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WO2007134118A2 - Composition à base de protéines et méthodes d'utilisation - Google Patents

Composition à base de protéines et méthodes d'utilisation Download PDF

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Publication number
WO2007134118A2
WO2007134118A2 PCT/US2007/068585 US2007068585W WO2007134118A2 WO 2007134118 A2 WO2007134118 A2 WO 2007134118A2 US 2007068585 W US2007068585 W US 2007068585W WO 2007134118 A2 WO2007134118 A2 WO 2007134118A2
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WO
WIPO (PCT)
Prior art keywords
composition
cancer
active ingredient
cross
recombinant
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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
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PCT/US2007/068585
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English (en)
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WO2007134118A3 (fr
Inventor
Chulso Moon
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Individual
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Individual
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Anticipated expiration legal-status Critical
Publication of WO2007134118A3 publication Critical patent/WO2007134118A3/fr
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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to pharmaceutical compositions comprising one or more cross-linked proteins and one or more active ingredients, to methods of making such compositions, and to methods of using such compositions in treatment of various diseases and disorders.
  • the invention provides pharmaceutical compositions comprising one or more cross-linked proteins and one or more active ingredients.
  • the protein comprises recombinant gelatin and the active ingredient comprises an antineoplastic agent.
  • the present invention provides methods of preparing such compositions.
  • the protein is cross-linked and combined with the active ingredient.
  • the step of combining the protein with the active ingredient can be performed prior to, during or after the cross-linking step.
  • the compositions are prepared by enzymatically cross-linking the protein without employing a chemical cross-linker.
  • the cross-linking is performed by electrostatic means, by microwaves or radiation (e.g. gamma-ray and electron beam radiation) or in any other suitable manner.
  • the present invention provides compositions prepared by any of the methods disclosed herein.
  • the present invention provides methods of treating subjects in need of therapy, for example antineoplastic therapy, with any of the compositions provided by or prepared according to various embodiments of the present invention.
  • the subject has been diagnosed with cancer, for example cancer of the head or neck, prior to initiation of treatment.
  • compositions of the invention comprise a protein or mixture of proteins.
  • the protein is a temperature-sensitive, gel-forming protein.
  • a "temperature-sensitive, gel- forming protein” herein is a protein that gels in response to a change in temperature.
  • suitable proteins include gelatin, collagen, casein, whey protein, synthetic polymers containing transglutaminase substrate sites and mixtures thereof.
  • the protein is derived from bovine or porcine material, for example skin, bone or tissue.
  • the protein is prepared using recombinant technology.
  • the protein contains substantially no human or animal component (e.g. skin, bone or tissue, etc).
  • the protein comprises recombinant human gelatin (rhGelatin).
  • Recombinant human gelatin may be prepared according to any suitable process, for example those processes described in U.S. Patent Nos. 6,413,742, 6,428,978 and 6,992,172, each of which is hereby incorporated herein by reference in its entirety.
  • the composition comprises rhGelatin
  • the rhGelatin molecules can be synthesized from human sequences of collagen, for example Type I (e.g. Type I ⁇ l) procollagen chains or fragments thereof.
  • the recombinant gelatin has a molecular weight range or average of about 1 to about 300 kDa, about 10 to about 250 kDa, or about 20 to about 200 kDa.
  • the recombinant gelatin has a bloom strength of about 25 to about 500, for example about 50, 100, 150, 200, 250, or 300.
  • the Bloom gel strength is a measure of the ability of a material to form a gel and is measured on an apparatus known as the "Bloom-gel-o-meter" in Bloom grams.
  • the Bloom gel strength is the weight in grams required to depress the gel a distance of 4 mm with a piston having a cross-sectional area of 1 cm 2 , the gel having first been cooled for a defined time under defined conditions.
  • the higher the Bloom value of a material the greater the ability of that material to form a gel.
  • the recombinant gelatin has a percentage hydroxylation of about 1% to about 100%, for example about 1% to about 20%, about 20% to about 80%, or about 80% to about 100%.
