WO2001045642A2

WO2001045642A2 - Pulmonary delivery of ribavirin or levovirin™ for systemic and quasi-systemic treatment of disease

Info

Publication number: WO2001045642A2
Application number: PCT/US2000/042821
Authority: WO
Inventors: Füsûn ZEYTINOGLU
Original assignee: Icn Pharmaceuticals, Inc.
Priority date: 1999-12-13
Filing date: 2000-12-13
Publication date: 2001-06-28
Also published as: AU5076601A; WO2001045642A3

Abstract

A method of treating a systemic viral disease in a patient has a first step in which the disease is correlated with an increase in Type 1 cytokine activity and a decrease in Type 2 activity. In a further step, a systemic dosage of a drug is identified that is effective to increase the Type 1 activity and decrease the type 2 activity, wherein the drug is Ribavirin or Levovirin™ and in a still further step, the dosage of the drug is administered to the patient via pulmonary delivery. A further method of treating a viral disease has a first step in which the disease is correlated with an infection of dendritic cells, and the dendritic cells are targeted by administering Ribavirin or Levovirin™ via a pulmonary aerosol.

Description

PULMONARY DELIVERY OF RIBAVIRIN OR LEVOVIRIN™ FOR SYSTEMIC AND QUASI-SYSTEMIC TREATMENT OF DISEASE

This application claims priority benefit of U.S. non-provisional application number 09/459,668 incorporated herein by reference in its entirety.

Field of The Invention

The field of the invention is pulmonary delivery of nucleosides.

Background of The Invention

Ribavirin (l-β-D-ribofuranosyl-l,2,4-triazole-3-carboxamide) has long been employed as an antiviral agent. For most indications oral and intravenous administration are preferred, and in such cases the dosage is commonly 1000 - 1200 mg/day.

In some pulmonary viral diseases, such as where the virus is readily accessible on the alveoli surfaces, Ribavirin is known to be administered by aerosol inhalation. In the specific case of respiratory syncytial virus (RSV), for example, aerosol administration of Ribavirin is the only approved therapy. Unfortunately, however, administration in these cases generally requires slow dosing of 12-20 hours per day of drug inhalation over at least a three-day period, all of which provides no more than a few hundred milligrams of drug. Higher concentrations have been attempted, but have been uniformly unsuccessful.

Recent studies with mice have demonstrated that pulmonary aerosols of Ribavirin in mice are cleared to the blood beginning within about 15 minutes of administration (Gilbert BE, Wyde PR, Pharmacokinetics Of Ribavirin Aerosol In Mice, Antimicrob Agents Chemother, 1988 Jan; 32(1):117-121). Ribavirin administered in that manner does not generally accumulate in the blood, (presumably because clearance from the blood is rapid relative to the rate at which the drug enters the blood), but does apparently accumulate in the brain. Accordingly, it has been suggested that pulmonary administration of Ribavirin could be used to treat viral encephalitis (Id). However, because it was thought that the dosage required could not realistically be carried through lung tissue, Ribavirin has not previously been administered systemically through inhalation therapy.

New research now indicates that particularly low dosages of Ribavirin (e.g. 200 mg/day to 800 mg/day) may be effective against viral infections and a host of other diseases, although these low dosages operate by a different mechanism than the previously known higher dosages. The recognition of effective lower dosages of Ribavirin, however, has not heretofore prompted suggestions of systemic treatment using inhalation therapy. The primary reasons are that inhalation therapy is still limited to delivering a few hundred milligrams of drug over a several day period, and that such delivery is still extremely inconvenient for a patient relative to oral or even IV administration.

Important advances have, however, been made in the field of pulmonary delivery during the last few years. US 5,622,166 to Eisele et al. (April 22, 1997), for example, describes a dry powder inhaler delivery system for drugs. Related patents are US 5,327,883 (July 1994), US 5,577,497 (Nov. 1996) and US 5,492112. The technology is presently being commercialized under the trade name SPIROS™ by Dura Pharmaceuticals, Inc. of San Diego California.

As another example, US 5,775,320 issued to Patton et al. (July 1998) describes a cyclone chamber for the delivery of drugs. This technology is being commercialized by Inhale Therapeutics of Palo Alto, California.

Preliminary trials show that some of these newer systems can deliver 20-30 mg per

"dose", but that the delivered dose varies widely on a drug-by-drug basis. It is therefore unknown what doses of Ribavirin can be effectively administered using the pulmonary route.

