WO2015195508A1 - Frozen therapeutic dose and package - Google Patents

Frozen therapeutic dose and package Download PDF

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Publication number
WO2015195508A1
WO2015195508A1 PCT/US2015/035749 US2015035749W WO2015195508A1 WO 2015195508 A1 WO2015195508 A1 WO 2015195508A1 US 2015035749 W US2015035749 W US 2015035749W WO 2015195508 A1 WO2015195508 A1 WO 2015195508A1
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WO
WIPO (PCT)
Prior art keywords
dose
frozen
therapeutic dose
compartment
therapeutic
Prior art date
Application number
PCT/US2015/035749
Other languages
French (fr)
Inventor
Bruce WERBER
Christian Beaudry
Terrell Suddarth
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
Application filed by Amnio Technology Llc filed Critical Amnio Technology Llc
Publication of WO2015195508A1 publication Critical patent/WO2015195508A1/en
Priority to US15/381,044 priority Critical patent/US10363278B2/en
Priority to US16/525,062 priority patent/US20190350984A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
    • 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
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/89—Polysiloxanes
    • A61K8/891—Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone
    • A61K8/892—Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone modified by a hydroxy group, e.g. dimethiconol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
    • A61K2800/24—Thermal properties
    • A61K2800/244—Endothermic; Cooling; Cooling sensation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a frozen therapeutic dose comprising an amniotic materia! and packaging for said dose.
  • a frozen therapeutic dose comprises iive amniotic stem DCis
  • compositions comprising amniotic fluid, tissue, and in particular amniotic stem ceils are being used to treat a wide variety of conditions and alignments. Active or live stem cells are critically important in the treatment of some conditions and patients hav to visit a doctors office to receive these treatments. Some conditions require the regular application, or injection of therapeutic compositions comprising amniotic stem cells which requires the patient to make frequent trips to the doctor's office. This is inconvenient and in some cases
  • Amniotic stem cel!s are somewhat fragile and can become damaged or die for an number of reasons including exposure to chemicals, exposure to excessive heat or simply time,
  • the invention is directed to a frozen therapeutic dose comprising an amniotic material and packaging for said dose.
  • a frozen therapeutic dose comprising an amniotic material and packaging for said dose.
  • a frozen therapeutic dose comprises live amniotic stem ceils.
  • a frozen therapeutic dose may be provided in a form, such as a mutti-pack form, to enable a person to administer a dose to a treatment location without the need of traveling to a doctor's office or clinic.
  • a frozen therapeutic dose package may be kept in a conventional freezer at -20°C, for example, for extended periods of time and a person may remove the package as needed for treatment. Many conditions require the administering of a therapeutic dose every day or multiple times a day and traveling to a treatment location that often is not practical for many people.
  • a frozen dose may keep the amnion material and in particular the live amniotic stem ceils viable for extended persods of time. Live amniotic stem cells may remain iive and viable even after being frozen for certain periods of time. A cryoprotectant may be required in some cases to protect the amnion materia! and in particular to preserver the viability of the amniotic stem cells.
  • cryprotectant Any suitable type of cyroprotectant may be used including, but not limited to, glycols, ethylene glycol, propylene glycol, glycerol, 2-methyi-2,4 ⁇ pentanediol (MFD), alcohols, dimethyl sulfoxide (DMSG), sugars, poiyols, glucose and the like, Some of the cryprotectamts may raise the pH and a buffer may be needed to reduce this elevated pH prior to administering to a treatment location.
  • MFD 2-methyi-2,4 ⁇ pentanediol
  • DMSG dimethyl sulfoxide
  • a therapeutic dose as used herein comprises amniotic materia! including, but not limited to, amniotic membrane, amniotic fluid, amniotic stem DCis, and/or cytokines, collagen, proteins, and growth factors derived from amnion materia!.
  • a frozen therapeutic dose comprises live amniotic stem ceils.
  • a therapeutic dose may aiso comprise a diluent, a
  • a therapeutic dose comprises amnion material and a buffer to reduce the Ph of a cryoprotectant
  • an therapeutic does comprises anti-inflammatory nano-particies and/or statins, HMG- CoA reductase inhibitors to reduce inflation at a treatment location.
  • a diluent may be comprise a saiine solution, water, a plasma containing solution, such as P!asma Lyte from Baxter Inc. in some embodiments, it may be desired to have a viscous frozen dose upon thawing or me!ting. It may be desirable to slow the absorption of the frozen dose into a treatment location.
  • a hydrogel may be used as a diluent and may provide for a high viscosity thawed frozen dose, and may prolong the time the therapeutic frozen dose is in contact with a treatment location. Any suitable type of hydfogei may be combined with the therapeutic composition.
  • a therapeutic dose comprise a concentration of live amniotic stem ceils of at least about 0.5 x 10 b celi/mi or more, about 1 x 10 6 cell/ml or more, about 2 x 10 s cell/mi or more and any range between and including the values provided.
  • amniotic stem cells are concentrated in the therapeutic dose, whereby the concentration is substantially higher than an initial concentration before processing.
  • a frozen therapeutic dose may be configured in a dosing package having a dose compartment and a compartment closure.
  • An individual dosing package may be relatively small, such as no more than about 100ml, no more than about 50ml, no more than about 25ml, no more than about 10ml, no more than about 5mi and an range between and including the volumes provided.
  • a frozen therapeutic dose is provided in a detachable dosing package that is part of a muiii-dose pack.
  • two or more detachable dosing packages may be coupled together in a multi-dose pack and a separation feature, such as perforations, may be used for detachment. Any number of detachable dosing packages may be configured in a muifi-dose pack including more than three, more than five, more than ten, more than twenty and the like.
  • a dosing package may comprise a frozen therapeutic dose and a secondary materia! within a singie compartment whereby the frozen materials are substantiall separate and will not mix until they thaw.
  • a frozen therapeutic dose of amniotic stem cells may be frozen and a cryoprotectant may be added to ensure that the stem celt are live upon thawing.
  • the cryoprotectant may be an irritant for some treatment locations, such as the eye, and therefore a buffer or buffer solution is added to the dosing package compartment in a frozen state.
  • the two solid materials within the dosing package compartment will stay substantially separate and will not mix until the contents of the compartment are thawed, !n this way, the therapeutic dose applied to a treatment location will not be irritating.
  • a secondary material may be configured within a single dose compartment including, but not limited to. a diluent, a buffer, a secondary therapeutic composition and the like.
  • a secondary materia! or component of a therapeutic dose is provided in a separate compartment, whereby the contents of the secondary compartment are added to the frozen dose before application to a treatment location.
  • a set of compartments, one with a frozen therapeutic dose of amnion materia!, and a another with a secondary materia! including, but not limited to, a diluent, a buffer, a secondary therapeutic composition and the like, may be coupled together.
  • a muiti-dose pack may comprise a separation feature that is configured to detach th two compartments.
  • a secondary therapeutic composition may comprise amnion material and may have a different composition than a first therapeutic composition.
  • a frozen dose may be configure to be removed from a dose
  • a frozen dose pellet may be removed from a dose compartment and placed on the eye or under an eyelid.
  • a frozen dose may be piaced in an applicator, such as a dropper, spray bottle, or syringe for example.
