WO2001019385A2 - The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses - Google Patents
The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses Download PDFInfo
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- WO2001019385A2 WO2001019385A2 PCT/US2000/025093 US0025093W WO0119385A2 WO 2001019385 A2 WO2001019385 A2 WO 2001019385A2 US 0025093 W US0025093 W US 0025093W WO 0119385 A2 WO0119385 A2 WO 0119385A2
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- enzyme
- lytic
- composition
- carrier
- holin
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/503—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/38—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P31/02—Local antiseptics
-
- 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
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/15—Suppositories
Definitions
- the present invention discloses a method and composition for the treatment of bacterial infections by the use of a lytic enzymes and holin enzymes blended with an appropriate carrier suitable for the treatment of the infection.
- U.S. Patent No. 5,260,292 discloses the topical treatment of acne with aminopenicillins.
- the method and composition for topically treating acne and acneiform dermal disorders includes applying an amount of an antibiotic
- ampicillin selected from the group consisting of ampicillin, amoxicillin, other air ⁇ nopemcillins, and
- Patent No. 5,688,501 discloses a method for treating an infectious disease caused by bacteria in an animal with lytic or non-lytic bacteriophages that are specific for particular bacteria.
- U.S. Patent No. 4,957,686 discloses a procedure of improved dental hygiene which comprises introducing into the mouth bacteriophages parasitic to bacteria which possess the property
- the phage must also be active enough.
- the phages are also inhibited by many things including bacterial debris from the organism it is going to attack. Further complicating the
- U.S. Patent No. 09/395,636 discloses a method and composition for the prophylactic or therapeutic treatment of bacterial infections, comprising administering an effective amount of at least one lytic enzyme produced by a bacteria infected with a bacteriophage specific for
- the lytic enzyme preferably comprises a carrier suitable for
- This method and treatment may be used for treating upper respiratory infections, topical infections, vaginal infections, eye infectionsear infections,
- the bacteriophage is known in the art.
- the phage enzyme that lyses the streptococcus organism may actually be a bacterial enzyme that is used to construct the cell wall and the phage. While replicating in the bacterium, a phage gene product may cause the upregulation or derepression of bacterial enzyme for the purpose of releasing the bacteriophage.
- These bacterial enzymes may be tightly regulated by the bacterial cell and are used by the bacteria for the construction and assembly of the cell wall.
- the present invention discloses the extraction and use of a variety of bacterial phage associated lytic enzymes, holin enzymes, chimeric enzymes, and shuffled enzymes for the treatment of a wide variety of illnesses caused by bacterial infections.
- phage associated lytic enzymes produced by the infection of a bacteria with a bacteria specific phage has numerous advantages for the treatment of diseases. As the phage are targeted for specific bacteria, the lytic enzymes do not interfere with normal flora. Also, lytic phages primarily attack cell wall structures which are not affected by plasmid variation. The actions of the lytic enzymes are fast and do not depend on bacterial growth.
- Lytic enzymes can be directed to the mucosal lining, where, in residence, they will be able to
- Shuffled enzymes are enzymes where more than one sequence of usually more than one
- shuffled enzymes are used to treat bacterial
- Chimeric enzymes are enzymes which are a combination of two or more enzymes having two
- chimeric enzyme can act independently on the same or different
- Chimeric enzymes may also be used to treat one bacterial infection by cleaving the cell wall in more than one location.
- Holin enzymes produce holes in the cell membrane. More specifically, holins form lethal membrane lesions thatterminates respiration. Like the lytic enzymes, the holin enzymes are coded for and carried by a phage. In fact, it is quite common for the genetic code for the holin enzyme is found next to or even within the code for the lytic enzyme in the phage. Most holin sequences are short, and overall, hydrophobic in nature, with a highly hydrophilic carboxy-terminal domain. In many cases, the putative holin is encoded on a different reading frame within the enzymatically active domain of the phage. In other cases, the holin is encoded on the DNA next or close to the DNA coding for the phage. The holin is frequently synthesized during the late stage of phage infection and found in the cytoplasmic membrane where it causes membrane lesions. Holins can be grouped into two general classes based on primary structurre analysis. Class
- I holins are usually 95 residues or longer and may have three potential transmembrane domains.
- holins are usually smaller, at approximately 65-95 residues, and the distribution of charged and hydrophobic residues indicatoing two TM domains (Young, et al. Trends in Microbiology v. 8, No. 4, March 2000). At least for the phages of gram-positive hosts, however, the dual-component lysis system may not be universal. Although the presence of holins has been shown or suggested for several reasons.
