WO2015134951A1 - Amnion derived therapeutic compositions and methods of use - Google Patents

Amnion derived therapeutic compositions and methods of use Download PDF

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Publication number
WO2015134951A1
WO2015134951A1 PCT/US2015/019318 US2015019318W WO2015134951A1 WO 2015134951 A1 WO2015134951 A1 WO 2015134951A1 US 2015019318 W US2015019318 W US 2015019318W WO 2015134951 A1 WO2015134951 A1 WO 2015134951A1
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WO
WIPO (PCT)
Prior art keywords
therapeutic composition
amniotic membrane
amniotic
fluid
method
Prior art date
Application number
PCT/US2015/019318
Other languages
French (fr)
Inventor
Bruce WERBER
Zain Ismail KHALPEY
Terrell Suddarth
Christian Beaudry
Original Assignee
Amnio Technology Llc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to US201461949135P priority Critical
Priority to US201461949066P priority
Priority to US61/949,135 priority
Priority to US61/949,066 priority
Application filed by Amnio Technology Llc filed Critical Amnio Technology Llc
Publication of WO2015134951A1 publication Critical patent/WO2015134951A1/en
Priority claimed from EP15877280.6A external-priority patent/EP3242672A4/en
Priority claimed from US14/853,889 external-priority patent/US9814746B2/en
Priority claimed from US15/257,870 external-priority patent/US20160375064A1/en
Priority claimed from US15/381,044 external-priority patent/US10363278B2/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18Growth factors; Growth regulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48Reproductive organs
    • A61K35/50Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/72Cosmetics or similar toilet preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toilet preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/89Polysiloxanes
    • A61K8/891Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone
    • A61K8/892Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone modified by a hydroxy group, e.g. dimethiconol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues ; Not used, see subgroups
    • C12N5/0602Vertebrate cells
    • C12N5/0603Embryonic cells ; Embryoid bodies
    • C12N5/0605Cells from extra-embryonic tissues, e.g. placenta, amnion, yolk sac, Wharton's jelly

Abstract

A therapeutic composition may include a fluid component and/or a matrix component derived from amnion. A matrix component may be an amniotic membrane that is free of chorion. A fluid component may be a fluid having a concentration of stem cells, such as amniotic stem cells, and/or micronized amniotic membrane particles. A preferred fluid component includes micronized amniotic membrane particles dispersed in an amniotic stem cell concentrated fluid. An amniotic stem cell concentrated fluid has at least 0.1 x 106 amniotic stem cells per milliliter of fluid or composition, A therapeutic composite may be used to treat any number of heart related conditions through topical application, injection or through introduction intravenously. A matrix component may be located on a treatment location and a fluid component may be subsequently introduced to the matrix component.

Description

AMNION DERIVED THERAPEUTIC COMPOSITIONS AND METHODS OF USE

BACKGROUND OF THE INVENTION

Cross Reference To Related Applications

[0001] This application claims the benefit of U.S. provisional patent application no. 61/949,066 to Amnio Cordis Technology LLC and U.S. provisional patent application no. 61/949,135 to Amnio Cordis Technology LLC, both filed on March 6, 2014; th entirety of both are incorporated herein by reference.

Field of the Invention

[0002] The present invention relates to therapeutic compositions derived from amnion materials and methods of use to treat the heart.

Background

[0003] Amniotic membranes are being used in clinical trials to treat a wide range of conditions. Amniotic membranes are typicaily placed directly on a treatment location, such as a wound or incision, in many cases however, amniotic membranes lack the proper architecture and ceil viability to effectively provide the desired therapeutic responses, such as tissue regenerations, immunomodulation, anti-inflammatory and antiftbrottc. Most amniotic membranes are dehydrated and cryogenicaily preserved. In other cases, the amniotic membranes are sterilized in a manner that damages the tissue and/or reduces cell viability. For example, many amniotic membranes are processed wit a gSutaraSdehyde which is known to significantly reduce ceil viability. In many treatment applications, it is desirable to provide a high concentration and/or specific type or biend of stem ceils. In addition, some therapeutic composites comprise components from two or more donors thereby limiting their use.

SUMMARY OF THE INVENTION

[0004] The invention is directed to therapeutic compositions that, in one embodiment, comprise a therapeutic fluid comprising amniotic fluid. An amniotic fiuid may comprise any number of cells, including stem ceils, growth factors, proteins

i and the like, in one embodiment, a therapeutic fluid comprises an amniotic fluid that is acellular. in another embodiment, a therapeutic composition comprises a matrix component, such as an amniotic membrane, in still another embodiment, a therapeutic composition comprises a matrix component and a fluid component, wherein a fiuid component may be imbibed into or coated onto one or more surfaces of the matrix component, in an exemplary embodiment, a therapeutic composition comprises an amniotic membrane in the matrix component and comprises amniotic fluid in the fiuid component.

