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WO2001087229A2 - Traitement d'infections - Google Patents

Traitement d'infections Download PDF

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Publication number
WO2001087229A2
WO2001087229A2 PCT/IB2001/000859 IB0100859W WO0187229A2 WO 2001087229 A2 WO2001087229 A2 WO 2001087229A2 IB 0100859 W IB0100859 W IB 0100859W WO 0187229 A2 WO0187229 A2 WO 0187229A2
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WO
WIPO (PCT)
Prior art keywords
infection
virus
composition
pharmaceutical formulation
substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2001/000859
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English (en)
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WO2001087229A3 (fr
Inventor
Christian Matthews Westinghouse
Andries Johannes Lategan
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LATWEST PHARMACEUTICALS Pty Ltd
Original Assignee
LATWEST PHARMACEUTICALS Pty Ltd
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Filing date
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Priority to AU2001258675A priority Critical patent/AU2001258675A1/en
Priority to PCT/IB2001/000859 priority patent/WO2001087229A2/fr
Publication of WO2001087229A2 publication Critical patent/WO2001087229A2/fr
Publication of WO2001087229A3 publication Critical patent/WO2001087229A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules

Definitions

  • the present invention relates to the field of medicine generally, in particular to the treatment of infections, protocols for the treatment of infections, particularly viral infections and more particularly, the encapsulation of pharmaceutical compositions, to specify delivery, for use in the treatment of the infections.
  • the acquired immune deficiency syndrome AIDS is a disease characterized by the loss of cell-mediated immunity. It is attributable to a virus that belongs to the family of retroviruses very prevalent in the animal kingdom and is called human immunodeficiency virus (HIV). Disturbances of the entire immunodefense mechanisms result from the HIV infection, because above all the T4 or helper cells of the T system of the specific immunodefense are prevented from carrying out their role in the regulation of the immunoresponse.
  • HIV- induced T4 reduction results in the development of frequent and eventually fatal opportunistic infections caused by pathogenic organisms such as viruses, bacteria, protozoa's or fungi, normally harmless if there is a normal balance between the different T cell populations.
  • Th1 T helper 1
  • Anti-viral agents that inhibit replication of viruses have been known since the mid 1980's. Hundreds of drugs are now available for inhibiting the replication of the HIV virus, however, they are very expensive, their side effects are often so severe that treatment must be halted and HIV resistant strains quickly develop. Furthermore, conventional anti-HIV agents do not provide sufficient effect. There is a need for new, less expensive, less toxic and more effective treatments that work against HIV. These new therapies would preferably be virus non-specific so as to prevent the promotion of resistant strains.
  • Bromelain has been long used as a digestive aid, as a cleansing agent to improve the texture of skin, and to treat wounds to promote healing. More recently, Bromelain is used as an adjunct in the treatment of soft tissue inflammation and oedema associated with trauma and surgery as disclosed in US 5,560,910. Additionally, Bromelain has the ability to block influenza viral activity, by cleaving influenza hemaglutinin necessary for viral entry as discussed by Bodian et al (Biochem. 32 2967-2978 (1 992). Furthermore, US 5,223,406 describes its use in the induction of tumour necrosis factor (TNF), a therapeutic anticancer agent. US 5,824,305 discloses its use in the treatment of cancer.
  • TNF tumour necrosis factor
  • a method is provided to treat or prevent an infection and/or immune dysregulation, the method comprising administering to a subject an effective amount of at least one phenolic antioxidant.
  • the present invention also provides the use of at least one phenolic antioxidant for the manufacture of a medicament for the treatment of infections and/or immune dysregulation.
  • the present invention also provides phenolic antioxidants for use in a method of treatment of infections and/or immune dysregulation, said method comprising administering one or more of said phenolic antioxidants to a subject in need thereof.
  • the present invention is directed to a composition characterized in that the composition comprises one or more phenolic antioxidants or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients, and a delivery vehicle which is configured to avoid releasing the phenolic antioxidants in the stomach of a subject.
  • compositions in a pharmaceutical formulation which includes a phenolic antioxidant for treatment, therapeutic or prophylactic, against an infection, particularly a viral infection and/or immune dysregulation.
  • the composition containing the phenolic antioxidant is designed so that upon administration, prior exposure to the stomach is not a requirement before the drug is released. This is because the phenolic antioxidant is encapsulated in a biodegradable microsphere or encapsulating body or delivered by a delivery vehicle which avoids releasing the phenolic antioxidant in the stomach. This satisfies the need for a non-specific, inexpensive antiviral treatment that is not exposed to the stomach.
  • the embodiments of the present invention provide a cheap but effective antiviral agent that is protected from the risk of it promoting stomach carcinogenesis by specifically designing the delivery system so that there is no risk of prior exposure to the stomach. This is effected by containing or carrying the phenolic antioxidant in or on a biodegradable microsphere or encapsulating body or delivery vehicle.
