizes interaction of the drug with extracellular virus particles, inhibits/reduces viral epithelial cell entry through potential interaction with sites of extracellular viral binding to epithelial cell membranes, and potentiates drug partitioning into epithelial cells.
For clarity, the following terms are defined as they apply herein:
To assist in the understanding of the present embodiments, the structure and physical/chemical (P/C) and pharmacokinetic (PK) properties of chloroquine (CQ) and its two analogs, hydroxychloroquine (HCQ) and amodiaquine (ADQ), as well as in vitro data of these compounds in cellular models of SARS CoV-2 infection, efficacy data in animal models of SARS CoV-2 infection, and the results of human clinical trials in COVID-19 patients are provided herein. The in vivo evaluations have all involved systemic drug administration. An analysis of the potential impact of drug P/C properties and drug PK properties upon the variable results of the in vitro, animal, and clinical studies is also provided. Mechanisms of the ability of these drugs to inhibit SARS CoV-2 in vitro, which are proposed in the literature, are also provided along with alternate drug administration studies suggested in the literature and registered in the US government's Clinical Trials website to improve the clinical efficacy of these drugs in COVID-19 patients.
Drug Properties
CQ, HCQ, and ADQ are 4-aminoquinolones somewhat related to the natural compound quinine and are traditionally used to prevent and treat malaria. These drugs are also used to treat liver infection caused by protozoa (extraintestinal amebiasis). Side effects may include heart rhythm problems such as QT prolongation, ventricular fibrillation, ventricular tachycardia, (Mayo Clinic Website). HCQ is considered to produce about 40% of the total side effects associated with CQ. All three drugs were developed in the 1930's and 1940's and CQ and HCQ are currently approved as prescription drug products for peroral administration in the U.S. AMQ was withdrawn from use in the United States due to rare occurrence of agranulocytosis and liver damage with high doses or prolonged treatment (referenced in Si, 2020).
Typical malaria treatment doses are 1000 mg (CQ) or 800 mg (HCQ, ADQ) on day 1, followed by 500 mg (CQ) or 400 mg (HCQ, ADQ) at 6, 24, and 36 hr after the first dose. (Mayo Clinic Website) All three drugs are administered perorally. The structures of CQ, HCQ, and ADQ as well as the active metabolite of the latter, desethylamodiaquine (DEAQ), are shown in
The probable sites of the molecule associated with efficacy (the conjugated ring structure and tertiary amine structure at the ends of the molecule) are essentially the same—HCQ has a hydroxy group on one of the ethyl groups of tertiary amine group. As shown in Table 1, this substitution slightly increases the hydrophilicity of HCQ relative to CQ. More importantly, ADQ differs from CQ and HCQ by having an aromatic ring containing a hydroxyl group between the secondary and tertiary amine structures instead of an isopentyl aliphatic structure. This difference appears to be responsible for the greatly reduced lipophilicity (as indicated by the log P values) and increased water solubility of ADQ relative to CQ and HCQ.
Although structures and properties of the free bases are shown above, CQ is primarily administered as the diphosphate salt and HCQ and ADQ as the dichloride salts. The free bases of CQ and HCQ are extremely lipophilic with log P values of 4.6 and 3.9 and exhibit very low water solubilities compared to the ADQ free base. Since the log P values of CQ and HCQ are well above the optimal values for peroral absorption of 1-3, it is likely that these compounds exhibit poor partitioning into and diffusion through tissue. Further, the very high volumes of distribution of CQ and HCQ indicates extensive binding and distribution to lipoidal tissues. Hence, these properties would tend to predict that ADQ will partition into and through multicellular tissues much more readily than CQ and HCQ.
Efficacy of CQ, HCQ, and ADQ in Preclinical Models of SARS-CoV-2 Infection and Human Clinical Studies.
CQ, HCQ, and ADQ have all exhibited good activity against SARS-CoV-2 infection in in vitro studies using either Huh-7 cells which are derived from a human liver tumor (Si, 2020) and Vero-6 cells derived kidney tissue of an African green monkey. (Osada, 2014). Huh-7 cells only express low levels of ACE2 and they do not express TMPRSS2, (Si, 2020) both of which are involved in SARS-CoV-2 cell infection. Verc-6 cells express both receptors. Table 2 summarizes the results of reported evaluations of CQ, HCQ, and AMQ in these in vitro cell models of SARS-Cov-2 infection.
The Huh-7 studies reported by Si, et al. employed SARS-CoV-2 pseudoparticulates (pp) instead of SARS-CoV-2 virus and therefore could only evaluate inhibition of viral entry into these cells. (Si, 2020) The studies employing Vero-6 used SARS-CoV-2 virus strains and evaluated other measures of infection, primarily virus titer in the infected cells. Various modes of drug presentation were used including pre-treatment with drug prior to and often subsequent to viral infection, treatment after viral infection, and treatment concurrent with viral infection.
