ANTIVIRAL PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF DENGUE, INFLUENZA AND HIV/AIDS

TECHNICAL FIELD

The present invention relates to an improved pharmaceutical formulation for treating viral diseases, especially Dengue fever, Influenza and human immunodeficiency virus causing acquired immunodeficiency syndrome (HIV/AIDS). In particular, the present invention relates to a more effective pharmaceutical formulation that promotes full recovery of patients suffering from classical Dengue fever, Dengue Hemorrhagic Fever (DHF) & Dengue Shock Syndrome (DSS), viral influenza, and HIV/AIDS.

BACKGROUND OF THE INVENTION

The World Health Organization (WHO) has provided a number of free publications about dengue and ranks it as the most important mosquito-borne viral disease in the world. In the past few years, dengue is recorded as occurring in over 100 countries with an estimated 50-100 million cases each year. Currently, there is still no specific antiviral treatment or effective vaccine for dengue. Research on this is still in various stages of development.

In actual practice, Dengue is managed only by supportive care with analgesics, fluid replacement, and bed rest. Severe dengue is managed by careful attention to fluid management and proactive treatment of hemorrhage. Study on single-dose methylprednisolone, for instance, showed no mortality benefit in the treatment of dengue shock syndrome (DSS) under a prospective, randomized, double-blind, placebo-controlled trial. There is no specific and effective treatment also for Dengue Hemorrhagic Fever (DHF) that is currently available. DHF is a potentially fatal complication of dengue fever that is characterized by high fever and internal hemorrhaging. DHF affects most Asian countries and has been identified already as the leading cause of hospitalization and death among children and adults in the region.

Influenza or better known as the flu is a highly contagious illness that can occur in children or adults of any age more often in the winter months as it is easily spread from person-to-person by coughing, sneezing, or touching surfaces. Every year, the United States alone have more than 200,000 people that are hospitalized due to complications of the flu. On some instances, flu outbreaks also occur in many parts of the world when new strains of influenza viruses formed.

Antiviral medicines, such as Oseltamivir (Tamiflu®), Zanamivir (Relenza®), Rimantadine (Flumadine®) and Amantadine (Symmetrel®), can be used to treat or prevent influenza. However, these medicines are generally no longer effective because most flu viruses are now resistant to them. Antiviral treatment is most effective only for seasonal influenza when it is taken within the first 48 hours of flu symptoms. WHO continuously monitors antiviral susceptibility of circulating influenza viruses to provide appropriate guidance for antiviral use in clinical management and potential chemo-prophylaxis.

Although there is no cure for acquired immunodeficiency syndrome (AIDS), several medications have been developed that are generally effective in fighting HIV and its complications, mainly by interrupting the virus from duplicating that will thereafter slow the spread of HIV. However, the use of treatment as prevention is still widely debated on a public health level since antiretroviral treatment can cause serious side effects and can lead to drug resistance if not taken exactly as prescribed. Thus, an HIV-positive person should be reminded of the right to decide whether or not to take the treatment by weighing up the potential disadvantages and benefits for their own health. On a community level, with the increase in access to medicines, it has been seen that as the number of people taking more effective HIV treatment has risen and thus community viral load has decreased. However, even with this condition, a need for an increase in access to a wider selection of treatment for HIV/AIDS still exists. US 5,922,340 of Langer et.al. teaches a high load formulation comprising dexamethasone and procaine in a biocompatible controlled release form selected from the group consisting of slabs, beads, pellets, microspheres, microcapsules, pastes, rods, fibers, and liposomes with prolonged anesthetic action. This patent discloses that procaine and dexamethasone mixture or formulation purely functions as an anesthetic, and not as an antiviral formulation. The disclosure suggests an on-demand and on-site manual mixing and/or administration of the injectable formulation.

PH 31161 of the same inventor for this case, Ruben G. Fabunan, M.D., utilized procaine hydrochloride with epinephrine as the hydrochloride, and dexamethasone sodium phosphate but for another therapeutic application. It was directed to an envenomation antidote for therapeutic use in the treatment of venomous animal bites or stings including snakes and catfish stings consisting essentially of procaine hydrochloride with epinephrine as the hydrochloride, and dexamethasone sodium phosphate. The antidote comprises effective amounts of procaine hydrochloride with epinephrine and dexamethasone sodium phosphate, preferably present from about 5 to about 20 milligrams of procaine per milliliter, 2% with epinephrine, and from about 4 to 8 milligrams of dexamethasone sodium phosphate per milliliter. Still, the present inventor, through US 6,172,053 (herein referred to as

