WO2012125941A1 - Traitement au lithium pour infections microbiennes - Google Patents

Traitement au lithium pour infections microbiennes Download PDF

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Publication number
WO2012125941A1
WO2012125941A1 PCT/US2012/029475 US2012029475W WO2012125941A1 WO 2012125941 A1 WO2012125941 A1 WO 2012125941A1 US 2012029475 W US2012029475 W US 2012029475W WO 2012125941 A1 WO2012125941 A1 WO 2012125941A1
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WIPO (PCT)
Prior art keywords
lithium
skin
lithium carbonate
acid
drug
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PCT/US2012/029475
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English (en)
Inventor
Shikha P. Barman
William D. Ju
Scott C. Kellogg
Stephen M. Prouty
Eric Schweiger
Seth Lederman
Mary Osbakken
Alan D. Schinazi
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Follica, Inc.
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Publication of WO2012125941A1 publication Critical patent/WO2012125941A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to lithium treatments for microbial infections and for colonization by microbes in human subjects.
  • Compositions containing compounds that liberate lithium ions are described, including formulations comprising lithium carbonate for topical administration.
  • the lithium treatment(s) can be used in combination with other treatments for microbial infections and for reduction of colonization by microbes.
  • the invention also relates to lithium treatments for scar revision and wound healing in human subjects.
  • the lithium treatments may be administered as a single pulse treatment or intermittently.
  • Compositions containing compounds that liberate lithium ions are described, including formulations comprising lithium carbonate for topical
  • compositions containing compounds that liberate lithium ions are described, including adjuvants and devices for administration.
  • the lithium treatment(s) can be administered via a drug sprayer device.
  • the lithium treatment(s) can be used in combination with other treatments for scar revision, wound healing, or for hair growth or hair development and follicle neogenesis. Such combination treatments may involve mechanical or physical treatments that modulate scar revision or wound healing, or that cause
  • integumental perturbation e.g. such as laser, surgical treatments, including skin graft or full thickness wounding, or dermabrasion, dermatome planing, etc.
  • chemical treatments that modulate wound healing, scar revision, or hair growth or hair follicle development, or that cause integumental perturbation or immune stimulation (e.g., such as adjuvants, antigens, cytokines, growth factors, etc.) for the treatment of wounds or revision of scars.
  • immune stimulation e.g., such as adjuvants, antigens, cytokines, growth factors, etc.
  • the combination treatment(s) may be administered concurrently with, or during the "holidays" between, cycles of intermittent lithium treatments; or concurrently with, or before and/or after the pulse lithium treatment.
  • the embodiments of the present invention also involve mechanical or physical treatments that cause integumental perturbation (e.g., dermabrasion) which may be used as part of a treatment for modulating hair growth in human subjects. Additionally, the embodiments of the present invention may involve mechanical or physical treatments that cause dermabrasion which may be used as part of a treatment for different skin conditions.
  • integumental perturbation e.g., dermabrasion
  • the embodiments of the present invention may involve mechanical or physical treatments that cause dermabrasion which may be used as part of a treatment for different skin conditions.
  • the skin usually provides a remarkably good barrier against pathogenic microorganisms, such as pathogenic bacteria and fungi.
  • the skin is colonized with resident bacterial flora. Although these bacteria are mostly non-pathogenic, colonization with potential pathogens also occurs, such as with Staphylococcus aureus, including methicillin- resistant strains.
  • Staphylococcus aureus including methicillin- resistant strains.
  • many microbes come in contact with or reside on the skin, they are normally unable to establish an infection. Cutaneous microbial infections often arise when there is a break in the continuity of the skin because the skin is torn, cut, or punctured, resulting in a wound. Microbial infections can also arise as a part of systemic infection.
  • Bacterial infections can be caused by several types of bacteria, including
  • Escherichia coli Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • the most common anti-bacterial agents prescribed to patients with bacterial infections are antibiotics. However, infections caused by antibiotic resistant strains have become a global problem.
  • MRSA methicillin resistant Staphylococcus aureus
  • VRE vancomycin resistant enterococci
  • ESBL extended spectrum beta-lactamase
  • Mycosis is a condition in which fungi pass the resistance barriers of the human or animal body and establish infections.
  • Superficial mycoses are limited to the outermost layers of the skin and hair. Cutaneous mycoses extend deeper into the epidermis, and also include invasive hair and nail diseases.
  • Anti-fungal agents that are currently used to treat cutaneous fungal infections include imidazoles, polyenes, thiocarbamates, ciclopirox, terbinafme, amorolfine, undecylenic alkanolamide and griseofulvin. Cutaneous fungal infections can be persistent and can often reoccur. Thus there is a need for alternative treatments to effectively and safely treat fungal infections, including novel topical treatments for conditions where current therapies generally require systemic administration (e.g. onychomycosis and tinea capitis).
  • Microbial biofilms are increasingly being implicated in the failure of antimicrobial agents to treat wound infections, which leads to delayed healing.
  • the presence of biofilms in various types of wounds has been shown directly by microscopic evaluation, revealing biofilms to consist of bacteria, fungi and mixed-species biofilms.
  • biofilms to consist of bacteria, fungi and mixed-species biofilms.
  • organisms in biofilms act synergistically, modulating the action of antimicrobial agents and other toxins, improving survival of organisms in various situations.
  • no antimicrobial class of compounds are available that effectively treat wound-related biofilms.
  • Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris.
  • Acne vulgaris (or cystic acne) is a common human skin disease, characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), nodules (large papules) and possibly scarring.
  • Acne affects mostly skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.
  • Acne is a multifactorial disease: genetic factors, stress, androgens, and excess sweating all influence its development and/or severity. Corticosteroids, oral contraceptives, iodides, bromides, lithium, and chemicals such as dioxins are known to induce acne eruptions.
  • Acne is a disease of the pilosebaceous units in the skin.
  • a changed keratinisation pattern in the hair follicle leads to blockage of sebum secretion. It is probable that hyperresponsiveness to the stimulation of sebocytes and follicular keratinocytes by androgens leads to the hyperplasia of sebaceous glands and seborrhea that characterise acne.
  • the enlarged follicular lumen attributable to inspissated keratin and lipid debris forms a closed comedone (whitehead).
  • the semisolid mass protrudes forming a plug, producing an open comedone (blackhead).
  • Propionobacterium acnes colonises the follicular duct and proliferates, breaking down the sebum to triglycerides, irritants that probably contribute to the development of inflammation.
  • the follicular epithelium When the follicular epithelium is invaded by inflammatory cells it ruptures, releasing sebum, micro-organisms, and keratin into the dermis.
  • Neutrophils, lymphocytes, and foreign body giant cells accumulate and produce the erythematous papules, pustules, and nodular swelling characteristic of inflammatory acne.
  • Acne may also refer to acne aestivalis (multiple, uniform, red, papular lesions reported to occur after sun exposure), acne conglobata (a highly inflammatory disease presenting with comedones, nodules, abscesses, and draining sinus tracts), acne cosmetica (acne caused by or made worse by cosmetics), acne fulminans (a severe form of acne, which can occur after unsuccessful treatment for another form of acne, acne conglobata), acne mechanica (an acneiform eruption that has been observed after repetitive physical trauma to the skin such as rubbing), acne medicamentosa (drug-induced acne), acne miliaris necrotica (acne consisting of follicular vesicopustules, sometimes occurring as solitary lesions that are usually very itchy), acne necrotica (acne in which the primary lesion is a pruritic or painful erythematous follicular-based papule that develops central necrosis and crusting and heals with a varioliform
  • Onychomycosis is used as a general term to denote any fungal nail infection.
  • the nail plate is a hard, thin (0.25-0.6 mm for fingernails and up to 1.3 mm for toenails) plate derived of highly disulfide-linked keratin.
  • the structure is made up of approximately 25 layers of dead, keratinized, flattened cells, which are tightly bound to one another via numerous intercellular links, membrane granules and desmosomes.
  • the nail plate is hydrophilic and is permeable to water and aqueous-based solutions, as opposed to oil, alcohol and hydrophobic molecules.
  • the term "dermatophytosis” is used to describe infection by members of the genera Microsporum, Trichophyton and Epidermophyton. The species that cause
  • Dermatophytes account for 90% of the cases of onychomycosis of the toenails and at least 50% of fingernail infections.
  • the fungal cells associated with dermatophytes manufacture keratinolytic proteases, which provide a means of entry into living cells.
  • Topical therapy for onychomycosis might be the treatment of choice, since it does not lead to adverse systemic effects or drug interactions.
  • antifungal drugs need to penetrate the nail plate to reach the infection sites under the nail.
  • the nail plate is a relatively thick structure that inhibits penetration of the drug being applied.
  • Nails that have been infected with onychomycosis have thicker nail plates, sometimes > 500 ⁇ .
  • the topical application of creams, solutions, lotions and gels is often dissipated in relatively short periods of time.
  • Attempts have been made to incorporate topically active antifungal drugs into film-forming compositions (e.g. nail polishes or lacquers to improve drug persistence). Thr removal of the nail (nail avulsion) can improve topical drug treatment.
  • Another recent means of treating onychomycosis include laser therapy on the affected nail, followed by topical administration of an antifungal agent.
  • Penlac® Cosmetic Acids Company 8% solution
  • Penlac® works by disruption of DNA, RNA and protein synthesis, thereby killing the fungus responsible for these infections. It requires long term treatment, and although about 1 out 15 patients demonstrate improvement, recurrence is common.
  • Wound healing is an intricate process in which the skin (or some other organ) repairs itself after injury.
  • the epidermis outermost layer
  • dermis inner or deeper layer
  • the classic model of wound healing is divided into three or four sequential, yet overlapping, phases: (1) hemostasis (not considered a phase by some authors); (2) inflammation; (3) proliferation; and (4) maturation and remodeling.
  • wound healing normally progress in a predictable, timely manner; if they do not, healing may progress inappropriately to either a chronic wound, such as a venous ulcer, or pathological scarring such as a keloid scar and other forms of scarring.
  • a chronic wound such as a venous ulcer, or pathological scarring such as a keloid scar and other forms of scarring.
  • wounds may heal by primary intention. Such wounds may be referred to as "closed wounds.”
  • Scarring is often minimal, but can be variable depending on the size and location of the wound, the tension on tissue and other factors.
  • Healing by secondary intention occurs when the extent of skin separation or skin tissue removed is too great for the edges of the wound to be placed in proximity (e.g., by bandages or sutures).
  • wounds may be referred to as "open wounds.”
  • Healing by secondary intention follows the same basic steps as wounds that heal by primary intention, but each sequence may take much longer, especially the proliferative phase.
  • wound healing by tertiary intention delayed primary closure
  • the wound is initially cleaned, debrided, and observed, and typically 4 or 5 days elapse before closure.
  • the wound is purposely left open. Examples include healing of wounds by use of tissue grafts.
  • a major component of wound healing in humans is scar formation.
  • a scar (“cicatrix”; plural, “cicatrices”) is an area of fibrous tissue that forms as part of the healing process to replace normal skin after injury.
  • a hallmark of scars is altered extracellular matrix, notably a reduction of elastin fibers (De Vries et al., 1995).
  • Scars result from damage to the dermis, and with the exception of very minor lesions, every wound results in some degree of scarring. Scars generally form in proportion to the extent of damage.
  • Human skin appendages also referred to as "adnexal” structures, include hair and hair follicles, sebaceous glands (which secrete sebum onto hair follicle to oil the hair), eccrine and apocrine sweat glands, and nails.
  • hair follicles to skin biology is now known not to be restricted to production of hair shafts and sebum. Rather, the hair follicle and other adnexal structures appear to be regenerative organs that play a central role in normal skin homeostasis and in response to wounding.
  • hair follicles and other skin adnexal structures have the potential to provide skin with stem cells and other elements that are important for skin regeneration. These data suggest that hair follicles participate in the regeneration of normal dermis and epidermis in healing wounds, thereby preventing or possibly reversing scarring or contributing to the formation of scars that are not disfiguring or dysfunctional.
  • Acute treatment of wounds is generally focused on hemostasis and antimicrobial considerations. The treatment depends on the type, cause, and depth of the wound as well as whether other structures beyond the skin are involved. Appropriate treatment of chronic wounds seeks to address the problems at the root of chronic wounds, including ischemia, hypoxia, bacterial load, and imbalance of proteases. Scar revision and wound management are limited by the limited regenerative capacity of adult human skin. Current therapies (skin grafting, pressure application) have modest functional and cosmetic results and are limited by the availability of donor skin, and by morbidity of donor and graft sites. There is an urgent need for improved therapies to treat wounds and scars.
  • the epidermis is the outer layer of the skin providing the body's major barrier against the environment. In humans, the epidermis is thinnest on the eyelids at 0.10 mm and thickest on the palms and soles at 1.5mm. Epidermal thickness is reduced by certain factors (age, smoking status). If the epidermis is thinning because of age, smoking, or other environmental factors, it is desirable to increase epidermal thickness.
  • the present invention provides methods for increasing epidermal thickness.
  • hair follicle neogenesis can be associated with wound healing in animals (e.g., rabbits, mice). See, Stenn & Paus, 2001, Physiol. Revs. 81 :449-494. In a mouse study, Dr. George Cotsarelis showed that physically disrupting the skin and existing hair follicles, in a defined fashion, can lead to hair follicle neogenesis (Ito et al, 2007, Nature 447:316-321).
  • hair follicle neogenesis was never proven because of an incomplete understanding of the fundamental biology of the follicle and the lack of tools needed to demonstrate the occurrence or hair follicle neogenesis (see, Argyris et al, 1959, Dev. Biol. 1 : 269-80; Miller, 1973, J. Invest. Dermatol. 58: 1-9; and Kligman, 1959, Ann NY Acad Sci 83: 507-511).
  • Cotsarelis showed, in mice, that following wound closure of large healed wounds created by full thickness excision (FTE) (1 cm 2 square wounds) new hairs are formed at the center of the wound (Ito et al, 2007, Nature 447:316-321). Cotsarelis' findings (Nature, 447, p.7142, 2007) constitute a breakthrough in biology because they change the
  • mice can regenerate new follicles during a specific time window.
  • the rotating wheel presents significant challenges when used in areas of thinning hair as part of a follicular growth treatment. Specifically, as can be seen in
  • a device directed to addressing the above- discussed drawbacks with conventional dermabrasion units.
  • the embodiments of the present invention describe a skin disruption system leveraging traditional dermabrasion technology but modifying it for use on the scalp and other hairy areas. 3. SUMMARY OF THE INVENTION
  • Novel lithium treatments for microbial infections i.e., bacterial, fungal, or parasitic infections
  • the lithium treatments described herein can be administered to treat cutaneous microbial infections, e.g., cutaneous bacterial infections or cutaneous fungal infections.
  • the lithium treatments can be administered to treat infected wounds, e.g., wounds infected by bacteria or wounds infected by fungi, and to treat skin colonized by microbes.
  • Described herein are methods for treating microbial infections and microbial colonizations, comprising administering a lithium composition to a human subject in need thereof. Also described herein are methods for treating microbial infections and
  • the lithium composition administered for treatment of a microbial infection or colonization comprises lithium carbonate.
  • mupirocin and lithium carbonate are co-mixed as a simple cream.
  • the lithium composition administered for treatment of a microbial infection or colonization comprises lithium gluconate or lithium succinate.
  • the lithium composition administered for treatment of a microbial infection does not comprise lithium chloride.
  • the microbial infections and colonizations treated with the lithium compositions described herein can be bacterial infections or bacterial colonizations.
  • the bacterial infection or colonization that is treated with the lithium composition is a cutaneous bacterial infection or colonization.
  • the cutaneous bacterial infection is an infected wound.
  • the bacterial infections that are treated with the lithium compositions described herein can be caused by any bacteria, including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • the cutaneous bacterial infection is an infected rash, including but not limited to eczema, cellulitis, or erysipelas.
  • the bacterial infections that are treated with the lithium compositions described herein can be caused by any bacteria, including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram- positive aerobes, and Bacteroides fragilis.
  • the cutaneous bacterial colonization is on clinically non- wounded skin.
  • the bacterial colonizations that are treated with the lithium compositions described herein can be caused by any bacteria, including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa,
  • Propionibacterium acnes Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • the microbial infections treated with the lithium compositions described herein can also be fungal infections.
  • the fungal infection that is treated with the lithium composition is a cutaneous fungal infection.
  • the cutaneous fungal infection is an infected wound.
  • the fungal infections that are treated with the lithium compositions described herein can be caused by any fungus, including, but not limited to, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Microsporum gypseum, Microsporum gypseum, Microsporum canis, Epidermophyton floccosum, Candida albicans, and Candida parapsilosis, Malassezia furfur, and Aspergillus fumigatus.
  • any fungus including, but not limited to, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Microsporum gypseum, Microsporum gypseum, Microsporum canis, Epidermophyton floccosum, Candida albicans, and Candida parapsilosis, Malassezia furfur, and Aspergillus fumigatus.
  • the lithium compositions described herein are not used to treat infections caused by viruses.
  • the lithium compositions described herein are not used to treat infections caused by DNA viruses.
  • the lithium compositions described herein are not used to treat infections caused by Herpes Simplex Virus (HSV).
  • HSV Herpes Simplex Virus
  • the lithium compositions described herein are administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes, including but limited to Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Enterococci, and drug-resistant Enterococci, and multi-drug resistant
  • a combination treatment comprising a lithium compound and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes, including but limited to Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Enterococci, and drug- resistant Enterococci.
