Slow-release plastic formulation

Abstract

A plastic material for sustained release of a bioactive agent is provided, the plastic material comprising a structural polymer, at least one bioactive component embedded in the structural polymer as solid islands, a liquid binder embedded in the structural polymer as granules, and a carrier liquid absorbed into the liquid-absorbing material. The carrier liquid may be sufficiently incompatible with the structural polymer such that at least a portion of the carrier liquid is released from the liquid-absorbing material through the structural polymer to the exterior surface of the plastic material over a period of time, e.g., one week or more, one month or more, or about three months. The bioactive agent contained in the at least one bioactive component may be sufficiently soluble in the carrier liquid at room or body temperature such that the carrier liquid released to the exterior surface contains the bioactive agent in solution.

Description

Detailed Description of the Invention

[0001] [Related Applications]

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 955,461, filed December 31, 2019, the disclosure of which is incorporated herein by reference.

[0002] [background] Administerable bioactive agents, such as therapeutic agents and nutritional supplements, can be administered into the body by several different routes. Oral administration is a common route, but this route has various drawbacks, such as first-pass metabolism, where the stomach environment and liver metabolize the bioactive agent, thus greatly reducing its concentration before it reaches the systemic circulation. In addition, oral administration can be ineffective in patients experiencing nausea and vomiting. Another problem with oral administration is that patients absorb the bioactive agent as a bolus, resulting in peaks and troughs in systemic concentrations in the bloodstream, which can result in unwanted side effects and inconsistencies in the desired effect over time.

[0003]

[0003] Transdermal delivery is another promising route of administration because it avoids the gastric system and increases bioavailability. Although the skin acts as an effective barrier against microorganisms and foreign molecules, small molecules can diffuse across the skin. Creams and lotions may be used as a means of administration, but they have the disadvantage of being short-acting and can be accidentally rubbed or washed off the skin, resulting in difficulty in achieving consistent or effective bloodstream concentrations. Thus, there is a need for a method of transdermal delivery of bioactive agents over an extended period of time, such as a week, a month, or even up to several months.

[0004] [overview]

[0004] An aspect of the present disclosure relates to a solid composition comprising a plastic material having embedded therein one or more bioactive agents, such as therapeutic agents and nutritional supplements, wherein the plastic material is formulated for sustained release of the embedded one or more bioactive agents.

[0005] For ease of description, a plastic matrix having one or more bioactive agents embedded therein according to embodiments of the present invention may be referred to herein as an extended release plastic matrix (ERPM).

[0006]

[0006] Throughout this specification, "sustained release" refers to the release of an agent from a material and / or into the bloodstream of a subject over an extended period of time, for example, about one week, about two weeks, about one month, or one month. This term may be used interchangeably with "delayed release" or "sustained release."

[0007]

[0007] In an embodiment of the present disclosure, the ERPM comprises a structural polymer, a liquid binder embedded in the structural polymer, a carrier liquid absorbed into the liquid binder, and optionally at least one bioactive component comprising or consisting of a bioactive agent embedded in the structural polymer as a solid island.

[0008] In embodiments of the present disclosure, the carrier liquid is partially absorbable and partially incompatible in the structural polymer and is capable of dissolving the bioactive agent at room or body temperature.

[0009]

[0009] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

[0010]

[0010] Non-limiting examples of embodiments of the present disclosure are described below with reference to the accompanying drawings listed following this paragraph. Identical features that appear in multiple drawings are generally labeled with the same label in all drawings in which they appear. Labels displaying icons representing a given feature of an embodiment of the present disclosure in the drawings may be used to refer to the given feature. Dimensions of features shown in the drawings are selected for convenience and clarity of illustration and are not necessarily drawn to scale. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1A is a schematic diagram of an ERPM in the form of a wristband, according to an embodiment of the present disclosure. [Diagram 2] FIG. 1 illustrates a flow chart of a method for manufacturing an ERPM according to an embodiment of the present disclosure.

[0012] [Detailed Description]

[0013] Aspects of the present disclosure relate to producing an ERPM comprising a structural polymer and one or more bioactive components embedded within the structural polymer, where a bioactive agent contained within the one or more bioactive components is released through a surface of the ERPM over an extended period of time. Release of the bioactive agent by the ERPM can occur at a therapeutically effective rate in the context of transdermal absorption.

[0013]

[0014] As used herein, a bioactive ingredient refers to a synthetic or natural substance that consists of or contains a bioactive agent, which may be a therapeutic agent or a nutritional supplement.

[0014]

[0015] 1, there is shown a schematic diagram of a wearable device 10 in the form of a wristband comprised of an ERPM 20 according to an embodiment of the present disclosure. Inset 40 shows a schematic diagram of an enlarged cross-sectional view of the ERPM 20 optionally formulated to include a structural polymer 22, granules 24 of a liquid binding material embedded in the structural polymer 22, a carrier liquid (not shown) absorbed in the granules, and at least one bioactive component embedded as islands 26 in the structural polymer.

[0015]

[0016] The carrier liquid and each component of the structural polymer 22 may be selected such that the carrier liquid is at least partially incompatible with the structural polymer 22. As used herein, a given carrier liquid may be characterized as being incompatible with a given structural polymer if the structural polymer does not readily absorb the carrier liquid and / or if at least a portion of the carrier liquid formulated with the structural polymer is spontaneously released or extruded from the structural polymer. The carrier liquid may additionally be characterized as being capable of at least partially dissolving the islands 26 at room or body temperature. Partially dissolving as used herein means that when a given bioactive component is a complex substance or compound, such as a dried plant that contains a bioactive agent among other substances, the carrier liquid is capable of at least dissolving the bioactive agent.