- lactococcal bacteriophage Tuc2009 lactococcal ⁇ LC3
- pneumococcal bacteriophage EJ-1 Lactobacil s gasseri bacteriophage ⁇ adh
- Staphylococcusaureus bacteriophage Twort,Z ;' _'tert- ⁇ /wonocyto ⁇ ewe_ bacteriophages, pneumococcal phage Cp-1, Bacillus subtillis phage ⁇ 29, Lactobacillus delbrueckki bacteriophage LL-H lysin, and
- holin enzymes are used in conjunction with the lytic
- Holin enzymes may be any organic radicals to accelerate the speed and efficiency at which the bacteria are killed.
- Holin enzymes may be any organic radicals to accelerate the speed and efficiency at which the bacteria are killed.
- Holin enzymes may also be used alone in
- chimeric or shuffled lytic enzymes to prophylactically and therapeutically treat bacterial diseases.
- chimeric lytic enzymes are used to prophylactically and therapeutically treat bacterial diseases.
- shuffled lytic enzymes are used to
- prophylactically and therapeutically treat bacterial infections prophylactically and therapeutically treat bacterial infections.
- holin enzymes are used in conjunction with phage
- holin enzymes alone are used to prophylactically and
- the holin enzymes are shuffled holin enzymes or
- chimeric holin enzymes either in combination with or independent of the lytic enzymes.
- the invention (which incorporates U. S . Patent No. 5, 604, 109 in its entirety by reference) uses a lytic enzyme produced by the bacterial organism after being infected with a particular bacteriophage
- the present invention is based upon the discovery that phage lytic enzymes specific for bacteria infected with a specific phage can effectively and efficiently break
- the lytic enzymes may be chimeric, shuffled or "natural,” and may be in combination with at least one holin enzyme, which may also be chimeric, shuffled, or "natural.”
- the prophylactic and therapeutic treatment of a variety of illnesses caused by Streptococcal pneumoniae, Streptococcus fasciae, and Hemophilus influenza are disclosed.
- gram negative bacterial infections caused by Listeria, Salmonella, E. coli, and Campylobacter are treated by the use of lytic enzymes.
- These and other bacteria, which can infect the digestive system can be treated by incorporating the lytic enzymes in suppository enemas, in syrups, or in other carriers to get directly to the site of the
- lytic enzymes are incorporated into bandages to prevent or treat infections of burns and wounds.
- the lytic enzymes are incorporated into bandages to prevent or treat infections of burns and wounds.
- Vaginal infections caused by Group B Streptococcus can cause premature birth and subsequent complications resulting in neonatal sepsis. Lysin incorporated into tampons specific for
- group B strep would prevent infection of the neonate during birth without disturbing normal vaginal
- eye drops containing lytic enzymes of Hemophilus In another embodiment of the invention, eye drops containing lytic enzymes of Hemophilus,
- Pseudomonas, and/or Staphylococcus can be used to directly treat eye infections. Treatment with
- lytic enzymes are faster and more expedient than with antibiotics.
- the lytic enzyme is administered in the form of a candy, chewing gum, lozenge, troche, tablet, a powder, an aerosol, a liquid, a liquid spray, or
- species specific lytic enzymes can be used in the
- the lytic enzyme in the form of a topical ointment or cream.
- the lytic enzyme in another embodiment of the invention, the lytic enzyme
- the enzyme which lyses Staphylococcus aureus can be included in the therapeutic agent.
- conventional antibiotics may be included in the therapeutic agent with
- lytic enzyme and with or without the presence of lysostaphin. More than one lytic enzyme may
- the method for treating bacterial infections comprises treating the infection with a therapeutic
- one lytic enzyme is selected from the group consisting of shuffled lytic enzymes, chimeric lytic
- the lytic enzyme is preferably in an environment having a pH
- a holin enzyme may be used in conjunction with the
- the holin enzyme may be in its "natural" state, may be shuffled holin enzymes or may be chimeric lytic enzymes.
- the shuffled and chimeric enzymes may be produced either enzymatically or through
- recombinant DNA means Any method may be used to produce these enzymes.
- the lytic enzyme can be used for the treatment or prevention of Hemophilus influenza, Pseudomonas, Streptococcus pneumoniae, Streptococcus fasciae, Streptococcus group B, Listeria,
- enzyme may be either supplemented by chimeric and/or shuffled lytic enzymes, or may be itself a
- a holin enzyme may be included, which may also be
- a chimeric and/or shuffled lytic enzyme a chimeric and/or shuffled lytic enzyme.
- the infection can be any suitable bacterial infection of the upper respiratory tract. For example, if there is a bacterial infection of the upper respiratory tract, the infection can be any suitable bacterial infection of the upper respiratory tract.