Summary of the Invention

The present invention is directed to a method of treating a systemic viral disease in a patient, in which in a first step the disease is correlated with an increase in Type 1 cytokine activity and a decrease in Type 2 activity. In a further step, a systemic dosage of a drug is identified that is effective to increase the Type 1 activity and decrease the type 2 activity, wherein the drug is Ribavirin or Levovirin™ (l-(5-Deoxy-β-L-ribofuranosyl)-l,2,4-triazole-3- carboxamide). In a still further step, the dosage of the drug is administered to the patient via pulmonary delivery.

In another aspect of the inventive subject matter, the disease is correlated with an infection of dendritic cells, and the dendritic cells are targeted by administering Ribavirin or Levovirin™ via a pulmonary aerosol.

In a further aspect of the inventive subject matter, the step of administering comprises administering a dry powder, wherein the administration comprises administering at least 200 mg/day, preferably at least 250 mg/day, more preferably at least 300 mg/day, and most preferably at least 350 mg/day.

Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components.

Brief Description of The Drawings

Fig. 1 is a flow chart depicting one method of treating a systemic viral disease according to the inventive subject matter.

Fig. 2 is a flow chart depicting another method of treating a viral disease according to the inventive subject matter.

Detailed Description The present applicant contemplates that despite the various drawbacks, systemic dosing of Ribavirin can be provided via a pulmonary route. For example, Ribavirin can be administered systemically using a dry powder method such as SPIROS™ discussed above, and additional improvements to inhalation therapy may render systemic treatment by Ribavirin via pulmonary route ever more advantageous. It is especially contemplated that Ribavirin may be dosed at a dosage of at least 150, 200, 250, 300 and 350 mg/day via the pulmonary route, and that such dosing is sufficient to achieve a significant systemic effect on the immune system.

It is particularly contemplated that such pulmonary dosing of Ribavirin is sufficient to produce a significant rise in Type 1 cytokine activity and a significant reduction in Type 2 cytokine activity. Mammalian immune systems contain two major classes of lymphocytes: B lymphocytes (B cells), which originate in the bone marrow; and T lymphocytes (T cells), which originate in the thymus. B cells are largely responsible for humoral immunity (i.e., antibody production), while T cells are largely responsible for cell-mediated immunity. T cells are generally considered to fall into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes, including B cells and cytotoxic T cells, and macrophages, by releasing soluble protein mediators called cytokines, which are involved in cell-mediated immunity. As used herein, lymphokines are a subset of cytokines produced by helper T cells, and are generally considered to fall into two subclasses - Thl and Th2. Thl cells (more modernly known as Type 1 cells) produce in.erleukin 2 (IL-2), tumor necrosis factor (TNFα), and interferon gamma (IFNγ). They are responsible primarily for cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. In contrast, Th2 cells (more modernly known as Type 2 cells) produce interleukins, IL4, IL-5, IL-6, IL-9, IL-10, and IL-13, that are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and IgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol, 7:145-173).

As further used herein, the terms Thl and Th2 "responses" are meant to include the entire range of effects resulting from induction of Thl and Th2 lymphocytes, respectively. Among other things, such responses include increased production of the corresponding cytokines, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including motility effects.

In Figure 1, a method of treating a systemic viral disease 100 has a first step 110 in which the disease is correlated with an increase in Type 1 cytokine activity and a decrease in Type 2 activity. In a further step 120, a systemic dosage of a drug is identified that is effective to increase the Type 1 activity and decrease the type 2 activity, wherein the drug is selected from the group consisting of Ribavirin and Levovirin. In a still further step 130, the dosage of the drug is administered to the patient via pulmonary delivery.

In a preferred method of treatment, an infection with PIV (Parainfluenza virus) is correlated with an increase in Type 1 cytokine activity and a decrease in Type 2 activity. A systemic dosage of 300mg/day Ribavirin is identified to be effective to increase the Type 1 activity and decrease the type 2 activity. The systemic dosage of Ribavirin is then administered to the patient via pulmonary delivery employing the SPIROS™ method.

In other aspects of the inventive subject matter, the systemic viral disease need not be limited to an infection with RSV, but may include infections with various viruses other than PIV. For example, contemplated viruses include retroviruses, single and double stranded DNA viruses, parvoviruses, etc. Particularly contemplated viruses include HIV viruses, HBV viruses, HCV viruses, influenza, parainfluenza viruses, and viruses associated with encephalopathy.

However, it should be appreciated that generally all viral diseases that correlate with an increase in Type 1 cytokine activity and a decrease in Type 2 activity are appropriate for treatment according to the inventive subject matter presented herein.