Nonetheless, the results presented in Table 2 indicate that the three drugs and active metabolite ADQ all exhibit very good antiviral activity for SARS-CoV-2 across the several protocols employed in these cell culture models. One aspect of the latter that should be noted is that the bioavailability of the drugs at the site of pharmacological activity, considered to be the cellular surfaces and interior is high as it depends only upon the relative abilities of the individual drugs to adsorb to the cellular surface, interact with extracellular virus, and partition into the intracellular structures under conditions of static exposure, i.e., in the cell culture media.
In addition to reporting cell culture results, Si, et al. describe the development of a three-dimensional in vitro lung tissue mimic structure using microfluidic culture technology termed Lung Airway Chips (LAC). (Si, 2020) The LAC (
Si, et al. used the LAC model to evaluate the ability of pharmaceutical salts of CQ (phosphate), HCQ (sulfate), and ADQ (hydrochloride) to inhibit the entry of SARS-CoV-2 pseudoparticulates (administered via airway channel). The evaluation protocol consisted of perfusion of the fluid channel of the LAC with drug at human blood maximum concentrations (clinically used doses) for 24 hour at a assumed flow rate of 60 μL/hr (actual flow rate not reported, but this is the flow rate employed in previous studies using the LAC) along with introduction of 30 μL of the drug at the same concentration statically (volume not reported, but this the volume used for subsequent introduction of drug and SARS-CoV-2pp). After 24 hr, SARS-CoV-2pp was introduced into the LAC airway channel in 30 μL medium containing the drug (same concentrations as in fluid channel and previous treatment of airway channel) with static incubation for 48 hour concurrent with continued perfusion of drug through the fluid channel. Hence, drug was available at the air interface of the epithelial cells along with the SARS-CoV-2pp as well as at the surfaces on the porous membrane in contact with the drug containing media in the fluid channel. Despite this “double treatment”, only ADQ hydrochloride inhibited SARS-CoV-2pp entry into LAC epithelial cells as measured by qPCR quantitation of viral mRNA in the epithelial cells. The authors then demonstrated that ADQ hydrochloride was able to reduce SARS-CoV-2 viral load in a COVID-19 hamster model as measured by RT-qPCR of the viral N transcript after Intraperitoneal (IP) administration (systemic) whereas HCQ sulfate was ineffective thereby indicating that the LAC model was predictive of in vivo performance of aminoquinoline drugs although drug administration in the LAC model involved presentation at both epithelial cell interfaces which is not representative of systemic delivery. However, it should be noted that the LAC model was limited to evaluation of drug effects upon viral cell entry whereas the in vivo hamster model would have included this antiviral mechanism of activity as well as any other putative antiviral mechanisms of activity.
One probable explanation for the differing effects of CQ/HCQ and ADQ in the cell culture efficacy models and the LAC lies in the physical/chemical properties of these compounds, specifically pertaining to the Log P values and water solubilities of the free base species of these drugs, and the impact of the latter upon drug bioavailability at the surface of and within the epithelial cells in the LAC. The pH partition theory predicts that only the non-ionized free base of each of these drugs will partition into the epithelial cells. The free bases of CQ and HCQ are extremely lipophilic with log P values of 4.6 and 3.9 and exhibit very low water solubilities compared to the free base of ADQ. Since the log P values of the free bases of CQ and HCQ are well above the optimal values for peroral absorption of 1-3 and have very low water solubilities, it is likely that these compounds will exhibit poor partitioning into and diffusion through tissue. Hence, these properties would tend to predict that ADQ with a free base Log P of 2.6 and a relatively high-water solubility will partition into cells and diffuse through multicellular tissues much more readily than CQ and HCQ. Since all three of the above aminoquinolines exhibit similar in vitro cell culture antiviral activity, the lack of efficacy of CQ phosphate and HCQ sulfate in the three-dimensional LAC in vitro model and animal models is almost certainly due to low bioavailability of CQ and HCQ administered as pharmaceutical salts at the site of viral infection relative to AQ similarly administered.