  • the at least one phenolic antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, butylhydroquinone, propylgallate, and 2,4,5trihydroxybutylphenone and their derivatives, metabolites, analogues and/or mimic molecules thereof.
  • the at least one phenolic antixoidant is selected from the group consisting of butylated hydroxyanisole or its metabolites their derivatives, metabolites, analogues, and/or mimic molecules thereof.
  • the delivery vehicle consists of an enteric coating.
  • the enteric coating may be of a polymer or copolymer.
  • the polymer or copolymer is selected from the group consisting of poly(lactic-glycolic acid) polyester, cellulose acetate phthalate, hydroxypropyl-methyl cellulose phthalate polyfbutyl methacrylate), (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate.
  • the delivery vehicle consists of enterically coated beads or micropellets of the pharmaceutical formulation incorporated into a common foodstuff or drink for ease and convenience of administration and increased compliance.
  • the delivery vehicle consists of a liposome.
  • the delivery vehicle consists of a suppository.
  • the delivery vehicle consists of an attached carrier molecule, preferably PEG.
  • the delivery vehicle consists of a transdermal patch.
  • the delivery vehicle consists of an implant.
  • the present invention is directed towards providing an improved method in the prophylaxis and therapy of infections, particularly viral infections or a complication or consequence thereof.
  • the invention relates to the use of encapsulated phenolic antioxidants in the prophylaxis and therapy of infections, particularly viral infections leading to a deficiency of the immune system resulting in the development of opportunistic infections and certain cancers.
  • the invention relates to the use of encapsulated phenolic antioxidants in the prophylaxis and therapy of infections, particularly viral infections, an example of which is the retrovirus, thought to be responsible for the Acquired Immune
  • AIDS AIDS and AIDS related syndromes, believed to result from infection from the Human Immunodeficiency Virus (HIV), antibodies to which are found in almost all individuals diagnosed with AIDS.
  • HIV Human Immunodeficiency Virus
  • the present invention is further directed to a method in the prophylaxis and therapy of AIDS related syndromes such as cachexia and/or wasting syndrome.
  • the present invention provides a pharmaceutical formulation for use in a method of treatment of an infection and/or immune dysregulation, preventing a future infection and/or minimizing the effect of a future infection and/or the regulation of the immune system, said formulation comprising at least one phenolic antioxidant; and a biodegradable microsphere; and said method comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of said formulation.
  • the present invention also provides a pharmaceutical formulation for use in a method of treatment of an infection and/or immune dysregulation, preventing a future infection and/or minimizing the effect of a future infection and/or regulation of the immune system, said formulation comprising at least one proteolytic enzyme; and said method comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of said proteolytic enzyme.
  • a pharmaceutical formulation for treating an infection and/or immune dysregulation comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a composition comprising at least a phenolic antioxidant; and a delivery vehicle as hereinbefore described, to prevent the release of the phenolic antioxidant into the stomach.
  • the advantage of the above described embodiments is that when the infection is a viral infection, a cheap effective antiviral agent is provided that has minimal risk of conferring resistance. By encapsulating or containing it in a suitable delivery vehicle, there is no exposure to the stomach.
  • the present invention also provides a pharmaceutical formulation for use in a protocol for treatment of an infection and/or immune dysregulation comprising: administering a prophylactically or therapeutically effective amount of a first composition to a patient in need thereof; during the treatment period.
  • the first composition is a composition as previously described.
  • composition further includes a halogen salt.
  • phenolic antioxidant is halogenated.
  • the halogen is selected from the group consisting of chlorine, fluorine, bromine and iodine.
  • phenolic antioxidants act to reduce viral loads by producing a generalized and non-specific immunological response on the part of the host, that manifests itself during infection.
  • production and/or activity of neutrophils and/or monocytes is enhanced in patients to whom (A) a halogenated salt of a phenolic antioxidant and/or (B) a halogen salt plus a phenolic antioxidant is administered.
  • A a halogenated salt of a phenolic antioxidant
  • B a halogen salt plus a phenolic antioxidant
  • Degranulated neutrophils contain a reduced amount of granules of myeloperoxidase, or contain no granules of myeloperoxidase, as a result of several mechanisms, many of which relate to conditions against which the present invention is directed.
  • Patients having low counts of neutrophils, and/or having a large portion of their neutrophil count degranulated will have low myeloperoxidase index (MPXI).
  • MPXI myeloperoxidase index
  • Such patients are immunosuppressed and have limited capability to remove opportunistic infections caused by pathogenic organisms such as viruses, bacteria, protozoa's or fungi.
  • neutrophils have a lifetime of about 2 or 3 days, so it is preferred that their supply be replenished on a regular basis to achieve the full benefits of the aspects of the present invention, which require myeloperoxidase presence in the patient.
  • a supply of myeloperoxidase is provided by stimulating production of fresh neutrophils, which will contain granules of myeloperoxidase and other anti-microbial enzymes.
  • myeloperoxidase can react with hydrogen peroxide (H 2 0 2 ) and halogen to generate hypohalogenous acid, e.g., hypobromous acid (HOBr).