  • a diluent, buffe or other secondary material may be added to an applicator.
  • a frozen dose may be allowed to thaw prior to application to a treatment location, or melt in a secondary material.
  • a frozen therapeutic dose is coupled with a compartment closure, whereby the compartment closure can be removed from the compartment and the therapeutic dose applied to a treatment location.
  • a frozen dose may be configured in a bliste pack having a peel off compartment closure.
  • the frozen dose may be attached to the pee! way compartment closure whereby upon removal of the closure it can be applied directly to a treatment location, such as the skin, eye, mouth, etc. !n another embodiment a frozen dose is attached to a closure cap and upon removal can be swabbed over a treatment area, or p!aeed in or on the mouth.
  • a f oze dose is configured in a dose package applicator comprising a compartment closure and at least one opening in a compartment cover.
  • the compartment closure such as a foil sheet, can be removed to expose the compartment cover having at least one opening therein.
  • the dose package applicator can be placed directly on a treatment location and the compartment can be pressed to enable the therapeutic composition to pass through the opening.
  • a compartment cover may be a porous materia! that enables the therapeutic composition to transfer therethrough as it thaws.
  • the therapeutic composition may also be administered by a syringe or iranscatheier.
  • a frozen dose may be removed from a dose package and then drawn into a syringe.
  • the syringe may then be used to inject the therapeutic composition to any suitable treatment location.
  • a therapeutic composition may be applied to a treatment location by topical application, ingestion, injection, transcatheter and the like.
  • som conditions may require some combination of the application methods described herein.
  • a therapeutic composition may be applied to any suitable treatment location including, but not limited to, topically to the exterior of the body including the skin, a wound, a scare, a wrinkle and the like, to the digestive system by ingestion or injeciion, to an organ by injection or by direct application during surgery, for example.
  • Figure 1A shows a cross-sectional diagram of amniotic membrane surrounding a fetus in uiero.
  • Figure 1 B shows a cross-section diagram of the layers of the amnion and chorion.
  • Figure 2A show a transmission electron micrograph (TEM) of the epithelium layer of the amniotic membrane having a single layer of amniotic stem ceils. The TEM was taken at 2500 X magnification.
  • TEM transmission electron micrograph
  • Figure 2B show a TEM: of the epithelium layer of the amniotic membrane having a single iayer of amniotic stem ceils.
  • the TEM is at 8200 X magnification.
  • Figure 3A is a scanning electron micrograph (SEM) of an amniotic membrane having amniotic stem cells
  • Figure 38 is a SEM of cryo-fractured amniotic membrane particles.
  • Figure 4A shows a top down view an exemplary multi-dose pack having a plurality of frozen doses
  • Figure 4B shows a side view of an exemplary multi-dose pack have a plurality of frozen doses.
  • Figure 5 shows an exemplary detached dosing package being opened for placement in an eye.
  • Figure 6 shows an exemplary compartment closure having a frozen dose attached thereto.
  • Figure 7 shows an exemplary f rozen dose.
  • Figure 8A shows an exemplary frozen dose being placed into a dropper applicator with a diluent configured therein.
  • Figure 88 shows the dropper applicator with the frozen therapeutic dose melted and dispersed therein.
  • Figure 9 shows an exemplary dropper applicator being used to administer a drop of therapeutic composition into an eye.
  • Figure 10A shows a top down view an exemplary multi-dose pack having a plurality of frozen doses wherein a set of compartments are configured to be detached from the multi-dose pack.
  • Figure 10B shows a side view of an exemplary multi-dose pack, wherein each set of compartments contains a frozen therapeutic dose in a first compartment and a buffer in a second compartment.
  • Figure 11 shows a side view an exemplary multi-dose pack, wherein each compartment comprises a frozen therapeutic dose that is substantially separated from a buffer.
  • Figure 12 shows an exemplary spray bottle administering a therapeutic composition to a affected area of the skin.
  • Figure 13 shows an exemplary syringe applicator drawing a therapeutic dose into the syringe.
  • Figure 14 shows an exemplary syringe applicator administering a therapeutic dose into an affected area by injection
  • Figure 15 shows an isometric view of a dose package applicator
  • Figure 16 shows a diagram of the eye and some of the parts of the eye that may be affected areas for treatment with a therapeutic dose.
  • Figure 17 shows a diagram of the some of the organs within the body that may be an affected area for treatment with a therapeutic dose.
  • Figure 18 shows a shows a diagram of the circulatory system.
  • Figure 19 shows a diagram of a process to produce a therapeutic composition comprising micronized amniotic membrane particles
  • Figure 20 shows a diagram of a process to produce a therapeutic composition comprising a concentrated stem eel! fluid.
  • the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
  • use of "a” or “an” ar employed to describe elements and components described herein. This is done merely for convenience and to give a general sense of the scope of the invention. This description should be read to include one or at least one and the singular also includes the plurai unless it is obvious that it is meant otherwise.
  • the amniotic membrane surround a fetus in utero.
  • the amniotic membrane comprises an amnion portion and a chorion portion.
  • the amnion portion may be separated from the chorion.
  • the epithelium, or Inner most layer of the amniotic membrane is removed and used to produce particles for the therapeutic composition, as described herein.
  • the particles may consists essentially of the epithelium, consists essentially of the epithelium and base membrane, consist essentially of the epithelium, base membrane and compact Iayer, or consist essentially of epithelium, base membrane, compact layer, and fibroblast layer.
  • the epithelium Iayer of the amniotic membrane has a single Iayer of amniotic stem ceils.
  • the tissue around the amniotic stem cells may protect and enhance the viability of these stem cells when the epithelium is cryo-fractured to produce particles for the therapeutic composition.
  • an amniotic membrane 20 comprises a plurality of amniotic stem cells 32.
  • particles of cryo-fractured amniotic membrane particles are on the order of 0.2 to 0.5pm in size.
  • the average particle size shown is less than 2pm.
  • the SEM shows that the micronized amniotic membrane particles are irregularly shaped. As shown, some of the particles have a planar surface,
  • an exemplary multi-dose pack 210 has a plurality of frozen doses 200.
  • the multi-dose pack 210 comprises a plurality of detachable dosing packages 211 and a separating feature 218, such as perforations.
  • the separating feature may be configured for the detachment of individual detachable dose packages or two or more detachable dose packages.
  • an exemplary multi-dose pack 210 has a plurality of frozen doses 200 in dose compartments.
  • the individual doses are contained with discrete compartments 212 and a compartment ciosure 214 is configured over the compartments.
  • the compartment ciosure 214 is shown being peeied away from the dose pack.
  • Some of the doses 210 are shown configured in the bottom of the compartment 212 and some of the dose 200' are shown being attached to the compartment closure 214.
  • a separating feature 216 is configured between each of the detachable dose packages.
  • an exemplary detached dosing package 211 is being opened for placement of a frozen dose 200 in an eye 250.
  • the dose may be piaced directly into the eye or under the eyeiid 252.
  • a user may separate an individual detachable dose package from a mufti-dose pack, allow the frozen dose configured therein to melt, and then administer to an affected area, such as the eye.
  • an exemplary compartment ciosure 214 has a frozen dose 200 attached thereto.