With respect to the step of correlating the viral disease with an increase in Type 1 cytokine activity and a decrease in Type 2 activity, it is preferred that a cytokine profile is prepared from the patient afflicted with the viral disease. Such profiling can be performed using standard laboratory procedures, preferably based on ELISA or RT-PCR based methods. However, alternative methods of correlating are also contemplated including diagnosing the disease by methods other than cytokine profiling (e.g. antibody based testing for presence of virus) and identifying the disease as correlating with an increase in Type 1 cytokine activity and a decrease in Type 2 activity by identifying the disease on a listing of diseases that are known to correlate with an increase in Type 1 cytokine activity and a decrease in Type 2 activity.

It is further contemplated that an increase of Type 1 cytokine activity may typically be characterized by a collective increase of all Type 1 cytokines, and the collective increase may thereby be balanced (i.e. all Type 1 cytokines exhibit significantly identical rates of increase) or unbalanced (i.e. the Type 1 cytokines exhibit significantly different rates of increase). Where the increase is substantially unbalanced, the increase may also be characterized by an exclusive increase of only one or two Type 1 cytokines. For example, a 35% increase of IL-2 with a concurrent 40% increase of TNFα and a 28% increase of EFNγ are considered an increase under the scope of this definition. Likewise, a 20% increase of IL-2 without increase in all other Type 1 cytokines is also considered an increase of Type 1 cytokine activity.

Similarly, it is contemplated that a decrease of Type 2 cytokine activity may be characterized by a collective decrease of all Type 2 cytokines, and the collective decrease may thereby be balanced (i.e. all Type 2 cytokines exhibit significantly identical rates of decrease) or unbalanced (i.e. the Type 2 cytokines exhibit significantly different rates of decrease). Where the decrease is substantially unbalanced, the decrease may also be characterized by an exclusive decrease of only one or two Type 2 cytokines. For example, a 42% decrease of IL-5 with a concurrent 21% decrease of IL-6, an 11% decrease of IL-9, and a 14% decrease of IL13 are considered a decrease under the scope of this definition. Likewise, a 22% decrease of IL-10 without concurrent decrease in all other Type 2 cytokines is also considered a decrease of Type 2 cytokine activity. With respect to the dosage, it is contemplated that depending on the viral disease, the progression of the disease, and the general health of the patient, many alternative dosages other than 300mg/day are also appropriate. For example, while some viral diseases may generally require relatively high dosages (i.e. dosages >300mg/day), other viral diseases may be treated with substantially lower dosages (i.e.<300mg/day). It should also be appreciated that even in the course of treatment of a single viral disease, dosages may vary substantially due to occurrence of side effects, treatment success, co-administration of other drugs, etc. Therefore, contemplated dosages may include a dosage of 350mg/day, 350-600mg/day, 600-800mg/day, and higher. Likewise, contemplated dosage ranges may include dosages of 250mg/day, 200mg/day, 200-100 mg/day, and less. Lower concentrations of Ribavirin are deemed especially beneficial since it is known that the normal dosages of Ribavirin cause anemia in some individuals, and therefore the lower doses discussed herein would tend to be advantageous in reducing the incidence of anemia.

It is further contemplated that the dosage may be administered following various schedules. For example, where higher concentrations of Ribavirin are absorbed less efficiently, or where high systemic daily dosages are required, multiple administrations are contemplated. Alternatively, administration in single dosages is contemplated where low daily concentrations are required, or where absorption of Ribavirin is relatively efficient. It is still further contemplated that the administration of the systemic dosage of Ribavirin need not entirely follow the pulmonary route, but may be assisted by alternative methods of administration, including injection, ingestion, or transdermal delivery, so long as at least part of the dosage is administered via pulmonary delivery.

Recognizing the viral disease on a listing that identifies a particular systemic dosage of Ribavirin for a particular viral disease preferably identifies the systemic dosage of Ribavirin effective to increase the Type 1 activity and decrease the Type 2 activity. Alternatively, the effective systemic dosage may be determined experimentally. Such experimental determination includes drawing blood from the patient, isolation of T helper cells, and incubation in vitro of the isolated T helper cells with various amounts of Ribavirin. The experimental amount that produces the desired result in increasing the Type 1 activity and decreasing the Type 2 activity is then employed to determine the systemic dosage (e.g. by determining the molarity of Ribavirin in vitro). In still further aspects of the inventive subject matter, the administration of Ribavirin need not be restricted to the patient via pulmonary delivery employing the SPIROS™ method, and various alternative methods of pulmonary administration are contemplated, including pulmonary delivery utilizing a cyclone chamber (vide supra). There are many potential benefits from pulmonary delivery. Among other things, pulmonary delivery of Ribavirin may be superior for particular populations, for lung-related indications in which the virus is not presented on the linings of the alveoli. Along these lines it is contemplated that Ribavirin may advantageously be administered via pulmonary route in children infected with parainfluenza virus (PIV), and to all ages for viral encepalopathy.