- At least one lytic enzyme produced by a bacteria being infected with a bacteriophage specific for that bacteria and a carrier for delivering the lytic enzyme to a mouth, throat, or nasal passage.
- the lytic enzyme is in an environment having a pH which allows for activity of the lytic
- Bacteriophage HP 1 a member of the P2-like phage family with strong similarities to coliphages P2 and 186, and some similarity to the retronphage Ec67
- the lytic enzyme for Streptococcus produces a lytic enzyme capable of lysing the bacteria.
- the therapeutic agent can contain
- either or both of the lytic enzymes produced by these two bacteria may contain other lytic
- composition which may be used for the prophylactic and therapeutic purposes.
- treatment of a strep infection includes the lysin enzyme and a means of application, (such as a carrier
- Another infection which can be treated prophylactically Streptococcus group A, which can produce what is
- a lysin enzyme is produced specific for the lysing of Streptococcus group A.
- the enzyme b e Prior to, or at the time the lysin enzyme is put in the carrier system or oral delivery mode, it is preferred that the enzyme b e in a stabilizing buffer environment for maintaining a pH range between about 4.0 and about 9.0, more preferably between about 5.5 and about 7.5 and most preferably at about 6.1.
- the stabilizing buffer should allow for the optimum activity of the lysin enzyme.
- the buffer may be a reducing reagent, such as dithiothreitol.
- the stabilizing buffer may also be or include a metal chelating reagent, such as ethylenediaminetetracetic acid disodium salt, or it may also contain a phosphate or citrate-phosphate buffer.
- Means of application include, but are not limited to direct, indirect, carrier and special means or any combination of means.
- Direct application of the lytic enzyme may be by nasal sprays, nasal drops, nasal ointments, nasal washes, nasal injections, nasal packings, bronchial sprays and inhalers, or indirectly through use of throat lozenges, or through use of mouthwashes or gargles, or through the use of ointments applied to the nasal nares, the bridge of the nose, or the face or any combination of these and similar methods of application.
- the forms in which the lysin enzyme may be administered include but are not limited to lozenges, troches, candies, injectants, chewing gums, tablets, powders,
- the lozenge, tablet, or gum into which the lytic enzyme is added may contain sugar, com syrup, a variety of dyes, non-sugar sweeteners, flavorings, any binders, or combinations thereof.
- any gum based products may contain acacia, camauba wax, citric acid, com starch, food colorings, flavorings, non-sugar sweeteners, gelatin, glucose, glycerin, gum base, shellac, sodium
- saccharin sugar, water, white wax, cellulose, other binders, and combinations thereof.
- Lozenges may further contain sucrose, com starch, acacia, gum tragacanth, anethole, linseed,
- sugar substitutes are used in place of dextrose, sucrose, or other sugars.
- the enzyme may also be placed in a nasal spray, wherein the nasal spray is the carrier.
- nasal spray can be a long acting or timed release spray, and can be manufactured by means well
- any of the carriers for the lytic enzyme may be manufactured by conventional means.
- any mouthwash or similar type products not contain alcohol to prevent
- the enzyme may be added to these substances ' in a liquid form or in a lyophilized state,
- the enzyme may also be any substance that is solubilized when it meets body fluids such as saliva.
- the enzyme may also be any substance that will be solubilized when it meets body fluids such as saliva.
- the enzyme may also be any substance that will be solubilized when it meets body fluids such as saliva.
- the enzyme may also be any substance that will be solubilized when it meets body fluids such as saliva.
- the enzyme may also be any substance that will be solubilized when it meets body fluids such as saliva.
- the duration of exposure in part on whether the lytic will be used therapeutically or prophylactically, the duration of exposure
- composition containing the enzyme also depends on whether the use is for prophylactic purposes, wherein the use may be hourly, daily or weekly, for a short time period, or whether the use
- composition will be for therapeutic purposes wherein a more intensive regimen of the use of the composition may
- Any dosage form employed should provide for a rmnimum number of units
- for an effective amount or dosage of enzyme may be in the range of about 100 units/ml to about 100,000 units/ml of fluid in the wet or damp environment of the nasal and oral passages, and possibly in the range of about 100 units/ml to about 10,000 units/ml. More specifically, time exposure to the active enzyme units may influence the desired concentration of active enzyme units per ml.
- carriers that are classified as “long” or “slow” release carriers could possess or provide a lower concentration of active (enzyme) units per ml, but over a longer period of time
- a "short” or “fast” release carrier such as, for example, a gargle
- the amount of active units per ml and the duration of time of exposure depends on the nature of infection, whether treatment is to be prophylactic or therapeutic, and other variables.