  • the recombinant gelatin is non-hydroxylated, is fully hydroxylated, or is partially hydroxylated.
  • the recombinant gelatin is fully hydrolyzed, partially hydrolyzed, or non-hydrolyzed.
  • the protein has a degree of cross-linking of about 5% to about 100%, for example at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
  • Degree of cross-linking can be determined according to any suitable method. In one embodiment, degree of cross-linking is determined by swelling behavior as a function of pH, temperature, and time.
  • the present invention provides a composition comprising recombinant gelatin, wherein the recombinant gelatin comprises a homogeneous mixture of recombinant gelatin polypeptides.
  • the recombinant gelatin comprises a heterogeneous mixture of recombinant gelatin polypeptides.
  • the present invention comprises recombinant gelatin wherein the recombinant gelatin is derived from collagen.
  • the collagen is selected from the group consisting of type I, type II, type III, type IV, type V, type VI, type VII, type VIII, type IX, type X, type XI, type XII, type XIII, type XIV, type XV, type XVI, type XVII, type XVIII, type XIX, type X collagen and mixtures thereof.
  • the recombinant gelatin has endotoxin levels of below about 1.000 EU/mg, below about 0.500 EU/mg, below about 0.050 EU/mg, or below about 0.005 EU/mg.
  • recombinant gelatin suitable for use in compositions of the invention are prepared by method comprising providing recombinant collagen or procollagen or fragments or variants thereof; and processing the recombinant collagen or procollagen or fragments or variants thereof to produce recombinant gelatin.
  • the recombinant collagen processed to recombinant gelatin is recombinant human collagen.
  • the recombinant collagen is produced by co-expressing at least one polynucleotide encoding a collagen or procollagen and at least one polynucleotide encoding a collagen post-translational enzyme or subunit thereof.
  • the post- translational enzyme is prolyl hydroxylase.
  • a composition of the invention can comprises any desired amount of protein, for example at least about 5%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 99%, by weight.
  • the protein itself constitutes about 30% to about 99%, about 40% to about 95%, or about 50% to about 85% of the total weight of the composition.
  • compositions of the invention comprise an active ingredient.
  • the active ingredient is capable of being transdermally or transmucosally absorbed by a mammal, for example a human, to achieve systemic blood levels of the active ingredient or a metabolite thereof.
  • a composition of the invention comprises the active ingredient(s) in an amount of about 0.001 mg to about 1000 mg, 0.01 mg to about 800 mg, about 0.1 mg to about 500 mg, or about 1 mg to about 250 mg.
  • the active ingredient comprises an antineoplastic agent.
  • antineoplastic agent includes agents that exert antineoplastic effects, i.e., that prevent the development, maturation, or spread of neoplastic cells, directly on the tumor cell, e.g., by cytostatic or cytocidal effects or indirectly through mechanisms such as biological response modification.
  • suitable antineoplastic agents for use in accordance with the present invention include ACE inhibitors, alkylating agents, angiogenesis inhibitors, anthracyclines/DNA intercalators, anti-cancer antibiotics or antibiotic-type agents, antimetabolites, antimetastatic compounds, asparaginases, bisphosphonates, cGMP phosphodiesterase inhibitors, camptothecins, DHA derivatives, DNA topoisomerase, endostatin, epipodophyllotoxins, hormonal anticancer agents, hydrophilic bile acids (URSO), immunomodulators or immunological agents, integrin antagonists, interferon antagonists or agents, MMP inhibitors, miscellaneous antineoplastic agents, monoclonal antibodies, nitrosoureas, ornithine decarboxylase inhibitors, pBATTS, platinum analogs, radio/chemo sensitizers/protectors, retinoids, selective inhibitors of proliferation and migration of endothelial cells, strom
  • URSO hydrophil
  • Taxane includes a family of diterpene alkaloids all of which contain a particular eight (8) member “taxane” ring structure. Taxanes such as paclitaxel prevent the normal post division breakdown of microtubules which form to pull and separate the newly duplicated chromosome pairs to opposite poles of the cell prior to cell division. In cancer cells which are rapidly dividing, taxane therapy causes the microtubules to accumulate which ultimately prevents further division of the cancer cell. Taxane therapy also affects other cell processes dependant on microtubules such as cell motility, cell shape and intracellular transport.
  • Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids.
  • Suitable antimetabolite antineoplastic agents include, but are not limited to acanthifolic acid, aminothiadiazole, anastrozole, bicalutamide, brequinar sodium, capecitabine, carmofur, cladribine, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, cytarabine ocfosfate, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, camrabine, floxuridine, fludarabine and fludarabine phosphate, N-(240 -furanidyl)-5- fluorouracil, fluorouracil (5-FU), 5-FU-fibrinogen,
  • Alkylating agents are believed to act by alkylating and cross-linking guanine and possibly other bases in DNA, arresting cell division.
  • Typical alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, platinum analogues (cisplatin, carboplatin, etc.), and various nitrosoureas.
  • Suitable alkylating- type antineoplastic agents include, but are not limited to, aldo-phosphamide analogues, altretamine, anaxirone, bestrabucil, budotitane, busulfan, carboplatin, carmustine (BiCNU), chlorambucil, cisplatin, cyclophosphamide, cyplatate, dacarbazine, diphenylspiromustine, diplatinum cytostatic, Erba distamycin derivatives, elmustine, estramustine phosphate sodium, etoposide phosphate, fotemustine, hepsul-fam, ifosfamide, iproplatin, lomustine (CCNU), mafosfamide, mechlorethamine, melphalan, mitolactol, mycophenolate, oxaliplatin, procarbazine prednimustine, ranimustine,
  • Suitable antibiotic-type antineoplastic agents include, but are not limited to, aclarubicin, actinomycin D, actinoplanone, , aeroplysinin derivative, , anthracycline, azino-mycin-A, bisucaberin, bleomycin sulfate, bryostatin-1, , calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin- Al, esperamicin-Alb, Erbamont FCE-21954, fostriecin, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirho
  • 5- fluorouracil 5- fluorouracil
  • 5-Fluorouracil has been used clinically in the treatment of malignant tumors, including, for example, carcinomas, sarcomas, skin cancer, cancer of the digestive organs, and breast cancer.
  • Derivatives of 5-FU with anti-cancer activity have been also been described in U.S. Pat. No. 4,336,381, hereby incorporated by reference herein.
  • Suitable hormonal agents that may be used as antineoplastic agents in accordance with in the present invention include, but are not limited to abarelix; abiraterone acetate; aminoglutethimide; anastrozole; antide; avorelin; aseranox; bicalutamide; buserelin; cetrolix; clastroban; clodronate disodium; cosudex; cytadren; crinone; deslorelin; droloxifene; dutasteride; elimina; epitiostanol; epristeride; exemestane; fadrozole;; flutamide; formestane; ganirelix; goserelin; idoxifene; isocordoin; ketanserin; lanreotide; letrozol; leuprolide; leuprorelin; liarozole; lisuride hydrogen maleate; loxiglumide
  • the antineoplastic agent is selected from anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, fluorouracil (5-FU), fiuoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone and eflornithine (DFMO).
  • anastrozole capecitabine
  • carboplatin cisplatin
  • cyclophosphamide docetaxe
  • compositions of the invention may comprise one or more of any of the foregoing antineoplastic agents.
  • compositions of the invention comprise one or more of 5-FU, cisplatin and/or paclitaxel.
  • compositions of the invention comprise one or more of methotrexate, bleomycin, hydroxyurea, doxorubicin, vincristine and/or vinorelbine.
  • a composition of the invention comprises a therapeutically effective amount of the active ingredient.