[0016]

[0017] For an ERPM 20 formulated with a given structural polymer and a given bioactive component, the composition of the carrier liquid may be selected such that the carrier liquid is partially absorbent and partially incompatible with the structural polymer and capable of dissolving the bioactive agent contained in the bioactive component. Without being bound by theory, as a result of the above properties (partial incompatibility with the structural polymer and ability to dissolve the bioactive agent), the carrier liquid is advantageously operable within the ERPM 20 to (a) migrate from the granules 24 of the liquid binder through the structural polymer 22 to contact the islands 26; (b) dissolve the bioactive agent contained in the islands 26 to form a bioactive solution 28; and (c) continue to migrate and be released onto the exterior surface 21 of the ERPM 20 to form an outer liquid layer 29 of the bioactive solution 28. The movement of the carrier liquid from the granules 24 through the structural polymer 22 and eventual release onto the surface 21 of the ERPM 20 as a component of the bioactive solution 28 is represented diagrammatically by block arrow 32.

[0017]

[0018] Without being limited by theory, it will be understood that the above movement of carrier liquid and release of bioactive solution 28 from exterior surface 21 is driven by a concentration gradient of carrier liquid in structural polymer 22, as explained below. Initially, after fabrication of ERPM 20, carrier liquid may only be present in granules 24 and nowhere else in ERPM 20, and the concentration gradient results in a net movement of carrier liquid from granules 24 into structural polymer 22, such that carrier liquid contacts islands 26, dissolves at least one bioactive agent present in the islands, and is released as bioactive solution 28 at exterior surface 21. However, once sufficient bioactive solution 28 has been released, the concentrations of carrier liquid on exterior surface 21 and granules 24 become equilibrated such that the net release of carrier liquid onto exterior surface 21 is substantially zero. As a result, without being limited by theory, once a threshold amount of exterior liquid layer 29 has formed, ERPM 20 advantageously does not continue to release excess bioactive solution 28 during storage. Similarly, without being limited by theory, the portion of the outer surface 21 that does not contact the skin or other absorbent surface advantageously does not release excess bioactive solution 28 that may cause discomfort or staining. The release of bioactive solution in response to the relative concentrations of carrier liquid on the outer surface 21 and the granules 24 also allows for, without being limited by theory, contact-sensitive release of the bioactive solution 28, where the bioactive solution 28 is selectively released at the portion of the outer surface 21 that contacts the skin or other absorbent surface. Without being limited by theory, contact of the ERPM 20 on the skin leads to percutaneous absorption of the bioactive solution 28 present in the outer liquid layer 29, introducing a concentration gradient of the carrier liquid between the contacting portion of the outer surface 21 and the granules 24, thereby driving further migration of the carrier liquid from the granules 24 to the contacting portion of the outer surface 21. This further migration of the carrier liquid leads to additional bioactive solution 28 being selectively released at the contacting portion, i.e., selectively released in a contact-dependent manner.

[0018]

[0019] The ERPM 20 may be formulated such that contact-sensitive release of the bioactive solution 28 occurs at a therapeutically effective rate for percutaneous absorption for at least one week, at least two weeks, or for about one month or more. The contact-sensitive sustained release of the bioactive solution 28 from the ERPM advantageously allows a wearer of a wearable device 10 that includes or is formed from an ERPM to wear the device for extended periods of time and benefit from the sustained release before needing replacement.

[0019]

[0020] 1, granules 24 are optionally embedded in a substantially uniform distribution within structural polymer 22. Islands 26 may also be embedded in a substantially uniform distribution within the structural polymer.

[0020]

[0021] The structural polymer 22 optionally comprises one or more flexible polymers or elastomers with viscoelastic properties. The one or more polymers included in the structural polymer may be non-toxic and suitable for long-term external contact on the skin of a human or animal subject. Optionally, the structural polymer comprises one or more selected from the group consisting of polyolefins, such as polyethylene (PE), polyvinyl chloride (PVC), polyurethane (PU), ethylene vinyl acetate (EVA), polyolefin elastomers, and synthetic rubbers. PE optionally comprises low density polyethylene (LDPE), linear low density polyethylene (LLDPE), or combinations thereof. The structural polymer may comprise a polyurethane, such as a thermoplastic polyurethane (TPU). Optionally, the synthetic rubber comprises styrene-butadiene rubber, also known as poly(styrene-butadiene-styrene) rubber ("SBS rubber"), and / or a silicone rubber, such as a polysiloxane. In an embodiment of the present disclosure, the structural polymer is formulated as an adhesive or non-adhesive polymer. In more specific embodiments, the structural polymer may optionally include a PE selected from the group consisting of LLDPE, LDPE, and a PE elastomer (e.g., one or more Dowlex™ resins). Optionally, the structural polymer includes or consists of an LLDPE, LDPE, and a PE elastomer. The polyolefin elastomer may be an ethylene-octene elastomer, an ethylene-butene elastomer, or an ethylene-hexene elastomer (e.g., one or more of Dow Engage™ or Sabic Fortify™ polyolefin elastomers).

[0021]

[0022] Optionally, the structural polymer is formulated to be a hydrophobic material, characterized by a "contact angle" of greater than 90 degrees exhibited by a drop of water on a flat solid surface of the structural polymer.

[0022]

[0023] The liquid binder granules 24 may include one or more combinations selected from the group consisting of silica gel, fumed silica (also known as pyrogenic silica), diatomaceous earth, carbon black, and activated carbon. Silica gel is a porous silicon dioxide available in a variety of particle sizes. Fumed silica consists of minute droplets of amorphous silica that are fused into branched three-dimensional secondary particles and then agglomerated into tertiary particles with a high surface area to volume ratio, typically having a size of about 5 nm to 50 nm. Diatomaceous earth is a natural fossil of diatoms composed mostly or entirely of silica, and is characterized by porosity and high surface area. Diatomaceous earth is typically in the form of a powder with particle sizes ranging from less than 3 μm to more than 1 mm, but typically between 10 μm and 200 μm. Activated carbon typically consists of charcoal that has been treated with either a combination of heat and pressure or strong acid or base, followed by dry distillation to make it highly porous. Carbon black is a material produced by the incomplete combustion of heavy petroleum products in the form of semicrystalline carbon with a high surface area to volume ratio, but typically lower than that of activated carbon. Subtypes of carbon black include acetylene black, channel black, furnace black, lamp black, and thermal black.