- composition and method may also be used for the treatment of Streptococcus A infections of the respiratory tract.
- the lysin phage enzyme should be used for the prophylactic prevention of Streptococcus infections.
- this method may be used for the therapeutic and, preferably, the prophylactic treatment of tuberculosis.
- this method may be used for the therapeutic and, preferably, the prophylactic treatment of tuberculosis.
- the phage associated lysing enzyme for Mycobacteria tuberculosis is placed in a carrier in an inhaler.
- the carrier may be sterile water or a water base, or any other carrier used in an inhaler for dispersing
- the phage associated lytic enzyme specific for tuberculosis is subject to the same conditions as the phage associated lytic enzyme for other lytic enzymes. Specifically, prior
- the enzyme be in a stabilizing buffer environment for maintaining a pH range between about 4.0 and about 9.0.
- the stabilizing buffer should allow for the optimum activity of the lytic enzyme.
- the buffer may be a reducing reagent, such as dithiothreitol.
- the stabilizing buffer may also be or include a metal chelating reagent, such as ethylenediaminetetracetic acid disodium salt, or it may also contain a phosphate or citrate-phosphate buffer.
- the phage associated lytic enzyme associated with tuberculosis may also be applied by direct, indirect, carriers and special means or any combination of means.
- Direct application of the lytic enzyme may be by nasal sprays, nasal drops, nasal ointments, nasal washes, nasal injections, nasal packings, bronchial sprays and inhalers, or indirectly through use of throat lozenges, or through use of mouthwashes or gargles, or through the use of ointments applied to the nasal nares, the bridge of the nose, or the face or any combination of these and similar methods of application.
- the forms in which the lytic enzyme may be administered include but are not limited to lozenges, troches, candies, injectants, chewing gums,
- bronchial sprays and aerosols are most beneficial, as these carriers, or means of distributing the composition, allow the lytic enzyme to reach the bronchial tubes and the lungs.
- appropriate transport carrier may be attached to the enzyme to transport the enzyme across the cell
- the lozenge, tablet, or gum into which the lytic enzyme is added may contain sugar, com
- syrup a variety of dyes, non-sugar sweeteners, flavorings, any binders, or combinations thereof.
- any gum based products may contain acacia, camauba wax, citric acid, com starch, food
- colorings flavorings, non-sugar sweeteners, gelatin, glucose, glycerin, gum base, shellac, sodium saccharin, sugar, water, white wax, cellulose, other binders, and combinations thereof.
- Lozenges may further contain sucrose, com starch, acacia, gum tragacanth, anethole, linseed,
- sugar substitutes are used in place of dextrose, sucrose, or other sugars.
- the use of an inhaler carrier the lytic enzyme in a carrier is preferred.
- Another use of a lytic enzyme is for the treatment of bacterial infections of the digestive tract.
- a bacteria infected with a bacteriophage specific for the bacteria and a carrier for delivering said lytic
- gram negative bacteria selected from the group consisting of
- a holin enzyme may be included, which
- ⁇ may also be a chimeric and/or shuffled lytic enzyme.
- the carrier is selected from the group consisting of:
- the enzyme should be incorporated into a carrier which does not contain alcohol, and which has been cooled to a temperature that will
- the enzyme may be incorporated in a lyophilized state, or
- the enzyme placed in the composition or carrier should be in an environment having a pH which
- the pH of the composition is preferably kept in a range of between about 2 and about 11, more preferably in a range of between about between about
- the pH can be moderated by the use of a buffer.
- the buffer may contain a reducing agent, and more specifically dithiothreitol.
- the buffer may also be a
- a metal chelating reagent such as ethylenediaminetetracetic disodium salt or the buffer may contain
- composition may ,
- bactericidal or bacteriostatic agent as a preservative.
- the lytic enzyme is preferably present in a concentration of about 100 to about 500,000 active
- enzyme units per milliliter of fluid in the wet environment of the gastrointestinal tract preferably
- concentration of about 100 to about 10,000 active enzyme units per milliliter of fluid in the wet environment of the gastrointestinal tract.
- the suppository is known in the art, and is made of glycerin, fatty acids, and similar type
- the phage associated lytic As the suppository dissolves, the phage associated lytic
- composition and use of the lytic enzyme is for the therapeutic or prophylactic
- composition comprises an
- the lytic enzyme(s) used for the topical treatment of bums may be either supplemented by chimeric and/or shuffled lytic enzymes, or may be itself a chimeric and/or shuffled lytic enzyme.
- a holin enzyme may be included, which may also be a chimeric and/or shuffled lytic enzyme.