  • the lithium compositions described herein are administered to a subject to prevent, reduce, or eradicate colonization of the nares, axillae, perineum, groin, chronic wounds or decubitus ulcer surface, around gastrostomy and tracheostomy sites, and in the sputum or urine.
  • a combination treatment comprising a lithium compound and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of the nares, axillae, perineum, groin, chronic wounds or decubitus ulcer surface, around gastrostomy and tracheostomy sites, and in the sputum or urine.
  • the lithium treatment can be administered topically, transdermally, intradermally, cutaneously, subcutaneously, intramuscularly, intravenously, orally, sublingually, or can be bucchal.
  • Topical lithium treatment is a preferred embodiment because high local
  • concentrations can be achieved while minimizing systemic exposure. In one such
  • lithium gluconate 8% weight/weight (w/w) gel ⁇ e.g., Lithioderm 8% gel) commercially available in France for the treatment of seborrheic dermatitis (Dreno B, 2007, Ann Dermatol Venereol. 134:347-351, incorporated herein by reference) can be used in the treatment methods described herein.
  • lithium is formulated into a modified release form that allows controlled release, over time, into the skin.
  • the lithium is formulated as part of a mesh scaffold that delivers lithium into the skin. More details on these and other lithium formulations and delivery methods for use in the treatment methods described herein are described in Sections 5.1-5.4 infra.
  • the lithium compositions described herein can be administered using an intermittent lithium treatment protocol, which involves multiple courses of lithium treatment interrupted by lithium treatment "holidays" (periods during which no lithium treatment is administered).
  • a lithium treatment holiday is a period of time during which the patient stops the lithium treatment with the intent of resuming treatment.
  • Lithium compositions can also be administered using a single pulse protocol, wherein a dose of lithium is administered over a short period of time.
  • the lithium treatments can be administered alone or in combination with other agents to enhance treatment of a microbial infection or a microbial colonization.
  • the other agent can be administered before, concurrently with, or after the lithium composition is administered.
  • a lithium composition is administered in combination with an antibiotic to treat a bacterial infection or a bacterial colonization.
  • a lithium composition is administered in combination with an anti-fungal agent to treat a fungal infection.
  • Human subjects who are candidates for lithium treatments described herein include any subject in need of treatment or prevention of a microbial infection or reduction of a microbial colonization, particularly with bacteria or fungi. Human subjects who are candidates for such treatments include any subject for whom improved wound healing is desired. Such human subjects include, but are not limited to, subjects with bacterial infections caused by any bacteria including, but not limited to Escherichia coli,
  • Staphylococcus aureus Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • Human subjects who are also candidates for such treatments include, but are not limited to, subjects with fungal infections caused by any fungi including, but not limited to Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Microsporum gypseum, Microsporum gypseum, Microsporum canis, Epidermophyton floccosum, Candida albicans, and Candida parapsilosis, Malassezia furfur, and Aspergillus fumigatus.
  • any fungi including, but not limited to Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Microsporum gypseum, Microsporum gypseum, Microsporum canis, Epidermophyton floccosum, Candida albicans, and Candida parapsilosis, Malassezia furfur, and Aspergillus fumigatus.
  • Topical formulations of the lithium treatments described herein can be administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram- positive aerobes, and Bacteroides fragilis.
  • bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Kleb
  • Topical formulations of the lithium treatments described herein can be administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • Topical formulations of the lithium treatments described herein can be administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • a combination treatment comprising a lithium compound described herein and chlorhexidine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination treatment comprising a lithium compound described herein and iodine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination treatment comprising a lithium compound described herein and povidone-iodine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • combination treatment comprising a lithium compound described herein can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, a hand sanitizer, a skin sanitizer, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a wound dressing which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, a hand sanitizer, a skin sanitizer, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • Any pharmaceutically acceptable compound that releases the lithium ion (also referred to herein as lithium cation, Li+, ionized lithium) can be used for a lithium treatment described herein; such compounds include, but are not limited to lithium gluconate, lithium succinate, and other organic salts/acids, lithium carbonate, lithium chloride and other inorganic salts/acids, and lithium hydroxide, as described in Section 5.1, infra.
  • compositions formulated for topical administration comprising a source of lithium ions formulated into aqueous formulations ⁇ e.g., hydrogels), ointments, or creams ⁇ e.g., emulsions) for topical administration.
  • a topical lithium ointment formulation comprising a source of lithium ions, petrolatum, mineral oil, and lanolin alcohol.
  • a topical lithium cream comprising a source of lithium ions in an emulsion of petrolatum and water.
  • a topical lithium aqueous hydrogel comprising a source of lithium ions, Carbopol 980, methyl paraben, propyl paraben, propylene glycol, glycerine, and water.
  • Sources of lithium ions include, for example, lithium carbonate, lithium citrate, lithium gluconate, lithium chloride, lithium succinate, or lithium hydroxide.
  • the source of lithium ions is lithium carbonate.
  • the source of lithium ions is lithium citrate.
  • the source of lithium ions is lithium hydroxide.
  • the topical formulation comprises 2.74 mg Li+/gram.
  • compositions formulated for topical administration wherein lithium hydroxide is the source of the Li+.
  • the pharmaceutical composition based on lithium hydroxide is formulated as a hydrogel.
  • the hydrogel formulation comprises lithium hydroxide monohydrate, citric acid, CMC, methyl paraben, propyl paraben, allantoin, alginate, and water.
  • pharmaceutical compositions formulated for topical administration comprising lithium carbonate and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is formulated as a hydrogel comprising 0.18%-5.66% w/w lithium carbonate, glycerol, carboxymethyl cellulose, allantoin, sodium alginate, methyl paraben, and propyl paraben.
  • the pharmaceutical composition is formulated as a cream comprising 0.18%-5.66 % w/w lithium carbonate, Citric Acid, Carbopol 980, Tween 20, Cetearyl Alcohol, Silicon 350 CSt, Silicon 12,500 CSt, Span 80, Lanolin Alcohol, and Emulsifier 10.
  • the pharmaceutical is formulated as a cream comprising 0.18%-5.66 % w/w lithium carbonate, Citric Acid, Carbopol 980, Tween 20, Cetearyl Alcohol, D350 Mineral Oil, Span 80, Lanolin Alcohol, and Emulsifier 10.
  • the pharmaceutical composition is formulated as a cream comprising 0.18%-5.66 % w/w lithium carbonate, Citric Acid, Carbopol 980, Tween 20, Lecithin, Silicon 350 CSt, D350 Mineral Oil, Span 80, Lanolin Alcohol, and Emulsifier 10.
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, allantoin, alginate, glycerol, citric acid, distilled water and lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1 %> allantoin, 0.1 %> alginate, 5%> glycerol, 5%> citric acid, distilled water and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 2.90% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1 %> allantoin, 0.1 %> alginate, 5%> glycerol, 5%> citric acid, distilled water and 1.46% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, allantoin, alginate, glycerol, citric acid, distilled water, mupirocin and lithium carbonate.
  • the pharmaceutical compisitoin is formulated as a hydrogel comprising 0.5% to 3% mupirocin.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1 %> allantoin, 0.1 %> alginate, 5%> glycerol, 5%> citric acid, distilled water, 2% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 0.5% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 0.5% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid,
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1 % alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1 % allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1 % allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin and 5.66% lithium carbonate.
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • the drug spraying device comprises a drug cartridge having two separate chambers that keep drug components isolated until the therapeutic compound is to be dispensed.
  • a device for spraying a therapeutic compound comprising:
  • a device for spraying a therapeutic compound comprises: (A) a control unit;
  • a hand piece including a housing and a plunger having a connecting portion
  • a drug cartridge housing having a front end and a back end
  • a drug cartridge for use in a device for spraying a therapeutic compound comprises:
  • the drug spraying device disclosed herein enables the sustained release of ionized lithium (Li+), without the use of highly hydrophobic, occlusive matrices.
  • the drug spraying device enables the delivery of ionized lithium in microspheres (e.g., PLG microspheres) such that the microspheres stay at the wound site for a prolonged period of time and are not cleared rapidly by phagocytosis.
  • a prolonged period of time can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or at least 20 days.
  • the drug spraying device disclosed herein enables the sustained release of ionized lithium (Li+) and uptake by the skin through a scab.
  • the drug spraying device enables the delivery of ionized lithium such that the delivery system is incorporated into the scab. This can be accomplished by placing a lithium containing thin, gauze-like, pliable biodegradable scaffold on the fresh wound. The material properties of the scaffold will be adjusted such the gauze is able to absorb the blood and other exudates from the wound.
  • the biodegradable scaffold has high content of void space, to absorb blood, fibrin and fibrinogen.
  • an in-situ crosslinking hydrogel is applied on top to cover the entire site as a wound dressing.
  • the drug spraying device disclosed herein enables the concurrent delivery of two or more drugs with different solubility properties and/or physical/chemical incompatibilities (such as different excipient requirements; binding and / or reaction of the two or more drugs with each other).
  • the drug spraying device disclosed herein enables the cleansing and administration of one or more drugs with one single device.
  • the contents of each chamber could be sprayed separately.
  • Once chamber can contain the cleansing solution; the liquid in the other chamber contains lithium. Any wound- cleansing solution known to the skilled artisan can be used with these embodiments.
  • ionized lithium is a monovalent cation
  • the lithium treatments, combination treatments and/or pharmaceutical compositions described herein are administered to treat, reduce, or prevent a microbial biofilm.
  • the microbial biofilm is a wound-related microbial biofilm.
  • the microbial biofilm is caused by bacteria and/or fungi.
  • the lithium treatments, combination treatments and/or pharmaceutical compositions described herein are administered to prevent planktonic forms of bacteria and/or fungi from developing in to biofilms.
  • the lithium treatments, described herein result in 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% reduction of a biofilm.
  • Novel lithium treatments such as a single pulse lithium treatment or intermittent lithium treatments, that promote wound healing, scar prevention, and scar revision are described.
  • the lithium treatments can be administered in situ to acute wounds, chronic wounds, to scars, and/or surrounding skin.
  • the lithium treatments can be administered to the wound site or surrounding skin before, at the time of, and/or subsequent to, either acute wounding or, more typically, the wounding that is induced in scar revision.
  • the lithium treatments may also be administered to skin-derived cells or skin tissue ex vivo.
  • a lithium treatment such as pulse or intermittent lithium treatments, to enhance deposition of skin adnexal structures into wound sites (e.g. , by inducing hair follicle neogenesis in the site of a scar revision), which in turn enhances wound healing, are described.
  • a lithium treatment may be used to enhance hair follicle neogenesis or enhance the re-association of dissociated hair follicle cells into follicles and facilitate their growth and expansion either in situ, or, alternatively, in culture for their implantation into fresh wounds and scar revisions.
  • hair follicles can be introduced to the wound by migration or de novo hair follicle neogenesis, or by transplanting one or more of the following skin elements: full skin (xeno-; autologous human), follicular units, dissociated cells (donor dominance; recipient effects), ex vivo-expanded skin and/or follicular units, or human skin equivalents in vivo (universal donors).
  • Engineered human skin, or human skin equivalents can also be used for hair follicle neogenesis and scar revision platforms.
  • Lithium treatments are used to revise scars and heal wounds in human subjects.
  • intermittent lithium treatment protocols involving multiple courses of lithium treatment interrupted by lithium treatment "holidays" (periods during which no lithium treatment is administered).
  • a lithium treatment holiday is a period of time during which the patient stops the lithium treatment with the intent of resuming treatment.
  • single pulse lithium treatment protocols in which a dose of lithium is administered over a short period of time.
  • the lithium treatment can be administered topically, transdermally, intradermally, cutaneously, subcutaneously, intramuscularly, intravenously, orally, sublingually, or can be bucchal.
  • Topical lithium treatment is a preferred embodiment because high local concentrations can be achieved while minimizing systemic exposure.
  • lithium gluconate 8% weight/weight (w/w) gel e.g., Lithioderm 8% gel
  • w/w weight/weight
  • adjuvants that target the treatment can be used in the treatment methods described herein.
  • Compound to the desired hair follicles or site on the skin may be included in the formulations used.
  • Adjuvants may be incorporated into the formulation to recruit cells from surrounding tissue to the target tissue.
  • lithium is formulated into a modified release form that allows controlled release, over time, into the skin.
  • the modified release form may be formulated to release lithium in a sustained fashion, or in a "pulsed" fashion. In order to achieve a pulsed mode of administration, the lithium
  • the lithium formulation may be administered multiple times. Another way to achieve pulsed delivery is to formulate the lithium in beads with multiple coatings, with the lithium contained in alternate coating layers.
  • the lithium is formulated as part of a mesh scaffold that delivers lithium into the skin. More details on these and other lithium formulations and delivery methods for use in the treatment methods described herein are described in Sections 5.1-5.4 infra.
  • the lithium formulations, including various modified release forms may be delivered topically as additives to shampoos and other hair products, as a lotion, cream, or ointment, may be delivered using devices such as iontophoresis, micro-needle injection arrays, auto-injector, or drug sprayer devices.
  • the lithium treatments can be administered alone to wounded skin (e.g., prior to, during, or subsequent to scar revision, or acute skin wounding, or chronic skin wounding) or in combination with other treatments to enhance wound healing or scar revision, or with other antimicrobial treatments or treatments to enhance the texture or appearance of skin.
  • the lithium treatments can also be administered in combination with other treatments that facilitate hair follicle development and deposition into the wounded skin.
  • Embodiments of the invention include combination therapies, involving the addition of other treatment(s) concurrently with, or during the breaks between, the cycles of intermittent lithium treatments; or the addition of other treatment(s) concurrently with, or before and/or after the pulse lithium treatment.
  • Such combination therapies can include, but are not limited to, the concurrent or sequential use of other chemical agents, or mechanical or physical treatments including but not limited to, laser (e.g., Fraxel), dermatome planing, laser abrasion, low voltage electric current, electrology, intense pulsed light, or surgical treatments (e.g., hair transplant, skin graft, strip harvesting, scalp reduction, or follicular unit extraction (FUE), etc.) that promote scar revision or wound healing.
  • laser e.g., Fraxel
  • dermatome planing e.g., dermatome planing
  • laser abrasion e.g., low voltage electric current, electrology, intense pulsed light
  • surgical treatments e.g., hair transplant, skin graft, strip harvesting, scalp reduction, or follicular unit extraction (FUE), etc.
  • lithium treatments in combination with perturbation e.g. , debriding, peeling, or wounding
  • perturbation e.g. , debriding, peeling, or wounding
  • methods such as laser treatment, dermabrasion, needling (using, e.g., microneedles), electromagnetic disruption, electroporation, or sonoporation; chemically (e.g., to induce inflammation); or by any other method described herein or known in the art, prior to or concurrent with administration of a lithium formulation described herein.
  • the integumental perturbation procedure can be any "wounding" procedure used for scar revision.
  • the procedure can be controlled to limit perturbation to the epidermis, or extend deeper into the dermis and/or hypodermis.
  • the occurrence of pinpoint bleeding would indicate removal of the epidermis and portions of the upper layer of the dermis.
  • the occurrence of increased bleeding would indicate deeper penetration (and thus perturbation) into the dermis layer.
  • Lasers particularly fractional lasers, and skin graft, follicular unit, and skin component transplant technologies have the capacity to induce regenerative changes in skin that mimic wounding and have applications in revision of scars.
  • laser techniques may "mimic" the plastic, embryonic-like, state of the epidermis created by other wound signals, but with laser's precision, versatility, and demonstrated efficacy in small scars. Consequently, when laser treatments are combined with lithium treatment, the outcome of revising extensive scars, particularly those that limit function (e.g., eye or mouth closure; joint contractions), may be vastly improved.
  • lithium treatments e.g., intermittent lithium treatments and pulse lithium treatments, administered concurrently or in sequential/alternating combination with other agents or treatments that modulate the wound healing process.
  • the lithium treatments may be administered with treatments that either promote or delay the wound healing process, such as described in Section 5.5 infra.
  • the lithium treatments described herein can be administered concurrently or alternating sequentially with one or more treatments that promote hair growth or prevent or delay hair loss.
  • a lithium treatment described herein may be used with a treatment that prevents follicle senescence (for example, anti-oxidants, mTOR inhibitors, sirtuins); promotes hair growth (for example, minoxidil, kopexil (for example, the product KeraniqueTM), finasteride, bimatoprost (Latisse), CaCl 2 , or adenosine); or techniques of integumental perturbation.
  • follicle senescence for example, anti-oxidants, mTOR inhibitors, sirtuins
  • promotes hair growth for example, minoxidil, kopexil (for example, the product KeraniqueTM), finasteride, bimatoprost (Latisse), CaCl 2 , or adenosine
  • techniques of integumental perturbation for example, anti-oxidants,
  • Treatments that promote hair growth, or, alternatively, treatments that prevent hair growth may also be used in combination with a lithium treatment, e.g., an intermittent lithium treatment or a pulse lithium treatment, described herein in order to promote the establishment of desired hair patterning in the healed wound or revised scar, thereby improving the appearance of the treated skin.
  • a lithium treatment may be used concurrently or in sequential combination with either a treatment that enhances hair growth (described above) or a cytotoxic drug, a hair growth retardant, such as eflornithine HCl (Vaniqa), 5-fluorouracil (5-FU) (e.g., Efudex 5% cream), or other epilation or depilation methods to prevent or reduce hair growth.
