WO2005039623A1

WO2005039623A1 - Spray formulation for the treatment of viral infections

Info

Publication number: WO2005039623A1
Application number: PCT/EP2004/011721
Authority: WO
Inventors: Giulio Tarro; Renzo Brozzo
Original assignee: Unihart Corporation
Priority date: 2003-10-23
Filing date: 2004-10-18
Publication date: 2005-05-06
Also published as: ITMI20032067A1

Abstract

Disclosed is a spray formulation containing interferon-α for the preventive and therapeutic treatment of viral infections, in particular infections caused by HCV, HPV, Herpes Virus and Rhinovirus.

Description

SPRAY FORMULATION FOR THE TREATMENT OF VIRAL INFECTIONS

This invention relates to a spray formulation containing interferon-α for the preventive and therapeutic treatment of viral infections, in particular infections caused by HCV, HPV, Herpes Virus and Rhinovirus. Background of the invention Human interferon-alpha (IFNα) is produced in vivo by the leucocytes after a viral infection and, together with interferon-beta (IFNβ), constitutes the family of type I interferons (IFN-I). The IFN-I family have a marked cytostatic and immunomodulating capacity, and induce a state of antiviral resistance. IFNα interacts with specific membrane receptors (1) and, by activation of Jak-STAT (2), leads to the synthesis of new proteins, including protein kinases PKR, which have antiviral (3), antiproliferative and oncogenesis-inhibiting effects. Natural or synthetic IFNα, alone or in combination with chemotherapy agents, has been used in the treatment of hepatitis B (4, 5) and C (6), herpes, sexually transmitted HPV infections (7, 8), and tumours such as Kaposi's sarcoma, hairy-cell leukaemia, myeloid leukaemia, cervical intraepithelial carcinoma (9), melanoma, and others. It has been found that high doses of IFNα, especially when administered by the parenteral route, produce serious adverse effects (10), often associated with a state of immune depression, whereas lower doses (under 3 million IU per sq.m of body area) are better tolerated and more effective, as in the case of treatment of chronic hepatitis C, where 1.5 million IU of IFNα is used. In view of the protein nature of IFNα, the intramuscular and subcutaneous administration routes are preferred and the intravenous route is not recommended, although recent data demonstrate the usefulness of this approach in melanoma. The oral administration route allows IFNα to come into contact with the membrane receptors on the immunocompetent cells of the oropharyngeal mucous membranes and to trigger a cascade reaction that involves the immune system at systemic level (11, 12, 13, 14). The oral administration route of IFNα at low doses has therefore been studied in different animal models. The results of these studies are controversial, however, especially as regards the effective dose of IFNα, the application time and the correct distribution of the active substance. European patent EP 886527 describes pharmaceutical compositions for peroral administration containing low doses of IFN-α which are particularly useful for the treatment of hepatitis. Patent application MI2003A000826 describes a liquid pharmaceutical composition containing interferon for peroral administration, and its use in the treatment of HPV infections. Description of the invention It has now been found that oral administration of interferon-α by means of a liquid spray formulation improves therapeutic efficacy against viral infections responsive to interferon treatment. In particular, interferon-α applied in spray form reduces the side effects found with other administration routes, and allows more effective treatment of the infectious disease; for example, interferon-α normalises the chemical and clinical parameters associated with the viral infection more effectively when administered in spray form than by the peroral route. Object of the invention is therefore the use of a spray formulation of human interferon-α for the treatment of viral infections. The spray formulation can be administered to healthy subjects at risk of infection or to infected patients, or it can be used to prevent relapses or new episodes of infection. Any viral infection sensitive to interferon-α, and in particular infections caused by HCV (Hepatitis C Virus), HPV (Human Papilloma Virus), Herpes Virus and Rhinovirus can be treated with the spray formulation according to the invention. To prepare the spray formulation, human interferon-α, either natural, recombinant or synthetic, is dissolved in a suitable solvent, preferably water, together with pharmaceutically acceptable excipients, and the solution thus obtained is introduced into a suitable bottle fitted with a dispenser. The preferred excipients are adsorption or absorption activators and stabilising agents. According to a preferred embodiment, human interferon-α is dissolved in an aqueous solution at 150 IU/ml concentration. The dose of interferon-α will depend on the type and severity of the viral disease and the subject's overall state of health. The use of a monodose container or of a metered multidose device allows administering the desired quantity of active constituent. Unlike other forms designed for oral administration, the spray formulation delivers a precise, constant dose. In addition, the small volume of drug sprayed adheres to the oropharyngeal mucous membranes, and needs not be swallowed or spat out. Due to the effect of the pressure, the interferon is diffused uniformly in the oral cavity, including the mucosa of the tonsils, thereby exerting an effective pharmacological activity. The examples below illustrate the invention in greater detail. EXAMPLES A bottle with a dispenser/measuring cap was prepared, containing a solution of IFNα having the following composition per 100 ml (extractable volume: 0.1 ml/dose):