  • hypohalogenous acid e.g., hypobromous acid (HOBr).
  • the selected halogen may be selected from the group consisting of chlorine, bromine, fluorine and iodine.
  • Halogenated salts or halogenated phenolic antioxidants can provide the halogen needed in the reaction described in the preceding paragraph.
  • Hypohalogenous acid is a potent sterilant, which is effective for eradicating the deleterious agent or agents in the circulatory system, thereby providing benefits to the patient, e.g., reducing viral quantitative culture measurement in plasma and serum.
  • hypohalogenous acid is very toxic, such that it could not be administered to a patient in amounts sufficient to provide the desired effects without being unduly toxic.
  • the reason for this is that the hypohalogenous acid has a very short half-life.
  • the advantage of administering a pharmaceutical formulation containing a halogenated salt of phenolic antioxidant or a halogen salt plus a phenolic antioxidant in a delivery vehicle as hereinbefore described is three fold:
  • the phenolic antioxidant eliminates the virus by a specific mechanism, perhaps by immunomodulation.
  • the protocol or method of the invention comprises the additional administration of a second composition.
  • the second composition may comprise one or more proteolytic enzymes with pharmaceutical acceptable additives, diluents, carriers, excipients and pharmaceutical salts thereof.
  • the proteolytic enzymes may be selected from the group consisting of bromelain, chymotrypsin, trypsin, pepsin, carboxypepsidase, aminopepsidase and urokinase.
  • the proteolytic enzyme is bromelain.
  • composition further includes bromelain and/or a combination of any proteolytic enzyme.
  • bromelain has known anticancer activity, but also has antiviral activity.
  • the two compounds act synergistically to reduce viral loads with minimal risk of stomach cancer.
  • the phenolic antioxidants enhance the immune system and this results in increased "apparent" viral replication, detectable using PCR.
  • the viral replication is described as "apparent” as the majority of the viruses detected are not functional. However, their detectable presence might question the effectiveness of the composition.
  • proteolytic enzymes such as bromelain, the viruses are digested, counteracting the immunomodulating effects of the phenolic antioxidants. This results in a profile of reduced viral load and enhanced immunity.
  • the protocol or method of the invention comprises the additional administration of a third compound or composition, comprising one or more antioxidants or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients.
  • the antioxidants may be selected from the group consisting of vitamin C, selenium, beta-carotene, and vitamin A.
  • the antioxidant is vitamin C.
  • the protocol or method of the invention comprises the additional administration of a fourth composition, comprising zinc gluconate or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients.
  • phenolic antioxidants, proteolytic enzymes, antioxidants and/or zinc gluconate can be administered individually or in a single composition.
  • the suitable formulation will depend on the nature of the disorder to be treated, the nature of the medicament chosen, and the judgment of the attending physician. In general, these compounds are formulated either for rectal or oral administration, although other modes of administration such as transmucosal or transdermal routes may be employed. Suitable formulations for these compounds can be found, for example, in Remington's Pharmaceutical Sciences (latest edition), Mack Publishing Company, Easton, Pa.
  • the compounds of the invention can be formulated and administered as free bases or in the form of their pharmaceutically acceptable salts for purposes of stability, convenience of crystallization, increased solubility, and the like.
  • the immune dysregulation may be caused by an infection.
  • the infection is a viral infection.
  • the viral infection may be selected from the group consisting of a retrovirus infection, a togavirus infection, a flavivirus infection, a rubivirus infection, a pestivirus infection, a lipid envelope virus infection, a picornavirus infection, a rhinovirus infection, a coronavirus infection, a respiratory syncytial virus infection, a poliovirus infection, a filovirus, a parainfluenza virus infection, influenza virus infection and a hantavirus infection.
  • the viral infection may be selected from the group consisting of an infection by one or more of HIV, HTLV-1 , HTLV- 3, Kaposi's sarcoma-associated herpes virus, HHV-6, HHV-8, the viruses of the genus
  • the viral infection is caused by HIV or AIDS virus, Epstein Barr virus, Herpes virus, cytomegalovirus, or an animal virus.
  • the viral infection may be a filovirus infection.
  • the filoviral infection may be Ebola virus or Marburg virus infection.
  • the pharmaceutical formulation is used to treat AIDS related syndromes, including cachexia and/or wasting syndrome.
  • the pharmaceutical formulation according to the present invention can be administered to a patient in any of a wide range of routes, with the stipulation that the active ingredient is not released into the stomach.
  • suitable routes include enteric, parenteral, topical, oral, rectal, nasal or vaginal routes.
  • Parenteral routes include subcutaneous, intramuscular, intravenous, intraperitoneal, intradermal and sublingual administration.
  • compositions may be implanted into a patient or injected using a drug delivery system.
  • the pharmaceutical formulation according to the present invention may be administered locally or systemically.
  • systemic administration is meant any mode or route of administration which results in effective amounts of active ingredient appearing in the blood or at a site remote from the route of administration of the active ingredient.