  • a lithium treatment may be used concurrently or in sequential combination with either a treatment that enhances hair growth (described above) or a cytotoxic drug, a hair growth retardant, such as eflornithine HCl (Vaniqa), 5-fluorouracil
  • Success of a lithium treatment such as a pulse or intermittent lithium treatment, described herein can be measured by one or more of the following outcomes:
  • Such human subjects include, but are not limited to, subjects with photodamaged skin, acne scars, chicken pox scars, scarring (cicatricial) alopecia, chronic non-healing wounds or scars due to, e.g., diabetes, venous or arterial disease, old age or senescence, infection, medication, chemotherapy, trauma, burns, stress, autoimmune disease, malnutrition, or endocrine dysfunction.
  • Surgical subjects who are candidates for such treatments include, but are not limited to, patients with skin graft, hair transplantation, skin cancer surgery, or Mohs surgery.
  • Subjects who are candidates for such treatments also include subjects with any other form of wounding or scarring or disease or disorder associated with wounding or scarring as discussed infra and/or known in the art.
  • the subject has a wound or scar on a cosmetically sensitive location, such as the face or neck.
  • the invention is based in part on the recognition that the timing of the
  • lithium treatment results, indirectly, in increasing Wnt signaling, but agents that increase Wnt signaling have had conflicting effects on hair follicle development and wound healing.
  • agents that increase Wnt signaling have had conflicting effects on hair follicle development and wound healing.
  • they stimulate follicle morphogenesis but also induce hair follicle tumors (Gat et al , 1998, Cell 95: 605-614), and lead to decreased hair growth (Millar et al, 1999, Dev. Biol. 207: 133-149).
  • it has been shown to arrest mitosis (Wolniak, 1987, Eur. J. Cell Biol.
  • the invention is also based, in part, on the principle that human skin is replenished by bone-marrow derived and tissue-derived stem cells throughout life.
  • the lithium treatment(s) is used in combination with methods that mobilize tissue stem cells (e.g., using integumental perturbation) and/or methods that mobilize bone marrow-derived stem cells (e.g., growth factors such as G-CSF and/or chemical agents such as plerixafor (Mozobil®)).
  • the lithium treatments described herein are used together with methods that regulate the differentiation of these stem cells into specialized human hair follicles in order to facilitate the desired hair patterning at the acceptor site, using agents such as finasteride, fluconazole, spironolactone, flutamide, diazoxide, 11-alpha-hydroxyprogesterone, ketoconazole, RU58841, dutasteride, fluridil, or QLT-7704, an antiandrogen oligonucleotide, cyoctol, topical progesterone, topical estrogen, cyproterone acetate, RU58841, combination 5 alpha reductase inhibitors, oral contraceptive pills, and others in Poulos & Mirmirani, 2005, Expert Opin.
  • agents such as finasteride, fluconazole, spironolactone, flutamide, diazoxide, 11-alpha-hydroxyprogesterone, ketoconazole, RU58841, dutaster
  • Investig. Drugs 14: 177-184 incorporated herein by reference, or any other antiestrogen, an estrogen, or estrogen-like drug (alone or in combination with agents that increase stem cell plasticity; e.g., such as valproate), etc., known in the art.
  • Such combination treatments can further include the use of agents that modulate hair growth or that modulate wound healing.
  • uses of the lithium compounds, alone or in combination with another treatment, described herein are disclosed.
  • a lithium compound described herein in the manufacture of a medicament for treatment and/or prevention of a microbial infection and/or prevention of microbial colonization.
  • a lithium compound described herein in the manufacture of a medicament for treatment and/or prevention of acne.
  • a lithium compound described herein in the manufacture of a medicament for wound healing or scar revision.
  • Figure 1 depicts the minimum inhibitory concentrations (mM) of lithium gluconate, lithium succinate, and lithium carbonate against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus,
  • Propionibacterium acnes Candida albicans, Malassezia furfur, and Aspergillus fumigatus.
  • Figure 2A-D depicts the minimum inhibitory concentrations (mM) of lithium carbonate and lithium gluconate, tested with or without serum, with the following wound- associated micro-organisms: Staphylococcus, epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, Candida albicans, Enterobacter cloacae.
  • Figure 3 depicts a time-dependent kill curve (log reduction of colony forming units (CFU)/mL) of Methicillin-resistant Staphylococcus aureus treated with lithium carbonate. The time points depicted are 30 minutes, 2 hours, and 4 hours.
  • CFU colony forming units
  • Figure 4 depicts a time-dependent kill curve (log reduction of colony forming units (CFU)/mL) of Escherichia coli treated with lithium carbonate. The time points depicted are 30 minutes, 2 hours, and 4 hours.
  • CFU colony forming units
  • Figure 5 depicts a time-dependent kill curve (log reduction of colony forming units (CFU)/mL) of Pseudomonas aeruginosa treated with lithium carbonate.
  • the time points depicted are 30 minutes, 2 hours, and 4 hours.
  • Figure 6 depicts a standard calibration curve for Li+ determination in polyvinyl alcohol (PVA) film.
  • Figure 7 In vitro release profiles from Petrolatum/Mineral Oil/Lanolin Alcohol formulations containing 8% lithium gluconate.
  • FIG. 13 Percent cumulative in vitro release rates from Lithioderm® and lithium carbonate hydrogel Formulation A (lithium carbonate at the indicated strength, glycerol (10.4%), carboxymethyl cellulose (2% w/w), allantoin (0.16%), sodium alginate (0.12%)), methyl paraben (0.1%>), propyl paraben (0.048%>), water (Q.S.), and sodium hydroxide (pH adjusted to 6.5-7.5)). Error bars are expressed as standard error, "mg/g” refers to mg Li+/g.
  • Figure 14 Pharmacokinetics study design of lithium carbonate hydrogel Formulation A compared to Lithioderm®. Samples were taken at lh, 24h, 25h, 28h, 48h, 49h, 52h, 192h. Two tissue samples were taken per time point.
  • Figure 15 Pharmacokinetic profile in skin of lithium carbonate hydrogel Formulation A at various doses (skin levels, DA). The 192 h data point was taken 18h after 6 days of twice daily administration.
  • Figure 16 Comparison of skin and blood concentrations of Li+ from lithium carbonate hydrogel Formulation A at the following concentrations compared: 0.34 mg Li+/g, 2.74 mg Li+/g, 5.48 mg Li+/g.
  • FIG. 1 Cmax (A) and trough (B) values of Li+ in skin, from the following concentrations of lithium carbonate hydrogel Formulation A: 0.34 mg Li+/g, 2.74 mg Li+/g, 5.48 mg Li+/g. Cmax values were measured 1 hour post-dosing after the first dose each day. Trough values were measured approximately 18 hours after the previous day's dose.
  • FIG. 1 Cmax (A) and trough (B) values of Li+ in blood, from the following concentrations of lithium carbonate hydrogel Formulation A: 0.34 mg Li+/g, 2.74 mg Li+/g, 5.48 mg Li+/g. Cmax values were measured 1 hour post-dosing after the first dose each day. Trough values were measured approximately 18 hours after the previous day's dose.
  • FIG. 19 Pharmacokinetic profiles of lithium carbonate hydrogel Formulation A and lithium gluconate in skin (A) and blood (B).
  • A Pharmacokinetic profile of Li+ concentrations in skin with twice-daily dosing of lithium gluconate (2.74 mg Li+/g) compared with lithium carbonate hydrogel (2.74 mg Li+/g).
  • Data are mean ⁇ range, of 2 animals per time point.
  • Li+ concentrations in blood with twice-daily dosing of lithium gluconate (2.74 mg Li+/g) compared with lithium carbonate hydrogel (2.74 mg Li+/g).
  • Figure 20 The absorbance vs. lithium ion concentration in standard solutions.
  • Figure 21 Matrix effect evaluations of other ions on the measurement of Li+ in a lithium carbonate cream formulation.
  • Figure 22 Release profile of Li+ from immediate release lithium carbonate cream formulation Lot# TH-001-081.
  • Figure 23 Release profile of Li+ from intermediate release lithium carbonate cream formulation Lot # TH-001 -084b.
  • Figure 24 The release profile of sustained release lithium carbonate cream formulation with lot # TH-001 -084a.
  • Figure 25 is a cross-linking reaction between PEG- AM and PEG-NHS.
  • Figure 26 is a graph depicting the gel time as a function of pH for PEG- NHS/PEG-AM hydrogels.
  • Figure 27 is a graph depicting the gel time as a function of PEG concentration for PEG-NHS/PEG-AM hydrogels.
  • Figure 28 is a graph depicting the gel time as a function of total PEG
  • Figure 29 is a graph depicting gel time as a function of PEI concentration in Phosphate buffer (0.1M, 0.2M and 0.5M) for PEG-NHS/PEL hydrogels.
  • Figure 30 is a graph depicting the log reduction of bacterial counts against untreated (y-axis), as a function of 5.66% Li-Carb, 11.5% Li-Carb, Vehicle and 2%
  • Figure 31 is a scanning electron micrograph of lithium carbonate-containing PLG microspheres lyophilized with PEG3.3K-NHS.
  • Figure 32 is a graph depicting the in vitro release of ionized lithium from PLG microspheres.
  • Figure 33 is a graph depicting the gel time as a function of total percent crosslinkable solids (PEG-AM, PEI, PEG-NHS).
  • Figure 34 is a graph depicting the degree of swelling for PEG-NHS/PEG-AM hydrogels, PEG-NHS/PEI hydrogels, and PEG-NHS/PEG-AM/Chitosan hydrogels.
  • Figure 35 is a graph depicting the viscosity of PVA solutions as a function of temperature.
  • the left-hand bar for each concentration (x-axis) represents the viscosity at 25 °C and the right-hand bar for each concentration (x-axis) represents the viscosity at 30 °C.
  • Figure 36 shows the release of lithium gluconate can be controlled by blend ratio of polymers. Shown is a plot of Percent Cumulative Release of Li+ as a Function of Time in Days, which demonstrates release profiles of four different blends. The micrographs to the left and bottom of the graph show two different polymer blends.
  • Figure 37A is a front perspective view of a spraying device, according to an embodiment of the present invention.
  • Figure 37B is a rear perspective view of a spraying device, according to an embodiment of the present invention.
  • Figure 38 is a front perspective view of a spraying device, according to an embodiment of the present invention.
  • Figure 39A is a plan view of showing the components of a hand piece depicted in Figures 33A and 33B.
  • Figure 39B is a rear perspective view of a hand piece, according to an embodiment of the present invention.
  • Figure 40A is a plan view of a drug cartridge, according to an embodiment of the present invention.
  • Figure 40B is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 40C is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 40D is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 41A is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 41B is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 41C is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 41D is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 41E is a plan view of a drug cartridge and the front end of a hand piece, according to an embodiment of the present invention.
  • Figure 42 depicts the log reduction of colony forming units (CFU)/mL) of MRSA ATCC 33591 treated with (1) 5.66% w/w Lithium Carbonate gel (10.64 mg Li+/g); (2) 11.5% w/w Lithium Carbonate gel (20 mg Li+/g); (3) 5.66%> w/w Lithium Carbonate emulsion (10.64 mg Li+/g); (4) 11.5% w/w Lithium Carbonate emulsion (20 mg Li+/g); (5)Vehicle; and (6) 2% Mupirocin.
  • CFU colony forming units
  • Figure 43 depicts the log reduction of colony forming units (CFU)/mL) of MRSA ATCC 33591 treated with (1) 2% Mupirocin; (2) Aqueous gel (Vehicle Control); (3) 2% Mupirocin + Placebo (aqueous gel); (4) 2% Mupirocin + 1.46% w/w Lithium Carbonate (2.74 mg Li+/g); (5) 2% Mupirocin + 5.66% w/w Lithium Carbonate (10.64 mg Li+/g); (6) 2% Mupirocin + 11.5% w/w Lithium Carbonate (20 mg Li+/g).
  • CFU colony forming units
  • Figure 44 depicts the log reduction of colony forming units (CFU/mL) of MRSA strain ATCC 33591 in two duplicate experiments and MRSA strain NEMC 89-4 treated with (1) 2% Mupirocin + 11.5% w/w Lithium Carbonate (20 mg Li+/g); (2) 2% Mupirocin; and (3) Aqueous gel (Vehicle Control).
  • Figure 45 depicts the percent inhibition of various concentrations (Fold-MIC) of lithium carbonate and ciprofloxacin on S. aureaus DNA synthesis.
  • Figure 46 depicts the percent inhibition of various concentrations (Fold-MIC) of lithium carbonate and linezolid on S. aureaus protein synthesis.
  • Figure 47 depicts the percent inhibition of various concentrations (Fold-MIC) of lithium carbonate and cerulenin on S. aureaus lipid synthesis.
  • Figure 48 depicts the percent inhibition of various concentrations (Fold-MIC) of lithium carbonate and vancomycin on S. aureaus cell wall synthesis.
  • Figure 49 depicts the percent inhibition of various concentrations (Fold-MIC) of lithium carbonate and rifampicin on S. aureaus RNA synthesis.
  • Figure 50 depicts the percent inhibition of lithium carbonate on S. aureaus DNA, lipid, protein and cell wall synthesis at 1, 2-, 4-, and 8-fold the MIC.
  • Figure 51 shows the Franz Cell set-up for diffusion studies.
  • Figure 52 shows Li + flux from formulation TH-003-070a, as a function of diffusion time through the nail, as a function of nail thickness, with red bars denoting Li + flux through a nail of thickness of 0.448 cm and blue bars denoting Li + flux through a nail of thickness of 0.04775 cm.
  • the nails received no iontophoretic treatment.
  • Figure 53 shows Li + flux from formulation TH-003-070b, as a function of diffusion time through the nail, as a function of nail thickness, with red bars denoting Li + flux through a nail of thickness of 0.0625 cm and blue bars denoting Li + flux through a nail of thickness of 0.248 cm.
  • the nails received no iontophoretic treatment.
  • Figure 54A compares the flux between formulations TH-003-070a, TH-003-070b and TH-003-070C.
  • Figure 54B shows percent Li permeated per time interval, for all three formulations, without iontophoresis.
  • Figure 55A shows a comparison of diffusive flux of Li + via formulation TH-003- 070a with, and without iontophoresis.
  • Figure 55B shows the percent Li + permeation using via formulation TH-003-070a over each time interval.
  • Figure 55C shows a comparison of diffusive flux of Li + across the nail plate with iontophoresis, plotted as a function of formulation composition (TH-003 -070a, TH-003 -070b and TH-003-070c).
  • Figure 55D shows the Li+ concentrations in nail and nail bed using formulation TH-003-070a over each time interval.
  • Figure 56A is a schematic Schematic representation of human nail mounted in a gasket with the relative position of the formulation and organism.
  • Figure 56B compares the percentages of ATP recovered (mean ⁇ range) following the dosing regimen summarised in Example 23 for 14 days against T. rubrum.
  • Figure 57 depicts a prior art dermabrasion rotating wheel ejecting blood and debris.
  • Figure 58 depicts a prior art dermabrasion rotating wheel in use.
  • Figure 59 depicts a prior art dermabrasion rotating wheel in use.
  • Figure 60 depicts a prior art dermabrasion hand piece and wheel in use.
  • Figure 61 depicts a dermabrasion tip according to an embodiment of the present invention attached to a conventional dermabrasion hand piece.
  • Figure 62 depicts a conventional dermabrader.
  • Figure 63 is a schematic drawing of a dermabrasion tip according to an embodiment of the present invention.
  • Figure 64 is a schematic drawing of a linkage assembly according to an embodiment of the present invention.
  • Figure 65 depicts a dermabrasion tip according to an embodiment of the present invention.
  • Figure 66 depicts a dermabrasion tip in use, according to an embodiment of the present invention.
  • Figure 67 depicts a dermabrasion tip in use, according to an embodiment of the present invention.
  • Figure 68 depicts a portion of the transmission assembly according to an embodiment of the present invention.
  • Figure 69 is a schematic drawing of a dermabrasion tip according to an embodiment of the present invention.
  • Figure 70 is a schematic drawing of a dermabrasion tip according to an embodiment of the present invention.
  • Figure 71 depicts a dermabrasion tip according to an embodiment of the present invention.
  • Figure 72 A is a rear view of a dermabrasion tip according to an embodiment of the present invention.
  • Figure 72B is a side view of a dermabrasion tip according to an embodiment of the present invention.
  • Figure 73 depicts a linear reciprocating converting dermabrasion tip according to an embodiment of the present invention.
  • Figure 74 depicts a combination radial and linear reciprocating converting dermabrasion tip according to an embodiment of the present invention.
  • FIG 77 Representative histological images showing that 8% lithium gluconate treatment results in an increased number and area of neogenic hair follicles (regeneration zone) and a reduction in the scar zone.
  • Figure 78 Elastin immunohistochemistry indicates that elastin is associated with neogenic hair follicles (NHFs) in the center of the wound (regeneration zone) (left), whereas elastin is undetectable in the scar zone (middle). Adjacent (non- wounded) skin is shown on the right. Dashed line: dermal-epidermal junction; NHF, neogenic hair follicle; HF, hair follicle.
  • any compound or composition that can release a lithium ion (also referred to herein as lithium cation, Li+, or ionized lithium) is suitable for use in the compositions and methods.
  • Such compounds include but are not limited to a pharmaceutically acceptable prodrug, salt or solvate (e.g., a hydrate) of lithium (sometimes referred to herein as "lithium compounds").
  • the lithium ion is provided by lithium hydroxide, such as, e.g., lithium hydroxide monohydrate.
  • the lithium compounds can be formulated with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
  • lithium-polymer complexes can be utilized to developed various sustained release lithium matrices.