No reports of preclinical animal studies of the effects of CQ against SARS-CoV-2 infection are presently known. One study of ADQ hydrochloride in hamsters, three studies of HCQ sulfate in hamsters, and one study of HCQ sulfate in Rhesus Macaque monkeys have been reported and are summarized in Table 3. In the one report involving ADQ hydrochloride evaluation it was found to be effective as a prophylactic treatment of 50 mg/kg administered subcutaneously (SC) QD in reducing SARS-CoV-2 infection from virus introduced either intranasally to hamsters or by transfection of healthy animals through association with nasally infected animals. However, HCQ sulfate was ineffective in similar prophylactic treatment protocols in both nasally infected hamsters and in hamsters infected by transfection at an IP dose of 50 mg/kg QD (600 mg/kg loading dose in the transfected protocol) in a study reported by Kapstein, et al. (Kapstein, 2020). HCQ sulfate was also ineffective in a study using a similar prophylactic protocol with HCQ IP doses of 50 mg/kg QD reported by Rosenke, et al. and also in a therapeutic protocol using IP doses of 50 mg/kg QD. Finally, HCQ sulfate was ineffective in both prophylactic and therapeutic protocols in Rhesus Macaque monkeys using peroral (PO) doses of 6 mg/kg QD.
Rosenke, et al. have also summarized clinical experience with HCQ for treatment of COVID-19, the disease associated with SARS-CoV-2 infection as follows: “HCQ has been promoted as a COVID-19 treatment option and became part of multiple large-scale clinical trials including one of four initial treatment options in the multinational WHO “Solidarity” clinical trial for COVID-19 (WHO, 2020). However, HCQ treatment does not come without risks as the 4-aminoquinolines are associated with multiple adverse effects such cutaneous adverse reactions, hepatic failure, and ventricular arrythmia; overdose is also difficult to treat (AHFS, 2020). The US FDA recently updated its guidance by waming against use of HCQ outside of the hospital setting because of the potential for serious adverse effects (US FDA, 2020). Further, “the WHO Solidarity study . . . ” has “been excluded HCQ arms due to a lack of evidence for therapeutic efficacy, and an increase level of adverse effects in COVID-19 patients (WHO, 2020).”
Analysis of Reported Efficacy Results of CQ, HCQ, and ADQ Preclinical Models of SARS-CoV-2 Infection and Human Clinical Studies
Therefore, despite a number of studies documenting the effectiveness of HCQ against SARS-CoV-2 infection in in vitro cell culture models, the drug has repeatedly failed in (1) an in vitro three-dimensional tissue model requiring partitioning of HCQ into epithelial cells to reach the presumed site(s) of pharmacological activity and in (2) preclinical animal models using systemic dosing (IP and PO) which requires circulatory biodistribution and tissue diffusion to reach the presumed site(s) of pharmacological activity in the lung. However, although the efficacy of ADQ in in vitro cell models of SARS-CoV-2 infection is similar to that of HCQ, this drug DID exhibit prophylactic efficacy against SARS-CoV-2 infection in hamsters at the same systemic dose of 50 mg/kg SC QD as used for HCQ sulfate dosing in hamster studies. This comparison clearly indicates that ADQ is more bioavailable at the putative sites of action in the in vitro three-dimensional tissue model and in vivo in animal models.
Kapstein, et al. also measured HCQ lung concentrations post-mortem in their hamster study and found that while the endosomal/lysosomal concentrations were quite high, the cytosolic and interstitial HCQ concentrations were well below the estimated EC50. The authors point out that:
CQ and HCQ have similar P/C, PK, and antiviral activity against SARS-CoV-2 in in vitro cell culture models and it would be expected that CQ would also be ineffective (as is HCQ) when administered systemically (e.g., through injection or peroral) in animal models, particularly given its lack of efficacy in an in vitro three-dimensional tissue model (LAC). Since another 4-aminoquinoline drug, ADQ, with differing P/C properties more favorable to drug tissue partitioning and diffusion and PK properties suggestive of less extensive binding to lipoidal tissue (adipocytes), but with similar in vitro SARS-CoV-2 antiviral activity does exhibit efficacy in an animal model, a reasonable conclusion is that CQ (and HCQ) has insufficient bioavailability at the putative site(s) at which it can affect SARS-CoV-2 infection and/or replication when administered systemically.
Proposed Mechanisms of Aminoquinoline Drugs SARS CoV-2 Antiviral Activity
CQ has been shown to exhibit in vitro antiviral activity against RNA viruses as diverse as rabies virus, poliovirus, HIV, hepatitis A virus, hepatitis C virus, influenza A and B viruses, influenza A H5N1 virus, Chikungunya virus, Dengue virus, Zika virus, Lassa virus, Hendra and Nipah viruses, Crimean-Congo hemorrhagic fever virus and Ebola virus, as well as various DNA viruses such as hepatitis B virus and herpes simplex virus. (reviewed in Devaux, 2020). Based upon the mechanisms of action of CQ against the above viruses, Devaux, et al. reviewed the modes of action of CQ that may be responsible for its demonstrated in vitro antiviral activity against SARS-CoV-2 in cell culture models. These may be summarized as follows: (Devaux, 2020)
These putative mechanisms of action of CQ against SARS-CoV-2 suggest that drug should be present in sufficiently effective amounts at the epithelial membranes of alveoli lung tissue to putatively affect SARS-CoV-2 binding to epithelial ACE and TMPRSS receptors and pH mediated epithelial membrane fusion for entry into the lung cells, and also at both epithelial and epithelial membranes to facilitate partitioning of the drug into the lung cells to exert effects intracellularly.