[0023]

[0024] Additionally or alternatively, the liquid binder of granules 24 comprises a polymer suitable for use as a structural polymer formed in a porous form using suitable manufacturing procedures known in the art. The porous polymer may include polyethylene vinyl acetate (PEVA) or a polyolefin, such as LDPE. Optionally, the porous polymer is formulated to have a higher melting point compared to the structural polymer used in ERPM 20 such that the porous polymer is not substantially degraded or removed during incorporation into the ERPM or during incorporation into wearable device 10 if the ERPM is molded, for example, by injection molding.

[0024]

[0025] The granules may have one or more of a variety of shapes, such as a sphere, a flattened sphere, a cylinder, or an irregular shape, depending on how the granules are manufactured. The granules 24 may have a maximum cross-sectional distance, which may be the diameter of a substantially spherical granule, of about 1 nm to about 5 mm. The granules are optionally in the form of a powder, with each granule having a cross-sectional distance of about 1 nm to about 10 microns. When the granules comprise a porous polymer, each granule may have a cross-sectional distance of 0.5 mm to 5 mm.

[0025]

[0026] When the granules 24 of the liquid binder infused with the carrier liquid are blended with the structural polymer 22, the resulting embedded granules optionally act as reservoirs for the carrier liquid. Optionally, the granules 24 are blended into the structural polymer 22 softened by heating during the manufacture of the ERPM. The granules 24 may be in a quantity sufficient to absorb the carrier liquid prior to blending with the structural polymer 22. By way of example, one gram of fumed silica may be capable of absorbing up to 10-20 grams of oil, while one gram of porous polymer may be capable of absorbing up to 3 or 4 grams of oil. Thus, the relative content of granules 24 in the ERPM 20 may depend on the liquid binder used.

[0026]

[0027] The carrier liquid injected into the granules 24 may comprise 5-40% of the total composition of the ERPM 20 by weight.

[0027]

[0028] Optionally, the carrier liquid includes one or more non-volatile oils characterized by a vapor pressure such that the oil does not substantially evaporate at near room temperature and near standard atmospheric pressure. Optionally, the one or more non-volatile oils are (1) compatible as a solvent for the bioactive agent included in the islands 26, (2) liquid at room and / or body temperature, and (3) compatible for topical administration on human skin. Optionally, the non-volatile oil includes paraffin oil (also referred to in the art as mineral oil) and / or one or more plant-derived oils, such as hemp seed oil, palm oil, canola oil, linseed oil, sunflower oil, rapeseed oil, cocoa butter, olive oil, and rice bran oil. Paraffin oil has been demonstrated to promote skin permeability through lipid mobilization in the outer layer of the skin (stratum corneum), and therefore, without being bound by theory, paraffin oil may be included in the carrier liquid to enhance transdermal penetration of the bioactive agent into the skin of a subject contacted with the ERPM 20.

[0028]

[0029] Additionally or alternatively, the carrier liquid, as used herein, includes a volatile oil characterized by a vapor pressure such that the oil tends to evaporate near room temperature and near standard atmospheric pressure. Without being bound by theory, the addition of a volatile oil in the carrier liquid enhances the release of the carrier liquid onto the exterior surface 21 because the evaporation of the volatile oil from the exterior surface creates a concentration gradient that draws more of the carrier liquid to the surface along with the bioactive agent dissolved in the carrier liquid. Optionally, the volatile oil includes or is included in a natural extract or essential oil that is added to provide an odor that is generally perceived as pleasant. The natural extract or essential oil may be a mixture of volatile and non-volatile oils. Examples of natural extracts that can be incorporated include, but are not limited to, the following essential oils: lavender oil, valerian oil, geranium oil, Passiflora Edulis seed oil, and chamomile oil.

[0029]

[0030] Additionally or alternatively, the carrier liquid optionally comprises one or more selections from the group consisting of chlorinated paraffins, triacetin, naphthenic hydrocarbons, aliphatic hydrocarbons, dioctyl terephthalate (DOTP), diisononyl phthalate (DINP), and epoxidized triglycerides. The epoxidized triglycerides may be epoxidized vegetable-derived oils, such as epoxidized soybean oil (ESBO), epoxidized palm oil, epoxidized canola oil, epoxidized linseed oil, epoxidized sunflower oil, epoxidized rapeseed oil, epoxidized cocoa butter, epoxidized olive oil, and epoxidized rice bran oil, among others.

[0030]

[0031] Additionally or alternatively, the carrier liquid includes glycerol.

[0031]

[0032] In an embodiment of the present disclosure, the ERPM at least initially comprises one or more bioactive components, each comprising or consisting of a respective bioactive agent, such that the one or more bioactive components are between 0.1% and 40% of the initial total weight (% w / w) of the ERPM, or between 0.5% w / w and 2.5% w / w of the initial total weight of the ERPM.

[0032]

[0033] In embodiments of the present disclosure, the bioactive components embedded as islands in the ERPM may be therapeutic agents and / or nutritional supplements that have nutritional and / or therapeutic value when administered to a subject. The bioactive components and / or bioactive agents contained therein may be in solid form at standard atmospheric pressure and at room temperature, about 20 degrees Celsius (° C.), and at body temperature, about 37° C., and are at least partially soluble in a suitable carrier liquid under the same temperature and pressure conditions.

[0033]

[0034] The bioactive ingredient may be a plant or animal derived substance, a mineral, a chemical composition, or a combination thereof, that comprises or consists of a bioactive agent. The bioactive agent may be suitable for transdermal administration and may have one or more of the following properties: analgesic, anti-inflammatory, antioxidant properties, and soothing or relaxing properties. Optionally, the subject is an animal subject or a human subject.

[0034]

[0035] The bioactive ingredient, which may comprise or consist of a bioactive agent having analgesic properties, may be selected from the group consisting of aloe vera, methylsulfonylmethane (MSM), emu oil, menthol, glucosamine, chondroitin, capsaicinoids, arnica, coriander, Roman chamomile, willow bark, feverfew, St. John's wort, kava kava, nettle leaf, acetylsalicylic acid, bala, black cohosh, black snake root, cimicifuga, squawroot, bupleurum, calendula, camphor, cayenne, devil's claw root, evening primrose oil, ginger, gotu kola, ginkgo, juniper, lavender, licorice, marjoram, meadowsweet, passionflower, quercetin, salicinum, wild yam, and the like. yam, wintergreen, wood betony, wormwood, and combinations thereof.