  • lithium is best known as a mood stabilizing drug, primarily in the treatment of bipolar disorder, for which lithium carbonate (L1 2 CO 3 ), sold under several trade names, is the most commonly used.
  • Other commonly used lithium salts include lithium citrate (L13C6H5O7), lithium sulfate (L1 2 SO 4 ), lithium aspartate, lithium orotate, lithium succinate, and lithium gluconate.
  • lithium gluconate for example, a topical ointment of 8% lithium gluconate (LithiodermTM), is approved for the treatment of seborrheic dermatitis, can be used in the methods disclosed herein. See, e.g., Dreno and Moyse, 2002, Eur J Dermatol 12:549-552; Dreno et al, 2007, Ann Dermatol Venereol 134:347-351 (abstract); and
  • a lithium formulation well-suited for use in the methods disclosed herein is lithium carbonate, for example, a topical ointment of 1.46 % lithium carbonate, 2.91 % lithium carbonate, 5.66% lithium carbonate or 11.5% lithium carbonate.
  • Another lithium formulation for use in the methods disclosed herein is lithium succinate, for example, an ointment comprising 8% lithium succinate, which is also used to treat seborrheic dermatitis.
  • the lithium formulation is an ointment comprising 8% lithium succinate and 0.05% zinc sulfate (marketed in the U.K. as Efalith). See, e.g., Efalith Multicenter Trial Group, 1992, J Am Acad Dermatol 26:452-457, which is incorporated by reference herein in its entirety.
  • lithium carbonate is more effective in its antimicrobial activity than lithium gluconate and lithium succinate.
  • MIC minimum inhibitory concentration
  • In vitro minimum inhibitory concentration (MIC) assays for six microbial species revealed that lithium carbonate was more effective at inhibiting bacteria, by a factor of 2 to 4 over lithium succinate and by a factor of 8 to 32 over lithium gluconate ⁇ see Example 1).
  • Minimum inhibitory concentration (MIC) assays for nine microbial species that are associated with wounds revealed that lithium inhibited the growth of all the organisms tested and lithium carbonate was a more potent anti-microbial than the gluconate salt form with respect to P. aeruginosa and S. aureus (see Example 2).
  • a lithium composition formulated for topical administration comprises lithium carbonate.
  • a lithium composition formulated for topical administration comprises lithium hydroxide.
  • the lithium ions in a composition formulated for topical administration are provided by lithium carbonate.
  • the lithium ions in a composition formulated for topical administration are provided by lithium hydroxide, such as, e.g., lithium hydroxide monohydrate.
  • any pharmaceutically acceptable lithium salt may be used as a source of lithium ions in the lithium treatment. It will be understood by one of ordinary skill in the art that pharmaceutically acceptable lithium salts are preferred. See, e.g., Berge et al, J. Pharm. Sci. 1977, 66: 1-19; Stahl & Wermuth, eds., 2002, Handbook of ' Pharmaceutical Salts, Properties, and Use, Zurich, Switzerland: Wiley-VCH and VHCA; Remington 's Pharmaceutical Sciences, 1990, 18 th eds., Easton, PA: Mack Publishing; Remington: The Science and Practice of Pharmacy, 1995, 19 th eds., Easton, PA: Mack Publishing.
  • the compositions used for a lithium treatment comprise mixtures of one or more lithium salts.
  • a mixture of a fast-dissolving lithium salt can be mixed with a slow dissolving lithium salt proportionately to achieve the release profile.
  • the lithium salts do not comprise lithium chloride.
  • the lithium salt can be the salt form of anionic amino acids or poly(amino) acids. Examples of these are glutamic acid, aspartic acid, polyglutamic acid, polyaspartic acid.
  • lithium salts of the acids set forth above, applicants do not mean only the lithium salts prepared directly from the specifically recited acids. In contrast, applicants mean to encompass the lithium salts of the acids made by any method known to one of ordinary skill in the art, including but not limited to acid-base chemistry and cation-exchange chemistry.
  • lithium salts of anionic drugs that positively affect hair growth can be administered.
  • a large anion or multianionic polymer such as polyacrylic acid can be complexed with lithium, then complexed with a cationic compound, such as finasteride, to achieve a slow release formulation of both lithium ion and finasteride.
  • a lithium complex with a polyanion can be complexed further with the amines of minoxidil, at pHs greater than 5.
  • Lithium compounds for use in the methods provided herein may contain an acidic or basic moiety, which may also be provided as a pharmaceutically acceptable salt. See, Berge et al, J. Pharm. Sci. 1977, 66:1-19; Stahl & Wermuth, eds., 2002, Handbook of Pharmaceutical Salts, Properties, and Use Zurich, Switzerland: Wiley-VCH and VHCA. 5.1.2 ORGANIC LITHIUM SALTS
  • the lithium salts are organic lithium salts.
  • Organic lithium salts for use in these embodiments include lithium 2,2-dichloroacetate, lithium salts of acylated amino acids (e.g., lithium N-acetylcysteinate or lithium N-stearoylcysteinate), a lithium salt of poly(lactic acid), a lithium salt of a polysaccharides or derivative thereof, lithium acetylsalicylate, lithium adipate, lithium hyaluronate and derivatives thereof, lithium polyacrylate and derivatives thereof, lithium chondroitin sulfate and derivatives thereof, lithium stearate, lithium linoleate, lithium oleate, lithium taurocholate, lithium cholate, lithium glycocholate, lithium deoxycholate, lithium alginate and derivatives thereof, lithium ascorbate, lithium L-aspartate, lithium benzenesulfonate, lithium benzoate, lithium 4- acetamidobenzoate, lithium (+
  • the organic lithium salt for use in these embodiments is lithium (S)-2- alkylthio-2-phenylacetate or lithium (R)-2-alkylthio-2-phenylacetate (e.g. , wherein the alkyl is C2-C22 straight chain alkyl, preferably C8-16). See, e.g., International Patent Application Publication No. WO 2009/019385, published February 12, 2009, which is incorporated herein by reference in its entirety.
  • the organic lithium salts used for a lithium treatment comprise the lithium salts of acetic acid, 2,2-dichloroacetic acid, acetylsalicylic acid, acylated amino acids, adipic acid, hyaluronic acid and derivatives thereof, polyacrylic acid and derivatives thereof, chondroitin sulfate and derivatives thereof, poly(lactic acid-co-glycolic acid), poly(lactic acid), poly(glycolic acid), pegylated lactic acid, stearic acid, linoleic acid, oleic acid, taurocholic acid, cholic acid, glycocholic acid, deoxycholic acid, alginic acid and derivatives thereof, anionic derivatives of polysaccharides, poly(sebacic anhydride)s and derivatives thereof, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, (+)
  • ethanesulfonic acid 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, (+)-L-lactic acid, ( ⁇ )-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, ( ⁇ )-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene- 1, 5 -disulfonic acid, 1- hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, L-pyroglutamic acid, saccharic acid, salicy
  • the organic lithium salt can be modified to create sustained release lithium salts. Due to the size of the lithium ion, it is possible that the residence time of ion at the treatment site will be short. In efforts to generate sustained release lithium salts, the hydrophobicity of the salt can be enhanced and made "lipid-like," to, for example, lower the rate of ionization of the salt into lithium ions. For example, lithium chloride has a much faster rate of ionizing into lithium ions, than lithium stearate or lithium orotate. In that regard, the lithium salt can be that of a cholesterol derivative, or a long chain fatty acids or alcohols.
  • Lipid complexed lithium salts of size less than 10 microns can also be effectively targeted to the skin pores or hair follicles and "tethered" to the sebaceous glands, by hydrophobic- hydrophobic interactions.
  • the organic lithium salt can be in the form of complexes with anionic compounds or anionic poly(amino acids) and other polymers.
  • the complexes can be neutral, wherein all of the negative charges of the complexation agent are balanced by equimolar concentrations of Li ions.
  • the complexes can be negatively charged, with Lithium ions bound to an anionic polymer.
  • the complexes can be in the form of nano-complexes, or micro-complexes, small enough to be targeted to the skin pores or hair follicles. If the complexes are targeted to the dermis, the charged nature of the complexes will "tether" the complexes to the positively charged collagen. This mode of tethering holds the Li ions at the site of delivery, thereby hindering fast in-vivo clearance.
  • negatively charged polymers that can be used in this application are poly(acrylates) and its copolymers and derivatives thereof, hyaluronic acid and its derivatives, alginate and its derivatives, etc.
  • the anionic lithium complexes formed as described above can be further complexed with a cationic polymer such as chitosan, or polyethylimine form cell-permeable delivery systems.
  • the salt can be that of a fatty acid, e.g., lithium stearate, thereby promoting absorption through skin tissues and extraction into the lipid compartments of the skin.
  • the lithium salt of sebacic acid can be administered to the skin for higher absorption and targeting into structures of the skin, such as hair follicles.
  • the lithium salts are inorganic lithium salts.
  • Inorganic lithium salts for use in these embodiments include halide salts, such as lithium bromide, lithium chloride, lithium fluoride, or lithium iodide.
  • the inorganic lithium salt is lithium fluoride.
  • the inorganic lithium salt is lithium iodide.
  • the lithium salts do not comprise lithium chloride.
  • Other inorganic lithium salts for use in these embodiments include lithium borate, lithium carbonate, lithium nitrate, lithium perchlorate, lithium phosphate, or lithium sulfate.
  • the inorganic lithium salts used for a lithium treatment comprise the lithium salts of boric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, nitric acid, perchloric acid, phosphoric acid, or sulfuric acid.
  • the inorganic lithium salt for use in the embodiments described herein is lithium carbonate.
  • the lithium compounds used for a lithium treatment may be formulated with a pharmaceutically acceptable carrier (also referred to as a pharmaceutically acceptable excipients), i.e., a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, an encapsulating material, or a complexation agent.
  • a pharmaceutically acceptable carrier also referred to as a pharmaceutically acceptable excipients
  • each component is "pharmaceutically acceptable” in the sense of being chemically compatible with the other ingredients of a pharmaceutical formulation, and biocompatible, when in contact with the biological tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Suitable excipients are well known to those skilled in the art, and non- limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, forms for topical administration such as a cream may contain excipients not suited for use in transdermal or intravenous administration. The suitability of a particular excipient depends on the specific active ingredients in the dosage form.
  • Exemplary, non-limiting, pharmaceutically acceptable carriers for use in the lithium formulations described herein are the cosmetically acceptable vehicles provided in
  • the lithium compounds suitable for use in a lithium treatment may be formulated to include an appropriate aqueous vehicle, including, but not limited to, water, saline, physiological saline or buffered saline ⁇ e.g., phosphate buffered saline (PBS)), sodium chloride for injection, Ringers for injection, isotonic dextrose for injection, sterile water for injection, dextrose lactated Ringers for injection, sodium bicarbonate, or albumin for injection.
  • PBS phosphate buffered saline
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, lanolin oil, lanolin alcohol, linoleic acid, linolenic acid and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, wool alcohol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO).
  • liquid polyethylene glycol e.g., polyethylene glycol 300 and polyethylene glycol 400
  • propylene glycol glycerin
  • NMP N-methyl-2-pyrrolidone
  • DMA N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • the water-miscible vehicle is not DMSO.
  • the lithium compounds for use in the methods disclosed herein may also be formulated with one or more of the following additional agents.
  • Suitable anti-microbial agents or preservatives include, but are not limited to, alkyl esters of p-hydroxybenzoic acid, hydantoins derivatives, propionate salts, phenols, cresols, mercurials, phenyoxyethanol, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), butyl, methyl- and propyl-parabens, sorbic acid, and any of a variety of quarternary ammonium compounds.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate, glutamate and citrate.
  • Suitable antioxidants are those as described herein, including ascorbate, bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine
  • suspending and dispersing agents include but are not limited to sodium carboxymethylcelluose (CMC), hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP).
  • CMC carboxymethylcelluose
  • HPMC hydroxypropyl methylcellulose
  • PVA polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • Suitable emulsifying agents include but are not limited to, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to, EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including a-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- -cyclodextrin, sulfobutylether- ⁇ - cyclodextrin, and sulfobutylether 7- -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • Soothing preparations e.g., for topical administration, may contain sodium bicarbonate (baking soda), and coal tar based products. Formulations may also optionally contain a sunscreen or other skin protectant, or a waterproofing agent.
  • a product for application to skin may additionally be formulated so that it has easy rinsing, minimal skin/eye irritation, no damage to existing skin or hair, has a thick and/or creamy feel, pleasant fragrance, low toxicity, good biodegradability, and, for application to skin with hair, a slightly acidic pH (pH less than 7), since a basic environment weakens the hair by breaking the disulfide bonds in hair keratin.
  • lithium can be used, such as, e.g., lithium carbonate; lithium gluconate - for example 8% lithium gluconate (LithiodermTM), which is approved for the treatment of seborrheic dermatitis (see, e.g., Dreno and Moyse, 2002, Eur J Dermatol 12:549-552; Dreno et al., 2007, Ann Dermatol Venereol 134:347-351 (abstract); and Ballanger et al, 2008, Arch Dermatol Res 300:215-223, each of which is incorporated by reference herein in its entirety); lithium succinate (see, e.g., Langtry et al., 1996, Clinical and Experimental Dermatology 22:216-219; and Cuelenaere et al., 1992, Dermatology 184: 194-197, each of which is incorporated by reference herein in its entirety); and or 8% lithium succinate with
  • a topical preparation of lithium carbonate is used.
  • a preparation of lithium or lithium salt comprises an anionic polymer (such as, e.g., crosslinked polyacrylic acid), which may form a gel.
  • an anionic polymer such as, e.g., crosslinked polyacrylic acid
  • a preparation provided in the examples of Section 6 below may be used.
  • modified release refers to a dosage form in which the rate or place of release of the lithium or other active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed- release, and gastric retention dosage forms.
  • the compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
  • the controlled release is achieved by using an adjuvant that causes a depot effect, i.e., that causes an active agent or antigen to be released slowly, leading to prolonged exposure to a target cell or tissue (e.g. , cells of the follicle, an infected skin or wound, or, in the case of
  • a target cell or tissue e.g. , cells of the follicle, an infected skin or wound, or, in the case of
  • Examples of formulations for modified release to skin or hair include those described in International Patent Application Publication No. WO 2008/115961, published September 25, 2008, which is incorporated herein by reference in its entirety.
  • Other examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;
  • the modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et ah, 1999, in Encyclopedia of Controlled Drug Delivery, Mathiowitz E, ed., Vol. 2, Wiley.
  • the modified release dosage form is formulated using an erodible matrix device, which is water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen;
  • cellulosics such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT ® , Rohm America, Inc., Piscataway, NJ);
  • degradable lactic acid-glycolic acid copolymers poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
  • the compositions are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene,
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • modified release dosage forms can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • the modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • an osmotic agent which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water- swellable hydrophilic polymers, which are also referred to as "osmopolymers" and
  • hydrogels Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
  • hydrophilic vinyl and acrylic polymers polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
  • polyvinylpyrrolidone PVP
  • crosslinked PVP polyvinyl alcohol
  • PVA polyvinyl alcohol
  • PVA/PVP copolymers PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
  • HEC hydroxyethyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • CMC carboxymethyl cellulose
  • CEC carboxyethyl
  • sodium alginate sodium carbcarbophil
  • gelatin xanthan gum
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, ed
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEM TM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • a semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
  • Such hydrophobic but water- vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • An osmotic controlled-re lease dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al, Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al., J. Controlled Release 2002, 79, 7-27.
  • compositions are formulated as AMT controlled- release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • compositions are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • the lithium-containing compound can be loaded into a polymeric solution that consists of a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C.
  • the lithium-containing solution can be cooled to 2-8°C to impart a soothing effect, while being sprayed as a liquid spray on the tissue surface. Once sprayed on, the lithium- loaded solution will thicken into a gel, releasing the lithium-containing compound slowly over time.
  • the lithium-loaded solution can be injected as a liquid, to form an in situ depot within the tissue.
  • the lithium-loaded solution can be delivered as a solution, which can flow into orifices of the tissue, such as hair follicles, and then, form a gel to release lithium for cutaneous microbial infections, follicle-associated conditions, such as MPHL, folliculitis, or another condition described herein.
  • the temperature and time of gelation can be correlated to the concentration of the polymers and the length of the polymer blocks that constitute the polymers.
  • a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ to about 3 mm, about 50 ⁇ to about 2.5 mm, or from about 100 ⁇ to about 1 mm in diameter.
  • Such multiparticulates can be made by the processes known to those skilled in the art, including microfluidization, membrane-controlled emulsification, oil-in-water, water-oil- water and oil-in oil emulsification and homogenization processes, complex coacervation, wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt- congealing, and by spray-coating seed cores. See, for example, Ghebre-Sellassie, ed., 1994, Multiparticulate Oral Drug Delivery, Marcel Dekke; and Ghebre-Sellassie ed., 1989, Pharmaceutical Pelletization Technology, Marcel Dekker.
  • compositions can be blended with the compositions to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film- forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • the lithium compounds for use herein may be formulated with a carrier that delivers the lithium to the site of action, for example, an infected wound, or a follicle in a particular tissue. Such targeted delivery may be preferable in formulations for systemic administration, in order to reduce side effects associated with lithium therapy and/or ensure that the lithium reaches only the infected wound or tissue, or follicles of particular tissues.