Present Embodiments for Aminoquinoline COVID-19 Treatment Strategy by Pulmonary Aminoquinoline Administration
Since CQ (or HCQ) is apparently not sufficiently bioavailable at the epithelial membranes of alveoli cells after systemic administration of their pharmaceutical salts (e.g., through injection, ingestion of peroral dosage forms, and the like) due to its P/C and PK properties, the present embodiments provide methods and compositions for pulmonary administration of CQ (or HCQ) free base. Pulmonary delivery of CQ (or HCQ) free base provides direct contact of administered drug free base with the alveoli epithelial membranes to permit activity against viral receptor binding and potential pH mediated viral—alveoli epithelial membrane fusion to reduce viral entry into alveoli cells. Drug free base concentrations in contact with the alveoli epithelial membrane resulting from successful pulmonary delivery are higher than those reaching the epithelial membrane from systemic administration and provide the potential for increased intracellular partitioning of the drug.
There are over 65 different approved drug products (twenty plus active ingredients) utilizing pulmonary delivery, (Labris, 2003) including many directly targeting lower respiratory infections. (Zhou, 2015) The latter include both nebulized liquid systems and dry powder systems with defined particle size distributions. Some articles have even generally proposed the use of pulmonary delivery with CQ and HCQ, albeit using the pharmaceutical salts thereof that are primarily used for peroral administration. (Fassihhi, 2020; Kimke, 2020; Kavanagh, 2020) The referenced articles describe potential use of nebulized aqueous solutions of HCQ disulfate or other water-soluble salt.
Reported human pulmonary administration HCQ sulfate include Phase I and Phase II trials to assay safety and efficacy in treatment of asthma (Kavanah, 2020) and a personal use study (Kimke, 2020).
Kimke, et al. described a personal use study as follows:
Inhalation was well tolerated without relevant side effects. The only observation was after 4 days the feeling of a transient bitter taste in the mouth which lasted 2-3 h after the inhalations.”
Kavanah, et al. include information from Phase I and Phase II clinical trials of nebulized hypertonic 100 mg/mL HCQ sulfate to assay safety and efficacy in treatment of asthma conducted for Adradigm Corporation in 2004 and 2006. Although the Phase II study did not meet its clinical endpoints for asthma, the two studies demonstrated that pulmonary doses of up to 20 mg HCQ sulfate QD are well tolerated with minimal side effects. (Kavanah, 2020)
The authors also note that HCQ sulfate (as well as CQ and other quinoline derivatives) has an extremely and unpleasant bitter taste and that Adradigm applied for a US patent (US20080138397A1, abandoned).
The authors of Fasshihi SC, Nabar NR, Fassihi R, Novel approach for low-dose pulmonary delivery of hydroxychloroquine in COVID-19, Br J Pharmacol 177:4997 (2020) propose dosing an aqueous solution of about 10-20 mg hydroxychloroquine sulfate (7.7-15.7 free base equivalent) QD to the lungs via nebulization of a volume of about 3-5 mL which translates to a range of about 0.4 to 5.2 mg/mL free base. This differs significantly from the present embodiments of, for example, 3-4 doses of 3 mL of a 1 mg/mL micellar solution of chloroquine (could be hydroxychloroquine) base (not salt) formulated to create a liquid lipoidal system that is subsequent solubilized into a micellar surfactant solution. Care is taken to not create conditions under which a salt of the active pharmaceutical compound is formed. It is also probable that 6 mL is an insufficient volume to cover the surface area of the lungs at a 2 um average particle size.
Second, hydroxychloroquine has three basic functional groups with pKa values of <4.0, 8.3 and 9.7, two of which would be protonated at pH 7.4. Hence, that hydroxychloroquine is neutral at physiological pH is therefore subject to challenge. Furthermore, as a neutral species in an aqueous physiological system, it may be able to freely diffuse in cells. However, this neglects to account for the extremely low water solubility of the neutral free base which is 0.026 mg/mL. If most of the drug proposed by the Fasshihi et al. dosing system would be altered from the protonated sulfate salt to the free base upon administration into the lung, the drug would precipitate and not be available for absorption.
The described technology herein involves use of a liposomal formulation of HCQ or a pharmaceutical salt thereof interchangeably and therefore does not teach the advantages of administration of the HCQ free base to improve drug bioavailability on the surface of and within the alveoli cells.