[0035]

[0036] The bioactive ingredients, which include or consist of bioactive agents having anti-inflammatory properties, include aloe vera, methylsulfonylmethane (MSM), emu oil, chondroitin, glucosamine, capsaicinoids, arnica, grape seed, coriander, marigold, nettle leaf, Roman chamomile, cornflower, St. John's wort, willow bark, witch hazel, feverfew, barley grass, black cohosh, black snake root, cimicifuga salicina, Conofolis americana, boswellia, borage, bromelain, burdock, calendula, powdered capsicum, dandelion, devil's claw root, DHEA (dehydroepiandrosterone), echinacea, elderflower, evening primrose, flaxseed, ginkgo, ginger, ginseng, hawthorn, kaempferol, licorice, groundsel, golden senecio, squaw weed, weed, golden groundsel, cocash weed, coughweed, ragwort, golden ragwort, marjoram, meadowsweet, quercetin, turmeric, curcumin, wild yam, wormwood, yucca, and combinations thereof.

[0036]

[0037] The bioactive ingredient comprising or consisting of a bioactive agent with antioxidant properties may be selected from the group consisting of chondroitin, vitamin C, grape seed, St. John's wort, coriander, barley grass, bilberry, echinacea, garlic, ginger, ginkgo, ginseng, grape seed proanthocyanidin extract, green tea, hawthorn, lemon balm, milk thistle, oregano, peppermint, pomegranate extract, purslane, pycnogenol, rosemary, Schisandra chinensis, wuweizi, wurenchun extract, trilinolein, sanchi, turmeric, curcumin and combinations thereof.

[0037]

[0038] The bioactive ingredient comprising or consisting of a bioactive agent with soothing or relaxing properties is selected from the group consisting of MSM, kava kava, Roman chamomile, feverfew extract, Hypericum perforatum, bee pollen, bergamot, black cohosh, black horehound, burdock, California poppy, clary sage, cowslip, damiana, DHEA, geranium, ginseng, gotu kola, grapefruit, hyssop, Jamaican dogwood, lady's slip, lavender, lemon balm, licorice, linden, lobelia, yerba mate, mistletoe, motherwort, artemisia, oat straw, passion flower, peppermint, rosemary, skullcap, valerian root, vervain, wild lettuce, wood betony, cannabis flower or bud, and combinations thereof.

[0038]

[0039] Many of the optional bioactive ingredients listed herein are herbal ingredients. When the bioactive ingredient is an herbal ingredient, it can be included in the ERPM in the form of a powdered plant or a powdered extract thereof that is rich in the desired bioactive agent contained in the plant. The extract can be prepared by immersing the natural product in a liquid medium such as water, alcohol, or volatile oil, and then evaporating to form a dry powder.

[0039]

[0040] Additionally or alternatively, the bioactive ingredient included in the ERPM may be one or more of the following: collagen, coenzyme Q, or vitamins. The vitamins may be vitamin A, vitamin B, or vitamin C. The B vitamins may be one or more of thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12).

[0040]

[0041] 1, the ERPM 20 is molded into a wearable device 10 having a wristband shape suitable for wearing on a subject's wrist. However, in other embodiments of the present disclosure, the ERPM 20 may be molded into other wearable shapes, such as a necklace, a shape suitable for wearing around a subject's arm or leg, a patch, an anklet, a collar, or a shoe insole. Optionally, the ERPM 20 is molded into a shape like and to function as a watch band.

[0041]

[0042] The ERPM 20 may be manufactured according to the following method 100. In block 102, a carrier liquid is combined with granules 24 of liquid binder and mixed until the carrier liquid is substantially or completely absorbed into the granules, resulting in a carrier liquid infused granule. In block 104, the carrier infused granules 24 and at least one bioactive ingredient in granular or powder form are blended with a structural polymer 22. Blending may be performed in a heated environment at a temperature high enough to melt the structural polymer 22 but not the granules 24 or the at least one bioactive ingredient, optionally between 110° C. and 160° C., to form the ERPM 20 in liquid form, and then optionally cooled. Optionally, the ERPM is formed in a compounding extruder.

[0042]

[0043] In block 106, the ERPM is optionally formed into a desired shape to form the wearable device 10. The ERPM may be granulated to form ERPM granules, which are then injection molded in a mold. It will be appreciated that the ERPM granules may be formed into a variety of shapes to form different wearable devices 10, such as, for example, wristbands (as shown in FIG. 1), anklets, patches, shoe insoles, and necklaces. It will also be appreciated that the exact temperature to which the structural polymer or ERPM is heated in blocks 104 and 106 will depend on the polymers contained in the structural polymer 22 and the granules 24 and at least one bioactive ingredient contained in a given ERPM.

[0043]

[0044] Exemplary, non-limiting formulations of the ERPM 20 are described below. In each of the formulations below, the carrier liquid migrates from the liquid binder granules 24 through the structural polymer 22 to contact the islands of bioactive components 26, dissolves the bioactive agents contained within the islands to form a bioactive solution 28, and continues to migrate and is released to the exterior surface 21 of the ERPM 20 to form an outer liquid layer 29 of the bioactive solution. Moreover, in a wearable device that includes or consists of one of the ERPM examples described below, the bioactive solution 28 is released to the surface in a contact-sensitive manner in response to absorption of the bioactive solution away from the exterior surface of the ERPM onto said exterior surface, illustratively via percutaneous absorption through the skin of a subject wearing the wearable device. Moreover, each of the ERPM examples described below is formulated to release each bioactive agent contained within the bioactive solution via percutaneous absorption at a therapeutically effective rate for a period of at least three months.