  • the carrier may be an aptamer targeted to a particular protein or cell type in the infected wound or tissue, or the follicle, an antibody or antigen-binding fragment thereof, a virus, virus-like particle, virosome, liposome, micelle, microsphere, nanoparticle, or any other suitable compound.
  • compositions for use in the methods provided herein can also be formulated to be targeted to a particular tissue, follicle, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 5,709,874; 5,759,542;
  • targeting is accomplished by the attachment of specific targeting moieties to the delivery systems containing the drug.
  • Targeting moieties can be in the form of antibodies, aptamers or small molecules that bind to specific proteins expressed in specific tissues.
  • Specific or guided targeting can "channel" the drug only to the specific tissue type, thus minimizing distribution to all tissues. This concept is especially useful if the drug causes side effects.
  • Microspheres and nanospheres can be utilized, to deliver drugs into infected skin or infected wounds. Entry into infected skin or infected wounds or the hair follicle is governed by the size of the drug-containing spheres, with microspheres of size 0.5- 0.7 microns of ideal size for entry.
  • the surface of the microspheres can be functionalized with moieties that bind to specific surfaces in the follicular orifice to "retain" them at the site.
  • moieties can be non-specific, such as hydrophobic coatings, or cationic coatings, in order to be bioadhesive to cells within infected skin, wound, or tissue.
  • the moieties can be specific and targeted to certain proteins that are expressed specifically on specific cell membranes.
  • proteins over-expressed on the follicular lymphoma cell surfaces can be targeted by delivery systems that have antibodies or aptamers designed to bind to these proteins.
  • the surface of the delivery systems can also be functionalized with cell-penetrating moieties such as cell-permeable peptides, positively charged polymers that bind to anionic cell surfaces.
  • an intermittent lithium treatment or a pulse lithium treatment described herein may have a decreased risk of such side effects because of the intermittent or temporary nature of the treatment. Another way in which such side effects may be circumvented is to deliver the lithium treatment locally to the site of the microbial infection.
  • the lithium treatments described herein may be delivered locally to any part of the subject in which treatment or prevention of a microbial infection or reduction of colonization, or wound healing or scar revision, is desired, including, e.g., the head ⁇ e.g., the scalp, cheek, chin, lips, ears, ear canals, nose, nostrils, eyelid or eyebrow), neck, abdomen, chest, breast, back, arms, armpits, stomach, genital area, perineum, buttocks, legs, hands, feet, skin of a subject.
  • the lithium treatment is applied to an infected wound, or wounded or scarred skin.
  • lithium treatment is applied to skin infected by microbes.
  • lithium treatment is applied to skin colonized by microbes.
  • the lithium treatment is applied before the wound is infected.
  • the lithium treatment is applied before the skin is wounded or scarred.
  • Such local delivery of the lithium treatment can be achieved by topical administration, transdermal, intradermal, subcutaneous (depot effect), or by intramuscular, intravenous and oral routes of delivery in formulations for systemically delivering lithiums, or targeting delivered lithium to desired follicles. Such modes of delivery are discussed supra.
  • treatment of a cutaneous microbial infection or treatment of a cutaneous microbial colonization, or enhancement of wound healing or scar revision in wounded or otherwise integumentally perturbed skin is accomplished by a lithium treatment described herein in combination with a "scaffold," a pre-designed biomaterial dressing that may serve as a substrate to encourage a step-wise attachment of keratinocytes and epithelial cells to it, such that formation of an organized extra-cellular matrix (ECM) is enhanced in order to promote wound healing.
  • a lithium treatment described herein in combination with a "scaffold" a pre-designed biomaterial dressing that may serve as a substrate to encourage a step-wise attachment of keratinocytes and epithelial cells to it, such that formation of an organized extra-cellular matrix (ECM) is enhanced in order to promote wound healing.
  • ECM extra-cellular matrix
  • enhancement of wound healing or scar revision in wounded or otherwise integumentally perturbed skin is accomplished by a lithium treatment described herein in combination with a "scaffold," a pre-designed biomaterial dressing that may serve as a substrate to encourage a step-wise attachment of keratinocytes and epithelial cells to it, such that formation of an organized extra-cellular matrix (ECM) is enhanced in order to promote wound healing.
  • a lithium treatment described herein in combination with a "scaffold”
  • a pre-designed biomaterial dressing that may serve as a substrate to encourage a step-wise attachment of keratinocytes and epithelial cells to it, such that formation of an organized extra-cellular matrix (ECM) is enhanced in order to promote wound healing.
  • ECM extra-cellular matrix
  • the scaffold for use in combination with lithium treatment may be comprised of a mesh of a biocompatible, bioabsorbable material that cells recognize and attach to, preferably with ease.
  • these materials can be collagen type I/III, hyaluronic acid, chitosan, alginates, or combinations and derivatives thereof or any other such material described herein or known in the art.
  • the mesh scaffold may be neutral, or charged. If the mesh is positively charged, it may permit cells (which are negatively charged) to adhere to it more effectively. If the mesh scaffold is negatively charged, it may contain signaling moieties that the cells will recognize and attach to. For example, polymers such as hyaluronic acid are present already in skin, and thus a mesh comprised of this material is thought to be compatible with cells.
  • the scaffold is pre-fabricated with a fine microstructure that is of the dimension of cells, for example, red blood cells that will initially diffuse throughout the scaffold, or epithelial cells and keratinocytes from surrounding tissue.
  • epitophelial tongue can move with greater ease and organization by crawling on the scaffold mesh.
  • the mesh scaffold has an "open-cell” structure, with the pores inter-connected, much like an open-celled foam.
  • the open, interconnecting nature of the scaffold may allow free diffusion of oxygen and cells, so that optimal organized wound healing can occur.
  • the mesh scaffold has the capacity to hydrate and remain hydrated throughout the wound healing period. This is useful because, without being bound by any theory, drying out of the wound results in a impermeable granular structure that the keratinocytes cannot "crawl upon.”
  • the mesh scaffold has moieties that act as molecular signals to the cells, for example, to aid their proliferation.
  • moieties include, but are not limited to, peptidoglycans and RGD integrin recognition sequences that encourage cell attachment and subsequent proliferation.
  • the mesh scaffold has incorporated within it one or more active agents, for example, a small molecule, or a nucleic acid, or a protein.
  • the additional active agent is a protein, such as noggin or WNT, or is a nucleic acid that encodes noggin or WNT.
  • a small molecule is incorporated into the scaffold, such as, e.g. , a GSK inhibitor, BMP inhibitor, or PPAR antagonist.
  • the compound incorporated in the mesh scaffold is a compound considered for use in the combination therapies described herein, for example, in Section 5.5.
  • the scaffold may incorporate superoxide dismutase, a free radical quenching molecule that functions in the reduction of inflammation.
  • compounds are included in the mesh scaffold that alter the kinetics of wound healing, for example, that slow wound healing. Such compounds are known in the art and described elsewhere herein.
  • Other compounds that may be incorporated in the mesh scaffold include growth factors that aid in cell proliferation and tissue regeneration. In some embodiments, the compounds aid in hair follicle migration or hair follicle neogenesis in the wound site.
  • the lithium compound itself is incorporated within the mesh scaffold.
  • the lithium compound is incorporated within one or more layers of a multilayered mesh scaffold.
  • the mesh scaffold contains the lithium compound in alternating layers, which may achieve a pulsatile delivery of lithium.
  • the lithium compound in incorporated in microspheres in the scaffold, enabling a controlled release of lithium from the scaffold.
  • the mesh scaffold can be fibrin gels that additionally contain lithium.
  • a fibrin network is the first scaffold that a cell encounters as it performs its role in healing wounds due to trauma (such as, e.g. , acute cutaneous trauma) or other insults to tissue.
  • the fibrin network (the "scab") assemble rapidly by a modified polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade— the result is a three-dimensional network of branching fibers, What is envisioned is a fibrin delivery matrix containing lithium, fibrinogen and thrombin, that "gels" in-situ.
  • scab Unlike the extracellular matrices and basement membranes that are formed by collagen, laminin and proteoglycans, which assemble slowly in an ordered manner, the fibrin network (the "scab”) assemble rapidly by a modified polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade— the result is a three-dimensional network of branching fibers, What is envisioned is a fibrin delivery matrix containing lithium, fibrinogen and thrombin, that "gels"
  • the mesh scaffold is a synthetic biodegradable dressing and lithium delivery system that also acts as a "sponge" and absorbs the exudates/bloods from a wound.
  • These exudates intercalating with the synthetic scaffold contain an abundance of fibrinogen, thrombin, fibronectin, cell adhesion proteins, growth factors and hyaluronic acid, all of which create an integrated structure that is an attractive matrix for cell attachment /differentiation and delivery of lithium.
  • the release rate of lithium can be modulated by varying the composition of polymers that comprise the synthetic scaffold, or sponge.
  • a synthetic scaffold fabricated out of poly(lactide)-co-(glycolide) (PLG) and poly(lactide) (PLA) can be developed to have varied release profiles of lithium. Changing the ratio of PLA to PLG will change the release profile of the lithium from the scaffold.
  • Other polymers that can utilized to generate synthetic scaffolds are chitosan, carrageenan, alginate, poly( vinyl alcohol), poly(ethylene oxide) (PEO), poly(ethylene oxide)-co-poly(propylene oxide)-co-poly(ethylene oxide) (PEO-PPO-PEO), poly(acrylates) and poly( vinyl pyrrolidone) (PVP).
  • the rate of lithium release from the formulation can be controlled, so that it takes anywhere from 2 hours to 30 days for most (e.g., 80% or more, 85% or more, 90%> or more, 95% or more, 98%> or more, or 100%) of the lithium ion to be released.
  • most of the lithium is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • the mesh scaffold releases the aforementioned compounds in a timed release manner, acting as a controlled release formulation such as described in Section 5.2 above.
  • the compounds may be bound to the mesh scaffold, and are then released at a sustained release manner as a result of de-binding kinetics from the mesh.
  • the compound may be bound to a polymer, which is then incorporated to the mesh scaffold, and which may allow the compound to diffuse from the mesh at a slow rate, resulting in sustained release.
  • the mesh scaffold is extruded as a gel, with certain components of the gel precipitating out to form a mesh in situ.
  • the in situ mesh can be sprayed on the wounded or otherwise perturbed surface, such as tissue that has been extensively burned. A large area can be covered in this manner.
  • the mesh scaffold is pre-fabricated as a dressing or a wrap, to cover large areas of wounded tissue.
  • the mesh scaffold can be cut to size to fit the size of the wound to present a compatible surface for favorable movement of the epithelial tongue.
  • the scaffold is prepared by melt spinning, electrospinning, micromachining, weaving, or other methods known in the art in which open cell foams are fabricated.
  • the mesh scaffold can be fabricated by these methods, with the optional incorporation of additional compound(s) (which are optionally sterilized), then sterilized by gentle ethylene oxide sterilization.
  • the additional compounds are sterilized, and then added to the sterile mesh scaffold.
  • a combinatorial strategy that uses a biodegradable scaffold combined with administration of a lithium formulation described herein (alone or in combination with another treatment, such as described in Section 5.5) is applied, which may result in the in situ generation of embryonic stem cells or recruitment of cells required for wound healing following wounding.
  • This approach may be used together with a form of integumental perturbation described in Section 5.5 ⁇ e.g., dermabrasion accomplished by a standard dermabrader or a laser, deep full-thickness excision (as for deep burns)
  • integumental perturbation accomplished by a bulk ablative laser) or integumental perturbation by acute wounds, chronic wounds, or wounds generated for the purpose of scar revision. While not being bound by any theory of how the invention works, such integumental perturbation in combination with a scaffold that administers drug results in the in situ generation of stem cells or recruitment of other cells required for the wound healing process and may facilitate more effective wound healing with little or no scarring.
  • the scaffold is biodegradable. Placement of a 3-dimensional biodegradable scaffold in the wound assists the attachment, growth and differentiation of cells.
  • tissue repair has been by autologous cell/tissue transplantation— however, autografts are associated with donor site morbidity and limited availability.
  • An alternative is allografts, but these are susceptible to immune responses and also carry the risk of disease transfer.
  • tissue engineering has emerged as an interdisciplinary field that makes use of biomaterials, cells and factors either alone, or in combination to restore tissues. The tissue engineering strategy generally involves isolation of healthy cells from a patient, followed by their expansion in vitro.
  • a fibrin network is the natural network that forms rapidly due to a polycondensation reaction from fibrinogen, an abundant constituent of blood plasma, as soon as the protease thrombin is activated in the clotting cascade.
  • the fibrin clot then forms a three-dimensional network for cells to attach, for re-epithelialization.
  • the biodegradability of the scaffold is modulated.
  • the biodegradability of the scaffold should be matched to the formation of the new epithelium due to wound healing.
  • One skilled in the art would know how to measure whether a synthetic matrix is biodegradable.
  • biodegradability can be measured ex vivo in implants or using rats or another animal model, by histological and HPLC analysis.
  • biodegradability by hydrolysis can be assessed.
  • the scaffold structure of choice is incubated in phosphate buffered saline, pH 7.4 and 37 °C.
  • the incubation buffer includes enzymes.
  • the scaffolds are weighed prior to incubation.
  • the scaffolds are retrieved two-at-a-time at predetermined time points and dried in a vacuum oven.
  • the scaffolds are weighed at each time point and a plot of weight versus time is generated to develop the rate of biodegradability.
  • the biodegradability of the scaffold matrix is modulated to coincide with the healing process, and can be modulated by changing the composition of polymers utilized to fabricate the mesh.
  • a percentage of polyethylene glycol (PEG) can be included in a composition with PLG to increase biodegradation (for example, see ASTM El 279 - 89, 2008, Standard Test Method for Biodegradation By a Shake-Flask Die-Away Method).
  • PEG polyethylene glycol
  • Biodegradable synthetic matrices can be created to mimic the extra-cellular micro- environment for the enhanced cellular attachment necessary for tissue regeneration.
  • cell-recognition motifs such as RGD peptides may be incorporated to encourage cells to attach themselves to the scaffold.
  • biodegradable synthetic matrix has biomimetic properties.
  • biomimetic properties for example, in one embodiment, the
  • biomimetic nature of the scaffold is judged on the basis of the content of the mesh and resultant intercalating fibrin.
  • the properties of the synthetic scaffold are dependent upon the three-dimensional geometry, matching of the modulus of the matrix with the tissue type and the porosity. It has been shown that the differentiation process can be modulated if the modulus of the tissue type is matched with the modulus of the scaffold.
  • the modulus of the scaffold is matched with the modulus of the tissue type.
  • the compressive modulus of a scaffold or hydrogel can be measured by a standard Instron instrument (e.g., using the TA Instruments DMA Q800).
  • micro-environment created by the cells is optimally highly
  • biocompatible to the cells present at the site namely keratinocytes and stem cells derived from the dermal papilla.
  • this can be accomplished through the use of hydrophilic components that can absorb water.
  • hydrophobic components such as petrolatum is likely to be occlusive and prevent rapid cell proliferation.
  • the scaffold is incubated with human foreskin fibroblasts (HFF) in vitro and the scaffold is considered to be biocompatible if the cells maintain their shape and attach appropriately.
  • HFF human foreskin fibroblasts
  • the biodegradable scaffold is permeable to water, nutrients, oxygen and growth factors, enabling easy exchange of nutrients between tissues and cells (see, e.g., ASTM D39857). In some embodiments, a non-occlusive, non-permeable barrier is avoided.
  • the scaffold is used to "fill" a deep wound, as is common in a deep burn, to provide a matrix for the cells to attach, grow and differentiate - existence of the scaffold will likely minimize the scar formation normally observed in deep, large-area wounds.
  • a loose, dry, highly porous network or scaffold or mesh is placed in the bleeding site of the wound to gently absorb the blood and the cell adhesion proteins released at the site, as a result of wounding.
  • This will result in creation of a highly rich environment that consists of a combination of a 3 -dimensional scaffold combined with fibrinogen and thrombin, which will ultimately result in a highly biocompatible hydrogel suitable for cell attachment and growth.
  • inclusion of blood components and cell adhesion proteins into the network is critical for establishment of the ECM
  • extracellular matrix necessary to form continuous tissue in-growth, particularly in the case of large-area and deep wounds.
  • a dry scaffold has the added advantage of absorbing the blood at the wound site.
  • a person's own blood components can be used to create a combined synthetic/natural ECM.
  • the scaffold has an added advantage of serving as a blood absorbing gauze.
  • the scaffold has cell-recognition motifs, such as RGD peptides, to recruit cells to the site and attachment, thereof. Once attached, cells will proliferate. Without being bound by any theory, it is hypothesized that the primary attachment of cells to the scaffold is a critical step to prevent premature cell death.
  • a dry, sterile biodegradable scaffold is placed onto the freshly formed wound.
  • the properties of the scaffold will be such that it will transform into an adherent hydrogel upon water absorption.
  • Methods that may be employed to fabricate the scaffold are known in the art, and include electrospinning, micromachining, and others. Nano-fiber meshes fabricated by electrospinning, hydrogel imprint technologies have been utilized to create three-dimensional microstructures that match the supramolecular architecture of the tissue type. In situ forming scaffolds are also contemplated.
  • the active agents are administered using an active agent-containing spray-on hydrogel.
  • the active agent after placement of the biodegradable scaffold, the active agent is sprayed on the tissue.
  • the active agent (or combination of active agents, e.g., lithium and another stem cell signaling agent) may be incorporated into a spray-on hydrogel that will be sprayed on as a liquid, but which transforms into a hydrogel after it is sprayed on the tissue. This will be especially useful if the area of the wound is large and uniform coverage is needed.