  • the compartment closure may be removed from a dosing package 211 and piaced onto an affected area with the frozen dose attached.
  • the compartment ciosure 214 is used as an applicator 18 in this embodiment. After the dose has dissolved, the compartment ciosure may be removed from the affected area, such as an eye. This embodiment allows for safe application of the dose to an affected area with minimal handling.
  • an exemplar frozen dose 200 comprises a therapeutic composition 10.
  • the frozen dose pellet 202 has a partial spherical shape as it conformed to the compartment in which it was provided.
  • the frozen therapeutic dose comprises amnion material, in addition, a secondary therapeutic material and/or diluent, cyroprotectant and/or buffer may be configured within a single frozen dose pellet. Any suitable shape and size of frozen dose pellet may be configured fo application to a specific treatment location.
  • a thin planar sheet frozen dose may be used for application to the skin such as a wound or scar.
  • a pellet with rounded surface may be configured for placement under an eyelid, to reduce any discomfort.
  • an exemplary frozen dose 200 is being placed into a dropper applicator 221 with a diluent 230 configured therein.
  • the applicator cap 222 is open and the compartment closure 214 is being peeled off to drop the frozen dose pellet 202 into the dropper.
  • Figure SB shows the dropper applicator 221 with a diluted frozen therapeutic dose 236 therein. i ' 005$ ' i
  • an exemplary dropper applicator 221 is being used to administer a drop of therapeutic composition 10 into an eye 250.
  • an exemplary multi-dose pack 210 has a plurality of frozen doses 200 and buffers configured in sets of compartments.
  • a separation feature 218 is configured to enable the detachment of a frozen dose compartment 212 and a buffer compartment 212', or compartment set.
  • a frozen dose comprises a therapeutic composition 10 and a cyroprotectant.
  • the cryoprotectant may cause the frozen dose to have high pH and may irritate affected areas.
  • the buffer 232 may be configured to mix with the frozen dose upon thawing and reduce the pH prior to administering the mixture to an affected area or treatment iocation. It is to be understood that a second
  • compartment of a compartment set may comprise a secondary therapeutic composition of different composition, a therapeutic composition that does not comprise amnion material, an acellu!ar amnion derived therapeutic composition, a composition enhancer, an anti-inflammatory, a diluent and the like,
  • an exemplary multi-dose pack 210 comprises sets of compartments having a frozen therapeutic dose 200 in a first compartment 212 and a buffer 232 in a second compartment 212'.
  • an exemplary multi-dose pack 210 comprises a frozen therapeutic dose 200 that is substantially separated from a buffer 232 in dose compartment 212 and a frozen therapeuitc dose 200 that is substantially separated from a diluent 230 as shown in the dose compartment 212 : .
  • a therapeutic composition may be frozen separately from a buffer or diluent whereby they are configured in the dose compartment in a frozen state and substantially separate from each other.
  • the concentration of the frozen dose and secondary material, such as diluent, buffer, or secondary therapeutic composition ma remain substantially different while maintained in a frozen state.
  • the single dose compartment 2 2 may be opened and place onto a treatment locationo or the contents of the compartment may b allowed to thaw, whereby the contents will mix prior to administering to a treatment Iocation.
  • an exemplary spray bottle 84 type applicator 18 is administering a therapeutic composition 10 to an affected area or treatment location 248 of the skin.
  • an exemplary syringe 80 applicator is drawing a iherapeuiic composition 10 into the syringe.
  • the therapeutic composition 10 within the enclosure 70 comprises live amniotic stem cells 30,
  • the therapeutic composition may also comprise a diiueni and a frozen dose may have been thawed in the diluent,
  • an exemplary syringe 80 applicator is
  • the therapeutic dose is a composition derived from thawing a frozen dose, as described herein and comprises live amniotic stem cells 30, a cyroprotectant 234 and a buffer 232.
  • the therapeutic dose is being injected into a joint.
  • a dose package applicator comprises a dose compartment 212 with a therapeutic composition 10 therein.
  • the dose package applicator may be one of a plurality of individual dose package applicators couple together in a multi-dose pack.
  • the dose package applicator 224 comprises a compartment closure 214 that is being peel off to expose openings 226 in a compartment cover portion 228,
  • a compartment cover portion may be a portion of a detachable dosing package and may be a sheet of plastic material, for example.
  • the compartment cover portion comprises opening 226 to allow the administering of the therapeutic dose 204 by pressing on the dose compartment, as indicated by the arrow pointing up.
  • the therapeutic dose 204 is squeezed through the opening an onto a treatment location. It is to be understood thai a frozen dose package with a compartment cover having at least one opening may be configured for placement onto a treatment location to allow the frozen dose to transfer through the opening as the frozen dose thaws and melts
  • Figure 16 shows a diagram of an eye 250 and some of the parts of the eye that may be treatment locations for treatment with a therapeutic dose derived from a frozen dose, as described herein.
  • a therapeutic composition as described herein, may be applied topically and/or injected into the iris, anterior chamber, lens, vitreous humor, ciiliary muscle, cornea, extraocular muscle, sclera, choroid, retina and the like.
  • Figure 17 shows a diagram of the some of the organs within the body that may be an affected area for treatment with a therapeutic dose derived from a frozen dose, as described herein.
  • a therapeutic composition, as described herein, may be introduced into any anatomy shown in FIG. 17 by direct injection, topical application, or transcatheter.
  • FIG. 18 shows a diagram of the circulatory system that may be an affected area for treatment with a therapeutic dose derived from a frozen dose, as described herein.
  • the circulator system may be used to transport a therapeutic composition to an affected area, such as an organ, for example.
  • FIG. 19 shows a diagram of a process to produce a therapeutic composition comprising micronized amniotic membrane particles.
  • an exemplary process to produce a therapeutic composition comprises the steps of cryo-fracturtng amniotic membrane fragments to produce micronized amniotic membrane particles.
  • the amniotic membrane fragments may be cryo-fraeture with a blunt object, such as a bar, that reduces shear and damage to the particles.
  • the fragments are cryo-fractured with an object having substantially no sharp edges.
  • the micronized particles are combined with any suiiable carrier fluid to produce a therapeutic composition.
  • the micronized particles are dispersed in a fluid comprising amniotic fluid and amniotic stem ceils.
  • the micronized particles are dispersed in a concentrated amniotic stem cell fluid.
  • Figure 20 shows a diagram of a process to produce a therapeutic composition comprising a concentrated stem cell fluid.
  • the exempiary process comprises the steps concentrating amniotic stem ceils in a fluid component comprising Plasma Lyte-A, available from Baxter Inc.
  • An amniotic fluid may be processed in any suiiable way to concentrate the amniotic stem cells in the fluid.
  • the amniotic fiuid is centrifuged to remove debris and excess liquid, and concentrate the amniotic stem ceils in the therapeutic composition
  • Amnion material includes amniotic membrane, amniotic stem cells, amniotic fluid, and/or eytokines, collagen, proteins and growth factors derived from amnion or amniotic fluid.
  • Treatment location and affected area are used interchangeable through the specification.
  • a therapeutic dose comprises a frozen therapeutic dose comprising amnion material, and may be thawed and combined with secondary material, such as buffer, diluent, a secondary therapeutic composition and the like.