USPN Ό53), has initially provided treatment for a broad spectrum of diseases for which dengue, influenza and HIV/AIDS are included. However, USPN Ό53 broadly disclosed a method of treatment for human individuals infected with Dengue fever virus, influenza virus or HIV/AIDS virus comprising administering to said individuals, a liquid mixture of procaine hydrochloride in the range of 5 to 40 mg and dexamethasone sodium phosphate in the range of 1 to 4 mg., that is compounded manually right or just before the administration by mixing a prescribed amount of an US FDA (Food and Drugs Administration)-approved aqueous solution of procaine hydrochloride with a prescribed amount of an US FDA-approved aqueous solution of dexamethasone sodium phosphate. Generally, the composition is used to treat and/or cure a number of known pathogenic viruses, including but not limited to HIV causing AIDS, Dengue fever virus, influenza virus, rhinovirus causing common colds, herpes zoster virus, mumps virus, measles virus, hepatitis virus, conjunctivitis virus, rabies virus, chicken pox virus and other viruses commonly found in equatorial environments common to Third World and developing countries, as well as in industrialized nations.

Though already found to be effective in the treatment of such diseases, the present inventor has devoted further research and study on the most effective doses and treatment regimen of said combination so as to promote increase and faster medication for said life-threatening diseases. The inventor had further explored specific ratios/proportions that are most effective and faster in providing full treatment. Most often, patients suffering from these diseases are diagnosed only during severe condition already, and thus may require a more effective and faster treatment for their conditions. Prior disclosure refers to a broad spectrum of diseases, while the inventor has now found a specific range, which is most effective in said specifically identified three (3) diseases. Therefore, this present invention aims to provide solution to the existing need for a more effective composition and dosage regimen to treat effectively dengue virus, influenza, and HIV/AIDS.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a more effective and immediate relief and treatment of life-threatening diseases such as Dengue fever virus, influenza and HIV/AIDS. Specifically, this invention provides an injectable preparation comprising the pharmaceutical composition of definite range of procaine and dexamethasone.

Accordingly, the present invention provides specific doses of the active components procaine hydrochloride and dexamethasone sodium phosphate for a more effective and faster treatment of Dengue fever virus.

Specifically, this invention provides a pharmaceutical combination having synergistic effect for patient infected with dengue virus including Dengue Hemorrhagic Fever and Dengue Shock Syndrome with optimum result than prior disclosed treatment regimen.

Also, the present invention provides specific doses of the active components procaine hydrochloride and dexamethasone sodium phosphate for a more effective and faster treatment of influenza. Specifically, this invention provides a pharmaceutical combination having synergistic effect for patient infected with influenza virus which will result to full recovery.

Further, the present invention provides specific doses of the active components procaine hydrochloride and dexamethasone sodium phosphate for a more effective and faster treatment of HIV. Prior disclosed formulation and treatment regimen described in USPN '053 does not deliver complete treatment, but merely mitigates and maintains survival of HIV patients. The present invention enables faster and full recovery of HIV positive patient in a carrier state.

Accordingly, the present invention also provides methods for the treatment of human virus diseases in an individual infected with Dengue fever virus, influenza virus and HIV/AIDS comprising administering to said individual in need thereof an effective amount of an antiviral formulation comprising the combination of procaine and dexamethasone.

Generally, the present invention provides different and specific optimum ratio of procaine hydrochloride to dexamethasone sodium phosphate effective for each of Dengue fever, influenza virus, and HIV. Most importantly, the present invention provides a wider/increase access to treatments of these life- threatening diseases.

DETAILED DESCRIPTION

The present invention includes a formulation of procaine hydrochloride, USP, combined with dexamethasone sodium phosphate, USP, in a more effective and faster treatment and recovery of viral infections, particularly Dengue virus, influenza virus, and HIV. The specific doses and dosing intervals to be described herein set forth the best and more effective mode of promoting full recovery and treatment of patients suffering from said life- threatening viral diseases. The specification of USPN '053 is incorporated herein by way of reference, and the differences of the present formulation will be emphasized.

Procaine hydrochloride is a local anesthetic that blocks the conduction of nerve impulses. It is readily absorbed following parenteral administration and is directly bio-transformed in the bloodstream being hydrolyzed by plasma cholinesterase to para-aminobenzoic acid and diethylaminoethanol within one and one half hours from time of administration. Procaine hydrochloride is the ester of diethylaminoethanol and para-aminobenzoic acid and is related chemically and pharmacologically to ester type local anesthetics. Its chemical name is benzoic acid 4-amino, 2-diethyl(amino)ethyl ester monohydrochloride, and is a water soluble inorganic ester of dexamethasone.