  • the active agent-containing spray-on hydrogel is applied on the wound site, forming a cross-linked hydrogel that releases active agent over the time period of healing or a shorter or longer time period, as necessary.
  • the active agent will either be incorporated in microencapsulates or nano-encapsulates and suspended into the pre-hydrogel solution.
  • the active agent can also be dissolved into the pre-hydrogel solution.
  • the "pre-hydrogel” solution is defined as the solution that will be sprayed on the tissue and which also contains the active agent.
  • the active agent is contained within microspheres that can be positively charged to rapidly bind themselves to the negatively charged collagen present in the dermis. Binding the microspheres to the dermis renders the active agent-releasing moiety immobile at the site.
  • the wound may be covered with a breathable, non-occlusive spray-on hydrogel to cover the wound from infection during healing.
  • the intermittent lithium treatments or a pulse lithium treatment can be provided by administration of the lithium compound (or combination treatments, discussed in Section 5.5 infra) in forms suitable for topical ⁇ e.g., applied directly to the skin, transdermal, or intradermal), subcutaneous, intramuscular, intravenous or by other parenteral means, oral administration, sublingual administration, or bucchal administration.
  • topical ⁇ e.g. , applied directly to the skin, transdermal, or intradermal) administration is accomplished with the use of a mechanical device, such as, e.g., an iontophoretic device.
  • the lithium compounds can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art ⁇ see, Rathbone et ah, eds., 2008, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed., New York, NY: Marcel Dekker, Inc.).
  • a lithium treatment can be administered by a health care practitioner or by the subject. In some embodiments, the subject administers the lithium treatment to him or herself.
  • lithium can be applied topically, e.g., as a cream, gel, ointment, or other form for topical administration as described in Section 5.2 supra.
  • Topical lithium may be administered to wounded or unwounded skin.
  • compositions formulated for topical administration comprising a source of lithium ions formulated into aqueous formulations (e.g., hydrogels), ointments, or creams (e.g., emulsions) for topical administration.
  • a source of lithium ions formulated into aqueous formulations (e.g., hydrogels), ointments, or creams (e.g., emulsions) for topical administration.
  • the formulation of the pharmaceutical composition for topical administration is varied in order to control the rate of lithium release. This may be accomplished by, for example, varying the molecular fluidity of the carrier, without changing its hydrophobicity, such as by varying the petrolatum to mineral oil ratio. In one
  • the pharmaceutical formulation is an ointment, comprising a source of lithium ions, petrolatum, mineral oil, and lanolin alcohol.
  • exemplary formulations prepared in accordance with such embodiments are provided in Example 7 below.
  • Li+ release can be modulated by varying the
  • hydrophobic/ hydrophilic ratio of the formulation for example, by preparing a
  • Sources of lithium ions for use in the foregoing pharmaceutical compositions include, but are not limited to, lithium carbonate, lithium citrate, lithium gluconate, lithium chloride, lithium succinate, or lithium hydroxide.
  • the source of lithium ions is lithium carbonate.
  • the source of lithium ions is lithium citrate.
  • the source of lithium ions is lithium hydroxide.
  • the topical formulation comprises 2.74 mg Li+/gram.
  • a salt form of lithium such as but not limited to lithium carbonate, lithium citrate, lithium chloride, and lithium succinate, is formulated into an aqueous formulation for topical administration.
  • the aqueous formulation is an aqueous hydrogel, comprising a source of lithium ions, Carbopol 980, methyl paraben, propyl paraben, propylene glycol, glycerine, and water. Exemplary formulations prepared in accordance with such embodiments are provided in Example 9 below.
  • an aqueous lithium formulation is generated using lithium hydroxide.
  • Lithium hydroxide is listed as an inactive ingredient in the FDA database, and is available in pharmaceutical grade form as lithium hydroxide, monohydrate. Formulations containing lithium hydroxide may be desirable because they lack a counterion to Li+. For example, formulations containing lithium gluconate are expected to have equimolar concentrations of ionized, cationic Li+ and its counterion, the gluconate anion, whereas when lithium hydroxide is dissolved, it ionizes into the hydroxyl anion and Li+.
  • a hydrogel formulation comprises lithium hydroxide monohydrate, citric acid, CMC, methyl paraben, propyl paraben, allantoin, alginate, and water.
  • an emulsion formulation comprises lithium hydroxide monohydrate.
  • Lithium hydroxide hydrogels containing different amounts of Li+ may be generated in accordance with the following table, as described in more detail in Example 13 below.
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, allantoin, alginate, glycerol, citric acid, distilled water and lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 1% to 15% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%) carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 1 1.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 2.90% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water and 1.46% lithium carbonate.
  • Concentrations of citric acid may be varied from 5%-10% w/w. Concentrations of lithium carbonate can be varied from 1%-15%. Concentrations of glycerol may be varied from 1%- 10%). Boric acid may be used instead of citric acid, in concentrations 5-10% w/w.
  • Hydrochloric acid may be used in conjunction with citric acid or boric acid, for the purpose of adjusting pH to a physiologically acceptable formulation for wounds.
  • Hyaluronic acid at concentrations 0.1-2% may be used instead of carboxymethylcellulose (CMC).
  • CMC carboxymethylcellulose
  • Other polymers to be used instead of CMC may be hydroxyethyl cellulose (0.1-2%),
  • hydroxypropylmethyl cellulose 0.1%), Xanthan Gum (0.1-1%), Guar Gum (0.1-1%).
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, allantoin, alginate, glycerol, citric acid, distilled water, mupirocin and lithium carbonate.
  • the pharmaceutical compisitoin is formulated as a hydrogel comprising 0.5% to 3% mupirocin.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin, and 1 1.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin, and 1 1.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, 0.1% allantoin, 0.1% alginate,
  • composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1 % alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin and 5.66% lithium carbonate.
  • a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1 % alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin and 5.66% lithium carbonate.
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 0.5% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 0.5% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid,
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid,
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • topical administration is to the skin, either to the skin surface, transdermally, or intradermally. Topical administration can be with or without occlusion with a bandage or other type of dressing. In some embodiments, topical administration is to orifices or mucosa, or conjunctival, intracorneal, intraocular, ophthalmic, auricular, nasal, vaginal, urethral, respiratory, and rectal administration. The formulation used for topical administration can be designed to retain the lithium in the skin or to deliver a dose of lithium systematically. In some embodiments, topical administration of a lithium compound is combined with another treatment described herein, such as, but not limited to, a technique of integumental perturbation or an antimicrobial agent.
  • Dosage forms that are suitable for topical administration for preferably local but also possible systemic effect, include emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, powders, crystals, foams, films, aerosols, irrigations, sprays, suppositories, sticks, bars, ointments, sutures, bandages, wound dressings, microdermabrasion or dermabrasion particles, drops, and transdermal or dermal patches.
  • the topical formulations can also comprise micro- and nano-sized capsules, liposomes, micelles, microspheres, microparticles, nanosystems, e.g., nanoparticles, nano-coacervates and mixtures thereof. See, e.g.,
  • the nano-sized delivery matrix is fabricated through a well-defined process, such as a process to produce lithium encapsulated in a polymer.
  • the lithium-releasing compound is spontaneously assembled in aqueous solutions, such as in liposomes and micelles.
  • the formulation for topical administration is a shampoo or other hair product, tanning product or sun protectant, skin lotion, or cosmetic.
  • a selected formulation will penetrate into the skin.
  • the selected formulation will penetrate into the skin and reach the hair follicle.
  • the stratum corneum and/or epidermis have been or are removed by a method of integumental perturbation described herein (including by wounding or scar revision procedure, by laser, or by dermabrasion or microdermabrasion, which is a less vigorous form of dermabrasion), permitting application of the dosage form for topical administration directly into the exposed dermis.
  • the formulation for topical administration will be lipid-based, so that it will penetrate the stratum corneum.
  • the formulation for topical administration will contain a skin penetrant substance, such as, e.g., propylene glycol or transcutol.
  • a skin penetrant substance such as, e.g., propylene glycol or transcutol. See, e.g., International Patent Application Publication No. WO 2004/103353, published December 2, 2004, which is incorporated herein by reference in its entirety.
  • the ability to penetrate into the skin can be tested using any method known in the art, such as, e.g. , the method described in International Patent Application Publication No. WO 2005/107710, which is incorporated herein by reference in its entirety.
  • a formulation in ointment form comprises one or more of the following ingredients: wool alcohol (acetylated lanolin alcohol), hard paraffin, white soft paraffin, liquid paraffin, and water.
  • the selected formulation is inconspicuous when applied to the skin, for example, is colorless, odorless, quickly-absorbing, etc.
  • the selected formulation is applied on the skin surface as a solution, which can crosslink into a hydrogel within a few minutes, thus creating a biocompatible dressing.
  • the hydrogel may be biodegradable.
  • the solution will absorb into the skin and crosslink into depots releasing drug.
  • the lithium ion will be used to crosslink the polymer, with release of the lithium ion controlled by the rate of degradation of the hydrogel.
  • compositions suitable for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles, anti-microbial agents or preservatives against the growth of
  • Forms for topical administration can also be in the form of ointments, creams, and gels.
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, mineral oil and other oils, white petrolatum, paraffins; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, wool alcohol (acetylated lanolin alcohol), and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives.
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single -phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • lithium can be used for topical administration in the methods described herein.
  • these include, e.g., lithium carbonate, lithium gluconate, e.g., 8% lithium gluconate (LithiodermTM), approved for the treatment of seborrheic dermatitis (see, e.g., Dreno and Moyse, 2002, Eur J Dermatol 12:549- 552; Dreno et al, 2007, Ann Dermatol Venereol 134:347-351 (abstract); and Ballanger et al., 2008, Arch Dermatol Res 300:215-223, each of which is incorporated by reference herein in its entirety); 8% lithium succinate (see, e.g., Langtry et al, 1996, Clinical and Experimental Dermatology 22:216-219; and Cuelenaere et al., 1992, Dermatology 184: 194-197, each of which is incorporated by reference
  • Each of these methods of topical administration may be used alone to administer lithium compounds or in combination with one or more other treatments as described in Section 5.5 infra.
  • topical administration is by electrical current, ultrasound, laser light, or mechanical disruption or integumental perturbation. These include
  • electroporation electroporation, RF ablation, laserporation, laser ablation (fractional or non-fractional), non- ablative use of a laser, iontophoresis, phonophoresis, sonophoresis, ultrasound poration, or using a device that accomplishes skin abrasion, or microneedle or needle-free injection, such as topical spray or POWDERJECTTM (Chiron Corp., Emeryville, CA), BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR), or JetPeelTM (from TavTech, Tel Aviv, Israel), which uses supersonically accelerated saline to remove epidermis.
  • POWDERJECTTM Chiron Corp., Emeryville, CA
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • JetPeelTM from TavTech, Tel Aviv, Israel
  • the device for topical administration of lithium compounds is an automatic injection device worn continuously but delivers lithium intermittently.
  • the device for topical administration of lithium compounds is an automatic injection device that is inconspicuous, for example, can be worn without undue discomfort under clothes, in the hair, under a hairpiece, etc.
  • a device for administration of the intermittent lithium treatment or a pulse lithium treatment delivers the lithium at a controlled depth in the skin, but entry into the circulation is minimized.
  • a device for administration of the intermittent lithium treatment or a pulse lithium treatment delivers the lithium at a controlled depth in the skin so that it reaches hair follicles, but entry into the circulation is minimized.
  • the stratum corneum and epidermis is previously removed using a method of integumental perturbation (or by integumental perturbation as a result of wounding) described herein, and thus the required delivery pressures and velocities can be reduced. This reduction reduces the required complexity of the firing mechanisms.
  • a narrow firing stream is used, particularly to accomplish systemic delivery.
  • the particle injection system administers the lithium compound over a broad area of skin.
  • An exemplary particle delivery device compatible with broad-based skin delivery includes a low pressure / low velocity firing mechanism with a spray nozzle designed to deliver to a broad area.
  • a single- shot device that delivers to a 25 -cm 2 area could be fired or used multiple times on the scalp or other skin surface until the entire area is treated.
  • a dry particle spraying mechanism similar to an airbrush or miniature grit-blaster can be used to "paint" drug or drug particles onto the infected perturbed, wounded, or scarred area.
  • the stratum corneum and epidermis are already removed, e.g., by a method of integumental perturbation ⁇ e.g., wounding) described herein, and thus permits effective use of the mechanism using lowered pressure and velocity requirements to achieve dermal delivery.
  • the lithium compound (and/or additional drug) is present in an aqueous suspension, permitting use of standard aerosol spray can technology to deliver the lithium compound to the desired skin area.
  • dermabrasion ⁇ e.g., using a mechanical device, including microdermabrasion devices that can be used to dermabrade, or alumina-, silica- or ice-based dermabrasion (as described by Webber, U.S. 6,764,493; U.S. 6,726,693; and U.S. 6,306,119) is customized to include a drug particle delivery feature using methods readily known in the art.
  • the device fires ablation particles at the skin, it could also fire smaller drug particles that would simultaneously embed in the exposed dermis.
  • the device could switch over to firing drug particles once it is determined that adequate skin disruption has occurred. See, International Patent Application Publication No. WO 2009/061349, which is incorporated herein by reference in its entirety.
  • a standard dermabrasion device can be modified to incorporate any of the devices described above, e.g., a spraying/painting device.
  • a spray nozzle is located behind the dermabrasion wheel such that drug is sprayed into the dermis as it is exposed by the wheel.
  • the dermabrasion device via internal controls, could turn off the abrasion wheel once it is determined that adequate skin disruption has occurred, and switch on the drug spray to convert to drug painting mode.
  • a pulsed dye laser (585-595 nm) is combined with drug spraying either before or without skin perturbation, in conjunction with skin perturbation, or following skin perturbation.
  • a non-fractional C0 2 or Erbium- Y AG laser is combined with drug spraying either without or before skin disruption, in conjunction with skin disruption, or following skin disruption.
  • the lithium compound (and/or additional drug) can be administered using a two-chamber sprayer device, wherein the lithium compound (and/or additional drug) is dispersed, solubilized, or emulsified in a liquid contained in one of the chambers.
  • the other chamber of the device would contain a liquid that is capable of reacting with the drug-containing liquid in the first chamber, to form a physically crosslinked hydrogel or a covalently linked hydrogel.
  • the liquids can react and form a drug-containing bioadhesive hydrogel to deliver the lithium compound (and/or additional drug) to the desired area.
  • the drug-containing hydrogel will have additional features of supporting cell attachment and proliferation.
  • the lithium compound (and/or additional drug) will be sprayed as a dry powder that is adherent to the underlying tissue.
  • a fractional non-ablative laser ⁇ e.g. , an Erbium- Y AG laser used at 1540-1550 nm
  • drug spraying either before or without skin perturbation, in conjunction with skin perturbation, or following skin perturbation.
  • a fractional ablative laser ⁇ e.g. , an Erbium- Y AG laser used at 2940 nm or a C0 2 laser used at 10,600 nm
  • drug spraying either before or without skin perturbation, in conjunction with skin perturbation, or following skin perturbation.
  • fractional ablative laser treatment of the skin e.g., an Erbium- Y AG laser used at 2940 nm or a C0 2 laser used at 10,600 nm
  • lithium compound delivery e.g., lithium compound delivery.
  • fractional laser could be combined with a precise delivery means such that as the laser forms a hole in the skin, the inkjet-like delivery component could fill that same hole with drug.
  • fractional ablative laser treatment of the skin e.g., an Erbium- Y AG laser used at 2940 nm or a C0 2 laser used at 10,600 nm
  • lithium compound delivery e.g., an Erbium- Y AG laser used at 2940 nm or a C0 2 laser used at 10,600 nm
  • topical administration comprises administration of lithium- containing particles.
  • the particles can be delivered to the skin in combination with any of the means above and described elsewhere infra. Additionally, the particles can be designed for intermittent or pulse delivery of lithium. In one embodiment, particles with different release properties are be delivered simultaneously to achieve pulse delivery.
  • topical administration comprises administration of a lithium-containing formulation that is delivered through channels that are created by the use of needling or micro-needle technology.
  • the formulation can be, e.g., a liquid, a gel or a dry spray.
  • topical administration may be through delivery of a lithium- containing formulation through hollow needles.
  • topical administration comprises administration of a lithium-containing formulation that is delivered into the skin by an iontophoretic patch.
  • a patch can be developed in which the lithium-containing formulation is incorporated.
  • the lithium compound (and/or additional drug) will be sprayed as a dry powder that is adherent to the underlying tissue.
  • topical administration comprises administration of a lithium-containing formulation that is incorporated into micro-needle shaped biodegradable polymers.
  • the biodegradable microneedles penetrate the targeted skin tissue, and are optionally left in place to deliver the lithium ions in a sustained fashion over time.
  • compositions comprising lithium carbonate formulated for topical administration.
  • the lithium carbonate compositions may additionally comprise a pharmaceutically acceptable carrier or excipient, such as described in this section or Section 5.2 supra.
  • the lithium carbonate compositions may also comprise one or more additional ingredients, such as described in Section 5.5.
  • Lithium carbonate compositions provided herein may be formulated as aqueous compositions, emulsions, creams, gels ⁇ e.g., a hydrogel), etc.
  • a lithium carbonate composition described herein is occlusive.
  • the lithium carbonate composition is non-occlusive.
  • the lithium carbonate compositions described herein may be administered via any topical means of delivery known in the art.