- aqueous liquid which include, but are not limited to an aqueous liquid, an alcohol base liquid, a water soluble gel, a lotion, an ointment, a nonaqueous liquid base, a mineral oil base, a blend of mineral oil and
- petrolatum petrolatum, lanolin, liposomes, protein carriers such as serum albumin or gelatin, powdered cellulose
- a mode of delivery of the carrier containing the therapeutic agent is a mode of delivery of the carrier containing the therapeutic agent
- a smear includes but is not limited to a smear, spray, a time-release patch, a liquid absorbed wipe, and
- the lytic enzyme may be applied to a bandage either directly or in one of the
- bandages may be sold damp or dry, wherein the enzyme is in a lyophilized form
- the carriers of the compositions of the present invention may comprise semi-solid and gel-like
- Polymer thickeners that may be used include those known to one skilled in the art, such as
- hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and pharmaceutical
- the hydrophilic or hydroalcoholic gelling agent comprises
- CARBOPOL.RTM B. F. Goodrich, Cleveland, Ohio
- HYPAN.RTM Kingston Technologies, Dayton, N.J.
- NATROSOL.RTM Aqualon, Wilmington, Del
- KLUCEL.RTM KLUCEL.RTM
- the gelling agent comprises between about 0.2% to about 4% by weight of the composition. More particularly, the preferred compositional weight percent range for "CARBOPOL.RTM.” is between about 0.5%
- CARBOPOL.RTM is one of numerous cross-linked acrylic acid polymers that are given the
- KLUCEL.RTM is a cellulose polymer that is dispersed in
- hydroxyethylcellulose cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, or
- Preservatives may also be used in this invention and preferably comprise about 0.05% to 0.5% by weight of the total composition. The use of preservatives assures that if the product is microbially
- the formulation will prevent or diminish microorganism growth.
- methylparaben useful in this invention include methylparaben, propylparaben, butylparaben, chloroxylenol, sodium
- Titanium dioxide may be used as a sunscreen to serve as prophylaxis against photosensitization.
- Alternative sun screens include methyl cinnamate.
- BHA may be used as an antioxidant, as well as to protect ethoxydiglycol and or dapsone from discoloration due to oxidation.
- An alternate antioxidant is BHT.
- Pharmaceuticals for use in all embodiments of the invention include antimicrobial agents, anti- inflammatory agents, antiviral agents, local anesthetic agents, corticosteroids, destructive therapy agents, antifungals, and antiandrogens.
- active pharmaceuticals that may be used include antimicrobial agents, especially those having anti-inflammatory properties such as dapsone, erythromycin, minocycline, tetracycline, clindamycin, and other antimicrobials.
- antimicrobial agents especially those having anti-inflammatory properties such as dapsone, erythromycin, minocycline, tetracycline, clindamycin, and other antimicrobials.
- the preferred weight percentages for the antimicrobials are 0.5% to 10%.
- Local anesthetics include tetracaine, tetracaine hydrochloride, lidocaine, lidocaine hydrochloride, dyclonine, dyclonine hydrochloride, dimethisoquin hydrochloride, dibucaine, dibucaine hydrochloride,
- butambenpicrate and pramoxine hydrochloride.
- a preferred concentration for local anesthetics is about 0.025% to 5% by weight of the total composition.
- Anesthetics such as benzocaine may also be used.
- Corticosteroids that may be used include betamethasone dipropionate, fluocinolone actinide,
- betamethasone valerate triamcinolone actinide, clobetasol propionate, desoximetasone, diflorasone diacetate, amcinonide, flurandrenolide, hydrocortisone valerate, hydrocortisone butyrate, and
- desonide are recommended at concentrations of about 0.01% to 1.0% by weight.
- concentrations for corticosteroids such as hydrocortisone or methylprednisolone acetate are from about 0.2% to about 5.0% by weight.
- Destructive therapy agents such as salicylic acid or lactic acid may also be used.
- a concentration of about 2% to about 40% by weight is preferred.
- Cantharidin is preferably utilized in a concentration of about 5% to about 30% by weight.
- Typical antifungals that may be used in this invention and their preferred weight concentrations include: oxiconazole nitrate (0.1% to 5.0%), ciclopirox olamine (0.1% to 5.0%), ketoconazole (0.1% to 5.0%), miconazole nitrate (0.1% to 5.0%), andbutoconazole nitrate (0.1% to 5.0%).
- the active pharmaceutical may include an antiandrogen such as flutamide or finasteride in preferred weight percentages of about 0.5% to 10%.
- treatments using a combination of drugs include antibiotics in combination with local anesthetics such as polymycin B sulfate and neomycin sulfate in combination with tetracaine for topical antibiotic gels to provide prophylaxis against infection and relief of pain.