  • therapeutically effective amount refers to an amount of active ingredient or agent that is sufficient to elicit the required or desired therapeutic and/or prophylactic response, as the particular treatment context may require.
  • a therapeutically effective amount of the active ingredient is an amount sufficient to treat the disease or disorder in question or to provide a therapeutic effect.
  • treat or “treatment” in relation a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder.
  • a therapeutically effective amount of the active ingredient is an amount sufficient to prevent the disease or disorder in question.
  • prevent or prevention in relation a given disease or disorder means preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
  • a "therapeutic effect" in reference to the treatment of a cancer refers to one or more of the following: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, or stopping) of cancer cell infiltration into peripheral organs; 4) inhibition (i.e., slowing to some extent, or stopping) of tumor metastasis; 5) inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or more of the symptoms associated with the disorder; and/or 7) relieving or reducing the side effects associated with the administration of antineoplastic agents.
  • a composition of the invention is in the form of a dose unit or dosage unit.
  • dose unit and/or “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a active ingredient suitable for a single administration to provide a therapeutic or prophylactic effect.
  • dosage units may be administered one to a small plurality of times per day, or as many times as needed to elicit a therapeutic response.
  • small plurality herein means more than one but less than about 10. For example, a small plurality in the present context could illustratively represent about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 dosage units or administrations.
  • compositions of the invention can be prepared in any suitable dosage form.
  • the composition is topically administrable.
  • topically administrable herein refers to a pharmaceutical composition suitable for administration to the skin of a subject, for example a human subject, to result in topical (e.g. local) or transdermal (systemic) effect.
  • dosage forms include pastes, liquids, gels, ointments, lotions creams, topical solutions, etc.
  • topically administrable compositions of the invention comprise more than one active ingredient and provides timed release of the active ingredients.
  • timed release herein means that the dosage form delivers the active ingredients to the blood of the subject at a predetermined time after administration.
  • a topically administrable composition of the invention comprises an active ingredient substantially dispersed within a protein matrix, for example a protein film.
  • the dispersion can be homogeneous or heterogeneous.
  • upon contacting the composition to the skin of a subject at least a portion of the active ingredient migrates from the protein matrix to the skin of the subject to provide topical or transdermal effect.
  • a topically administrable composition of the invention comprises two or more active ingredients dispersed within a protein matrix.
  • degree of cross-linking of the protein and depth of penetration of the active ingredient(s) within the matrix can be predetermined (e.g. by specifying incubation time, type of cross-linker, and other process parameters, etc) to provide desired time release profiles of each of the active ingredients.
  • compositions of the invention comprise protein microcapsules which encapsulate at least a portion of the active ingredient(s). The microcapsules can be of a predetermined size dispersion so as to control timing of release of the active ingredient(s).
  • Topically administrable compositions of the invention can also be combined with a drug delivery system that helps deliver uniform quantities of drug to the skin over a period of time.
  • a drug delivery system that helps deliver uniform quantities of drug to the skin over a period of time.
  • Such systems can include adhesive or non-adhesive patches, bandages, pads, etc.
  • the system may be monolithic (incorporating an active ingredient matrix layer between backing and frontal layers) or membrane-controlled (where the composition is in a reservoir sandwiched together with one or more of a rate controlling membrane, backing, adhesive and/or protecting layers).
  • the membrane comprises a cross-linked protein as described herein.
  • a dosage form of the invention contains substantially no, or no amount of microcapsules or microspheres.
  • compositions of the invention are suitable for parenteral administration (injection into any site of the body), including but not limited to intra articular, intraspinal, intra-arterial, intracardiac, intravenous, intradermal, intramuscular, subcutaneous delivery.
  • compositions can further comprise one or more vehicles for injection such as water for injection, USP (WFI), purified water, USP, sterile water for injection , USP, bacteriostatic water for injection, USP, sodium chloride injection, USP, bacteriostatic sodium chloride injection, USP, Ringer's injection, USP, lactated Ringer's injection, USP or non-aqueous vehicles such as vegetable oils, glycerin, polyethylene glycols, propylene glycol, alcohol, ethyl oleate, isopropyl myristate and dimethyletamide.