  • the lithium carbonate composition is administered as part of an article of manufacture, such as a bandage or other wound dressing, such as described in Section 5.2 supra.
  • the lithium carbonate composition is administered using a drug delivery system, such as described in Section 5.11 infra.
  • a topical formulation of lithium comprises 0.10%-0.25%, 0.25%-0.75%, 0.75%-1.5%, 1.5%-3%, 3%-4.5%, or 4.5-6% or more (w/w) lithium carbonate.
  • Lithium carbonate is a well characterized active pharmaceutical ingredient (API), with numerous cost effective cGMP sources. Lithium carbonate is approved in the United States as an oral medication for the treatment of bipolar disorder and has an extensively characterized safety profile in humans. Systemic lithium exposure from the topical use of lithium carbonate is anticipated to be significantly lower than the levels from oral dosing.
  • API active pharmaceutical ingredient
  • Lithium carbonate is highly stable as bulk substance, lacking known degradation products as determined by forced degradation studies under stressed conditions of heat, humidity, acid/base and oxidation. Lithium carbonate products are inert to near and far UV irradiation and lack a photo-reactive chromophore. Thus, in certain embodiments, a lithium carbonate composition described herein will not need to be refrigerated and, optionally, will have a shelf-life of 24 months or longer.
  • the stability of a lithium carbonate composition described herein may be determined using methods known in the art, as summarized, for example, in the following table. Storage Conditions 4°C and 25°C/60%RH 40°C/75%R] H
  • Some challenges to generating lithium formulations using lithium carbonate as the salt form may be that the manufacturing process generates carbon dioxide gas, and dissolved carbonic acid from the carbonate moiety may impair stability of the formulation.
  • these formulation challenges have been overcome, permitting the successful generation of various compositions for topical administration, including hydrogels and creams (such as emulsions), using lithium carbonate, as described in this section and the examples of Section 6.
  • the lithium carbonate composition formulated for topical administration is in the form of a hydrogel.
  • the lithium carbonate hydrogel contains from 0.18% lithium carbonate (which contains 0.34 mg Li+/g gel) to 5.66% lithium carbonate (10.64 mg Li+/g gel).
  • the invention is not to be so limited, and other variations with higher percentages of lithium carbonate can be prepared.
  • a lithium carbonate hydrogel has the following composition (referred to herein as "lithium carbonate hydrogel Formulation A"): lithium carbonate at a chosen strength (0.18%>-5.66 % w/w; or 0.34 mg Li+/g -10.64 mg Li+/g ), glycerol (10.4%), carboxymethyl cellulose (2% w/w), allantoin (0.16%), sodium alginate (0.12%)), methyl paraben (0.1%>), propyl paraben (0.048%>), water (Q.S.), and sodium hydroxide (pH adjusted to 6.5-7.5).
  • lithium carbonate hydrogel Formulation A contains 0.18% w/w lithium carbonate (0.34 mg Li+/g gel). In another embodiment, lithium carbonate hydrogel Formulation A contains 1.46% w/w lithium carbonate (2.74 mg Li+/g gel). In another embodiment, lithium carbonate hydrogel
  • Formulation A contains 2.91% w/w lithium carbonate (5.48 mg Li+/g gel). In another embodiment, lithium carbonate hydrogel Formulation A contains 5.66% w/w lithium carbonate (10.64 mg Li+/g gel). Methods for formulating lithium carbonate hydrogel Formulation A at different Li+ strengths are described in detail in Example 10 below. These methods may be adapted to generate other lithium carbonate hydrogel formulations using methods known in the art and described herein. [00313] In certain embodiments, a lithium carbonate hydrogel contains approximately 75%, 80%, 85%o, 90%o, or 95% water. In a particular embodiment, the lithium carbonate hydrogel contains 90% water.
  • the lithium carbonate hydrogel has one or more or all of the following characteristics: is transparent, odorless, colorless, has a viscosity (at 25 °C) of, e.g., 2,000-10,000 cP, 2,000-8,000 cP, or 6,000-10,000 cP (measured using, for example, a rheometer), has assay and dose uniformity (which can be measured by, e.g., flame photometry or atomic adsorption spectrometry (AAS)), has an emollient "smooth-feel" texture, could be easily applied to skin, readily spreads over a surface, has minimal migration to surrounding sites, has minimal run off, has a neutral pH (e.g., pH 6.5-7.5), is sterile, is stable for an extended period (e.g.
  • the hydrogel is stable at room temperature for up to 4 weeks or more. In one embodiment, the hydrogel is stable at room temperature for up to 8 weeks or more. In one embodiment, the hydrogel is stable at 4 °C for up to 6 months or more. In one embodiment, the hydrogel is stable at 4 °C for up to 1 year or more.
  • a lithium carbonate hydrogel is prepared with the excipients and an amount of active ingredient chosen to contribute to one or more of the foregoing or following attributes, which may be desirable for a topical formulation for use in the methods described herein: viscosity (e.g., imparted by
  • carboxymethyl cellulose carboxymethyl cellulose
  • surface wetting ability and prevention of "dry-out” e.g., imparted by glycerol
  • preservative effectiveness e.g., imparted by parabens, such as methyl or propyl parabens, although in certain embodiments, a paraben-free formulation may also be generated
  • maintenance of pH e.g., imparted by altering the strength of surfactants used in the hydrogel
  • pharmacokinetic properties such as rate of Li+ release from the formulation, and peak and trough concentrations in skin and blood.
  • excipients that are wound compatible, contribute to sterility, wound healing, and/or aid in cell attachment and/or proliferation may be included, such as, e.g., allantoin or sodium alginate.
  • the lithium carbonate hydrogel is formulated so that it releases Li+ at varying rates.
  • Release rate of Li+ may be modified by one or more of the following: incorporating the formulation into different scaffolds, such as described in Section 5.2 supra, modifying the concentration of lithium carbonate in the formulation, or modifying the types and concentrations of excipients.
  • most or all of the Li+ is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 10 hours, within 12 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • the formulation is an "immediate release” formulation, i.e., releases 90-100% of Li+ within the first day of administration. In another embodiment, the formulation is an "Intermediate Release” formulation, i.e., releases 90-100% of Li+ within 1 to 3 days of administration. In another embodiment, the formulation is a "Sustained Release"
  • formulation i.e., releases 90-100% of Li+ within 3 to 7 days of administration.
  • the lithium carbonate composition formulated for topical administration is in the form of a cream.
  • the lithium carbonate cream is an oil/water emulsion.
  • the lithium carbonate cream contains from 0.18% lithium carbonate (which contains 0.34 mg Li+/g) to 5.66% lithium carbonate (10.64 mg Li+/g).
  • the cream contains at least 3.38 mg/g Li+, equivalent to 1.80% w/w lithium carbonate.
  • the invention is not to be so limited, and other variations with lower or higher percentages of lithium carbonate can be prepared.
  • a lithium carbonate cream contains approximately 75%, 80%), 85%), 90%), or 95% water.
  • the lithium carbonate cream ⁇ e.g., dispersion, suspension, colloid or emulsion
  • the cream is stable at room temperature for up to 4 weeks or more. In one embodiment, the cream is stable at room temperature for up to 8 weeks or more. In one embodiment, the cream is stable at 4 °C for up to 6 months or more. In one embodiment, the cream is stable at 4 °C for up to 1 year or more.
  • a lithium carbonate cream is prepared with the excipients and an amount of active ingredient chosen to contribute to one or more of the foregoing or following attributes, which may be desirable for a topical formulation for use in the methods described herein: viscosity, surface wetting ability and prevention of "dry-out,” preservative effectiveness, maintenance of pH, stability (e.g., imparted by altering the strength of surfactants used in the cream), and pharmacokinetic properties (such as rate of Li+ release from the formulation, and peak and trough concentrations in skin and blood).
  • attributes which may be desirable for a topical formulation for use in the methods described herein: viscosity, surface wetting ability and prevention of "dry-out,” preservative effectiveness, maintenance of pH, stability (e.g., imparted by altering the strength of surfactants used in the cream), and pharmacokinetic properties (such as rate of Li+ release from the formulation, and peak and trough concentrations in skin and blood).
  • excipients that are wound compatible, contribute to wound healing, and/or aid in cell attachment and/or proliferation may be included, such as, e.g., allantoin or sodium alginate.
  • the rate of Li+ release from the cream may be modified by one or more of the following: incorporating the formulation into different scaffolds, such as described in Section 5.2 supra, modifying the concentration of lithium carbonate in the formulation, or modifying the types and concentrations of excipients.
  • the rate of Li+ release from the cream may be decreased by decreasing the concentration of hydrophilic polymers in the cream.
  • the rate of Li+ release from the cream may be altered by varying the concentration of cetearyl alcohol, lanolin alcohol, or by varying the types of aqueous or non-aqueous carrier(s), and preferably non-aqueous carrier(s) (e.g., silicone, mineral oil, petrolatum, etc.), used.
  • most or all of the Li+ is released from the formulation within 2 hours, within 4 hours, within 8 hours, within 10 hours, within 12 hours, within 16 hours, within 24 hours, within 36 hours, within 48 hours, within 3 days, within 5 days, within 7 days, within 10 days, within 14 days, within 30 days, or within 2 months or more.
  • most or all of the Li+ is released from a lithium carbonate cream described herein within 10 hours.
  • all of the Li+ is released from the cream within 10 hours.
  • most or all of the Li+ is released from a lithium carbonate cream described herein within 24 hours.
  • the formulation is an "immediate release” formulation, i.e., releases 90-100% of Li+ within the first day of administration.
  • the formulation is an "Intermediate Release” formulation, i.e., releases 90-100% of Li+ within 1 to 3 days of administration.
  • the formulation is a "Sustained Release” formulation, i.e., releases 90- 100% of Li+ within 3 to 7 days of administration.
  • the lithium carbonate cream is an immediate release formulation.
  • a formulation may be generated using a two-phase system: (i) an aqueous phase for dissolving lithium carbonate and hydrophilic excipients and (ii) a non-aqueous phase for dissolving hydrophobic polymers.
  • the cream is a water-in-oil emulsion, which acts not only act as a biocompatible skin emollient, but also as a delivery system for Li+.
  • an immediate release lithium carbonate cream is generated as follows, as described in greater detail in Section 6.12.1 infra:
  • This method may be adapted to generate other lithium carbonate cream immediate release formulations using methods known in the art and described herein.
  • the lithium carbonate cream is an intermediate release formulation.
  • the intermediate release cream formulation is an emulsion prepared by homogenization of two phases, as described, e.g., for the immediate release cream formulation above.
  • an intermediate release lithium carbonate cream is generated as follows, as described in greater detail in Section 6.12.2 infra:
  • the lithium carbonate cream is a sustained release formulation.
  • the sustained release cream formulation is prepared by homogenization of two phases (an aqueous phase and a non-aqueous phase), as described, e.g., for the immediate and intermediate release cream formulations above, but by decreasing the concentration of hydrophilic polymers in the non-aqueous phase.
  • a sustained release lithium carbonate cream is generated as follows, as described in greater detail in Section 6.12.3 infra:
  • Emulsifier 10 0.8 8 0.34 0.84
  • lithium carbonate formulations for topical administration may be administered in accordance with any embodiments described herein.
  • a 50 kg patient is administered a single droplet of a lithium carbonate hydrogel described herein - approximately 0.1 ml of 0.10%-0.25%, 0.25%-0.75%, 0.75%-1.5%, 1.5%- 3%, 3%-4.5%, or 4.5-6% (w/w) lithium carbonate - at 3 sites, twice daily.
  • the lithium carbonate hydrogel is administered once daily.
  • the lithium carbonate hydrogel is administered twice daily.
  • doses are administered 6 hours apart, or 7 hours apart, or 8 hours apart, or 9 hours apart, or 10 hours apart, or 11 hours apart, or 12 hours apart.
  • the doses are administered 7 to 8 hours apart.
  • a 50 kg patient is administered a single droplet of a lithium carbonate cream described herein - approximately 0.1 ml of 0.10%-0.25%, 0.25%-0.75%, 0.75%- 1.5%, 1.5%-3%, 3%-4.5%, or 4.5-6% (w/w) lithium carbonate - at 3 sites, twice daily.
  • the lithium carbonate cream is administered once daily.
  • the lithium carbonate cream is administered twice daily.
  • doses are administered 6 hours apart, or 7 hours apart, or 8 hours apart, or 9 hours apart, or 10 hours apart, or 11 hours apart, or 12 hours apart. In a particular embodiment, the doses are administered 7 to 8 hours apart.
  • Administration can be parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • Compositions for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, anti-microbial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, anti-microbial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and
  • compositions for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the compositions are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene -vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene,
  • polypropylene ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl
  • compositions comprising lithium compounds for oral
  • administration can be provided in solid, semisolid, or liquid dosage forms for oral
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Compositions for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • oral formulations approved for treating mood disorders e.g., lithium carbonate (Li 2 C0 3 ), sold under several trade names, lithium citrate (Li 3 C 6 H 5 0 7 ), lithium sulfate (L1 2 SO 4 ), lithium aspartate, or lithium orotate, may be administered in accordance with the methods described herein.
  • lithium carbonate Li 2 C0 3
  • lithium citrate Li 3 C 6 H 5 0 7
  • lithium sulfate Li1 2 SO 4
  • lithium aspartate e.g., lithium aspartate, or lithium orotate
  • the lithium treatments described herein may also be administered to skin-derived cells or skin tissue ex vivo.
  • a lithium treatment may be used to enhance the re- association of dissociated hair follicle cells into follicles and their growth and expansion in culture for their implantation into fresh wounds and scar revisions.
  • hair follicles promoted by lithium treatments are added to the wound before, at the time of, and/or subsequent to, either acute wounding or, more typically, during the wounding that is induced in scar revision.
  • traditional approaches to scar revision such as human skin transplantation, can be efficiently replaced with transplantation of follicular units or other smaller appendage structures from skin.
  • hair follicles can be introduced to the wound by migration or de novo hair follicle neogenesis, or by transplanting one or more of the following skin elements: full skin (xeno-; autologous human), follicular units, dissociated cells (donor dominance; recipient effects), ex vivo-expanded skin and/or follicular units, or human skin equivalents in vivo (universal donors).
  • Engineered human skin, or human skin equivalents can also be used for hair follicle neogenesis and scar revision platforms.
  • Human skin equivalents can be grown and assembled in vitro, with the advantage that they can be grown to theoretically to any size/shape; can be comprised of different types of cells, including keratinocytes (hair follicle derived and non-hair follicle derived), dermal cells (hair follicle derived and non-hair follicle derived), other cell types ⁇ e.g., mesenchymal stem cells); can contain cells that are genetically modified to include, e.g., markers or "inducible" signaling molecules; provide an unlimited and uniform source of human cells; from normal skin based on histology and marker studies; are generally devoid of skin appendages; and can be wounded and show similar wound healing events as in vivo.
  • keratinocytes hair follicle derived and non-hair follicle derived
  • dermal cells hair follicle derived and non-hair follicle derived
  • other cell types ⁇ e.g., mesenchymal stem cells
  • the device or drug sprayer 2 includes a control unit or generator 4, a foot switch 6, a hand piece 8, and a power module 10.
  • the control unit 4 is the interface between the foot switch 6, the hand piece 8, and the power module 10. It serves as the central point of connectivity and provides a user with a means to power the system on or off, load/eject a drug cartridge into/from the hand piece 8, and select the drug delivery speed. To control all of this functionality, the control unit 4 includes at least one circuit board that controls operation of the hand piece 8 via embedded software.
  • the control unit 4 comprises a housing 12 that includes a hand piece connection port 14, a load/eject button 16, a means 18 to control the drug delivery or spray speed, a means 20 to display the drug delivery speed, an on/off switch 22, and a handle 24.
  • the means 18 to control the drug delivery speed includes a pair of up/down buttons and the means 20 to display the drug delivery speed comprises 8 discreet LEDs (light-emitting diodes) that light up to indicate the drug delivery speed.
  • Examples of materials that can be used for the load/eject button 16, the up/down buttons 18, and the on/off switch 22 include, but are not limited to, elastomeric materials such as silicon rubber, plastics, and metals.
  • the housing 12 can be made from an injection molded thermoplastic material such as, for example, acrylonitrile butadiene styrene.
  • FIGS 39A and 39B depict an embodiment of the drug sprayer's hand piece 8.
  • the hand piece 8 comprises a housing 26, a drive motor 28, a universal joint 30 and at least one plunger 32. Attached to the end of the hand piece 8 is a drug cartridge 34 that can either be disposable or reusable.
  • the hand piece's housing 26 can be made from an injection molded thermoplastic material such as, for example, acrylonitrile butadiene styrene. It will be readily apparent to those skilled in the art that other materials may be used to construct the hand piece's housing 26.
  • Figures 40 and 41 depict embodiments of a drug cartridge having two separate chambers that keep the drug components isolated until the therapeutic compound is to be dispensed.
  • Figures 40A-40D depict a drug cartridge 40 that contains two liquid components and its associated hand piece 42.
  • the drug cartridge 40 includes a housing 44 having a front end 46, a back end 48, a nozzle 50, a static mixer 52 having a mixing chamber 54 and two piercing elements 56 that extend from the back end 48 thereof and which are in fluid communication with the mixing chamber 54, two liquid component chambers 58, 60, a first liquid component 62 stored in the first component chamber 58, a second liquid component 64 stored in the second component chamber 60, and a piston 66 inserted into the back end 48 of each component chamber 58, 60 to rearwardly confine each liquid component 62, 64 within its respective component chamber 58, 60.