- local anesthetics such as polymycin B sulfate and neomycin sulfate in combination with tetracaine
- minoxidil in combination with a corticosteroid such as betamethasone diproprionate for the treatment of alopecia ereata.
- an anti-inflammatory such as cortisone with an antifungal such as ketoconazole for the treatment of tinea infections is also an example.
- the invention comprises a dermatological composition having about 0.5%
- a pharmaceutical that exists in both a dissolved state and a micro particulate state.
- the dissolved pharmaceutical has the capacity to cross the stratum corneum, whereas the micro particulate pharmaceutical does not.
- Addition of an amine base, potassium, hydroxide solution, or sodium hydroxide solution completes the formation of the gel. More
- the pharmaceutical may include dapsone, an antimicrobial agent having anti-inflammatory
- a preferred ratio of micro particulate to dissolved dapsone is five or less.
- the invention comprises about 1% carbomer, about 80-90% water,
- the carbomer may include "CARBOPOL.RTM. 980" and the caustic material may include sodium
- the composition comprises dapsone and ethoxydiglycol, which allows for an optimized ratio of micro particulate drug to dissolved drug. This ratio determines the amount of drug delivered, compared to the amount of drug retained in or above the stratum comeum to function in the supracomeum domain.
- the system of dapsone and ethoxydiglycol may include purified water combined with "CARBOPOL.RTM. " gelling polymer, methylparaben, propylparaben, titanium dioxide, BHA, and a caustic material to neutralize the "CARBOPOL.RTM..” Any of the carriers for the lytic enzyme may be manufactured by conventional means.
- the enzyme should be in a micelle, liposome, or a "reverse" Uposome, to prevent denaturing of the enzyme.
- the lytic enzyme when the lytic enzyme is being placed in the carrier, and the carrier is, or has been heated, such placement should be made after the carrier has cooled somewhat, to avoid heat denaturation of the enzyme.
- the carrier is sterile.
- the enzyme may be added to these substances in a liquid form or in a lyophilized state,
- duration of treatment will depend in part on the seriousness of the infection, the duration of exposure
- the composition may be applied anywhere from once to several times a day, and may be applied for a short or long term period. The usage may last for days or weeks. Any dosage form employed should provide for a minimum number of units for a minimum amount of time.
- the concentration of the active units of enzyme believed to provide for an effective amount or dosage of enzyme may be in the range of about 100 units/ml to about 500,000 units/ml of composition, preferably in the range of about 1000 units/ml to about 100,000 units/ml, and most preferably from about 10,000 to 100,000 units/ml.
- the amount of active units per ml and the duration of time of exposure depends on the nature of infection, and the amount of contact the carrier allows the lytic enzyme to have. It is to be remembered that the enzyme works best when in a fluid environment.
- a mild surfactant in an amount effective to potentiate the therapeutic effect of the lytic enzyme.
- suitable mild surfactants include, inter alia, esters of polyoxyethylene sorbitan and fatty acids (Tween series), octylphenoxy polyethoxy ethanol (Triton-X series), n-Octyl-.beta.-D-glucopyranoside, n-Octyl-.beta.-D-thioglucopyranoside, n-Decyl-.beta.-D- glucopyranoside, n-Dodecyl-.beta.-D-glucopyranoside, and biologically occurring surfactants, e.g.,
- fatty acids glycerides, monoglycerides, deoxycholate and esters of deoxycholate.
- the therapeutic agent may further include at least one complementary agent which can also potentiate the bactericidal activity of the lytic enzyme.
- the complementary agent can be penicillin, synthetic penicillins bacitracin, methicillin,
- cephalosporin polymyxin, cefaclor.
- Cefadroxil cefamandolenafate, cefazolin, cefixime, cefinetazole,
- cefonioid cefoperazone, ceforanide, cefotanme, cefotaxime, cefotetan, cefoxitin, cefpodoxime
- ceftazidime ceftizoxime
- ceftriaxone cefriaxone moxalactam
- cefiiroxime cephalexin
- cephalosporin C cephalosporin C sodium salt, cephalothin, cephalothin sodium salt, cephapirin,
- the therapeutic agent may further comprise the enzyme lysostaphin for the treatment of any Staphylococcus aureus bacteria.
- Muco lytic peptides such as lysostaphin, have been
- Lysostaphin a gene product of Staphylococcus simulans, exerts
- 3,278,378 describes fermentation methods for producing lysostaphin from culture media of S.