Ribavirin may also be administered via pulmonary route for treatment of "quasi- systemic" diseases, those that may have relatively localized symptoms but in which the etiology is at least partially systemic. Asthma is a particularly important example of a "quasi-systemic" disease, since the symptoms are particularly related to the lungs, but the etiology has roots in systemic aspects of the immune system. Asthma, for example, is generally associated with systemically depressed Type 1 and systemically elevated Type 2 cytokine profiles.

With respect to the administration of the drug for treatment of a viral infection, it is contemplated that appropriate treatments are not exclusively limited to Ribavirin, may but may also include Levovirin™, the L-isomer of Ribavirin. The administration of Levovirin™ is especially advantageous because Levovirin™ has a considerably lower cytotoxicity than Ribavirin at comparable concentrations.

It is still further contemplated that drugs other than Ribavirin or Levovirin™ may be co-administered, where co-administration is beneficial for enhanced drug action or reduced side effects. For example, erythropoietin (e.g., Amgen's Epogen) may be administered along with Ribavirin to reduce any tendency of Ribavirin to cause anemia. As used herein, the term "along with" means that the two treatments are both present in the patient in sufficient quantities to achieve a reasonable degree of effectiveness. It is preferred that both drugs be administered concurrently via pulmonary route, but the drugs could be administered in different pulmonary doses, or Ribavirin could be administered via pulmonary route, and the erythropoietin could be administered via another route.

Another aspect of pulmonary delivery of Ribavirin is the contemplated effect of

Ribavirin on dendritic cells. It is known, for example, that dendritic cells become infected with influenza virus, and without having a full understanding of the mechanisms involved, it is contemplated that pulmonary delivery of Ribavirin will assist the dendritic in the lungs and elsewhere in provoking a suitable immune response. The dendritic cells of particular interest in the lungs are Langerhans cells, but it is contemplated that other antigen presenting cells (APCs) may also be involved. Therefore, as depicted in Figure 2, an alternative method, 200 of treating a viral disease in a patient may comprise a step 210 in which the disease is correlated with an infection of dendritic cells. In a subsequent step 220, the dendritic cells are targeted by administering a drug to the patient via a pulmonary aerosol, wherein the drug is selected from the group consisting of Ribavirin and Levovirin.

The step of correlating is preferably performed by identifying the viral disease in a listing of viral diseases that correlates the viral infection with an infection of dendritic cells. Such listing need not be limited to any particular format, and may be in the form of a scientific publication, a text book for medicine, an information brochure for physicians, etc. Alternatively, the step of correlation maybe performed by experiment, including the steps of isolating dendritic cells from the patient, and determining the infection of at least a portion of the isolated dendritic cells with the virus by direct or indirect methods. Direct methods may include cell and virus culture, while indirect methods may include antibody based tests (Virus-hapten or anti-virus Ig- specific) or nucleic acid based tests such as RT-PCR, quantitative PCR, LCR, etc. With respect to the virus, the dosage and other limitations in the step of targeting the dendritic cells, the same considerations as discussed above apply.

Thus, specific embodiments and applications of pulmonary delivery of Ribavirin or Levovirin™ for systemic and quasi-systemic treatment of disease have been disclosed. It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a systemic viral disease in a patient, comprising:

correlating the disease with an increase in Type 1 cytokine activity and a decrease in Type 2 activity;

identifying a systemic dosage of a drug that is effective to increase the Type 1 activity and decrease the type 2 activity, wherein the drug is selected from the group consisting of Ribavirin and Levovirin; and

administering the dosage of the drug to the patient via pulmonary delivery.

2. The method of claim 1 wherein the step of administering comprises administering a dry powder.

3. The method of claim 1 wherein the step of administering the drug comprises administering at least 200 mg/day.

4. The method of claim 1 wherein the step of administering the drug comprises administering at least 250 mg/day.

5. The method of claim 1 wherein the step of administering the drug comprises administering at least 300 mg/day.

6. The method of claim 1 wherein the step of administering the drug comprises administering at least 350 mg/day.

7. A method of treating a viral disease in a patient, comprising:

correlating the disease with an infection of a population of dendritic cells; and

targeting the dendritic cells by administering a drug to the patient via a pulmonary aerosol, wherein the drug is selected from the group consisting of Ribavirin and Levovirin.

8. The method of claim 7 wherein the step of administering the drug comprises administering at least 200 mg/day.

9. The method of claim 7 wherein the step of administering the drug comprises administering at least 250 mg/day.

10. The method of claim 7 wherein the step of administering the drug comprises administering at least 300 mg/day.

11. The method of claim 7 wherein the step of administering the drug comprises administering at least 350 mg/day.

12. The method of claim 7 wherein the viral disease is a systemic disease.