[0044]

[0045] Example 1 - Polyolefin elastomer-based Joint Health ERPM

[0045]

[0046] An example of a "Joint Health" ERPM containing glucosamine, chondroitin sulfate, and methylsulfonylmethane (MSM) as bioactive ingredients and a carrier liquid containing ESBO was formulated as follows. [Table 1]

[0046]

[0047] The ESBO, lavender essential oil (together forming the carrier liquid) and fumed silica were mixed until the carrier liquid was absorbed into the fumed silica to form carrier infused granules. The carrier infused granules were then combined with glucosamine, chondroitin sulfate and MSM (each in powder form) and structural polymers (polyolefin elastomer and LDPE) in a compounding extruder at a temperature above the melting point of one or more polyolefins to form a "joint support" ERPM comprising islands of glucosamine, chondroitin sulfate and MEM embedded in a polyolefin structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded into a wristband shaped mold to form a wristband shaped wearable device.

[0047]

[0048] Example 2 - Polyolefin Elastomer-Based Collagen ERPM

[0048]

[0049] An example of a collagen ERPM containing collagen as the bioactive component, glycerol as the carrier liquid, and structural polymers including LDPE and polyolefin elastomer was formulated as follows. [Table 2]

[0049]

[0050] Similar to that described in Example 1 above, the carrier liquid (glycerol) and liquid-bound granules (fumed silica) were mixed together to form carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive component (collagen in powder form) and the structural polymer (polyolefin elastomer), in a compounding extruder at a temperature above the melting point of the structural polymer to form a collagen-embedded ERPM comprising islands of collagen embedded in the structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape such as a wristband, necklace, or collar.

[0050]

[0051] Example 3 - Polyolefin Elastomer-Based Curcumin ERPM

[0051]

[0052] An example of a curcumin ERPM containing curcumin as the bioactive ingredient, glycerol as the carrier liquid, and structural polymers including LDPE and polyolefin elastomer was formulated as follows. [Table 3]

[0052]

[0053] Similar to that described in other examples above, the carrier liquid (glycerol) and liquid-bound granules (fumed silica) were mixed together to form carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredient (curcumin in powder form) and the structural polymer (polyolefin elastomer), in a compounding extruder at a temperature above the melting point of the structural polymer to form a curcumin-embedded ERPM comprising islands of curcumin embedded in the structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape such as a wristband, necklace, or collar.

[0053]

[0054] It will be appreciated that the bioactive solution released from the curcumin-embedded ERPM is similar and functionally equivalent to a glycerol tincture of turmeric (glycerin agent), which is known to be abundant in curcumin. It will also be appreciated that a similar formulation can be applied to make an ERPM embedded with islets of powdered turmeric. It will also be appreciated that the same or similar formulation can be used to make an herbal ERPM containing one or a combination of various herbal ingredients typically used to make glycerin agents as bioactive ingredients, such as, but not limited to, burdock, chamomile, dandelion, echinacea, elderflower, ginger root, goldenseal, hawthorn, mugwort, nettle, ginseng, or valerian.

[0054]

[0055] It will be understood that an herbal ERPM formulation will have a higher relative content of the bioactive ingredient when the bioactive ingredient is the powdered plant of the herb, as compared to an extract of the same herb which is typically rich in the desired bioactive agent contained in the herb.

[0055]

[0056] In some embodiments, an ERPM with embedded islets of powdered herbal ingredients may utilize a carrier liquid containing non-volatile oil instead of glycerol. At least one bioactive ingredient contained within the islets may be one or a mixture of herbs in powder form typically used to make oil-based tinctures, such as, but not limited to, lavender, rosemary, ginger root, curcumin, or valerian. An example of such a formulation of an ERPM with islets of non-volatile oil as the carrier liquid and powdered herbs as the bioactive ingredients is described below.

[0056]

[0057] Example 4 - Polyolefin elastomer-based ERPM containing powdered lavender

[0057]

[0058] An example of a "Lavender" ERPM containing powdered lavender as the bioactive ingredient, non-volatile oil as a carrier, and structural polymers including LDPE and polyolefin elastomer was formulated as follows. [Table 4]

[0058]

[0059] Similar to the other examples described above, the carrier liquid (paraffin oil) and liquid-bound granules (fumed silica) were mixed together to form carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredient (powdered lavender) and the structural polymer (polyolefin elastomer), in a compounding extruder at a temperature above the melting point of the structural polymer to form a lavender-embedded ERPM comprising islands of powdered lavender embedded in the structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape such as a wristband, necklace, or collar.

[0059]

[0060] Example 5 - Polyolefin elastomer-based vitamin B12 ERPM

[0060]

[0061] The ERPM may also be used as a vehicle for extended administration of vitamin supplements.

[0061]

[0062] An example of an ERPM containing Vitamin B12 as a bioactive ingredient, a carrier liquid containing ESBO, and a structural polymer containing LDPE and a polyolefin elastomer was formulated as follows. [Table 5]

[0062]

[0063] Similar to the other examples described above, the carrier liquid (ESBO and chamomile essential oil) and liquid-bound granules (fumed silica) were mixed together to form carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredient (vitamin B12 in powder form) and the structural polymer (polyolefin elastomer), in a compounding extruder at a temperature above the melting point of the structural polymer to form a B12-embedded ERPM, which includes islands of B12 embedded in the structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape, such as a wristband, necklace, or collar.

[0063]

[0064] Example 6 - TPU-based collagen ERPM

[0064]

[0065] Another example of a collagen ERPM containing collagen as the bioactive component (and bioactive agent) and glycerol as the carrier liquid was formulated as follows. [Table 6]

[0065]

[0066] Similar to the other examples above, the carrier liquid (glycerol) and liquid-bound granules (fumed silica) were mixed together to form the carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive component (collagen in powder form) and the structural polymer (TPU), in a compounding extruder at a temperature above the melting point of the structural polymer to form a collagen-embedded ERPM comprising islands of collagen embedded in the structural polymer. The ERPM was then granulated to form the ERPM granules. The ERPM granules were then injection molded to form a wearable shape such as a wristband, necklace, or collar.