With regard to liposomal HCQ administration to lungs, Tai, et al. report a PK study conducted in Sprague-Dawley rats using intravenous (IV) and intratracheal (IT) instillation of HCQ sulfate with IT of a liposomal formulation of HCQ sulfate. (Tai, 2020) As shown in
A recent study on inhaled hydroxychloroquine showed doses of up to 4 mg/day of the drug was well-tolerated (Br J Pharmacol. 2020; 177:4997-4998., Letter to the Editor) (https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.15167). Two other current clinical studies involving pulmonary administered HCQ are described in the ClinicalTrials.gov website as follows:
The present embodiments use formulation strategies to rapidly potentiate the topical respiratory tract epithelial bioavailability of approved drugs with in-vitro viral activity, while showing no apparent in-vivo antiviral activity after systemic administration, by mitigating drug physical properties that adversely affect topical drug topical respiratory tract epithelial bioavailability. Advantages over the prior art include administration of non-ionized form of the drug, changing the physical form thereof from a solid to a lipophilic liquid with a high chemical activity of the drug (>0.5), and incorporation of said lipophilic liquid into a submicron micellar solution. These combine to increase the bioavailability of the drug on the surface of and within the alveoli cells. Also, a novel therapeutic strategy for the use of CQ in the prophylactic and therapeutic treatment of COVID-19 is provided.
Despite the evidence that chloroquine and hydroxychloroquine can inhibit the membrane fusion associated with coronaviruses cell entry, and subsequent respiratory infections, they may have side effects, including problems with vision, muscle damage, seizures, and low blood cell levels, when administered systemically (through injection or peroral). These side, or unwanted, effects are the result of systemic treatment using these compounds resulting in whole body exposure and an inability to control the duration of exposure. Thus, there is a desire and need for a site-specific delivery of a pharmaceutically active compound to the respiratory tract of an animal/human.
To address these issues, the present embodiments use chloroquine and hydroxychloroquine compounds as the pharmaceutically active ingredients for delivery to the lower respiratory tracts and the lung periphery to be combined with an excipient and surfactant, which are chosen to provide effective antiviral activity in the targeted delivery region and for realizing the desired duration of release of the active ingredients. Optimization of this medication occurs by regulating, jointly through the choice of excipient and surfactant, the quality (absorption of drug with minimal levels of the excipient and surfactant to minimize absorption of these components) and quantity to achieve optimal effectiveness.
The present embodiments localize delivery of the formulations to targeted respiratory infections, for example, corona virus cell entry points in the lower respiratory tracts and the lung periphery. The present embodiments can deliver medication that target the site of effectiveness and optimally only the site of effectiveness. The formulations and delivery ensure the presence of the antiviral's active ingredients in optimized quality and minimal quantity and for an adequate duration in those regions (e.g., 1 day to 80 days assuming a 40 day half-life of tissue residence time) and ensures that the active ingredients be dispelled from the body after the targeted region of the respiratory tract has been treated sufficiently (e.g., in the case of chloroquine and hydroxychloroquine compounds to avoid the over-alkalinization of the lungs).
To illustrate one approach of the present embodiments, exemplary treatments of chloroquine and hydroxychloroquine compounds are demonstrated. To understand the mechanisms of action addressed by the present embodiments, we begin with lysosomes.
Lysosomes are organelles in the cytoplasm of eukaryotic cells which have degradative enzymes enclosed in a membrane. Lysosomes act as the waste disposal system of the cell by digesting in-use materials in the cytoplasm, from both inside and outside the cell. Material from outside the cell is taken-up through endocytosis, while material from the inside of the cell is digested through autophagy.
Cell entry of coronaviruses involves two principal steps: receptor binding and membrane fusion, the latter of which requires activation by host proteases, particularly lysosomal proteases. An important mode of action of chloroquine and hydroxychloroquine is the interference of lysosomal activity and autophagy. It is widely accepted that chloroquine and hydroxychloroquine accumulate in lysosomes (lysosomotropism) and inhibit their function and, to that degree, may inhibit the membrane fusion critical to the cell entry of coronaviruses. The effect of this is inhibiting the subsequent spread of respiratory infection, which is the primary cause of severe respiratory illness, morbidity and mortality through inhibited absorption of oxygen and release of carbon dioxide in the lower lungs, which include the trachea, the bronchi and bronchioles, and the alveoli. Diminished oxygen absorption leads to reduced muscle strength, including the muscles that enable the lower tract to draw inhaled air into the lower respiratory tract.
In one approach of the present embodiments, pulmonary site-specific pharmaceutical therapy uses drugs with antiviral activity formulated in aerosolized systems, such as aerosolized aqueous systems. The formulated solution uses a chloroquine compound and delivery mechanism together to meet these pulmonary delivery requirements mentioned herein.