  • the pharmaceutical formulation according to the present invention may be administered intermittently.
  • the advantage of this is that it allows the patient to suspend therapy for periods without the worry of inactivity of the drug resulting from the development of a resistant strain. Additionally, the pharmaceutical formulation according to the present invention can be administered simultaneously.
  • the pharmaceutical formulation according to the invention may be formulated for enteral, parenteral or topical administration. Indeed all three types of formulations may be used simultaneously to achieve systemic administration of the active ingredient.
  • micronized means that the compositions have been micronized in accordance with any process for micronizing, a number of which are known in the art.
  • the micronized particles preferably include a percentage of particles, which are of a diameter, which is about 10 microns, or less, preferably 5 microns or less.
  • at least 80% of the particles in a formulation of micronized particles have a diameter of less than 5 microns.
  • An alternative to micronizing a compound is to solubilize the compound and put it into liposomes of appropriate size. The manufacture of liposomes and the insertion of active ingredients into such liposomes are well known in the art.
  • the compound can be formulated into solid or liquid preparations.
  • suitable formulations for oral administration include hard or soft gelatin capsules, dragees, pills, tablets, including soft-coated tablets, troches, lozenges, melts, powders, micronized particles, non-micronized particles, solutions, emulsions, elixrs, suspensions, syrups or inhalations and controlled release forms thereof.
  • all formulations shall be surrounded or delivered by a biodegradable microsphere or encapsulating bodies or delivery vehicles to ensure that the active ingredient is not released into the stomach.
  • a preferred feature of the present invention is that the first composition is formulated into a suppository and administered rectally, while the second composition is administered orally and the formulation is enterically coated.
  • An additional preferred feature of the present invention is that the first composition is administered orally and the formulation is enterically coated.
  • the tolerance of oral compositions of phenolic antioxidants and their salts and esters can be improved if such compositions contain a buffering agent or an enteric coating agent such that the compounds of the invention do not have any contact with the stomach, thereby minimizing the risk of cancer.
  • Such buffered or enterically coated compositions may be prepared in accordance with conventional pharmaceutical practice.
  • Solid dosage forms in addition to those formulated for oral administration include rectal suppositories.
  • the delivery vehicle consists of a suppository.
  • the delivery vehicle consists of a liposome.
  • a liposome The advantage of using a liposome is that the phenolic antioxidants can be incorporated into the lipid layer, while the bromelain or other proteolytic enzymes can be incorporated into the aqueous phase, thus providing an ideal delivery system for the composition.
  • Suitable injectable solutions include intravenous, subcutaneous and intramuscular injectable solutions. Examples of injectable forms include solutions, suspensions and emulsions.
  • the compound(s) is injected in association with a pharmaceutical carrier such as normal saline, Ringers solution, dextrose solution and other aqueous carriers known in the art.
  • non-aqueous carriers may also be used and examples include cyclodextrin, fixed oils and ethyl oleate.
  • a preferred carrier is 5% dextrose in saline.
  • additives in the carrier such as buffers and preservatives or other substances to enhance isotonicity and chemical stability.
  • a preferred feature of the present invention is that the compound is attached to a carrier molecule and is injected.
  • the pharmaceutical formulation can also be administered topically.
  • Suitable formulations for topical administration include creams, gels, jellies, mucliages, pastes and ointments.
  • the compounds may be formulated for transdermal administration, for example in the form of transdermal patches so as to achieve systemic administration.
  • the pharmaceutical formulation may also be administered in the form of an implant.
  • the pharmaceutical formulation may also be administered in the form of an infusion solution or as a nasal inhalation or spray.
  • compositions are incorporated in a pharmaceutically acceptable carrier, diluents, vehicles and the like for systemic administration by feeding.
  • a pharmaceutically acceptable carrier is cyclodextrin (alpha-cyclodextrin, beta-cyclodextrin (beta- hydroxypropylcyclodextrin), gamma-cyclodextrin).
  • dosage and duration of treatment it is recognized that the ability of an artisan skilled in pharmaceutical administration of drugs to determine suitable dosages depending on many inter-related factors is well known, and skilled artisans are readily able to monitor patients to determine whether treatment should be started, continued, discontinued or resumed at any given time.
  • dosages of the compounds are suitably determined depending on the individual cases taking symptoms, age and sex of the subject and the like into consideration.
  • the amount of the compound to be incorporated into the pharmaceutical composition of the invention varies with dosage route, solubility and chemical properties of the compound, administration route, administration scheme and the like.
  • An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient and the method route and dose of administration.
  • the clinician using parameters known in the art makes determination of the appropriate dose.
  • the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved.
  • Suitable dosages can be determined by further taking into account relevant disclosure in the known art.
  • the phenolic antioxidants according to the present invention are administered at doses that far exceed the levels determined for preservatives in food.
  • the invention provides use of the pharmaceutical formulation in the manufacture of a medicament for use in the prophylaxis or therapy of an infection, particularly a viral infection or a complication or consequence thereof.