[0066]

[0067] The present disclosure also includes an SBS-based formulation for a collagen ERPM that is identical to the formulation described in Table 6 and was formulated as described above, with the exception that the structural polymer is an SBS rubber instead of a TPU.

[0067]

[0068] Example 7 - PVC-based Joint Health ERPM

[0068]

[0069] Another example of the "Joint Health" ERPM containing glucosamine, chondroitin sulfate, and curcumin as the bioactive ingredients (and bioactive agents), glycerol as the carrier liquid, and PVC as the structural polymer was formulated as follows. [Table 7]

[0069]

[0070] Similar to the other examples above, the carrier liquid (glycerol) and liquid-bound granules (fumed silica) were mixed together to form a carrier-infused granule until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredients (glucosamine, chondroitin sulfate, and curcumin, each in powder form) and the structural polymer (PVC) in a compounding extruder at a temperature above the melting point of the structural polymer to form a Joint Health ERPM, which includes islands of glucosamine, chondroitin sulfate, and curcumin embedded in the structural polymer. The ERPM was then granulated to form an ERPM granule. The ERPM granules were then injection molded to form a wearable shape, such as a wristband, necklace, or collar.

[0070]

[0071] Example 8 - TPU-based quenched ERPM

[0071]

[0072] An example of a "calming" ERPM containing a relaxation-inducing bioactive component, glycerol as a carrier liquid, and a structural polymer including TPU was formulated as follows. [Table 8]

[0072]

[0073] Similar to the other examples described above, the carrier liquid (glycerol) and liquid-bound granules (fumed silica) were mixed together to form carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredients (5-hydroxytryptophan, saffron extract, and Hypericum perforatum extract, each in powder form) and the structural polymer (TPU) in a compounding extruder at a temperature above the melting point of the structural polymer to form a "calmed" ERPM containing islands of 5-hydroxytryptophan, saffron extract, and Hypericum perforatum extract embedded in the structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape, such as a wristband, necklace, or collar.

[0073]

[0074] The present disclosure also includes an SBS-based formulation for a collagen ERPM that is identical to the formulation described in Table 6 and was formulated as described above, with the exception that the structural polymer is an SBS rubber instead of a TPU.

[0074]

[0075] Example 9 - Thermoplastic elastomer-based quenching ERPM

[0075]

[0076] Another example of a "calming" ERPM containing a relaxation-inducing bioactive component, glycerol as a carrier liquid, and structural polymers including LDPE and polyolefin elastomers was formulated as follows. [Table 9]

[0076]

[0077] Similar to the other examples described above, the carrier liquid (glycerol) and liquid-bound granules (fumed silica) were mixed together to form carrier-infused granules until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredients (5-hydroxytryptophan, saffron extract, and Hypericum perforatum extract, each in powder form) and the structural polymer (a combination of LDPE and Dow's Engage™ polyolefin), in a compounding extruder at a temperature above the melting point of the structural polymer to form a "calmed" ERPM containing islands of 5-hydroxytryptophan, saffron extract, and Hypericum perforatum extract embedded in the structural polymer. The ERPM was then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape, such as a wristband, necklace, or collar.

[0077]

[0078] Example 10 – TPU-based Energy ERPM

[0078]

[0079] An example of an "Energy" ERPM containing glycerol as a carrier liquid and a structural polymer containing TPU was formulated as follows. [Table 10]

[0079]

[0080] Similar to the other examples described above, the carrier liquid (glycerol) and the liquid-bound granules (fumed silica) were mixed together to form a carrier-infused granule until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredients (L-arginine and L-citrulline, each in powder form) and the structural polymer (TPU) in a compounding extruder at a temperature above the melting point of the structural polymer to form an "energy" ERPM containing islands of L-arginine and L-citrulline embedded in the structural polymer. The ERPM was then granulated to form an ERPM granule. The ERPM granules were then injection molded to form a wearable shape, such as a wristband, necklace, or collar.

[0080]

[0081] This disclosure also includes SBS-based formulations for Energy ERPMs that are identical to the formulations described in Table 6 and were formulated as described above, with the exception that the structural polymer is an SBS rubber instead of a TPU.

[0081]

[0082] Example 11 - Polyolefin Elastomer-Based Energy ERPM

[0082]

[0083] Another example of an "Energy" ERPM containing glycerol as a carrier liquid and structural polymers including LDPE and polyolefin elastomer was formulated as follows. [Table 11]

[0083]

[0084] Similar to the other examples described above, the carrier liquid (glycerol) and the liquid-bound granules (fumed silica) were mixed together to form a carrier-infused granule until the carrier liquid was absorbed into the liquid-bound granules. The carrier-infused granules were then combined with the remaining ingredients, including the bioactive ingredients (L-arginine and L-citrulline, each in powder form) and the structural polymer (a combination of LDPE and Dow's Engage™ polyolefin), in a compounding extruder at a temperature above the melting point of the structural polymer to form an "energy" ERPM containing islands of L-arginine and L-citrulline embedded in the structural polymer. The ERPM was then granulated to form an ERPM granule. The ERPM granules were then injection molded to form a wearable shape, such as a wristband, necklace, or collar.

[0084]

[0085] Example 12 - Polyolefin elastomer-based Joint Health ERPM

[0085]

[0086] Another example of a Joint Health ERPM containing glucosamine, chondroitin sulfate, and methylsulfonylmethane (MSM) as bioactive ingredients, glycerol as a carrier liquid, and a structural polymer comprising a polyolefin elastomer was formulated as follows. [Table 12]

[0086]

[0087] The fumed silica was mixed with a first volume of glycerol until the glycerol was absorbed into the fumed silica to form a carrier infused granules. The MSM was dissolved in a second volume of glycerol at a weight ratio of about 2:1 (MSM:glycerol) at a temperature of 50°C to 60°C to form an MSM-glycerol solution. The carrier infused granules and the MSM-glycerol solution were combined with the remaining ingredients, including glucosamine and chondroitin sulfate, each in powder form, along with a polyolefin elastomer in a compounding extruder at a temperature above the melting point of the polyolefin elastomer to form the "joint support" ERPM. The ERPM was cooled and then granulated to form ERPM granules. The ERPM granules were then injection molded to form a wearable shape such as a wristband, necklace, or collar. Once the ERPM returned to room temperature, most of the MSM that was previously dissolved in the glycerol returned to a solid form as a precipitate in the structural polymer matrix. As such, the Joint Support ERPM Wristband contains islets of glucosamine, chondroitin sulfate and MSM embedded in a polymer matrix.