Byway of example, in one embodiment aerosolized droplets of less than 5 μm are configured to penetrate reach deep lung sites. Nano-sized lipoidal particles containing approved drugs (less than 100 nm) may be stabilized with polymeric surfactants. This approach may be used, for example, to facilitate availability of lipoidal structures to interact with lipid coated SARS-CoV-2.
The dosage form of the present embodiments is formulated so that improvement of the bioavailability of drugs with SARS-CoV-2 antiviral activity in in-vitro cell-based assays at the site of infection will significantly enhance clinical efficacy. This requires pulmonary administration of a dosage form formulated to improve the absorption of such drugs into alveoli epical membranes. An ionizable, cationic drug such as chloroquine is typically administered perorally (approved dosage route) and pulmonarily (subject of experimental studies) as a salt (diphosphate in the case of chloroquine). The positive charge of the ionized species precludes apical absorption, and the low water solubility and very high lipophilicity of chloroquine base reduces both the amount and absorption of this species which is in equilibrium with the charged species in aqueous solution.
The primary formulation uses non-charged chloroquine base formulated in “liquid complexes” (typically 1:1 ratios with an “excipient” such as propylene glycol, USP) that are lipophilic and liquid at body temperature presented in a isotonic “micellar solution” using a surfactant suitable for pulmonary administration such as tocopheryl polyethylene glycol succinate (TPGS) (typically at a 4:1 mass ratio with the liquid complex). The amount of surfactant (TPGS for example) can be about 4:1 to the complex or about 8:1 to the drug. By way of a non-limiting example, one formulation may be 4 parts surfactant; 0.5 parts drug; and 0.5 excipient.
The ability to meet requirements for drug delivery to the lower respiratory tracts and the lung periphery to inhibit membrane fusion and for excipient and surfactant to be effective in the targeted region and for realizing the desired duration of release of the active ingredients depend in part on the partition coefficient of a molecule, a standard measure of lipophilicity. The mass flux of a molecule at the interface of two immiscible solvents is governed by its lipophilicity. The more lipophilic a molecule is, the more soluble it is in lipophilic organic phase at ambient temperature. For the same reason, drug penetration into a biological membrane is also influenced by the lipophilicity of the drug. However, since biological membranes consist of bilayer structures consisting of both lipid and water, there is a recognized range of partition coefficient values that favors drug penetration into these membranes. Partition coefficient values outside of this range indicate a molecule is either too hydrophilic (low partition coefficient values) or too lipophilic, i.e., insufficiently water soluble (high partition coefficient values) for efficient partitioning into biological membranes. To address localized delivery to targeted respiratory infection, to ensure the presence of the antiviral's active ingredients in sufficient quality and quantity and for an adequate duration in those regions, and to ensure that the active ingredients be dispelled from the body after the targeted region of the respiratory tract has been treated sufficiently, the present embodiments may aerosolize the formulation with a nebulizer with adjustable aerosolization droplet size in the range of 1-10 μm. The size of the aerosolized droplets have been shown to determine the depth to which the aerosolized medication solution will penetrate the respiratory system, with for example 5-10 μm, preferably 5-7 micron size droplets penetrating to the lower respiratory tract, and 1-4 micron size droplets penetrating to the lung periphery portion, including the ‘air sacs’ or alveoli, where the lungs and the blood exchange oxygen and carbon dioxide.
The Figure provides a simplified schematic of the human respiratory anatomy 208. As shown, the anatomy 208 provides a nose 210, a mouth 212, a lower respiratory portion 214, a lung periphery portion 216, a nasal cavity 218, an oral cavity 219, a pharynx 220, a larynx 222, a trachea 224, lungs 226 and bronchi 228. According to A simplified view of the effect of aerosol particle size on the site of preferential deposition in the airways (presented by Gardenhire, D.S. Rau's Respiratory Care Pharmacology. St. Louis: Elsevier, 2016), as aerosol particles are inhaled orally or through the nose: the larger particles/droplets (>10 μm) are filtered in the nasal cavity 18; >15 μm are filtered by the oral cavity 19; 5-10 μm generally reach the proximal generations of the lower respiratory portion 14, and particles/droplets of 1-5 μm reach to the lung periphery 16. Although particle/droplet size plays an important role in lung deposition, particle/droplet velocity and settling time are also a factor. Thus, the particle/droplet sizes of 1-5 μm of the presented compositions are preferred for reaching the lung periphery, and 5-10 μm particles/droplets are preferred for deposition in the conducting airways. Particles/droplets >10 μm (such as 10-100 μm particles/droplets) are preferred for deposition mostly in the nose. It is noted that the particle/droplet size, produced during aerosolization, determines the deposition site in the respiratory system. Though a particular size may be desired, in practice the aerosol contains a range of sizes following a normal bell-shaped distribution having particle/droplet sizes varying from 0 to 15 micrometers. Droplet size, and thus expected deposition site in the respiratory system, is impacted by pressure, spray pattern type, spray angle, nozzle type, fluid specific gravity, fluid viscosity and surface tension.