  • the invention provides use of the pharmaceutical formulation to provide protection against infections, particularly viral infections in immunocompromised animals and humans. These compositions may be used prophylactically or therapeutically to protect animals or patients from the consequences of infection by pathogenic organisms.
  • the invention provides use of the pharmaceutical formulation in veterinary medicine, prophylactically and therapeutically in animal populations that are subject to infections, particularly viral infections that compromises immune response.
  • the invention provides use of the pharmaceutical formulation in the treatment of immunocompromised AIDS victims or those infected with a retrovirus such as HIV virus showing the AIDS related complex (ARC).
  • a retrovirus such as HIV virus showing the AIDS related complex (ARC).
  • the present invention is also broadly directed providing the use of the pharmaceutical formulation in the treatment (i.e., in the sense of treating an existing infection, preventing a future infection, minimizing the effect of a future infection and/or enhancing the performance of a vaccine) of all infections which are not retroviral infection and can also cause dysregulation of the immune system, treatment resulting in the regulation of the immune system , several representative examples of which include one or more kind of Mycoplasma, and/or one or more diseases caused by Mycoplasmas and/or one or more of the following infections: hairy leukoplakia, oral candidosis, mouth ulcerations aphthous/herpatic/bacterial, fungal Candida, squamous oral carcinoma, Kaposi's sarcoma oral lesions, periodontitis, necrotizing gingivitis, human papilloma virus, rhinovirus and arboviral molluscum contagiosum, orafacial herpes zoster, Epstein barr virus, rotaviruses
  • virus infections that may be treated include but are not limited to HIV, SIV, FIV, FELV, SHIV, Kaposi's Sarcom-associated herpes virus and other herpes viruses (e.g. HSV-1 , HSV-2, human herpes virus 6 (HHV-6) and HHV-8), the viruses associated with hepatitis (HAV, HBV, hepatitis C virus [HCV]), and human cytomegalovirus, togaviruses and flaviviruses, e.g., California encephalitis virus, St.
  • the pharmaceutical formulation is also useful to ameliorate one or more symptoms associated with viral infections, e.g., fever, pain or fatigue.
  • the present invention further provides a pharmaceutical formulation to prophylactically or therapeutically treat an infection and/or immune dysregulation, preventing a future infection, protecting those at risk of encountering the infection and/or minimizing the effect of a future infection and/or regulation of the immune system comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a composition comprising at least a phenolic antioxidant and a delivery vehicle as hereinbefore described.
  • the pharmaceutical formulation comprises at least a phenolic antioxidant, a proteolytic enzyme and said delivery vehicle. In another embodiment, the pharmaceutical formulation comprises at least a proteolytic enzyme and said delivery vehicle.
  • a method of treating a viral infection comprises: administering at least one phenolic antioxidant and at least one proteolytic enzyme during the treatment period.
  • the present invention further provides a pharmaceutical formulation, for use in a treatment protocol or method to prophylactically or therapeutically treat an infection and/or immune dysregulation, prevent a future infection, protect those at risk of encountering the infection and/or minimize the effect of a future infection, comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a first composition comprising at least one phenolic antioxidant and a delivery vehicle as hereinbefore described, later followed by a second composition comprising a proteolytic enzyme, antioxidant and/or zinc gluconate and a delivery vehicle as hereinbefore described, during the treatment protocol.
  • a pharmaceutical formulation for use in a treatment protocol or method to prophylactically or therapeutically treat an infection and/or immune dysregulation, prevent a future infection, protect those at risk of encountering the infection and/or minimize the effect of a future infection, comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a first composition comprising at least one phenolic antioxidant and a delivery vehicle as
  • the invention also provides a method of treating an infection wherein the treatment protocol or method comprises: administering at least one phenolic antioxidant and at least one proteolytic enzyme, antioxidant and/or zinc gluconate during the treatment period.
  • the invention further provides a pharmaceutical formulation comprising a composition comprising one or more phenolic antioxidants or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients and a delivery vehicle as hereinbefore described.
  • the present invention also provides a pharmaceutical formulation comprising a composition comprising one or more proteolytic enzymes or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients and a delivery vehicle as hereinbefore described.
  • the composition further includes a halogen salt.
  • the phenolic antioxidant is halogenated.
  • the halogen is selected from the group consisting of chlorine, fluorine, bromine and iodine.
  • the composition further includes one or more proteolytic enzymes or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients.
  • the proteolytic enzymes may be selected from the group consisting of bromelain, chymotrypsin, trypsin, pepsin, carboxypepsidase, aminopepsidase and urokinase.
  • the proteolytic enzyme is bromelain.
  • the composition further includes one or more antioxidants or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients.
  • the antioxidants may be selected from the group consisting of vitamin C, selenium, beta-carotene, and vitamin A.
  • the antioxidant is vitamin C.
  • composition further includes zinc gluconate or pharmaceutical salts thereof optionally with pharmaceutical acceptable additives, diluents, carriers, or excipients.