  • a cryoprotectant is a substance used to protect biological tissue from freezing damage from ice formation, for example.

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Abstract

A frozen therapeutic dose includes an amniotic material and is configured into a pack for easy administering of the dose to a treatment location, A frozen therapeutic dose may contain a concentration of live amniotic stem cells. A frozen therapeutic dose may be provided in a form, such as a multi-pack form, to enable a person to administer a dose to a treatment location without the need of traveling to a doctor's office or clinic, A frozen therapeutic dose package may be kept in a conventional freezer at -20°C, for example, for extended periods of time and a person may remove the package as needed for treatment- A frozen dose package or pack may contain a secondary material configured to mix with the frozen therapeutic dose. A secondary material may be configured within a single dose compartment with the frozen dose or within a separate compartment.

Description

FROZEN THERAPEUTIC DOSE AND PACKAGE
BACKGROUND OF THE INVENTION
Cross Reference to Related Application
[0001 ] This application claims the benefit and priority to U.S. provisional patent application no. 62012388, filed on June 15, 2014 and entitled Frozen
Therapeutic Dose and Package: the entirety of which is incorporated by reference herein.
Fieid of the invention
[0002] The present invention relates to a frozen therapeutic dose comprising an amniotic materia! and packaging for said dose. In an exemplary embodiment a frozen therapeutic dose comprises iive amniotic stem ceiis
Background
[0003] Therapeutic compositions comprising amniotic fluid, tissue, and in particular amniotic stem ceils are being used to treat a wide variety of conditions and alignments. Active or live stem cells are critically important in the treatment of some conditions and patients hav to visit a doctors office to receive these treatments. Some conditions require the regular application, or injection of therapeutic compositions comprising amniotic stem cells which requires the patient to make frequent trips to the doctor's office. This is inconvenient and in some cases
impractical, especially when a dose of an amniotic stem celi therapeutic composition is required multiple times a day,
[0004] Amniotic stem cel!s are somewhat fragile and can become damaged or die for an number of reasons including exposure to chemicals, exposure to excessive heat or simply time,
SUMMARY OF THE INVENTION
[0005] The invention is directed to a frozen therapeutic dose comprising an amniotic material and packaging for said dose. Any of the therapeutic compositions described in U.S. provisional patent application no,: 61/949,087, filed on March 30,
i 2014 and entitled Therapeutic Compositions and Methods of Use, or U.S. provisional patent application no.: 62/012394, filed on June 15, 2014 and entitled Aceliular Amnion Derived Therapeutic Composition, may be configured as a frozen
therapeutic dose, as described herein, and both of these references are incorporated by reference herein in their entirety, in an exemplary embodiment, a frozen therapeutic dose comprises live amniotic stem ceils. A frozen therapeutic dose may be provided in a form, such as a mutti-pack form, to enable a person to administer a dose to a treatment location without the need of traveling to a doctor's office or clinic. A frozen therapeutic dose package may be kept in a conventional freezer at -20°C, for example, for extended periods of time and a person may remove the package as needed for treatment. Many conditions require the administering of a therapeutic dose every day or multiple times a day and traveling to a treatment location that often is not practical for many people.
[0006] A frozen dose may keep the amnion material and in particular the live amniotic stem ceils viable for extended persods of time. Live amniotic stem cells may remain iive and viable even after being frozen for certain periods of time. A cryoprotectant may be required in some cases to protect the amnion materia! and in particular to preserver the viability of the amniotic stem cells. Any suitable type of cyroprotectant may be used including, but not limited to, glycols, ethylene glycol, propylene glycol, glycerol, 2-methyi-2,4~pentanediol (MFD), alcohols, dimethyl sulfoxide (DMSG), sugars, poiyols, glucose and the like, Some of the cryprotectamts may raise the pH and a buffer may be needed to reduce this elevated pH prior to administering to a treatment location.
[000? 3 A therapeutic dose, as used herein comprises amniotic materia! including, but not limited to, amniotic membrane, amniotic fluid, amniotic stem ceiis, and/or cytokines, collagen, proteins, and growth factors derived from amnion materia!. In an exemplary embodiment, a frozen therapeutic dose comprises live amniotic stem ceils. A therapeutic dose may aiso comprise a diluent, a
cryoprotectant, a buffer or other materials configured to enhance the effectiveness of the treatment, in one embodiment, a therapeutic dose comprises amnion material and a buffer to reduce the Ph of a cryoprotectant In another embodiment, an therapeutic does comprises anti-inflammatory nano-particies and/or statins, HMG- CoA reductase inhibitors to reduce inflation at a treatment location. A diluent may be comprise a saiine solution, water, a plasma containing solution, such as P!asma Lyte from Baxter Inc. in some embodiments, it may be desired to have a viscous frozen dose upon thawing or me!ting. It may be desirable to slow the absorption of the frozen dose into a treatment location. A hydrogel may be used as a diluent and may provide for a high viscosity thawed frozen dose, and may prolong the time the therapeutic frozen dose is in contact with a treatment location. Any suitable type of hydfogei may be combined with the therapeutic composition.
[0008] In an exemplary embodiment, a therapeutic dose comprise a concentration of live amniotic stem ceils of at least about 0.5 x 10b celi/mi or more, about 1 x 106 cell/ml or more, about 2 x 10s cell/mi or more and any range between and including the values provided. In one embodiment, amniotic stem cells are concentrated in the therapeutic dose, whereby the concentration is substantially higher than an initial concentration before processing.
jO009] A frozen therapeutic dose may be configured in a dosing package having a dose compartment and a compartment closure. An individual dosing package may be relatively small, such as no more than about 100ml, no more than about 50ml, no more than about 25ml, no more than about 10ml, no more than about 5mi and an range between and including the volumes provided. In an exemplary embodiment, a frozen therapeutic dose is provided in a detachable dosing package that is part of a muiii-dose pack. For example, two or more detachable dosing packages may be coupled together in a multi-dose pack and a separation feature, such as perforations, may be used for detachment. Any number of detachable dosing packages may be configured in a muifi-dose pack including more than three, more than five, more than ten, more than twenty and the like.
[00] j A dosing package may comprise a frozen therapeutic dose and a secondary materia! within a singie compartment whereby the frozen materials are substantiall separate and will not mix until they thaw. For example, a frozen therapeutic dose of amniotic stem cells may be frozen and a cryoprotectant may be added to ensure that the stem celt are live upon thawing. The cryoprotectant may be an irritant for some treatment locations, such as the eye, and therefore a buffer or buffer solution is added to the dosing package compartment in a frozen state. The two solid materials within the dosing package compartment will stay substantially separate and will not mix until the contents of the compartment are thawed, !n this way, the therapeutic dose applied to a treatment location will not be irritating. A secondary material may be configured within a single dose compartment including, but not limited to. a diluent, a buffer, a secondary therapeutic composition and the like.
[00! 1 ] In another embodiment, a secondary materia! or component of a therapeutic dose is provided in a separate compartment, whereby the contents of the secondary compartment are added to the frozen dose before application to a treatment location. A set of compartments, one with a frozen therapeutic dose of amnion materia!, and a another with a secondary materia! including, but not limited to, a diluent, a buffer, a secondary therapeutic composition and the like, may be coupled together. A muiti-dose pack may comprise a separation feature that is configured to detach th two compartments. A secondary therapeutic composition, may comprise amnion material and may have a different composition than a first therapeutic composition.