[0087]

[0088] In the above examples including polyolefin elastomers (such as Examples 1-5, 9, 11 and 12), the formulations presented in each table used Dow Engage™ 8407, an ethylene-octene elastomer as the polyolefin elastomer. However, other polyolefin elastomers were also used in or contemplated for alternative formulations, including Dow Engage™ 8137 (another ethylene-octene elastomer), as well as Dow Engage™ 11527 (an ethylene-butene elastomer), and Sabic Fortify™ 300700D. Other suitable polyolefin elastomers, including ethylene-butene, ethylene-hexene, and ethylene-octene elastomers, can be selected based on the guidance provided herein to achieve the desired physical properties, such as elasticity and melting point. In addition, LDPE was primarily used in combination with the polyolefin elastomers due to its cost and availability as compared to polyolefin elastomers. It is contemplated that alternative formulations of Examples 1-5, 9, 11 and 12 using primarily or exclusively polyolefin elastomer and some or no LDPE would also provide ERPM20 with the sustained release properties described above.

[0088]

[0089] Example 13: Treatment of dogs diagnosed with osteoarthritis with a joint support ERPM collar as described in one of Examples 1, 7 or 12

[0089]

[0090] Efficacy tests are carried out on 20 animals (dogs). For 120 days, 10 experimental animals wear a joint support ERPM (JS-ERPM) collar made with the formula described above in Example 12, and 10 control animals wear a placebo collar. All animals (experimental and control) participating in the test are selected based on a previous diagnosis of osteoarthritis. On test day 0 (one day before applying the collar), 30, 60, 90 and 120, each animal in each test group undergoes the following examinations: ultrasound examination in the problem area; a dog-adapted WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score test, which is used to evaluate the condition of subjects with osteoarthritis (including joint pain, stiffness, and physical function); routine veterinary observations for joint mobility, lameness, pain on palpation, clinical signs; and measurement of blood calcium / phosphorus (Ca / P) ratio.

[0090]

[0091] Experimental animals wearing the JS-ERPM collar have been found to exhibit substantial relief from osteoarthritis symptoms beginning with the first post-collar examination on day 30, as shown by ultrasound, WOMAC scores, routine veterinary observations, and Ca / P ratios. The relief of osteoarthritis in the experimental group continues throughout the 120-day study period, indicating that the JS-ERPM collar provides sustained relief from osteoarthritis symptoms beyond the 120-day study period. None of the experimental animals treated with the JS-ERPM collar show any adverse reactions. In contrast, control animals continue to exhibit no change in osteoarthritis symptoms throughout the 120-day study period.

[0091]

[0092] Example 14: Treatment of a cat diagnosed with osteoarthritis with a joint support ERPM collar as described in one of Examples 1, 7 or 12

[0092]

[0093] The efficacy test is carried out on 20 animals (cats). For 120 days, 10 experimental animals wear a joint support ERPM (JS-ERPM) collar made with the formula described above in Example 12, and 10 control animals wear a placebo collar. All animals (experimental and control) participating in the study are selected based on a previous diagnosis of osteoarthritis. On study day 0 (one day before the collar is applied), day 30, day 60, day 90 and day 120, each animal in each test group undergoes the following examinations: ultrasound examination in the problem area; a WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score test adapted for cats, which is used to evaluate the condition of subjects with osteoarthritis (including joint pain, stiffness and physical function); routine veterinary observations for joint mobility, lameness, pain on palpation, clinical signs; and measurement of blood calcium / phosphorus (Ca / P) ratio.

[0093]

[0094] Experimental animals wearing the JS-ERPM collar have been found to exhibit substantial relief from osteoarthritis symptoms beginning with the first post-collar examination on day 30, as shown by ultrasound, WOMAC scores, routine veterinary observations, and Ca / P ratios. The relief of osteoarthritis in the experimental group continues throughout the 120-day study period, indicating that the JS-ERPM collar provides sustained relief from osteoarthritis symptoms beyond the 120-day study period. None of the experimental animals treated with the JS-ERPM collar show any adverse reactions. In contrast, control animals continue to exhibit no change in osteoarthritis symptoms throughout the 120-day study period.

[0094]

[0095] Thus, there is provided a plastic material for sustained release of a bioactive agent, the plastic material comprising a structural polymer; at least one bioactive component embedded in the structural polymer as solid islands; a liquid binder embedded in the structural polymer as granules; and a carrier liquid absorbed in a liquid absorbent.

[0095]

[0096] In embodiments of the present disclosure, the carrier liquid is sufficiently incompatible with the structural polymer such that at least a portion of the carrier liquid is released from the liquid-absorbent material through the structural polymer to the exterior surface of the plastic material over a period of time, optionally at least one week, at least one month, or at least three months.

[0096]

[0097] In an embodiment of the present disclosure, the bioactive agent contained in the at least one bioactive component is sufficiently soluble in the carrier liquid at room or body temperature such that the carrier liquid delivered to the exterior surface contains the bioactive agent in solution.

[0097]

[0098] In an embodiment of the present disclosure, the structural polymer comprises a polyolefin. In an embodiment of the present disclosure, the structural polymer comprises one or a combination of two or more selections from the group consisting of polyolefin elastomers, polyethylene (PE), polyvinyl chloride (PVC), polyurethane (PU), ethylene vinyl acetate (EVA), and synthetic rubber. Optionally, the polyethylene comprises one or a combination of two or more selections from the group consisting of low density polyethylene (LDPE) and linear low density polyethylene (LLDPE). Optionally, the structural polymer is formulated to be hydrophobic.