[0005] in an exemplary embodiment, the therapeutic composition, as described herein, comprises a plurality of amniotic stem ceils, and preferably at a high concentration, such as greater than 0,1 x 10δ per milliliter and more preferably above 0,6 x 106 per milliliter of the therapeutic fiuid component within the therapeutic composition, A therapeutic fluid component may aiso be aceiiuSar, such as an acellular amniotic fluid. An acellular amniotic fluid is described in U.S. application no 14/593,415 to Amnio Technology LLC; the entirety of which is incorporated by reference herein. A therapeutic fluid component may be referred to herein as simply a fiuid component for brevity. In another embodiment, a fluid component comprises amniotic membrane that has been micronized and dispersed in a fluid. In one embodiment, a fluid component is a dispersion of micronized amniotic membrane combined with a fluid, such as plasma, saline, amniotic fluid, combinations thereof and the like, In another embodiment, a fluid component comprises a mixture of micronized amniotic membrane particles combined with an amniotic stem cell concentrated fluid, in still another embodiment, a therapeutic fluid consists essentially of a concentrated amniotic fluid wherein the quantity of amniotic stem cells is increased. The amniotic stems ceils in the therapeutic composite, as described herein, may be derived from amniotic fluid and the stem ceils may be concentrated by a centrifuge process. Additional fluids and agents may be added to the amniotic stem celis such as plasma, Plasma Lyte-A, from Baxter Inc., saline and the like. The concentration of amniotic stems cells in one milliliter of a fluid component of an exemplary therapeutic composition, as described herein, may be about 0.5 X 106 or more, 1 ,0 x 106 or more, 5.0 x 10s or more, 10 x 106 or more and any range between and including the concentrations values provided, A high concentration of amniotic stems cells may greatly improve the effectiveness of the therapeutic composition for many applications. The therapeutic composition, as described herein, may comprise endothelial cells, mesenchyma! stem cells, amniotic fluid stem ceils, fibroblasts, proteins, keritinocytes, epithelial and/or epidermal ceils, paratenacytes, keratinocytes, epithelial and/or epidermal cells, paratenacytes, keratinocytes and growth factors, in some embodiments, protein markers for mesenchymal stem cells may be analyzed to quantify the various types of ceils within the therapeutic composition. Flow cytometry may be used to identify proteins, CD44, CD105, CD73 and GD9Q. In one embodiment, a therapeutic composition comprises at least 30% of mesenchymal stem cells as identified by CD73,

Mesenchymal stem cells indicated by CD73 proteins may be more mobile and provide a more therapeutic effect that mesenchyma! stem cells identified by the other markers. A therapeutic fluid component, as described herein, may comprise antiinflammatory nano-partic!es and/or statins, HMG-CoA reductase inhibitors to reduce inflation at a treatment location.

[0006] In some embodiments, a therapeutic composition is doped with progenitor cells and the progenitor cells may be multipotent progenitor cells and/or pluripotent progenitor cells. Progenitor cells may be derived from a patient to be treated, such as from a stromal vascular fraction. Vascular fraction ceiis and/or progenitor cells may be included with a therapeutic composite to further improve effectiveness. Progenitor cells may be autologous or allogeneic.

[0007] A fluid component, as described herein, may comprise particles and/or a concentration of amniotic stem cells. The particles within the fluid component may comprise micronized amniotic membrane. The micronized amniotic membrane may comprise hydrated mammalian amniotic tissue having a percent hydration of at least about 25%, at feast about 50%, at least about 75% by weight or any range between the concentrations provided. Amniotic membrane maintained in a hydrated state may provide for more viable and regenerative properties. Amniotic membranes that are lyophilized have a great reduction in cell viability. The particles in the fluid component, as described herein, may consists essentially of amniotic membrane and be substantially free of chorion. The amnion layer may be removed from the chorion prior to processing. In one embodiment, the amniotic membrane particles consist essentially of epithelium wherein the concentration of the epithelium is about 70% or more, for example. The particles consisting essentially of epithelium may comprise stem ceiis and tissue that may substantially surround the stem cells. £0008] An amniotic membrane, or portion thereof, may be micronized while in a hydrated state thereby improving the viability of ceils. The amniotic membrane particles may be derived from dehydrated and/or decellularized amniotic tissue however. In addition, the amniotic membrane may be cryo-fractured, such as with a blunt object to minimize shear and damage to tissue, thereby improving therapeutic effectiveness. Particles of amniotic membrane may have any suitable particle size, average particle size and particl sized distribution. For example, the amniotic membrane derived particles, or micronized particles, may have a particle size, or an average particle size of no more than about 10pm, no more than about 5pm, no more than about 2pm, no more than about 1pm, no more than about O.Spm and any range between and including the average particle sizes provided. The particle size of the amniotic membrane particles can be determine through any suitable method, including image analysis, whereby a therapeutic composite is dried and imaged using a scanning electron micrograph (SEM).. The amniotic membrane derived particles may have an irregular shape and in some embodiments are planar having a first planar surface and a second planar surface. Cryo-fracturing of amniotic membrane with a blunt object provides particles with less shear and a more irregular shape than conventional cryo-miliing, thereby providing a higher surface area and more effective therapeutic effect.