10012] A frozen dose may be configure to be removed from a dose
compartment and placed directly onto a treatment location. For example, a frozen dose pellet may be removed from a dose compartment and placed on the eye or under an eyelid. In another embodiment, a frozen dose may be piaced in an applicator, such as a dropper, spray bottle, or syringe for example. A diluent, buffe or other secondary material ma be added to an applicator. A frozen dose may be allowed to thaw prior to application to a treatment location, or melt in a secondary material.
[0013] In another embodiment, a frozen therapeutic dose is coupled with a compartment closure, whereby the compartment closure can be removed from the compartment and the therapeutic dose applied to a treatment location. For example, a frozen dose may be configured in a bliste pack having a peel off compartment closure. The frozen dose may be attached to the pee! way compartment closure whereby upon removal of the closure it can be applied directly to a treatment location, such as the skin, eye, mouth, etc. !n another embodiment a frozen dose is attached to a closure cap and upon removal can be swabbed over a treatment area, or p!aeed in or on the mouth.
[0014] In stil! another embodiment, a f oze dose is configured in a dose package applicator comprising a compartment closure and at least one opening in a compartment cover. In this embodiment, the compartment closure, such as a foil sheet, can be removed to expose the compartment cover having at least one opening therein. The dose package applicator can be placed directly on a treatment location and the compartment can be pressed to enable the therapeutic composition to pass through the opening. In another embodiment, a compartment cover may be a porous materia! that enables the therapeutic composition to transfer therethrough as it thaws.
[00 i 5] The therapeutic composition may also be administered by a syringe or iranscatheier. A frozen dose may be removed from a dose package and then drawn into a syringe. The syringe may then be used to inject the therapeutic composition to any suitable treatment location.
[001 3 A therapeutic composition may be applied to a treatment location by topical application, ingestion, injection, transcatheter and the like. In addition, som conditions may require some combination of the application methods described herein.
|00ί 7] A therapeutic composition may be applied to any suitable treatment location including, but not limited to, topically to the exterior of the body including the skin, a wound, a scare, a wrinkle and the like, to the digestive system by ingestion or injeciion, to an organ by injection or by direct application during surgery, for example.
[0018] The summary of the invention is provided as a general introduction to some of the embodiments of the invention, and is not intended to be limiting.
Additional example embodiments including variations and alternative configurations of the invention are provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention, and together with the description serve to explain the principles of the invention .
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
[0020] Figure 1A shows a cross-sectional diagram of amniotic membrane surrounding a fetus in uiero.
[0021] Figure 1 B shows a cross-section diagram of the layers of the amnion and chorion. j 0022] Figure 2A show a transmission electron micrograph (TEM) of the epithelium layer of the amniotic membrane having a single layer of amniotic stem ceils. The TEM was taken at 2500 X magnification.
[0023] Figure 2B show a TEM: of the epithelium layer of the amniotic membrane having a single iayer of amniotic stem ceils. The TEM is at 8200 X magnification.
[0024] Figure 3A is a scanning electron micrograph (SEM) of an amniotic membrane having amniotic stem cells
[0025] Figure 38 is a SEM of cryo-fractured amniotic membrane particles.
[0026] Figure 4A shows a top down view an exemplary multi-dose pack having a plurality of frozen doses,
[0027] Figure 4B shows a side view of an exemplary multi-dose pack have a plurality of frozen doses.
[0028] Figure 5 shows an exemplary detached dosing package being opened for placement in an eye.
[0029] Figure 6 shows an exemplary compartment closure having a frozen dose attached thereto.
[0030] Figure 7 shows an exemplary f rozen dose.
[00311 Figure 8A shows an exemplary frozen dose being placed into a dropper applicator with a diluent configured therein. Figure 88 shows the dropper applicator with the frozen therapeutic dose melted and dispersed therein.
[0032] Figure 9 shows an exemplary dropper applicator being used to administer a drop of therapeutic composition into an eye.
[0033] Figure 10A shows a top down view an exemplary multi-dose pack having a plurality of frozen doses wherein a set of compartments are configured to be detached from the multi-dose pack.
[0034] Figure 10B shows a side view of an exemplary multi-dose pack, wherein each set of compartments contains a frozen therapeutic dose in a first compartment and a buffer in a second compartment.
[0035] Figure 11 shows a side view an exemplary multi-dose pack, wherein each compartment comprises a frozen therapeutic dose that is substantially separated from a buffer.
[0036] Figure 12 shows an exemplary spray bottle administering a therapeutic composition to a affected area of the skin. £00373 Figure 13 shows an exemplary syringe applicator drawing a therapeutic dose into the syringe.
[0038] Figure 14 shows an exemplary syringe applicator administering a therapeutic dose into an affected area by injection,
[00391 Figure 15 shows an isometric view of a dose package applicator,
[0040] Figure 16 shows a diagram of the eye and some of the parts of the eye that may be affected areas for treatment with a therapeutic dose.
[00 1 ] Figure 17 shows a diagram of the some of the organs within the body that may be an affected area for treatment with a therapeutic dose.
[0042] Figure 18 shows a shows a diagram of the circulatory system.
[0043] Figure 19 shows a diagram of a process to produce a therapeutic composition comprising micronized amniotic membrane particles
[0044] Figure 20 shows a diagram of a process to produce a therapeutic composition comprising a concentrated stem eel! fluid.
[0043] Corresponding reference characters indicate corresponding parts throughout the several views of the figures. The figures represent an illustration of some of the embodiments of the present invention and are not to be construed as limiting the scope of the invention in any manner. Further, the figures are not necessarily to scale, some features may be exaggerated to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.
[0046] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Also, use of "a" or "an" ar employed to describe elements and components described herein. This is done merely for convenience and to give a general sense of the scope of the invention. This description should be read to include one or at least one and the singular also includes the plurai unless it is obvious that it is meant otherwise.
[0047] Certain exemplary embodiments of the present invention are described herein and illustrated in the accompanying figures. The embodiments described are only for purposes of illustrating the present invention and should not be interpreted as limiting the scope of the invention. Other embodiments of the invention, and certain modifications, combinations and improvements of the described
embodiments, wili occur to those skilled in the art and ail such alternate
embodiments, combinations, modifications, improvements are within the scope of the present invention.
[0048] As shown if FIG. 1 A the amniotic membrane surround a fetus in utero. As shown in FIG. I B, the amniotic membrane comprises an amnion portion and a chorion portion. As described herein, the amnion portion may be separated from the chorion. In an exemplary embodiment, the epithelium, or Inner most layer of the amniotic membrane is removed and used to produce particles for the therapeutic composition, as described herein. The particles may consists essentially of the epithelium, consists essentially of the epithelium and base membrane, consist essentially of the epithelium, base membrane and compact Iayer, or consist essentially of epithelium, base membrane, compact layer, and fibroblast layer.