- recombinant mucolytic bactericidal protein such as r-lysostaphin
- lysostaphin is also active against non-dividing cells, while most antibiotics require actively dividing cells to mediate their effects (Dixon
- Lysostaphin in combination with the lysin
- Staphylococcus aureus produce penicillinase, such that Staphylococcus, Streptococcus, and other
- gram positive bacterial strains will not be killed by standard antibiotics. Consequently, the use of the lysin and lysostaphin, possibly in combination with antibiotics, can serve as the most rapid and
- the invention may be any suitable treatment of bacterial infections.
- the invention may be any suitable treatment of bacterial infections.
- the invention may be any suitable treatment of bacterial infections.
- the invention may be any suitable treatment of bacterial infections.
- the lytic enzymes for Pseudomonas, Staphylococcus, and Streptococcus may be incorporated into the carrier, or
- lytic enzymes are for the prophylactic or therapeutic treatment of vaginal
- This treatment comprises treating the vaginal infection with an effective amount of at least
- lytic enzyme is incorporated in a carrier to be placed in a vagina.
- enzyme(s) used to treat bacterial infections of the vagina may be either supplemented by chimeric
- a shuffled lytic enzyme may be itself a chimeric and/or shuffled lytic enzyme.
- a chimeric and/or shuffled lytic enzyme may be itself a chimeric and/or shuffled lytic enzyme.
- holin enzyme may be included, which may also be a chimeric and/or shuffled lytic enzyme.
- the preferred carrier is a tampon, or vaginal douche.
- a pad may also be used as a carrier, although it is
- Streptococcus can cause neonatal meningitis resulting in brain damage and premature death. Lytic
- the use of the lytic enzyme in the vagina would best provide a prophylactic effect, although therapeutic use would also be advisable.
- the lytic enzyme can be applied in a solution to the tampon, and allowed to dry.
- the lytic enzyme may be incorporated into the pad or
- tampon by any other means known in the art, including lyophilization, spraying, etc.
- the tampons and pads may also be kept slightly moist, and in a sealed wrapper until ready for use. In that case,
- bactericide and bacteriostatic compounds and inhibitors should be present in the tampons and pads.
- the method to be used for incorporating the lytic enzyme into the tampon or pad can be one of the
- the lytic enzyme is incorporated into a vaginal suppository.
- the vaginal suppository into
- vaginal suppository comprised of
- glyceride alginate, starch, other standard binders and any combinations thereof.
- the pH be kept in a range of about 4.0 and about 9.0 even more preferably at a pH range of between about 5.5 and about 7.5.
- the pH can be moderated by the use of a buffer.
- the buffer may
- the buffer may also contain a metal
- chelating reagent such as ethylenediaminetetracetic disodium salt or the buffer may be a citrate-
- composition may , further
- bactericidal or bacteriostatic agent as a preservative.
- the lytic enzyme is preferably present in a concentration of about 100 to about 500,000 active
- enzyme units per milliiiter of fluid in the wet environment of the vaginal tract preferably about 100
- Another use of the invention is for the prophylactic and therapeutic treatment of eye
- the method of treatment comprises administering eye drops which comprise an effective amount of at least one lytic enzyme produced by the bacteria being infected with a bacteriophage
- the bacteria being treated is a preferred embodiment of the invention.
- the eye drops are in the form of an isotonic solution.
- the pH of the eye drops are in the form of an isotonic solution.
- the solution should be adjusted so that there is no irritation of the eye, which in turn would lead to
- buffers of the sort described above for the other lytic enzymes should also be used.
- antibiotics which are suitable for use in eye drops may be added to the composition containing the lytic enzymes.
- Bactericides and bacteriostatic compounds may also be added.
- this lytic enzyme may be either supplemented by chimeric and or shuffled lytic enzymes, or may be
- a holin enzyme may be included, which may
- a carrier may have more than one lytic enzyme.
- a throat lozenge may comprise just a lysin enzyme (which lyses the Streptococcus A strain causing "strep" throat, or it may also include the lytic enzymes for Hemophilus.
- the carrier for treating bums and wounds, or infections of the skin may contain just one lytic enzyme, or a combination of lytic enzymes, for the treatment of Pseudomonas, Streptococcus, Staphylococcus, or any other of a number of bacteria.
- Lytic enzymes can also be used to fight dental caries. Specifically, a lytic enzyme specific for Streptococcus mutans may be incorporated in a toothpaste or oral wash. Similarly, this lytic enzyme may also be incorporated into a chewing gum or lozenge. Any other carrier can be used that allows for the exposure of the mouth, gums, and teeth to the lytic enzyme.
- the lytic enzyme may also be incorporated in a lyophilized or dried form in tooth powder. If
- the lytic enzyme is to be used in an oral wash, it is preferred that the oral wash not contain any alcohol, so as to not denature the enzyme.