  • vehicles for injection such as water for injection, USP (WFI), purified water, USP, sterile water for injection , USP, bacteriostatic water for injection, USP, sodium chloride injection, USP, bacteriostatic sodium chloride injection, USP, Ringer's injection, USP, lactated Ringer's injection, USP or non-aqueous vehicles such as vegetable oils, glycerin,
  • compositions of the invention are suitable for delivery by inhalation, for example as an aerosol, inhalation or spray.
  • a composition further comprises a propellant.
  • such a composition comprises an active ingredient in solution or having a mean particle size (by volume or weight) less than about 100, less than about 75, less than about 50, or less than about 40 ⁇ m.
  • compositions of the invention are suitable for transmucosal delivery.
  • transmucosal delivery refers to delivery of an active agent across a mucous membrane, for example in the mouth (sublingual), nasal passage or eye.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable excipients.
  • excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition or absorption of the active ingredient, and that does not produce unacceptable toxicity or interaction with other components in the composition.
  • a given excipient if desired, will be present in a composition of the invention in an amount of about 0.001% to about 70%, about 0.1% to about 50%, or about 1% to about 25%, by weight of the composition.
  • pharmaceutically acceptable herein means that the substance in question does not produce unacceptable toxicity or interaction with other components of the composition.
  • a composition of the invention comprises a penetration enhancer.
  • a penetration enhancer is a composition that enhances or optimizes percutaneous absorption of the active ingredient by any mechanism including reduction of resistance of the stratum corneum, alteration of hydration of the stratum corneum, imparting a change in the lipid or lipoprotein structure in intracellular channels, through solvent action, through carrier mechanisms, etc.
  • suitable penetration enhances include surfactants, azone, dimethylsulfoxide (DMSO), dimethylacetamide, dimethylformamide, alcohol, acetone, propylene glycol, polyethylene glycol, etc.
  • Suitable wetting agents that can be used as penetration enhancers include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients.
  • suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose (e.g.
  • CereloseTM 2000 and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of ⁇ - and amorphous cellulose (e.g., RexcelTM) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like.
  • RexcelTM ⁇ - and amorphous cellulose
  • Such diluents typically constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition.
  • the foregoing excipients can have multiple roles as is known in the art. The classification of excipients above is not to be construed as limiting in any manner. Excipients categorized in any way may also operate under various different categories of excipients as will be readily appreciated by one of ordinary skill in the art.
  • a composition of the invention upon storage in a closed container maintained at room temperature, refrigerated (e.g. about 5 °C to about 10 °C) temperature, or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, still exhibit at least about 90%, at least about 92.5%, at least about 95%, or at least about 97.5% of the active ingredient(s) originally present therein when the composition was prepared or formulated.
  • compositions of the invention can be prepared in any suitable manner.
  • the invention provides a method of preparing a composition comprising the steps of combining, in any order, an enzymatic cross-linker, a protein and an active ingredient, and incubating the resulting composition under time and temperature conditions sufficient to form a cross-linked gel composition.
  • a composition of the invention is prepared by cross-linking a protein according to any suitable method (for example chemically or enzymatically, electrostically, with radiation, etc.) t and combining the protein with the active ingredient.
  • the step of combining the protein with the active ingredient can be performed prior to, during or after the cross-linking step.
  • such compositions are prepared by enzymatically cross-linking the protein substantially in the absence of any chemical cross-linker, for example glutaraldehyde or carbodiimide.
  • the enzyme used in the cross-linking step comprises a transglutaminase or mushroom tyrosinase.
  • the invention provides a method of preparing a pharmaceutical composition, the method comprising (a) providing a solution of a protein, for example and aqueous solution of rhGelatin; (b) adding a cross-linker and an active ingredient to the solution to form a mixture or second solution; and (c) incubating the resulting mixture or second solution under time and temperature conditions under which an otherwise similar mixture or second solution lacking the cross-linker would gel.