[0098]

[0099] In an embodiment of the present disclosure, the liquid binder is selected from the group consisting of silica gel, fumed silica, diatomaceous earth, carbon black, and activated carbon.

[0099]

[0100] In an embodiment of the present disclosure, the liquid binder comprises a porous polymer. Optionally, the melting point of the porous polymer is higher than the melting point of the structural polymer.

[0100]

[0101] In an embodiment of the present disclosure, the carrier liquid comprises a non-volatile oil. Optionally, the non-volatile oil is paraffin oil or vegetable oil.

[0101]

[0102] In an embodiment of the present disclosure, the liquid comprises one or a combination of two or more selections from the group consisting of chlorinated paraffins, triacetin, naphthenic hydrocarbons, aliphatic hydrocarbons, dioctyl terephthalate (DOTP), diisononyl phthalate (DINP), and epoxidized triglycerides.

[0102]

[0103] In an embodiment of the present disclosure, the carrier liquid comprises glycerol.

[0103]

[0104] In an embodiment of the present disclosure, the solid island of at least one bioactive component consists of a bioactive agent in a purified form.

[0104]

[0105] In an embodiment of the present disclosure, the at least one solid island of bioactive ingredients comprises a natural product that is a mixture of a bioactive agent and a material that is insoluble in the carrier liquid. Optionally, the at least one solid island of bioactive ingredients comprises a powdered plant.

[0105]

[0106] In an embodiment of the present disclosure, the solid island of at least one bioactive ingredient comprises an extract prepared from a plant.

[0106]

[0107] In the discussion, unless otherwise specified, adjectives such as "substantially" and "about" modifying a condition or relationship characteristic of one or more features of an embodiment of the present disclosure are to be understood as meaning that the condition or characteristic is defined to be within acceptable limits permitted for the operation of the embodiment for the application for which the embodiment is intended. Whenever a general term of the present disclosure is exemplified by reference to an example or list of examples, the referenced example or examples are by way of non-limiting examples of the general term, and the general term is not intended to be limited to the specific examples referenced. Unless otherwise specified, the word "or" in this specification and claims is considered to be an inclusive "or" and not an exclusive "or", indicating at least one item or any combination of multiple items of the conjoined items.

[0107]

[0108] In the specification and claims of this application, the verbs "comprise," "include," and "have," as well as their conjugations, are used to indicate that the object or objects of the verb are not necessarily an exhaustive list of components, elements, or parts of the subject or subjects of the verb.

[0108]

[0109] The description of the embodiments disclosed in this application is provided for illustrative purposes and is not intended to limit the scope of the disclosure. The described embodiments include various features, not all of which are required for all embodiments. Some embodiments utilize only some features or possible combinations of features. Those skilled in the art will recognize variations of the described embodiments of the present disclosure, as well as embodiments including various combinations of the features noted in the described embodiments. The scope of the present invention is intended to be limited only by the claims.

Claims

1. A device for sustained release of a bioactive agent by transdermal delivery to animal or human skin, said device comprising: a structural polymer selected from the group consisting of polyolefin elastomers, polyethylene (PE), polyvinyl chloride (PVC), polyurethane (PU), ethylene vinyl acetate (EVA), and synthetic rubber; at least one bioactive component embedded in said structural polymer as a solid island; a liquid binder embedded as granules in the structural polymer; and Carrier liquid absorbed in liquid binder Including, A device wherein the carrier liquid is sufficiently incompatible with the structural polymer such that at least a portion of the carrier liquid solution released from the liquid binder, including the bioactive agent dissolved in the carrier liquid, migrates through the structural polymer to an exterior surface of the structural polymer over a period of time.

2. The device described in claim 1, wherein the bioactive agent is released at a therapeutically effective rate in the context of transdermal absorption.

3. The device of claim 1 , wherein the bioactive agent contained in the at least one bioactive component is sufficiently soluble in the carrier liquid at room or body temperature such that the carrier liquid released to the exterior surface contains the bioactive agent in solution.

4. The device of claim 1 , wherein the period is at least one week.

5. The device of claim 1 , wherein the period is at least one month.

6. The device of claim 1 , wherein the period is at least three months.

7. The device of claim 1, wherein the carrier liquid solution is selectively released at portions of the exterior surface of the structural polymer that are in contact with an exine surface.

8. 10. The device of claim 1, wherein the polyethylene comprises one or a combination of two or more selections from the group consisting of low density polyethylene (LDPE) and linear low density polyethylene (LLDPE).

9. The device of claim 1 , wherein the structural polymer is hydrophobic.

10. 10. The device of claim 1, wherein the liquid binder is selected from the group consisting of silica gel, fumed silica, diatomaceous earth, carbon black, and activated charcoal.

11. The device of claim 1 , wherein the liquid binder comprises a porous polymer.

12. The device of claim 11 , wherein the melting point of the porous polymer is higher than the melting point of the structural polymer.

13. The device of claim 1 , wherein the carrier liquid comprises a non-volatile oil.

14. The device of claim 13, wherein the non-volatile oil is paraffin oil or a vegetable-derived oil.

15. 14. The device of claim 13, wherein the carrier liquid comprises one or a combination of two or more selections from the group consisting of chlorinated paraffins, triacetin, naphthenic hydrocarbons, aliphatic hydrocarbons, dioctyl terephthalate (DOTP), diisononyl phthalate (DINP), and epoxidized triglycerides.

16. The device of claim 13 , wherein the carrier liquid comprises glycerol.

17. The device of claim 1 , wherein said solid islands of said at least one bioactive component consist of said bioactive agent in a purified form.

18. 10. The device of claim 1, wherein the solid islands of the at least one bioactive component comprise a natural product that is a mixture of the bioactive agent and a material that is insoluble in the carrier liquid.

19. 20. The device of claim 18, wherein said solid island of said at least one bioactive ingredient comprises a powdered plant.

20. 10. The device of claim 1, wherein said solid island of said at least one bioactive ingredient comprises an extract prepared from a plant.

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