  • the pharmaceutical formulation may be used to treat an infection and/or immune dysregulation.
  • Fig. 1 is a graph showing the effect of 3t-butyl-4-hydroxyanisole (BHA) on ROJO virus (%VC) in peripheral blood mononuclear cells (PBMC) and its effects on cell viability (%CC), while tables 1 and 1 A depict the individual data shown in figure 1 ;
  • BHA 3t-butyl-4-hydroxyanisole
  • %VC ROJO virus
  • PBMC peripheral blood mononuclear cells
  • %CC cell viability
  • Fig. 2 and tables 2 and 2A illustrate another embodiment or aspect of the invention, showing the effect of butylhydroquinone (BHQ) on ROJO virus (%VC) in PBMC cells and its effects on cell viability (%CC);
  • BHQ butylhydroquinone
  • Fig. 3 and tables 3 and 3A illustrate the effect of 3t-b ' utyl-4-hydroxyanisole (BHA) on Ba-L HIV virus (%VC) and cell viability in macrophages (%CC);
  • BHA 3t-b ' utyl-4-hydroxyanisole
  • Fig. 4 and tables 4 and 4A show the effect of butylhydroquinone (BHQ) on Ba-L HIV virus (%VC) and cell viability in macrophages (%CC);
  • Fig. 5 and tables 5 and 5A illustrate another embodiment or aspect of the invention, showing the effect of bromelain an ROJO HIV virus in PBMC cells;
  • Fig. 6 and tables 6 and 6A show the effect of bromelain on ADA HIV virus (%VC) and cell viability in macrophages (%CC);
  • Fig. 7 and tables 7 and 7A show the effect of bromelain on Ba-L HIV virus (%VC) and cell viability in macrophages (%CC);
  • Fig. 8 and tables 8 and 8A illustrate another embodiment or aspect of the invention, showing the effect of a 50:50 mixture of BHA:bromelain on ROJO virus (%VC) in PBMC cells and its effects on cell viability (%CC); and
  • Fig. 9 and tables 9 and 9A illustrate the effect of a 50:50 mixture of BHA:bromelain on Ba-L HIV virus (%VC) and cell viability in macrophages (%CC).
  • Examples 1 and 2 demonstrate the method and results of tests that were performed to determine the effectiveness of BHA and Butylhydroquinone at reducing the ability of HIV-1 to infect T-lymphocytes and macrophages. Tests were also carried out to determine the toxicological effect of BHA and Butylhydroquinone on uninfected T-lymphocytes and macrophages.
  • Example 3 shows the effectiveness of bromelain at reducing the ability of ROJO and Ba-L strains of HIV to infect T-lymplocytes and macrophages.
  • Example 4 shows the synergistic effectiveness of a 50:50 mixture of BHA:bromelain at reducing the ability of ROJO and Ba-L strains of HIV to infect T-lymplocytes and macrophages.
  • Examples 5 to 8 describe methods of how the phenolic antioxidants could be encapsulated, so that upon administration, by several routes of administration, there is no exposure to the stomach prior to drug release.
  • Anti-HIV activity in fresh human cells Assay in fresh human T-lvmphocvtes
  • Fresh human peripheral blood lymphocytes were isolated from voluntary Red Cross donors, seronegative for HIV and HBV. Leukophoresed blood was diluted 1 :1 with Dulbecco's phosphate buffered saline (PBS) and layered over 14 mL of Ficoll-Hypaque density gradient in a 50 ml centrifuge tube. Tubes were then centrifuged for 30 minutes at 600 X g. Banded PBLs were gently aspirated from the resulting interface and subsequently washed 2X with PBS by low speed centrifugation.
  • PBS Dulbecco's phosphate buffered saline
  • PHA-P stimulated cells from at least two normal donors were pooled, set in fresh medium at 2 x 10 6 /mL and plated in the interior wells of a 96 well round bottom microplate at 50 ⁇ L/well.
  • Test drug dilutions were prepared at a 2X concentration in microtiter tubes and 100 ⁇ L of each concentration was placed in appropriate wells in a standard format. Fifty microliters of a predetermined dilution of virus stock was placed in each test well. Wells with cells and virus alone were used for virus control. Separate plates were identically set without virus for drug cytotoxicity studies using an XTT assay system.
  • Tritiated thymidine triphosphate (NEN) TTP was resuspended in distilled H2O at 5 Ci/ml.
  • Poly rA and oligo dT were prepared as a stock solution which was kept at -20 C.
  • the RT reaction buffer was prepared fresh on a daily basis and consisted of 1 25 I 1 M EGTA, 125 I dH 2 0, 1 10 1 10% SDS, 50 I 1 M Tris (pH 7.4), 50 I 1 M DTT, and 40 I 1 M MgCI 2 .
  • FIG. 1 of the drawings it can be observed that T-lymphocyte cultures remain healthy at all concentrations of BHA used, while % HIV-1 levels decreased in a dose dependent manner.