Dexamethasone sodium phosphate is used to treat endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergic states, ophthalmic diseases, gastrointestinal diseases, respiratory diseases, hematologic disorders, neoplastic diseases and edematous states. It has the chemical name 9-fluoro-11 β, 17, 21-trihydroxy-16-methylpregna-1 , 4-diene-3, 20-dione 21-(dihydrogen phosphate) disodium salt.

In USPN Ό53, it came as a surprise that procaine hydrochloride and dexamethasone sodium phosphate, when used together, can have a positive and beneficial effect on the treatment of viral diseases. It is known that certain esters like procaine hydrochloride can act synergistically with esters of dexamethasone to prolong procaine hydrochloride anesthetic activity.

Procaine hydrochloride injection is available as a sterile solution in a concentration of 2% (20 mg of procaine hydrochloride in 1 ml solution). Dexamethasone sodium phosphate is available as a sterile solution in a concentration of 0.4% (4 mg dexamethasone sodium phosphate in 1 ml solution). The present invention includes a formulation comprising a mixture of procaine hydrochloride and dexamethasone sodium phosphate that is injected intramuscularly at specific dosages and regulated dosing intervals depending generally on the type of disease, patient's severity condition, age, body build and response to treatment.

Generally, the present invention relates to a specific formulation comprising 7 to 11 parts procaine hydrochloride in combination with 1 part dexamethasone sodium phosphate or the ratio of procaine hydrochloride to dexamethasone sodium phosphate is 7:1 to 11 : 1 , preferably 9:1 , for HIV treatment. For Dengue and Influenza virus the pharmaceutical formulation comprises 4 parts procaine hydrochloride with 1 part dexamethasone sodium phosphate or the ratio of procaine hydrochloride to dexamethasone sodium phosphate is 4:1. Surprisingly, the specific formulations of the present invention provide optimal effect compared with the formulations disclosed and taught in USPN Ό53.

Specifically, the present invention employs specific formulation comprising 20 mg procaine with 2.5 mg chlorobutanol per ml of solution, and 4 mg of dexamethasone sodium phosphate or 4 mg dexamethasone sodium phosphate with 10 mg benzyl alcohol as preservative per ml solution. For adults, the total volume of 1.5 ml comprising the two solution formulations is aseptically transferred into a sterile syringe. This is equivalent to 1.2 ml of procaine and 0.3 ml dexamethasone sodium phosphate or 4 to 1 optimal ratio. After said two formulations are gently mixed, the formulation- containing syringe is ready for injection. For Classical Dengue and Influenza, optimal effectiveness is achieved through treatment of 2 injections per day for 3 consecutive days. For Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS), optimal effectiveness is achieved through treatment of 2 injections per day for 5 consecutive days. For all the foregoing treatments, the interval between the 2 injections per day should be at least 1 and ½ to 2 hours apart or longer. For children 12 years and younger including infants, the combined volume to be injected is reduced to 1 ml. This is equivalent to 0.8 ml of procaine to 0.2 ml of dexamethasone sodium phosphate or 4 to 1 ratio. After said two formulations are gently mixed, the formulation-containing syringe is ready for injection. For Classical Dengue and Influenza, optimal effectiveness is achieved through treatment of 2 injections per day for 3 consecutive days. For Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS), optimal effectiveness is achieved through treatment of 2 injections per day for

5 consecutive days. For all the foregoing treatments, the interval between the 2 injections per day should be at least 1 and /2 to 2 hours apart or longer.

For the treatment of HIV/AIDS, the combined volume to be injected is 2 ml. This is equivalent to 1.75 ml to 1.83 ml of procaine hydrochloride to 0.17 ml to 0.25 ml of dexamethasone sodium phosphate, or to a ratio of from 7:1 to 11 : 1. Preferably, this is equivalent to 1.8 ml or procaine hydrochloride to 0.2 ml of dexamethasone sodium phosphate, or to a ratio of 9:1. After said two formulations are gently mixed, the formulation-containing syringe is ready for injection. Optimal effectiveness is achieved through continuous treatment of 2 injections per day for about 18 months. The interval between the 2 injections per day should be at least 1 and ½ to 2 hours apart or longer. One skilled in the art would readily determine the total mg of each of the procaine hydrochloride and dexamethasone sodium phosphate that is utilized for the described 2ml, 1.5 ml or 1 ml combined formulations. The examples 1 -

6 included herein clearly illustrate how the specific and desired proportions are achieved by specifically providing the illustrative amount in mg of procaine hydrochloride, dexamethasone sodium phosphate and corresponding preservatives.