[0049] As shown in FIGS. 2A and 2B, the epithelium Iayer of the amniotic membrane has a single Iayer of amniotic stem ceils. The tissue around the amniotic stem cells may protect and enhance the viability of these stem cells when the epithelium is cryo-fractured to produce particles for the therapeutic composition.
[0050] A s shown in FIG. 3A, an amniotic membrane 20 comprises a plurality of amniotic stem cells 32.
[0051 ] As shown in FIG, 38, particles of cryo-fractured amniotic membrane particles are on the order of 0.2 to 0.5pm in size. The average particle size shown is less than 2pm. There are no particles shown that are larger than 2pm and substantially all of the particles are less than 1 pm in size. The SEM shows that the micronized amniotic membrane particles are irregularly shaped. As shown, some of the particles have a planar surface,
[0052] As shown in FIG. 4A, an exemplary multi-dose pack 210 has a plurality of frozen doses 200. The multi-dose pack 210 comprises a plurality of detachable dosing packages 211 and a separating feature 218, such as perforations. The separating feature may be configured for the detachment of individual detachable dose packages or two or more detachable dose packages.
[0053] As shown in FIG. 4BS an exemplary multi-dose pack 210 has a plurality of frozen doses 200 in dose compartments. The individual doses are contained with discrete compartments 212 and a compartment ciosure 214 is configured over the compartments. The compartment ciosure 214 is shown being peeied away from the dose pack. Some of the doses 210 are shown configured in the bottom of the compartment 212 and some of the dose 200' are shown being attached to the compartment closure 214. A separating feature 216 is configured between each of the detachable dose packages.
[0054] As shown in FiG. 5 an exemplary detached dosing package 211 is being opened for placement of a frozen dose 200 in an eye 250. The dose may be piaced directly into the eye or under the eyeiid 252. In addition, a user may separate an individual detachable dose package from a mufti-dose pack, allow the frozen dose configured therein to melt, and then administer to an affected area, such as the eye.
iO()53j As shown in FiG. 6, an exemplary compartment ciosure 214 has a frozen dose 200 attached thereto. In this embodiment, the compartment closure may be removed from a dosing package 211 and piaced onto an affected area with the frozen dose attached. The compartment ciosure 214 is used as an applicator 18 in this embodiment. After the dose has dissolved, the compartment ciosure may be removed from the affected area, such as an eye. This embodiment allows for safe application of the dose to an affected area with minimal handling.
[0056] As shown in FiG. 7, an exemplar frozen dose 200 comprises a therapeutic composition 10. The frozen dose pellet 202 has a partial spherical shape as it conformed to the compartment in which it was provided. As described herein, the frozen therapeutic dose comprises amnion material, in addition, a secondary therapeutic material and/or diluent, cyroprotectant and/or buffer may be configured within a single frozen dose pellet. Any suitable shape and size of frozen dose pellet may be configured fo application to a specific treatment location. For example, a thin planar sheet frozen dose may be used for application to the skin such as a wound or scar. Sn another embodiment, a pellet with rounded surface may be configured for placement under an eyelid, to reduce any discomfort.
[0057] As shown in FiG. 8A, an exemplary frozen dose 200 is being placed into a dropper applicator 221 with a diluent 230 configured therein. The applicator cap 222 is open and the compartment closure 214 is being peeled off to drop the frozen dose pellet 202 into the dropper. Figure SB shows the dropper applicator 221 with a diluted frozen therapeutic dose 236 therein. i'005$'i As shown in FIG. 9, an exemplary dropper applicator 221 is being used to administer a drop of therapeutic composition 10 into an eye 250.
[0059] As shown in FIG. 10A, an exemplary multi-dose pack 210 has a plurality of frozen doses 200 and buffers configured in sets of compartments. A separation feature 218 is configured to enable the detachment of a frozen dose compartment 212 and a buffer compartment 212', or compartment set. in this embodiment, a frozen dose comprises a therapeutic composition 10 and a cyroprotectant. The cryoprotectant may cause the frozen dose to have high pH and may irritate affected areas. The buffer 232 may be configured to mix with the frozen dose upon thawing and reduce the pH prior to administering the mixture to an affected area or treatment iocation. It is to be understood that a second
compartment of a compartment set may comprise a secondary therapeutic composition of different composition, a therapeutic composition that does not comprise amnion material, an acellu!ar amnion derived therapeutic composition, a composition enhancer, an anti-inflammatory, a diluent and the like,
[0060] As shown in FIG.10B, an exemplary multi-dose pack 210, comprises sets of compartments having a frozen therapeutic dose 200 in a first compartment 212 and a buffer 232 in a second compartment 212'.
[00 1 ] As shown in FiG. 11 , an exemplary multi-dose pack 210 comprises a frozen therapeutic dose 200 that is substantially separated from a buffer 232 in dose compartment 212 and a frozen therapeuitc dose 200 that is substantially separated from a diluent 230 as shown in the dose compartment 212:. in this embodiment, a therapeutic composition may be frozen separately from a buffer or diluent whereby they are configured in the dose compartment in a frozen state and substantially separate from each other. The concentration of the frozen dose and secondary material, such as diluent, buffer, or secondary therapeutic composition ma remain substantially different while maintained in a frozen state. In this manner, the single dose compartment 2 2 may be opened and place onto a treatment locatio or the contents of the compartment may b allowed to thaw, whereby the contents will mix prior to administering to a treatment Iocation.
[0062] As shown in FIG, 12, an exemplary spray bottle 84 type applicator 18 is administering a therapeutic composition 10 to an affected area or treatment location 248 of the skin. 100631 As shown in FIG.13, an exemplary syringe 80 applicator is drawing a iherapeuiic composition 10 into the syringe. The therapeutic composition 10 within the enclosure 70 comprises live amniotic stem cells 30, The therapeutic composition may also comprise a diiueni and a frozen dose may have been thawed in the diluent,
[0064] As shown in FIG. 14, an exemplary syringe 80 applicator is
administering a therapeutic dose 204 into an affected area by injection. The therapeutic dose is a composition derived from thawing a frozen dose, as described herein and comprises live amniotic stem cells 30, a cyroprotectant 234 and a buffer 232. The therapeutic dose is being injected into a joint.
[0065] As shown in FIG. 15, a dose package applicator comprises a dose compartment 212 with a therapeutic composition 10 therein. The dose package applicator may be one of a plurality of individual dose package applicators couple together in a multi-dose pack. The dose package applicator 224 comprises a compartment closure 214 that is being peel off to expose openings 226 in a compartment cover portion 228, A compartment cover portion may be a portion of a detachable dosing package and may be a sheet of plastic material, for example. The compartment cover portion comprises opening 226 to allow the administering of the therapeutic dose 204 by pressing on the dose compartment, as indicated by the arrow pointing up. The therapeutic dose 204 is squeezed through the opening an onto a treatment location. It is to be understood thai a frozen dose package with a compartment cover having at least one opening may be configured for placement onto a treatment location to allow the frozen dose to transfer through the opening as the frozen dose thaws and melts
[0066] Figure 16 shows a diagram of an eye 250 and some of the parts of the eye that may be treatment locations for treatment with a therapeutic dose derived from a frozen dose, as described herein. For example, a therapeutic composition, as described herein, may be applied topically and/or injected into the iris, anterior chamber, lens, vitreous humor, ciiliary muscle, cornea, extraocular muscle, sclera, choroid, retina and the like.