[0009] The concentration of particles, such as micronized amniotic membrane, in the therapeutic composition and/or fluid component may be provided in any effective amount such as more than about 0,1%, more than about 0.5%., more than about 1%, more tha about 10%, more than about 25%, more than about 50%, more than about 75%,or more than about 90% by weight of therapeutic composition and any range between and Including the weight percentages listed. Likewise, the mass of particles, such as amniotic membrane particles, may be provided in a therapeutic fluid component of a therapeutic composition in any effective amount, such as more than about img/mi, more than about 5mg/ml, more than about 10mg/ml, more than about 50mg/mi, more than about lOOmg ml, more than about 500mg/mi, and any range between and including the mass concentrations provided. The particles in the therapeutic composition may comprise collagen, growth factors, stem cells, amniotic stem cells, mesenchymal stem cells, progenitor ceils, red blood ceils, white blood cells, proteins, fibroblasts, paratenacytes, keratinocytes and the tike. {0010] An exemplary therapeutic composition may comprise an oxygen-carrier component that may increase the effectiveness of the therapeutic composite by increasing oxygen availability and increase stem ceil viability. Any suitable oxygen- carrier component or combination of components may be included info a therapeutic compositing including, but not limited to, perfluorocarbon such as

perfSuorotributy!amine (PFTBA), perfluorooctyibromide (PFOS).

perf!uorodecyibromide, perfluoroperhydrophenanthrene and the like. An oxygen- carrier may be bonded, such as covalentiy bonded to a therapeutic composition, such as to a matrix component or to the micronized amniotic membrane, in one embodiment, a matrix component comprises a polymeric material, such a

fluoropoiymer, and an oxygen component is bonded thereto. An suitable means may be used to bond an oxygen component to a therapeutic composition component including, cross-linking agents, radiation, and the like. In still another embodiment, an oxygen-carrier component may form a emulsion, or micro-emulsion with another fluid component. A perfluorocarbon oxygen-carrier component is hydrophobic and when mixed with a fluid component that is hydrophilic or comprises water, an emulsion may be formed comprising an aqueous phase and a perfluorocarbon phase,

[001 1] Any of the fluid components described herein may be an injectable solution that will pass through a 20 gauge needle or a needle having a smaller diameter. In other embodiments, a fluid component Is provided in a thicker composition, such as a paste that may foe applied topically. The viscosity of the an injectable fluid component may be no more than about 1 mPa sec, no more than about 500 mPa sec, no more than about 1000 mPa sec, no more than 20.000 mPa sec, no more than 60,000 mPa sec. In other embodiments, a fluid component may be provided for topica! applications and the viscosity ma be more than about 20 Pa sec, more than about 50 Pa sec, more than about 100 Pa sec, more than about 250 Pa sec and any range between and including the viscosity values provided.

[0012] In an exemplary embodiment, a therapeutic composition is a

therapeutic composite and comprises an of the fluid components, as described herein, imbibed into or coated onto a matrix component, A matrix component is a sheet, block, tube or rod of material, for example, that may comprises porosity and pores for accepting a fluid component therein, A matrix component may be a biological materia! such as an amniotic membrane. In another embodiment, an amnioiic membrane may be provided as a matrix component in a muiti!ayered configuration or combined with any other suitable support iayer for a desired application. For example, a therapeutic composite, as described herein, may comprise an amniotic membrane iayer and a cover iayer. A cover iayer may be used to reduc the loss, wash-out, of a fluid component from the therapeutic composite. In another embodiment the therapeutic composite comprises an amniotic membrane and a support iayer, such as a polymer matrix materia! including, but not limited to, a bioresorbable or fluoropolymer membrane. A support layer may have a tensile break strength that is much greater, such as two times or more that of an amniotic membrane layer in a matrix component, in still another embodiment, a therapeutic composite comprises one or more layers of amniotic membrane that are tensiiized, whereby an amniotic membrane has been stretched in one or more directions to increase strength and/or area of the membrane. An amniotic membrane may be cross-linked, and a cross-linked amniotic membrane may be combined with a non- cross-linked amniotic membrane. Any suitable method, as known in the art of cross- linking an amniotic membrane may be used including chemical, such as treatment with g!utaraSdehyde, radiation and the like. A therapeutic composite as described herein, may comprise anti-inflammatory nano-particles and/or statins, H G-CoA reductase inhibitors to reduce inflation at a treatment location. An exemplary therapeutic composition, and in particular a fluid component, may comprise manriitol, saline, ringers lactate, vitamin B complex and the tike.

[0013] A therapeutic composite, as described herein, may be provided with the therapeutic fluid i