The bottles are aseptically filled with the extemporary solution by the filling machine, which automatically closes them by crimping the dispenser cap to the neck of the bottle. The formulation thus prepared was used in the following examples. Example 1 Treatment of viral hepatitis Trial design: The efficacy and safety of the liquid spray composition was evaluated in an open study conducted according to GCP rules on a group of 10 patients who tested positive for anti-HCV and HCV-RNA, genotypes 1, 2 and 3, with above-normal transaminase values. The patients were treated with 150 IU interferon b.i.d. (two doses, one in the morning and one in the evening) for 90 days, vs 10 patients, treated with oroferone under the same conditions (150 IU b.i.d. - EP no. 0886527). Where the trial showed positive results on the 90th day, the treatment continued for up to six months for the patients with genotypes 2 and 3 and up to 12 months for those with genotype 1. Efficacy was evaluated on the basis of the following criteria: a) variation in values (log 10) of the HCV viral load during treatment, compared with the values found before treatment (screening stage). The viral load, expressed in log units, is the number of viral particles per ml of blood sample: ► a blood sample with less than 100 copies/ml of HCV viral RNA, measured according to the National Genetics Institute test, is considered negative; ► as there is no universally accepted reference protocol for the PCR test, the results may vary from one laboratory to another; a reduction or increase of one log unit is considered a statistically significant variation in the viral load; b) variations in transaminase during treatment compared with those recorded before treatment. Results: Table A): each result is the average of 5 patients (HCV-genotype 1) treated with interferon liquid spray composition 150 IU b.i.d.

Table B): each result is the average of 5 patients (HCV-genotype 1) treated with oroferone 150 IU b.i.d.

Table C): each result is the average of 5 patients (HCV genotype 2 or 3) treated with interferon liquid spray composition 150 IU b.i.d.

Table D): each result is the average of 5 patients (HCV-genotype 2 or 3) treated with oroferone 150 IU b.i.d.

Example 2 Treatment of sexually transmitted viral infections (HPV, Herpes Virus). Trial design: The efficacy and safety of the antiviral liquid spray composition was evaluated in a double-blind placebo-controlled study conducted according to GCP rules on two groups of patients diagnosed positive for HPV infection: a group of 44 patients who underwent physical treatment (laser or LEEP) prior to pharmacological treatment with the preparation tested, and a group of 22 patients who only underwent pharmacological treatment with the preparation tested. The subjects treated with the drug received two doses, one in the morning and one in the evening (150 IU of interferon b.i.d.), for 90 days. The subjects treated with placebo received two doses (without active ingredient), one in the morning and one in the evening, for 90 days. Protocol design:

The following parameters were evaluated in the comparison of drug vs placebo groups: a) total no. of relapses (R no.) in each group b) percentage reduction in viral load (HPV) at the checkpoints for each group Results:

Example 3 Treatment/prevention of the common cold (Rhinovirus) . Unlike the 33 patients treated with placebo, the 10 patients with hepatitis and the 33 patients with HPV who were treated with the antiviral liquid spray composition did not present symptoms of the common cold, and demonstrated greater resistance to infection during the subsequent one-year observation period. Results:

REFERENCES

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2. J.E. Darnell Jr., Science 1994; 264: 1415-1421; 3. M.G. Katze, Trends Microbiol. 1995; 3 : 75-78;

4. S.K. Sarin, J. Epatol. 1996; 24: 391-396;

5. N.A.Terrault Adv. Exp. Med. Biol. 1996; 394: 189-205;

6. M.Y. Lai, Gastroenterology 1996; 111 : 1307-1312;

7. G. Gross, Genitourin Med., 1996; 72: 71 ; 8. E.K. Cardamakis, Arch. Gynecol. Obste , 1996; 258: 35-41;

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11. V. Bocci, Clin. Pharmacokinet, 1991; 21 : 411-417;

12. V. Bocci, J. Biol. Regul. Homeost. Agents, 1990; 4: 81-83; 13. V. Bocci, J. Biol. Regul. Homeost. Agents, 1991; 5: 121-124;

14. J.A. Georgiades, Biotherapy, 1996; 8: 205-212.

Claims

I. The use of human interferon-α to prepare a medicament in spray form for the preventive or therapeutic treatment of viral infections. 2. Use as claimed in claim 1 of an aqueous solution of human interferon-α.

3. Use as claimed in claim 2 of an aqueous solution containing 150 to 150,000 IU/ml of human interferon-α.

4. Use as claimed in claim 1, wherein the human interferon-α is natural, recombinant or synthetic. 5. Use of a solution of human interferon-α as claimed in the preceding claims for the preventive or therapeutic treatment of HCV, HPV, Herpes Virus and Rhino virus infections.

6. Spray bottle containing human interferon-α.

7. Spray bottle as claimed in claim 6, containing an aqueous solution of human interferon- α .

8. Spray bottle as claimed in claim 7, wherein the aqueous solution contains 150 to 150,000 IU/ml of human interferon-α.

9. Spray bottle as claimed in claim 8, containing 1 to 6 extractable doses of human interferon-α, at a concentration of 150-1500 IU/dose. 10. Spray bottle as claimed in claims 8 and 9, also containing an excipient selected from stabilizers, adsorption and absorption activators.

I I . Spray bottle as claimed in claims 6-10, for mucosal or cutaneous administration.

12. Spray bottle as claimed in claim 11, for peroral administration through the oropharyngeal mucous membranes.