  • cross-linking herein means formation of covalent bonds between polymer chains to make a single network with increased strength and resistance to solvents.
  • enzymatic cross-linker herein refers to any enzyme capable of cross-linking a temperature-sensitive, gel-forming protein. Chemical cross- linkers, on the other hand, tend to produce amorphous, non-uniform gels and can be toxic, immunogenic or inflammatory.
  • the enzymatic cross-linker comprises a transglutaminase, for example factor XIII.
  • Factor XIII includes complete factor XIII zymogen tetramer and factor XIIIa, as well as activation intermediates and subunits thereof.
  • the enzymatic cross-linker comprises mushroom tyrosinase.
  • transglutaminases useful within the present invention include those produced by microorganisms and higher organism, for example factor XIII, keratinocyte transglutaminase, tissue transglutaminase, prostate transglutaminase, and epidermal transglutaminase.
  • the transglutaminase can be recombinant (i.e., production using genetically engineered host cells) or naturally derived.
  • the step of providing a solution of a protein is performed by dissolving the protein (e.g. recombinant gelatin) in an aqueous solvent buffered at pH of about 5 to about 9 and of low to moderate ionic strength (equivalent to about 1 to 1000 mM NaCl or about 50 to 300 mM NaCl). While salt is not required in the buffer, certain proteins are more soluble in the presence of salt, and near- physiological concentrations of salt can be beneficial. In one embodiment, pH of the solution is about 5.5 to about 8.5 or about 6 to about 8.
  • An illustrative aqueous solvent is phosphate buffered saline (PBS; 10 mM sodium phosphate pH 7.4, 120 mM NaCl, 2.7 mM KCl).
  • PBS phosphate buffered saline
  • Other suitable buffers include borate, phosphate, HEPES (N-[2-Hydroxyethyl]piperazine-N'-[2- ethanesulfonic acid]), etc.
  • the concentration of protein in the solution will be determined according to intended dosage unit properties, but will generally be about 50% or less by weight, for example about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 1% to about 10% or about 1% to about 5% by weight.
  • active ingredient can be added to the solution at this point as well.
  • the protein is allowed to swell, typically for about 15 minutes to about three hours, and is then melted by raising the temperature to a temperature above the gel point of the solution, for example about 32 °C to about 100 °C.
  • the solution can then be gelled, for example, by allowing it to stand overnight at room temperature, and stored under refrigerated conditions until needed.
  • an active ingredient can be added prior, during or after gelling is complete.
  • an enzymatic cross-linker and optionally an active ingredient can be added to the protein solution to form a mixture or second solution, for example while the first solution is in a sol state. If a transglutaminase is used, the solution may also contain calcium (e.g.
  • transglutaminases including factor XIII, tissue transglutaminase, keratinocyte transglutaminase, epidermal transglutaminase, and prostate transglutaminase typically require Ca ++ for activity, while others, including certain bacterial transglutaminases do not require calcium ions.
  • the ratio of protein:transglutaminase in the solution will generally be about 1500:1 to 1 :100, about 1000:1 to about 50:1, about 500:1 to about 25:1, about 100:1 to about 10:1, or about 10:1 to about 5:1, by weight.
  • the concentration of transglutaminase within the solution will typically be about 0.1 mg/ml to about 5.0 mg/ml. The solution can then be incubated under conditions of time and temperature in which an otherwise similar solution lacking cross-linking enzyme (e.g.
  • transglutaminase will gel, for example about 4 °C up to the gel point, about 4 °C to about 33 °C, or about 10 °C up to about 32 °C and for about 15 minutes or more, for example about 30 minutes to about 10 hours.
  • time to gel formation is a factor of, inter alia, temperature and protein concentration, and the actual time and temperature of incubation will be determined with consideration of all relevant parameters.