[0067] Figure 17 shows a diagram of the some of the organs within the body that may be an affected area for treatment with a therapeutic dose derived from a frozen dose, as described herein. A therapeutic composition, as described herein, may be introduced into any anatomy shown in FIG. 17 by direct injection, topical application, or transcatheter.
1 t {00683 Figure 18 shows a diagram of the circulatory system that may be an affected area for treatment with a therapeutic dose derived from a frozen dose, as described herein. The circulator system may be used to transport a therapeutic composition to an affected area, such as an organ, for example.
[00691 Figure 19 shows a diagram of a process to produce a therapeutic composition comprising micronized amniotic membrane particles. As shown, an exemplary process to produce a therapeutic composition, as described herein, comprises the steps of cryo-fracturtng amniotic membrane fragments to produce micronized amniotic membrane particles. As described, the amniotic membrane fragments may be cryo-fraeture with a blunt object, such as a bar, that reduces shear and damage to the particles. In a preferred embodiment, the fragments are cryo-fractured with an object having substantially no sharp edges. The micronized particles are combined with any suiiable carrier fluid to produce a therapeutic composition. In an exempiary embodiment, the micronized particles are dispersed in a fluid comprising amniotic fluid and amniotic stem ceils. In another embodiment, the micronized particles are dispersed in a concentrated amniotic stem cell fluid.
[0070] Figure 20 shows a diagram of a process to produce a therapeutic composition comprising a concentrated stem cell fluid. The exempiary process comprises the steps concentrating amniotic stem ceils in a fluid component comprising Plasma Lyte-A, available from Baxter Inc. An amniotic fluid may be processed in any suiiable way to concentrate the amniotic stem cells in the fluid. In an exempiary embodiment, as described in FIG, 5, the amniotic fiuid is centrifuged to remove debris and excess liquid, and concentrate the amniotic stem ceils in the therapeutic composition
Definitions
[0071] Amnion material, as used herein, includes amniotic membrane, amniotic stem cells, amniotic fluid, and/or eytokines, collagen, proteins and growth factors derived from amnion or amniotic fluid.
[0072] Treatment location and affected area are used interchangeable through the specification.
[0073] A therapeutic dose, as used herein, comprises a frozen therapeutic dose comprising amnion material, and may be thawed and combined with secondary material, such as buffer, diluent, a secondary therapeutic composition and the like.
!2 £0074] A cryoprotectant is a substance used to protect biological tissue from freezing damage from ice formation, for example.
[0075] It will be apparent to those skilled in the art that various modifications, combinations and variations can be made in the present invention without departing from the spirit or scope of the invention. Specific embodiments, features and elements described herein may be modified, and/or combined in any suitable manner. Thus, it is intended that the present invention cover the modifications, combinations and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

What is claimed is;
1. A therapeuiic dose package comprising:
a, a first compartment comprising:
i, a frozen therapeutic dose comprising;
amnion materia!.
2. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose has a volume of no more than about 40mS.
3. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose comprises a plurality of amniotic stem cells.
4. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose comprises a pluraiity of live amniotic stem ceils.
5 The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose comprises a plurality of particles comprising mscronized amniotic membrane particles.
6. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose comprises amniotic fluid.
7. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose comprises amnion derived materials selected from the group consisting of: cytokines, proteins, growth factors, and collagen.
8. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose comprises:
a. a plurality of particles comprising micronized amniotic membrane
particles; and
b. amniotic fluid.
9. The therapeutic dose package of claims 5, wherein the frozen therapeutic dose comprises live amniotic stem ceils.
10. The therapeutic dose package of claims 6, wherein the frozen therapeutic dose comprises live amniotic stem cells,
11.The therapeutic dose package of claims 7, wherein the frozen therapeutic dose comprises live amniotic stem cells.
12. The therapeutic dose package of claims 8, wherein the frozen therapeutic dose comprises live amniotic stem ceils,
13. The iherapeutic dos package of claim 1 , wherein the frozen therapeutic dose is a solid.
14. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose further comprising a cryoprotectant.
15. The therapeutic dose package of claim 14, wherein the cryoprotectant
comprises D SO.
18. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose further comprising a buffer,
17. The therapeutic dose package of claim 16, wherein the buffer comprises a pH buffer,
18. The therapeutic dose package of claim 1 , wherein the frozen therapeutic dose further comprising a diluent.
19. The therapeutic dose package of claim 18, wherein the diluent comprises a plasma containing diluent.
20. The therapeutic dose package of claim 19, wherein th di!uent comprises an anti-inflammatory.
21. The therapeutic dose package of claim 1 , comprising a frozen buffer that is configured within the compartment with the frozen therapeutic dose but is substantially separated from the frozen therapeutic dose.
22. The therapeutic dose package of claim 1 , comprising a frozen diluent that is configured within the compartment with the frozen therapeutic dose but is substantially separated from the frozen therapeutic dose.
23. The therapeutic dose package of claim 1 , comprising a second compartment that is coupled with the first compartment and comprises a materia! selected from the group consisting of: a frozen therapeutic dose, a fro∑en buffer a frozen diluent an anti-inflammatory.
24. The therapeutic dose package of claim 1 comprising a second compartment that is coupled with the first compartment and comprises a frozen therapeutic dose.
25. The therapeutic dose package of claim 1 , comprising a second compartment that is coupled with the first compartment and comprises a frozen buffer.
26. The therapeutic dose package of claim 1 , comprising a second compartment that is coupled with the first compartment and comprises a frozen diluent. 27, The therapeutic dose package of claims 1 to 26, comprising a plurality of individual compartments coupled together in a multi-dose pack;
wherein at least one of said individual compartments comprises said frozen therapeutic dose.
28. The therapeutic dose package of claims 1 to 26, comprising a pluraliiy of individual compartments coupled together in a multi-dose pack;
wherein each of the plurality of individual compartments comprises said frozen iherapeutic dose.
29. The therapeutic dose package of claims 1 to 26, comprising a pluraliiy of individual compartments coupled together in a multi-dose pack;
wherein each of the plurality of Individual compartments comprises said frozen therapeutic dose, and
wherein the plurality of individual compartments are detachably attached together.
30, The therapeutic dose package of claims 1 to 26, comprising a pluraliiy of individual compartments coupled together in a multi-dose pack;
wherein the multi-dose pack comprises a frangible feature between individual compartments, and
whereby at least one of the individual compartments can be detached from the multi-dose pack.
31.The therapeutic dose package of claims 1 to 26, comprising a pluraliiy of individual compartments coupled together in a multi-dose pack;
wherein the multi-dose pack comprises a frangible feature between two or more of the individual compartments, and
whereby two or more of the individual compartments can be detached from the multi-dose pack.
32. The therapeutic dose package of claims i to 26, comprising a plurality of individual compartments coupled togethe in a multi-dose pack;
wherein the multi-dose pack comprises a frangible feature between two or more of the individual compartments,
whereby two or more of the individual compartments can be detached from the multi-dose pack; and
wherein the frangible feature is configured between a first set of two individual compartments and a second set of two individual compartments, wherein each set of two individual compartments comprises;
a first compartment comprising said frozen therapeutic dose; and a second compartment comprising a buffer,
33. The therapeutic dose package of claim 1 , comprising a detachable
compartment closure configured over a least a portion of said compartment,
34. The therapeutic dose package of claim 33, wherein the detachable
compartment ciosure comprises a metal foil.