- the enzyme can also be in a liposome when mixed in with the toothpaste or oral wash.
- concentrations of the enzyme units per ml of toothpaste or mouth wash can be in the range of from about 100 units/ml to about 500,000 units/ml of composition,
- the pH of the toothpaste or oral wash should be in a range that
- to treat dental caries may be either supplemented by chimeric and or shuffled lytic enzymes, or may
- a holin enzyme may be included, which
- ⁇ may also be a chimeric and/or shuffled lytic enzyme.
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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HU0203523A HUP0203523A3 (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
CA002384881A CA2384881A1 (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
MXPA02002920A MXPA02002920A (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses. |
EP00966719A EP1212080A2 (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
JP2001523017A JP2003509375A (en) | 1999-09-14 | 2000-09-14 | Use of bacteriophage-related lytic enzymes for the prevention and treatment of various diseases |
BR0013998-0A BR0013998A (en) | 1999-09-14 | 2000-09-14 | Use of breakdown enzymes associated with bacterial phage for the prophylactic and therapeutic treatment of various diseases |
KR1020027003396A KR20020043585A (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
NZ518058A NZ518058A (en) | 1999-09-14 | 2000-09-14 | Bacterial phage associated lytic enzymes for the prophylactic and therapeutic treatment of various illnesses |
IL14865100A IL148651A0 (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
AU77021/00A AU7702100A (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
HK02109050.6A HK1047888A1 (en) | 1999-09-14 | 2002-12-12 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
Applications Claiming Priority (2)
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US09/395,636 US6056954A (en) | 1997-10-31 | 1999-09-14 | Use of bacterial phage associated lysing enzymers for the prophylactic and therapeutic treatment of various illnesses |
US09/395,636 | 1999-09-14 |
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WO2001019385A2 true WO2001019385A2 (en) | 2001-03-22 |
WO2001019385A3 WO2001019385A3 (en) | 2001-11-22 |
WO2001019385A9 WO2001019385A9 (en) | 2002-09-26 |
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PCT/US2000/025093 WO2001019385A2 (en) | 1999-09-14 | 2000-09-14 | The use of bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of various illnesses |
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US (3) | US6056954A (en) |
EP (1) | EP1212080A2 (en) |
JP (1) | JP2003509375A (en) |
KR (1) | KR20020043585A (en) |
CN (1) | CN1390134A (en) |
AU (1) | AU7702100A (en) |
BR (1) | BR0013998A (en) |
CA (1) | CA2384881A1 (en) |
HK (1) | HK1047888A1 (en) |
HU (1) | HUP0203523A3 (en) |
IL (1) | IL148651A0 (en) |
MX (1) | MXPA02002920A (en) |
NZ (1) | NZ518058A (en) |
PL (1) | PL354259A1 (en) |
RU (1) | RU2002109596A (en) |
TR (1) | TR200201484T2 (en) |
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Cited By (2)
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EP1333854A1 (en) * | 2000-11-02 | 2003-08-13 | New Horizons Diagnostics, Corporation | The use of bacterial phage associated lytic enzymes to prevent food poisoning |
EP1333854A4 (en) * | 2000-11-02 | 2005-10-05 | New Horizons Diagnostics Corp | The use of bacterial phage associated lytic enzymes to prevent food poisoning |
Also Published As
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CN1390134A (en) | 2003-01-08 |
CA2384881A1 (en) | 2001-03-22 |
KR20020043585A (en) | 2002-06-10 |
AU7702100A (en) | 2001-04-17 |
US6685937B2 (en) | 2004-02-03 |
PL354259A1 (en) | 2003-12-29 |
MXPA02002920A (en) | 2005-04-19 |
ZA200202305B (en) | 2002-12-24 |
IL148651A0 (en) | 2002-09-12 |
EP1212080A2 (en) | 2002-06-12 |
TR200201484T2 (en) | 2003-02-21 |
RU2002109596A (en) | 2003-11-20 |
WO2001019385A9 (en) | 2002-09-26 |
JP2003509375A (en) | 2003-03-11 |
US6238661B1 (en) | 2001-05-29 |
WO2001019385A3 (en) | 2001-11-22 |
US6056954A (en) | 2000-05-02 |
HUP0203523A2 (en) | 2003-02-28 |
NZ518058A (en) | 2004-07-30 |
BR0013998A (en) | 2002-05-14 |
HK1047888A1 (en) | 2003-03-14 |
US20020127212A1 (en) | 2002-09-12 |
HUP0203523A3 (en) | 2006-03-28 |
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