  • Figure 2 shows similar effect with butylhydroquinone, with some effect on cell viability at higher doses.
  • Anti-HIV activity in fresh human cells Assay in fresh human monocyte-macrophaqes
  • 3 x 10 6 non-PHA stimulated peripheral blood cells were resuspended in Hanks buffered saline (with calcium and magnesium) supplemented with 10% human AB serum. The cells were placed in a 96-well microtiter plate at 37 C for 2 hours.
  • Non-adherent cells were removed by vigorously washing six times. The adherent cells were cultured for 7 days in RPMI 1640 tissue culture medium with 15% fetal bovine serum. The cultures were carefully monitored for confluency during this incubation period. Infection of the cells was performed with monocytotropic HIV-1 isolates. High titer pools of each of these viruses were harvested from infected cultures of peripheral blood adherent cells and frozen in 1 .0 ml aliquots at -80 C. Monocyte-macrophage monolayers were infected at an MOI of 0.1 . Compounds to be evaluated in the monocyte-macrophage assay were added to the monolayers shortly before infection in order to maximize the potential for identifying active compounds.
  • Bromelain was considered as an additional therapy to the phenolic antioxidants. Bromelain was tested in the above-described model to see if it was also effective at reducing levels of ROJO and Ba-L in T-lymphocytes and infected macrophages. The results are presented in figures 5 -7 and tables 5 -7A. It was surprisingly found that Bromelain was very effective at lowering HIV viral levels.
  • the example describes one method of encapsulating a phenolic antioxidant by enterically coating with a cellulose acetate phthalate film.
  • enteric coating targets the release of the composition in the lower gastrointestinal tract.
  • manufacture of enterically coated capsules, cachets, powders, tablets etc, is well known in the art. The following is provided by way of example:
  • the composition can include a phenolic antioxidant and/or bromelain or any proteolytic enzyme.
  • An alternative method to enterically coating compositions is to put them into liposomes of appropriate size.
  • the manufacture of liposomes and the insertion of active ingredients into such liposomes is well known in the art. The following is provided by way of example.
  • the mixture is then dried by rotary evaporation onto the sides of a round bottomed flask.
  • the resultant film is rehydrated by adding 8 mis of 0.9% w/v sodium chloride solution.
  • liposomes are measured by photon correlation spectroscopy using a Malvern Zetasizer 3000. 5. If required, liposomes can be produced below 400 nm by the use of sonication.
  • Formulations that comprise liposomes can be delivered to a subject by any standard route, e.g., oral, aerosol or parenteral (e.g., i.v. or i.m.).
  • Liposomes are ideal for the coadministration of phenolic antioxidants and proteolytic enzymes, particularly for oral, transdermal or IV routes.
  • the phenolic antioxidants can be inserted into the lipid layer, whilst the proteolytic enzymes can be inserted in the aqueous layer.
  • phenolic antioxidants prepared according to examples 3 to 4 enables the compounds to be administered, in particular orally, whereupon they bypass the stomach to be released into the lower gastrointestinal tract.
  • phenolic antioxidants in a suppository formulation, they can be administered rectally.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicyclate. The following is included by way of example:
  • BHA is weighed out accurately, the amount dependant on how many suppositories will be produced. There will be 500 mg per suppository.
  • the BHA is blended with the suppository base, forming an homogenous mixture of the two.
  • the suppository base can be a series of triglycerides derived from edible vegetable oils, which may resemble cocoa butter in their properties. They are extremely stable, uniform in condition, which results in precise melting characteristics and need no special storage conditions.
  • Typical properties may be:
  • Another method of administering the phenolic antioxidants to bypass the stomach is to administer them parenterally.
  • One method of achieving this is by attaching them to a carrier molecule, for example a biocompatible polymer.
  • a carrier molecule for example a biocompatible polymer.
  • biocompatible polymers is polyethylene glycol (PEG) due to its many useful properties including: lack of toxicity and immunogenicity, nonbiodegradability and ease of excretion from living organisms, increased circulating half-life in blood, potentially increasing bioavailability and potency.
  • PEG means an ethylene glycol polymer that contains about 20 to about 2000000 linked monomers, typically about 50 - 1000 linked monomers, usually about 100 -
  • Polyethylene glycols include PEGs containing various numbers of linked monomers e.g. PEG20, PEG30, PEG40, PEG60, PEG80, PEG 100, PEG1 15, PEG200, PEG300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG 1 1000, PEG 12000, PEG2000000 and any mixtures thereof.
  • PEGs containing various numbers of linked monomers e.g. PEG20, PEG30, PEG40, PEG60, PEG80, PEG 100, PEG1 15, PEG200, PEG300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG 1 1000, PEG 12000, PEG2000000 and any mixtures
  • excipient means a component or an ingredient that is acceptable in the sense of being compatible with the other ingredients of the invention compositions or formulations and not overly deleterious to the patient or animal to which the formulation is to be administered.