Also, to address localized delivery to targeted respiratory infection, to ensure the presence of the antiviral's active ingredients in sufficient quality and quantity and for an adequate duration in those regions, and to ensure that the active ingredients be dispelled from the body after the targeted region of the respiratory tract has been treated sufficiently, the present embodiments may aerosolize the formulation with respect to various viscosities. According to one approach, the viscosity of the formulation may lie about within a range of propyl alcohol needed to enable aerosolization to the targeted droplet size. Continuously variable droplet size, or particle size, within the range of 1 and 10 μm enables the delivery of the formulation in an aerosol to any specified depth of the respiratory system and allows targeting of that delivery to the region(s) of infectious activity. As shown in the following table, fresh water has a dynamic viscosity roughly half that of propyl alcohol; this formulation should have the viscosity of propyl alcohol +/−0.10 cP. It is noted that the aerosolization is impacted by fluid viscosity, propellant velocity and the surface geometry of the aerosolization device. Thus, this viscosity requirement may vary with both of the latter
The use of pulmonary administration of aminoquinolines as cationic salts should provide significantly increased exposure of the lung epithelial membrane to the drug relative to systemic administration. However, although both HQ and HCQ have good peroral bioavailability (good absorption from the gastrointestinal (GI) tract with low first-pass hepatic metabolism) when administered as cationic salts, this may not be applicable to the lung. The GI tract has a relatively large luminal fluid volume, prolonged residence time, and extremely large surface area (due to the presence of villi and microvilli in the small intestine) that greatly facilitate absorption of compounds that are ionized in the luminal fluid. The relatively large volume of the latter maintains the drug species (ionized and small amount of un-ionized) in solution and available for interaction with the epithelial cells. Only the (very small) amounts of un-ionized drug molecular species that are in equilibrium with the ionized molecular species in solution partition into the enterocytes of the small intestine. Upon depletion of the un-ionized species by absorption, the equilibrium is re-established producing more un-ionized drug for further absorption. This process can occur throughout the prolonged GI tract residence time and can result in substantial absorption of drugs that are ionized in the GI luminal fluid due to the length of the residence time, the relatively large luminal fluid volume, and especially the extremely large absorbing surface area.
For the above reasons, application of cationic salt drugs as solutions to other sites of administration such as the lung, skin, oral cavity, and rectum typically results in poor absorption due to one or more of the above factors. Typical pharmaceutical practice is to administer the drug as an uncharged species dissolved in a suitable vehicle; the free base in the case of CQ and HCQ. Therefore, sufficient vehicle is needed to solubilize the target drug dose, and ideally, the chemical activity of the drug in the selected vehicle is high in order to provide the highest possible chemical potential for absorption. Unfortunately, drug saturation solubility in many pharmaceutically acceptable vehicles is typically not very high (rarely exceeding 10%), requiring high ratios of vehicle to drug. This would be disadvantageous in the lung where it is desirable to limit the amounts of exogenous material administered.
In addition to the factors mentioned above, CQ and HCQ free base have P/C properties, especially their high partition coefficient (Log P values) and low water solubility, that are not conducive to absorption by biological membranes. One technique that has been successful in improving dermal absorption of topically applied drugs is the creation of a physical eutectic system or complex with an excipient that has a lower melting point than the drug. Such systems provide much better dermal absorption, especially if the complex melting point is below body temperature and is lipophilic in nature. One such example is a eutectic system of 1:1 lidocaine base: prilocaine base termed ELMA which was introduced in 1993 and is among the leading anesthetic products (Friedman, 2001). Subsequent work indicated that formulation of the ELMA eutectic system into a micellar solution with a particle size <20 nm using POE-35-castor oil polymeric surfactant increased dermal permeation of the system by about six-fold (Fiala, 2016). The function of the excipient-drug active liquid complexes described herein is to mimic the absorption enhancing properties of the above-described eutectic systems.
Treatment Strategy Components
The above factors suggest that a dosage form having the following components should have increased potential for treatment of COVID-19. The latter would derive from mitigation of the adverse P/C properties of these drugs with regard to lung epithelial absorption and increase the ability of pulmonary administered CQ/HCQ to exert potential intracellular antiviral activity in addition to potential extracellular antiviral activity. The dosage form should also be easily sterilized through filtration and amenable to nebulization. The objective for such a dosage form is to provide rapid and effective epithelial absorption during the typically short residence times in the respiratory tract rather than the sustained release apparently provided by liposomal formulations.