The Procaine Hydrochloride produces the DEAE (alcohol) that selectively kills the virus. It is directly bio-transformed in the human bloodstream by the plasma cholinesterase. The Dexamethasone Sodium Phosphate neutralizes the anesthetic effect of Procaine Hydrochloride and prolongs the duration of action of Procaine Hydrochloride in the human bloodstream. The present invention is novel and inventive as the narrow and specific sub-range proportion is characterized by the following: a) Specific range of procaine hydrochloride to dexamethasone sodium phosphate of 4:1 as being significantly more effective for Dengue or Influenza virus, and ratio of 7:1 to 1 1 :1 , preferably 9:1 as being significantly more effective for HIV treatment. These are equivalent to 24 mg of procaine hydrochloride to 1.2 mg of dexamethasone, and from 35 mg to 36.6 mg of procaine hydrochloride to 0.68 mg to 1 mg of dexamethasone sodium phosphate. These data, as shown in the examples hereinafter, are sufficiently specific and narrow from the broad scope of the prior art that claims 5 to 40 mg of Procaine with 2 mg of Dexamethasone. b) Not close to known value(s), and not specifically disclosed and identified in the prior invention. The actual dose used in case study from USPN '053 is 30 mg, 20 mg and 15 mg of procaine in combination with 2 mg of dexamethasone. c) Significantly effective and different technical effect. The comparative test shows that other ranges have only minimal, increment improvement as compared with the present invention wherein the patient infected with virus can achieve full recovery.

The following data show the improvement of product and selection invention. These identify optimum ratios, shortest recovery period, and additional tested ratios of the drugs that were sub-optimal in terms of effectiveness.

A1) For DENGUE Fever (classical dengue) patients:

Optimum ratio = 4 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 3 days will lead to full recovery. The synergistic effect of the combination of the two drugs is most effective at this ratio and this duration of treatment is found to be the optimal treatment for full recovery. Sub-optimal ratio = 1 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 2 days - never reached full recovery and minimal improvement of condition Sub-optimal ratio = 6 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 4 days - moderate improvement of condition

Sub-optimal ratio = 9 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 5 days - minimal improvement of condition

Sub-optimal ratio = 12 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 6 days - minimal improvement of condition

A2) For DENGUE Fever - (Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS)) patients:

Optimum ratio = 4 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 5 days will lead to full recovery. The synergistic effect of the combination of the two drugs is most effective at this ratio and this duration of treatment is found to be the optimal treatment for full recovery.

Sub-optimal ratio = 1 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 2 days - never reached full recovery and minimal improvement of condition

Sub-optimal ratio = 6 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 4 days - moderate improvement of condition

Sub-optimal ratio = 9 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 3 days - minimal improvement of condition

Sub-optimal ratio = 12 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 6 days - minimal improvement of condition B) For Viral Influenza patients:

Optimum ratio = 4 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 3 days will lead to full recovery. The synergistic effect of the combination of the two drugs is most effective at this ratio and this duration of treatment is found to be the optimal treatment for full recovery.

Sub-optimal ratio = 1 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 2 days - never reached full recovery and minimal improvement of condition

Sub-optimal ratio = 6 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 4 days - moderate improvement of condition Sub-optimal ratio = 9 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 5 days - minimal improvement of condition

Sub-optimal ratio = 12 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 6 days - minimal improvement of condition

C) For HIV/ AIDS patients:

Optimum ratio = 9 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 18 months will lead to full recovery, sterilizing cure, non-infectious. Still HIV positive in the carrier state but the HIV virus is selectively killed and inactivated in the bloodstream (2% in the circulating blood) and the other 98% found in the sanctuary sites and blood brain barrier (hiding places).

Sub-optimal ratio = 1 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 36 months - never reached full recovery and minimal improvement of condition Sub-optimal ratio = 3 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment for 24 months - improvement of condition but not full recovery Sub-optimal ratio = 6 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 12 months - improvement of condition but not full recovery

Sub-optimal ratio = 12 to 1 (Procaine to Dexamethasone), 2 times per day, with a Duration of Treatment of 6 months - improvement of condition but not full recovery

If Dexamethasone Sodium Phosphate to Procaine Hydrochloride ratio is reversed, for example 4 to 1 Dexamethasone to Procaine instead of 4 to 1 Procaine to Dexamethasone, there will be no antiviral effect, no synergistic combination of the two drugs, and no recovery. Only Procaine Hydrochloride produces the DEAE (alcohol) which selectively kills the virus. It is directly bio- transformed in the human bloodstream by the plasma cholinesterase. The Dexamethasone Sodium Phosphate neutralizes the anesthetic effect of Procaine Hydrochloride and prolongs the duration of action of Procaine Hydrochloride in the human bloodstream.