  • excipients are usually liquids, including benzyl benzoate, cottonseed oil, N,N-dimethylacetamide, an alcohol such as a C 2 . 12 alcohol (e.g. ethanol), glycerol, peanut oil, PEG, vitamin E, poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil and vegetable oil.
  • Excipients as used herein will usually exclude chloroform, dioxane and DMSO.
  • Excipients comprise one or more components typically used in the pharmaceutical formulation arts, e.g. fillers, binders, disintegrants and lubricants.
  • compositions suitable for parenteral delivery of phenolic antioxidants to humans or animals typically comprise two or three or more excipients.
  • Exemplary embodiments include (1 ) any two, three or four of propylene glycol, PEG200, PEG300, ethanol and benzyl benzoate and (2) any two, three or four of propylene glycol, PEG 100, PEG200, / PEG300, PEG400 and benzyl benzoate.
  • the term "lower gastrointestinal tract” means here the lower part of the small intestine (ileum) and the colon.
  • enteric coating means here a coating surrounding the core, the solubility of the coating being dependent on the pH in such a manner that it prevents the release of the drug in the stomach but permits the release of the drug at some stage after the formulation has emptied from the stomach.
  • biodegradable microsphere means a delivery vehicle for the composition, such that the composition is never released into the stomach.

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Abstract

L'invention concerne des antioxydants phénoliques combinés à un véhicule d'administration destiné à empêcher la libération de ces antioxydants phénoliques dans l'estomac d'un sujet. Lesdits antioxydants phénoliques servent à la prophylaxie et à la thérapie d'infections, en particulier d'infections rétrovirales par HIV et d'infections filovirales par le virus d'Ebola. Ces composés peuvent être administrés en combinaison avec des enzymes protéolytiques et/ou des antioxydants.
PCT/IB2001/000859 2000-05-19 2001-05-17 Traitement d'infections Ceased WO2001087229A2 (fr)

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AU2001258675A AU2001258675A1 (en) 2000-05-19 2001-05-17 Treating infections
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035089A1 (fr) * 2001-10-22 2003-05-01 Tanaka-Ai Co., Ltd. Prophylactiques et remedes contre la fievre aphteuse
WO2002098339A3 (fr) * 2001-06-05 2003-09-25 Jeffrey B Smith Compositions contenant du zinc a usage antiviral
US6855341B2 (en) 2002-11-04 2005-02-15 Jeffrey B. Smith Anti-viral compositions and methods of making and using the anti-viral compositions
WO2009074792A3 (fr) * 2007-12-13 2009-11-26 Syntopix Group Plc Nouvelle utilisation
US8168161B2 (en) * 2004-12-22 2012-05-01 Hill's Pet Nutrition, Inc. Method to promote oral health in companion animals
US20240216484A1 (en) * 2020-06-10 2024-07-04 Ursapharm Arzneimittel Gmbh Bromelain protease, bromelain, jacalin-like lectin, extract from the stem and/or the fruit of a pineapple plant, combination preparation, bromelain protease inhibitor, protein/protease mix, and glycated bromelain protein formed by exogenous non-enzymatic glycation, for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3785036D1 (de) * 1987-09-30 1993-04-29 Mucos Emulsionsgesellschaft Mb Verwendung katabolischer enzyme zur herstellung eines medikaments zum bekaempfen der erworbenen immunschwaeche (aids) und deren vorstadien (las, arc).
EP0482071B1 (fr) * 1989-07-14 1998-01-07 Biodor U.S. Holding Corporation Nouveaux agents antiviraux

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098339A3 (fr) * 2001-06-05 2003-09-25 Jeffrey B Smith Compositions contenant du zinc a usage antiviral
US6730329B1 (en) * 2001-06-05 2004-05-04 Jeffrey B. Smith Zinc containing compositions for anti-viral use
WO2003035089A1 (fr) * 2001-10-22 2003-05-01 Tanaka-Ai Co., Ltd. Prophylactiques et remedes contre la fievre aphteuse
US6855341B2 (en) 2002-11-04 2005-02-15 Jeffrey B. Smith Anti-viral compositions and methods of making and using the anti-viral compositions
US7462369B2 (en) 2002-11-04 2008-12-09 Jeffrey B. Smith Anti-viral compositions and methods of making and using the anti-viral compositions
US8168161B2 (en) * 2004-12-22 2012-05-01 Hill's Pet Nutrition, Inc. Method to promote oral health in companion animals
WO2009074792A3 (fr) * 2007-12-13 2009-11-26 Syntopix Group Plc Nouvelle utilisation
US20240216484A1 (en) * 2020-06-10 2024-07-04 Ursapharm Arzneimittel Gmbh Bromelain protease, bromelain, jacalin-like lectin, extract from the stem and/or the fruit of a pineapple plant, combination preparation, bromelain protease inhibitor, protein/protease mix, and glycated bromelain protein formed by exogenous non-enzymatic glycation, for use in the treatment or prophylaxis of virus infections caused by coronaviruses in a human or animal

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