An exemplary formulation may have at least the following:
Alternate strategies are also provided within the scope of the present embodiments. According to one approach, a formulation strategy is to create a lipophilic ion pair with the charged drug species that is essentially water insoluble. This creates a “salt” that does not disassociate in water to form charged species and has appropriate properties for apical absorption. It could be administered in a micellar solution, but also as a molecular inclusion complex using modified cyclodextrins.
According to another approach, the drug uncharged species may be formulated into stable homogenous nano-sized (less than about 100 nm) aqueous dispersions through formation of inclusion complexes with modified cyclodextrins at about 1:1 to 1:2 molecular ratios and formation of water-soluble complexes with excipients such as 2-ethylhexanoic acid at mass ratios of about 1:1 to 1:2.
Other potential strategies to improve chloroquine topical bioavailability in the lung are feasible. The formulations are configured as a combination of pulmonary administration with a topical formulation that may be aerosolized designed to reduce/eliminate the putative issues affecting chloroquine topical bioavailability, namely is positive charge at physiological pH when administered as the diphosphate salt (primary form of chloroquine indicated in prior art), and the poor water solubility and very high lipophilicity of the chloroquine free base which is the species actually absorbed. One formulation strategy is thus to:
In another approach, the formulation may incorporate chloroquine free base in an inclusion complex in hydroxypropyl-s-cyclodextrin. This strategy uses chloroquine free base as the drug source and reduces the impact of the poor water solubility of the base through the use of a molecular inclusion complex of the free base. The latter solubilization technology may be advantageous as release from the inclusion complex may be superior to that from a swollen surfactant micelle. This may not apply to a “liquid complex” because of the size of the complex is presumed to be too large to incorporate into the hydrophobic interior of the cyclodextrin molecule. This inclusion complex may be formulated by a preparation by dissolving chloroquine free base in ethanol and addition the resulting solution to an aqueous solution of hydroxypropyl-β-cyclodextrin (could be in saline) such that the final concentration of ethanol is less than 5% and the molar ratio of hydroxypropyl-β-cyclodextrin to chloroquine base is from about 2:1 to 1:1.
In another approach, an additional strategy may involve the creation of a lipophilic ion pair of chloroquine base with an appropriate organic acid such that the resulting “salt” does not appreciably ionize in water such as the inorganic chloroquine salts (chloroquine diphosphate) do and therefore chloroquine is not presented to the absorbing epithelial membrane as a charged species; and has reduced lipophilicity relative to the free base and is better able to partition into the absorbing membrane.
Other approaches may include unmodified chloroquine free base formulated into transparent, homogenous aqueous dispersions through formation of molecular inclusion complex using hydroxypropyl-β-cyclodextrin at a 1:2 molar ratio or formation of a water-soluble complex with 2-ethylhexanoic acid at a 1:1 mass ratio. In yet another approach combinations of antiviral and antibiotic and/or anti-inflammatory treatments are considered. Catalysts may also be used to activate and deactivate composition components. According to one approach, the formulation may include a CQ free base with hydroxypropyl-R-cyclodextrin and 2-ethylhexanoic acid as described herein.
It should also be recognized that the principles for effecting pulmonary administration of approved drugs with antiviral activity may also be applied to additional moieties with therapeutic properties that may be additive or synergistic with those of the aforementioned drugs with antiviral activity. Such additional therapeutic moieties should be formulated in a manner so as to potentiate partitioning into and diffusion through apical membranes in the lung and to permit incorporation in the pulmonary dosage forms heretofore described. Examples of such moieties include, but are not limited to, lipophilic zinc compounds and antibiotic molecules.
Although the present invention has been described in terms of specific embodiments, it is anticipated that alterations and modifications thereof will no doubt become apparent to those skilled in the art. It is therefore intended that the following claims be interpreted as covering all alterations and modifications that fall within the true spirit and scope of the invention. Throughout this specification numerical labels of previously shown or discussed features may be reused to indicate similar features. Further, the terms atomization, nebulization and aerosolization may be used interchangeably to describe producing a fine spray, mist, minute particles, particle stream and/or colloidal suspension in the air.
References: The following references are incorporated herein in their entirety for all purposes.
This application is a U.S. national phase application filed under 35 U.S.C. § 371 of International Application No. PCT/EP2021/051210, filed Sep. 21, 2021, designating the United States, which claims priority from U.S. provisional application 63/081,414 filed Sep. 22, 2020; U.S. provisional application 63/244,548 filed Sep. 15, 2021; and U.S. provisional application 63/246,150 filed Sep. 20, 2021, which are hereby incorporated herein by reference in their entirety for all purposes.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/051210 | 9/21/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63081414 | Sep 2020 | US | |
| 63244548 | Sep 2021 | US | |
| 63246150 | Sep 2021 | US |