  • the incubation time conditions comprise about 10 minutes to about 10 hours, about 10 minutes to about 8 hours, about 10 minutes to about 5 hours or about 10 minutes to about 2 hours
  • the incubation temperature conditions comprise about 1 °C to about 90 0 C, about 5 °C to about 70 0 C, about 10 0 C to about 50 °C, or about 15 0 C to about 30 0 C.
  • cross- linking enzyme can be added to a composition of a temperature-sensitive gel-forming protein during or subsequent to gelation, in the latter case allowing the enzyme to diffuse into the gel.
  • an aqueous solution of enzyme ⁇ e.g. transglutaminase
  • a previously-formed recombinant gelatin composition optionally containing an active ingredient
  • the gel and enzyme can then be incubated under conditions conducive to gel formation for the protein used within the gel. Diffusion time, and amount and concentration of enzyme can be adjusted to provide the desired depth of penetration and degree of cross-linking.
  • composition prepared according to any of the above described methods represent further embodiments of the present invention.
  • compositions of the invention are useful in treatment and prevention of various diseases and disorders.
  • compositions of the invention are useful in the treatment of cancer or neoplasia.
  • compositions of the present invention are useful in the treatment or prevention of neoplasia or neoplasia-related disorders including acral lentiginous melanoma, actinic keratoses, acute lymphocytic leukemia, acute myeloid leukemia, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectum cancer, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, benign cysts, biliary cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer, bronchial cancer, bronchial gland carcinomas, carcinoids, carcinoma, carcinos
  • compositions of the invention are administered to a subject in an amount sufficient to provide active ingredient in an amount of about 0.01 mg/kg body weight to about 500 mg/kg body weight per day, for example about 0.1 mg/kg to about 50 mg/kg or about 1 mg/kg to about 25 mg/kg.
  • the composition is administered to the subject to provide the subject with a daily dose of active ingredient(s) of about 5 mg to about 1000 mg/kg, about 10 mg/kg to about 800 mg/kg, or about 20 mg/kg to about 300 mg/kg, for example about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 10, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550
  • compositions of the invention are administered to a subject in an amount sufficient to provide active ingredient in an amount of about 0.001 mg/m 2 (BSA; body surface area) to about 5000 mg/kg BSA per day, 0.01 mg/m 2 to about 2500 mg/m 2 per day, or about 1 0.001 mg/m 2 to about 2000 mg/m 2 per day, for example for example about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 10, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about
  • compositions of the invention can be administered in combination with or as an adjunct to (e.g. before, during or after) additional cancer therapy including surgery, radiation, photodynamic treatment, laser therapy, angiogenesis inhibitors, bone marrow and peripheral blood stem cell transplantation, gene therapy, hyperthermia, biological therapies (e.g. cetuximab) and antiemetics.
  • additional cancer therapy including surgery, radiation, photodynamic treatment, laser therapy, angiogenesis inhibitors, bone marrow and peripheral blood stem cell transplantation, gene therapy, hyperthermia, biological therapies (e.g. cetuximab) and antiemetics.
  • topically administrable compositions of the invention can be administered in combination with one or more topical analgesics.
  • administered in combination with herein means that the compositions in question can be administered substantially simultaneously, or as part of a combined regimen in which the two or more compositions are administered in a desired sequence within a period of about 5 hours, 10 hours, 15 hours, 1 day, 2 to 15 days or 1 month.
  • topical analgesics include rubefacients (e.g. traditional formulations based on salicylate and nicotinate esters, capsaicin and capsicum extracts and derivatives), NSAIDs (e.g.
  • diclofenac diclofenac, felbinac, ibuprofen, ketoprofen, piroxicam, naproxen, flurbiprofen), local anesthetics and a miscellaneous group: including benzydamine, mucopolysaccharide polysulphate, salicylamide and cooling sprays.
  • Local anesthetics include, without limitation, amino esters (e.g. benzocaine, chloroprocaine, cocaine, procaine and tetracaine), amino amides (e.g. bupivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, articaine and trimecaine.