35. A process of producing a frozen dose package comprising the steps of. a. providing a therapeutic composition comprising;
i. amniotic material;
b. providing a dosing package comprising:
I. a first compartment;
c. providing a compartment closure;
d . freezing sa id therapeutic composition ;
e. configuring said therapeutic composition in said compartment to
provide a frozen therapeutic dose in said compartment;
f. sealing said compartment with said compartment ciosure to produce a frozen therapeutic dose in said dosing package .
36. The process of producing a frozen dose of claim 35, wherein the step of freezing said therapeutic composition is conducted after the step of configuring said therapeutic composition in the compartment,
37. The process of producing a frozen dose of claim 35, wherein the step of freezing said therapeutic composition is conducted before the step of configuring said therapeutic composition in the compartment.
38. The process of producing a frozen dose of claim 35, wherein the frozen therapeutic dose has a volume of no more than about 40rnl.
39. The process of producing a frozen dose of claim 35, wherein the frozen therapeutic dose comprises a plurality of amniotic stem ceils.
40. The process of producing a frozen dose of claim 35, wherein the frozen therapeutic dose comprises a plurality of live amniotic stem cells.
Π
41. The process of producing a frozen close of claim 35, wherein the frozen therapeutic dose comprises a plurality of particles comprising micronized amniotic membrane particles.
42. The t process of producing a frozen dose of claim 35, wherein the frozen therapeutic dose comprises amniotic fluid.
43. The process of producing a frozen dose of claim 35, wherein the frozen
therapeutic dose comprises amnion derived materials selected from the group consisting of; cytokines, proteins, growth factors, and collagen.
44. The process of producing a frozen dose of claim 35, wherein the frozen
therapeutic dose comprises:
a. a plurality of particles comprising micronized amniotic membrane
particles; and
b. amniotic fluid.
45. The process of producing a frozen dose of claims 35 through 44, wherein the frozen therapeutic dose comprises amniotic stem cells.
46. The process of producing a frozen dose of claims 35 through 44, wherein the frozen therapeutic dose comprises live amniotic stem ceiis.
47. The process of producing a frozen dose of claim 35, wherein the frozen
therapeutic dose is a solid.
48. The process of producing a frozen dose of claim 35„ wherein the frozen
therapeutic dose further comprising a cryoprotectant.
49. The process of producing a frozen dose of claim 48 wherein the
cryoprotectant comprises DMSO.
50. The process of producing a frozen dose of claim 35, wherein the frozen
therapeutic dose further comprising a buffer.
51. The process of producing a frozen dose of claim 50, wherein the buffer
comprises a pH buffer.
52. The process of producing a frozen dose of claim 35, wherein the frozen
therapeutic dose further comprising a diluent.
53. The process of producing a froze dose of claim 52, wherein the diluent comprises a plasma containing diluent.
54. The process of producing a frozen dose of claim 52, wherein the diluent comprises an anti-inflammatory. 55, The process of producing a frozen dose of claim 35, wherein a frozen buffer is configured within the compartment with the frozen therapeutic dose but is substantially separated from the frozen therapeutic dose whereby the process comprises the steps of;
a. separately configuring a therapeutic dose composition and a buffer into said compartment.
58. The process of producing a frozen dose of ciasm 35, wherein a frozen diluent is configured within the compartment with the frozen therapeutic dose but is substantially separated from the frozen therapeutic dose wherein the process comprises the steps of:
a. separately configuring a therapeutic dose composition and a diluent into said compartment
57. The process of producing a frozen dose of claim 35, further comprising the steps of:
a. providing a second compartment that is coupled with the first
compartment;
b. configuring in said second compartment, a material selected from the group consisting of: a frozen therapeutic dose, a frozen buffer and a frozen diluent.
58. The process of producing a frozen dose of claim 35„ further comprising the steps of
a. providing a second compartment that is coupled with the first
compartment;
b. configuring in said second compartment a material comprising a frozen therapeutic dose.
59. The process of producing a frozen dose of claim 35, further comprising the ste s of;
a. providing a second compartment that is coupled with the first
compartment;
b. configuring in said second compartment a material comprising a buffer.
60. The process of producing a frozen dose of eiaim 35, further comprising the steps of:
providing a second compartment that is coupled with the first compartment; and
configuring in said second compartment a materia! comprising a frozen therapeutic diluent,
61 The process of producing a frozen dose of claims 35 and 60, further
comprising the steps of:
a. providing a plurality of individua! compartments coupied together in a multi-dose pack.
62, The process of producing a frozen dose of claims 3S and 60, further
comprising the steps of:
providing a plurality of individua! compartments coupied together in a multi-dose pack; and
configuring in at ieast one of said individual compartments said frozen therapeutic dose.
83, The process of producing a frozen dose of claims 35 and 60, further
comprising the steps of;
providing a plurality of individua! compartments coupied together in a multi-dose pack; and
configuring in each of the plurality of individua! compartments a frozen therapeutic dose.
64. The process of producing a frozen dose of claims 35 and 60, further
comprising the steps of:
providing a plurality of individua! compartments coupied together in a multi-dose pack;
wherein the plurality of individua! compartments are detachab!y attached together.
65. The process of producing a frozen dose of claims 35 and 60, further
comprising the steps of:
providing a plurality of individual compartments coupied together in a multi-dose pack;
wherein the multi-dose pack comprises a frangible feature between individual compartments, whereby at least one of the individual compartments can be detached from the mu!ii-dose pack. , The process of producing a frozen dose of claims 35 and 60, further comprising the steps of:
providing a plurality of individual compartments coupled together in a multi-dose pack;
wherein the muiti-dose pack comprises a frangible feature between two or more of the individual compartments, and
whereby two or more of the individual compartments can be detached from the muiti-dose pack,
, The process of producing a frozen dose of claims 35 and 60, further comprising the steps of:
providing a plurality of individual compartments coupled together in a multi-dose pack;
wherein the muiti-dose pack comprises a frangible feature between two or more of the individual compartments,
whereby two or more of the individual compartments can be detached from the multi-dose pack, and
wherein a frangible feature is configured between a first set of two
individual compartments and a second set of two individual compartments, wherein each set of two individual compartments comprises:
a. a first compartment comprising a therapeutic dose; and
b. a second compartment comprising a buffer.
, The process of producing a frozen dose of claims 35, wherein the
compartment closure comprises a metai foil. , A method of administering a therapeutic composition comprising the steps of: a. providing a dosing package comprising:
i, a compartment;
is. a detachable compartment closure configured over at least a portion of said compartment;
iii, a frozen therapeutic dose configured in said compartment
comprising a therapeutic cornposition comprising:
15. The method of administering a therapeutic composition of claim 69, wherein the step of administering said dose to an affected area comprises injecting said dose into the venous system.
PCT/US2015/035749 2014-06-15 2015-06-15 Frozen therapeutic dose and package WO2015195508A1 (en)

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