  • amino esters e.g. benzocaine, chloroprocaine, cocaine, procaine and tetracaine
  • amino amides e.g. bupivacaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, articaine and trimecaine.
  • Example 1 rhGelatin-5-FU: Cream for Head and Neck.
  • rhGelatin-5-FU is used as a topical cream for head and neck cancer. rhGelatin-5-FU is applied directly to the recurrent or refractory tumor nodule itself.
  • Example 2 rhGelatin-paclitaxel: Intravenous injection for lung cancer. [0073] rhGelatin-paclitaxel will be tested as a second line therapy for lung cancer and will be compared to existing agents like Taxotere® (docetaxel) or Alamta® (pemetrexid).
  • Example 3 Primary, metastatic lung cancer.
  • rhGelatin-paclitaxel will be tested as a primary agent for metastatic lung cancer and will be compared to existing agents such as paclitaxel-based chemotherapy or a nanoalbumin paclitaxel-based regimen.
  • Example 4 Intravenous injection for primary, metastatic breast cancer.
  • rhGelatin-paclitaxel will be tested by intravenous injection as a second line agent for breast cancer and will be compared to existing agents like Taxol® or nanoalbumin-based Taxol®.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

La présente invention concerne, dans divers modes de réalisation, des compositions pharmaceutiques comprenant une ou plusieurs protéines réticulées et un ou plusieurs principes actifs, ainsi que des méthodes d'élaboration de telles compositions, et des méthodes d'utilisation de telles compositions dans le traitement de divers troubles et maladies.
PCT/US2007/068585 2006-05-09 2007-05-09 Composition à base de protéines et méthodes d'utilisation Ceased WO2007134118A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US9636433B2 (en) 2006-12-15 2017-05-02 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US10265413B2 (en) 2014-11-05 2019-04-23 University Of The Sciences In Philadelphia High molecular weight biodegradable gelatin-doxorubicin conjugate
CN113559051A (zh) * 2021-07-29 2021-10-29 北京赛升药业股份有限公司 一种可注射明胶载药缓释体系及其制备方法
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices
WO2025229134A1 (fr) * 2024-05-03 2025-11-06 Gelita Ag Procédé de production d'un composant de collagène gélifiant

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8043631B2 (en) * 2004-04-02 2011-10-25 Au Jessie L S Tumor targeting drug-loaded particles

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9636433B2 (en) 2006-12-15 2017-05-02 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US9655988B2 (en) 2006-12-15 2017-05-23 Lifebond Ltd Gelatin-transglutaminase hemostatic dressings and sealants
US9044456B2 (en) 2008-06-18 2015-06-02 Lifebond Ltd. Cross-linked compositions
US9066991B2 (en) 2009-12-22 2015-06-30 Lifebond Ltd. Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US10202585B2 (en) 2009-12-22 2019-02-12 Lifebond Ltd Modification of enzymatic crosslinkers for controlling properties of crosslinked matrices
US8961544B2 (en) 2010-08-05 2015-02-24 Lifebond Ltd. Dry composition wound dressings and adhesives comprising gelatin and transglutaminase in a cross-linked matrix
US10265413B2 (en) 2014-11-05 2019-04-23 University Of The Sciences In Philadelphia High molecular weight biodegradable gelatin-doxorubicin conjugate
US11998654B2 (en) 2018-07-12 2024-06-04 Bard Shannon Limited Securing implants and medical devices
CN113559051A (zh) * 2021-07-29 2021-10-29 北京赛升药业股份有限公司 一种可注射明胶载药缓释体系及其制备方法
CN113559051B (zh) * 2021-07-29 2023-06-23 北京赛升药业股份有限公司 一种可注射明胶载药缓释体系及其制备方法
WO2025229134A1 (fr) * 2024-05-03 2025-11-06 Gelita Ag Procédé de production d'un composant de collagène gélifiant

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