  • the pistons 66 form an airtight seal with the interior walls of their respective component chambers 58, 60.
  • a pierceable seal 68 is included.
  • the mixing chamber 54 includes mixing elements 70 therein.
  • these mixing elements 70 can be pathways or channels formed in the interior walls of the mixing chamber 54 or can be mixing vanes that cause the liquid components 62, 64 to swirl as they travel through the mixing chamber 54 resulting in turbulent fluid flow, thereby mixing the liquid components 62, 64 together.
  • a user inserts the drug cartridge 40 into the front end 72 of the hand piece 42.
  • detents 74 on the drug cartridge 40 engage detents 76 on the hand piece 42 and lock the drug cartridge 40 and the hand piece 42 together.
  • the connecting portions 78 of each plunger 80 engage a corresponding cavity 82 in the pistons 66, forming a press-fit connection between the two.
  • the pistons 66 move in a corresponding manner.
  • the user When a user desires to dispense the therapeutic compound, the user activates the hand piece 42 via the control unit 4. Activation of the hand piece 42 in turn energizes the drive motor 28, which acts through a universal joint (see Figures 39A and 39B) to move or drive the plungers 80 towards the front end 46 of the drug cartridge 40.
  • the pistons 66 move into the component chambers 58, 60 in a corresponding manner, forcing each separate liquid component 62, 64 through the piercing elements 56 and into the mixing chamber 54.
  • the turbulent flow created therein causes the liquid components 62, 64 to mix with each other.
  • the newly mixed components then exit the nozzle 50 as the mixed therapeutic compound 81.
  • the drug sprayer 2 can be used with a drug cartridge 84 that contains a liquid component 86 and a solid component 88.
  • the drug cartridge 84 includes a housing 90 having a front end 92, a back end 94, a lower chamber 96, a nozzle 98, a liquid component chamber 100 that houses the liquid component 86, a solid component chamber 102 that houses the solid component 88, a first piston 104 inserted into the back end of the liquid component chamber 100 to rearwardly confine the liquid component 86 therein, and a second piston 106 inserted into the back end of the solid component chamber 102 to rearwardly confine the solid component 88 therein.
  • the first and second pistons 104, 106 form an airtight seal with the interior walls of the liquid and solid component chambers 100, 102.
  • the front end 92 of the liquid component chamber 100 includes a first one-way or check valve 108 that confines the liquid component 86.
  • the front end 92 of the solid component chamber 102 does not include a check valve. Instead, a second check valve 110 is included at the back end of the of the lower chamber 96.
  • An example of such a one-way valve that can be used with the present drug cartridge 84 is a duck bill valve.
  • This configuration of the first and second check valves 108, 110 allows the liquid component 86 and the solid component 88 to be stored separate from each other and also closes the front ends of the liquid and solid component chambers 100, 102 forming a sealed volume of air between the first and second pistons 104, 106 and the first and second check valves 108, 110.
  • the drug cartridge 84 containing a liquid component 86 and a solid component 88 with the drug sprayer 2 As can be seen in Figures 41A-41E, a user inserts the drug cartridge 84 into the front end 112 of the hand piece 114. When inserted, detents 116 on the drug cartridge 84 engage detents 118 on the hand piece 114 and thereby lock the drug cartridge 84 and the hand piece 114 together.
  • the hand piece 114 for use with the liquid-solid drug cartridge 84 includes a single plunger 120, which is inserted into the solid component chamber 102.
  • the user When a user desires to dispense the therapeutic compound, the user activates the hand piece 114 via the control unit 4. Activation of the hand piece 114 in turn energizes the drive motor 28, which acts through a universal joint 30 (see Figures 39A and 39B) to move the plunger 120. Initially, the plunger 120 is retracted in the direction shown by arrow 126 in Figure 41D causing the second piston 106 to move in a corresponding manner. Because of the air tight seals created by the first and second pistons 104, 106 and the first and second check valves 108, 110, as can be seen in Figure 41D, as the second piston 106 retracts, negative pressure or suction is created in the solid component chamber 102.
  • This negative pressure or suction causes the first piston 104 to move in the direction of arrow 128 forcing the liquid component 86 through the first check valve 108 and into the liquid component chamber 102.
  • turbulent fluid flow is created, which operates to mix the liquid and solid components 86, 88 together.
  • the negative pressure within the closed system acts to keep the second check valve 110 closed.
  • the amount of the liquid component 86 that is added to the solid component 88 and, hence, the concentration of the mixed drug can be controlled by adjusting the distance that the plunger 120 is retracted before reversing the direction of travel of the plunger 120 and dispensing the mixed drug. Therefore, for example, the further back that the plunger 120 is retracted, the more liquid component 86 enters into the solid component chamber 102 and thus, the more dilute the therapeutic compound becomes.
  • the first liquid component 62 is a solution comprising a lithium salt and the second liquid component 64 is a polymeric solution that comprises a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C.
  • the lithium concentration in the lithium solution can be at least 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3 times, 4 times, or at least 5 times the concentration of the final concentration.
  • the lithium solution can be a water-based solution.
  • the liquid component 86 is a polymeric solution that comprises a water-soluble polymer that is a solution at room temperature (20-25°C) and below, but gels at physiological temperatures of 32-37°C and the solid component 88 comprises a lithium salt as described in Section 5.1.
  • the lithium salt is an organic lithium salt such as, e.g., lithium gluconate (see Section 5.1 ).
  • either the drug spraying device, the drug cartridge, or both may be manufactured as a disposable.
  • the drug spraying device may be altered so that it is battery powered.
  • the components of the present device can be modified to dispense a therapeutic compound that comprises more than two components that need to be mixed together prior to dispensing.
  • a device for spraying a therapeutic compound comprises:
  • a device for spraying a therapeutic compound comprises:
  • a hand piece including a housing and a plunger having a connecting portion
  • a drug cartridge housing having a front end and a back end
  • a drug cartridge for use in a device for spraying a therapeutic compound comprises:
  • the drug spraying device disclosed herein enables the sustained release of ionized lithium (Li+), without the use of highly hydrophobic, occlusive matrices.
  • the drug spraying device enables the delivery of ionized lithium in microspheres (e.g., PLG microspheres) such that the microspheres stay at the wound site for a prolonged period of time and are not cleared rapidly by phagocytosis.
  • a prolonged period of time can be at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or at least 20 days.
  • the drug spraying device enables the
  • the drug spraying device disclosed herein comprises two chambers.
  • the component of the first chamber comprises a polymer macromonomer (Polymer 1) (a polymer that can further crosslink with another component) and microspheres containing a lithium salt.
  • the component of the second chamber comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • the solid component (e.g., solid component 88 described above) comprises a polymer macromonomer (Polymer 1) (a polymer that can further crosslink with another component) and microspheres containing a lithium salt.
  • the liquid component (e.g., liquid component 86 described above) comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • Polymer 2 does not contain hydrolytically labile linkages and is stable in water.
  • Example 14 Illustrative embodiments of the use of the presently disclosed drug spraying device to deliver cross-linked microspheres to a wound site are set forth in Example 14.
  • the drug spraying device disclosed herein enables the sustained release of ionized lithium (Li+) and uptake by the skin through a scab.
  • the drug spraying device enables the delivery of ionized lithium such that the delivery system is incorporated into the scab. This can be accomplished by placing a lithium containing thin, gauze-like, pliable biodegradable scaffold on the fresh wound. The material properties of the scaffold will be adjusted such the gauze is able to absorb the blood and other exudates from the wound.
  • the biodegradable scaffold has high content of void space, to absorb blood, fibrin and fibrinogen.
  • this incorporation of the scaffold into the fibrin clot during its formation results in its incorporation into the fibrous network, also called a scab, after it solidifies.
  • an in-situ crosslinking hydrogel may be applied on top to cover the entire site as a wound dressing.
  • the solid component (e.g., solid component 88 described above) comprises a polymer macromonomer (Polymer 1) (a polymer that can further crosslink with another component) and the liquid component (e.g., liquid component 86 described above) comprises another polymer macromonomer (Polymer 2) that is capable of reacting with Polymer 1.
  • Polymer 2 does not contain hydrolytically labile linkages and is stable in water. Mixing of these two components yields a cross-linking hydrogel that is applied to the wound.
  • the cross-linking hydrogel is applied together with a biodegradable scaffold that comprises lithium.
  • the biodegradable scaffold can be in the form a pliable, gauze-like material that is a blend of PLG polymers.
  • the cross-linking hydrogel is applied to the wound before the scaffold is applied; the cross-linking hydrogel is applied to the wound at the same time when the scaffold is applied; the cross-linking hydrogel is applied to the wound after the scaffold is applied.
  • the biodegradable scaffold has an "open-cell" structure that would allow cells to attach themselves, differentiate and proliferate.
  • the scaffold can have other components such as RGD peptides, etc. incorporated to encourage cell attachment.
  • the scaffold can have bioadhesive attributes to keep it "in place.”
  • the drug spraying device disclosed herein enables the concurrent delivery of two or more drugs with different solubility properties and/or physical/chemical incompatibilities (such as different excipient requirements; binding and / or reaction of the two or more drugs with each other).
  • the first liquid component e.g., liquid component 62 described above
  • the second liquid component e.g., liquid component 64 described above
  • the presently disclosed drug spray device can be engaged for spraying each drug separately.
  • an alcoholic solution ⁇ drug
  • both chambers could contain the same drug, but in different forms and formulated differently to achieve different release profiles.
  • the first liquid component e.g., liquid component 62 described above
  • the second liquid component e.g., liquid component 64 described above
  • Co-spraying both forms of lithium provides instantly- bioavailable, ionized Li+ and a sustained form of Li+ made available as the micronized lithium carbonate dissolves.
  • Example 16 Illustrative embodiments of the use of the presently disclosed drug spraying device to deliver cross-linked biodegradable scaffold to a wound site are set forth in Example 16.
  • the drug spraying device disclosed herein enables the cleansing and administration of one or more drugs with one single device.
  • the contents of each chamber could be sprayed separately.
  • Once chamber can contain the cleansing solution; the liquid in the other chamber contains lithium. Any wound- cleansing solution known to the skilled artisan can be used with these embodiments.
  • Example 17 Illustrative embodiments of the use of the presently disclosed drug spraying device to deliver cross-linked biodegradable scaffold to a wound site are set forth in Example 17.
  • a drug spraying device is used to administer a combination treatment comprising a lithium compound described herein and chlorhexidine.
  • a combination treatment comprising a lithium compound described herein and chlorhexidine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a drug spraying device is used to administer a combination treatment comprising a lithium compound described herein and iodine.
  • a combination treatment comprising a lithium compound described herein and iodine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a drug spraying device is used to administer a combination treatment comprising a lithium compound described herein and povidone-iodine.
  • a combination treatment comprising a lithium compound described herein and povidone-iodine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • the lithium compound or formulation thereof can be administered topically, subcutaneously, orally, etc. Regardless of the route of administration used for lithium ion delivery, the dosing regimen should be adjusted to achieve peak concentrations of lithium in the target skin area of at least about 0.1 mM to 10 mM, and/or peak concentrations of lithium in the blood (serum or plasma samples) of at least about 1 mM (these values are sometimes referred to herein as the "target concentration").
  • ionized lithium is a monovalent cation
  • the peak concentration of lithium can be established by taking samples when peak concentrations are achieved and assaying them for lithium content using techniques well known to those skilled in the art (see, e.g., the examples of Sections 6 to 9 and the techniques described therein; see also Wood et al., 1986, Neuropharmacology 25: 1285-1288; and Smith, 1978, Acta Pharmacol et toxicol 43:51-54, each of which is incorporated herein by reference in its entirety).
  • samples can be taken when peak blood concentrations are typically achieved - for example, within 1 to 2 hours for standard release formulations, and 4-5 hours for sustained release formulations.
  • the peak concentration times for other formulations, including topical preparations, can be determined for the particular formulation used, and sampling can be adjusted accordingly.
  • the target concentration of lithium should be maintained in the skin and/or blood for at least 1 day; at least 2 days; at least 3 days; at least 4 days; at least 5 days; at least 6 days; at least 7 days; at least 10 days; at least 12 days; at least 14 days; at least 16 days; at least 19 days; or at least 21 days; and, in certain embodiments, not more than 21 days.
  • This can be accomplished using, e.g., repeated applications of the lithium compound or a single application of a sustained release or extended release lithium formulation.
  • Either the single pulse protocol or the intermittent treatments can be used to achieve the target concentration of lithium for the shorter maintenance periods (i.e., for at least 1, 2 or 3 days). Maintenance periods longer than 3 days may require repeated application of intermittent lithium treatments or a single pulse protocol.
  • topical administration of a lithium compound is preferred over oral or subcutaneous administration.
  • a topically administered lithium compound may achieve a higher concentration of lithium in skin than in the blood, thereby reducing the risk of toxicity associated with elevated blood levels of lithium.
  • a subcutaneously or orally administered lithium compound may be preferred in order to achieve a controlled release of lithium from the blood to the skin.
  • lithium doses should be adjusted on the basis of the blood concentration (serum or plasma) drawn (by convention) 12 or 24 hours after the last dose of the lithium compound; this trough blood concentration should be maintained below 2 mM Li+ and preferably, below about 1.5 mM Li+. In some embodiments, the steady state blood concentration of lithium should not exceed a maximum of 1.5 mM to 2 mM.
  • the relatively stable and characteristic pharmacokinetics of the lithium ion in individual patients makes it possible to predict dosage requirements for that individual based on the results of administration of a single test dose, followed by a skin and/or blood sample assay (plasma or serum) at the peak concentration time; followed by blood sample assays to monitor toxicity at the 12 hour or 24 hour trough concentration; and 24 hours later (when lithium is generally eliminated) which serves as the control value.
  • a skin and/or blood sample assay plasma or serum
  • blood sample assays to monitor toxicity at the 12 hour or 24 hour trough concentration; and 24 hours later (when lithium is generally eliminated) which serves as the control value.
  • a trough concentration of lithium in the skin of no less than 0.01 mM to 0.05 mM is preferred. In some embodiments, a trough concentration of lithium in the skin of 0.05 mM to 0.1 mM is preferred. In some embodiments, a trough concentration of lithium in the skin of less than 1 mM is preferred. In some embodiments, a trough concentration of lithium in the skin of less than 3 mM is preferred. In some embodiments, lithium concentrations at trough can be increased by twice daily dosing, or more frequent dosing. In such embodiments, topical administration of a lithium compound is preferred.
  • a pulsatile effect is achieved by the multiple dosing, but the trough concentrations do not decline as much as when once daily dosing is used.
  • a trough skin concentration of lithium is maintained at 0.25 mM or higher, for example from 0.25 mM to 0.5 mM or 0.5 mM to 0.75 mM.
  • the trough concentration is maintained at approximately 0.6 mM to 1.4 mM lithium.
  • a trough skin concentration is maintained at 1 mM to 3 mM lithium. In some such
  • the trough skin concentration is maintained at less than 0.5 mM, or less than 0.75 mM, or less than 1 mM, or less than 2 mM, or less than 3 mM of lithium.
  • a peak concentration of lithium in the skin of no more than 0.1 mM to 10 mM is preferred. In some embodiments, a peak concentration of lithium in the skin of at least about 1 mM is preferred. In some embodiments, an average concentration of lithium in the skin of about 3 to 6 mM is preferred. In some embodiments, an average concentration of lithium in the skin of about 4 to 5 mM is preferred.
  • an effective amount of a lithium compound is administered such that the target concentration of lithium ions in plasma or serum, as measured 30 minutes to 1 hour after the lithium treatment, is 0.10-0.20 ⁇ , 0.20-0.50 ⁇ , 0.50-1.0 ⁇ , 1.0-5.0 ⁇ , 5.0-10 ⁇ , 10-20 ⁇ , 20-50 ⁇ , 50-100 ⁇ , 100-500 ⁇ , 0.1- 0.5 mM, 0.5-1.0 mM, 1.0 mM-2.0 mM, 2.0-2.5 mM, 2.5-3.0 mM, 3.0-4.0 mM, 4.0 mM-5.0 mM, 5.0-7.0 mM, or 7.0 mM or greater.
  • an effective amount of lithium is administered such that the plasma or serum lithium ion concentration measured either 8 hours, 16 hours, 1 day, 1 week, 2 weeks, or 1 month after the lithium treatment, is 0.1 to 0.5 ⁇ , 0.1 to 1.0 ⁇ , 0.5 to 1.0 ⁇ , 0.5 to 1.5 ⁇ , 1 to 10 ⁇ , 10 to 50 ⁇ , 50 to 100 ⁇ , 100 to 150 ⁇ , 150 to 200 ⁇ , 250 to 300 ⁇ , 100 to 250 ⁇ , 100 to 500 ⁇ , 200 to 400 ⁇ , 500 to 1000 ⁇ ; or 1000 to less than 1500 ⁇ .
  • the plasma or serum lithium concentration reaches at least 1 ⁇ . In one embodiment, the plasma or serum lithium concentration reaches at least 100 ⁇ .
  • the plasma or serum lithium concentration reaches at least 1 mM. In one embodiment, the plasma or serum lithium concentration does not exceed 1 mM. In another embodiments, the plasma or serum concentration of lithium does not exceed 1.5 mM. Serum lithium concentration may be measured using any technique known in the art, such as described in Sampson et ah, 1992, Trace Elements in Medicine 9:7-8.
  • an amount of a lithium compound is administered such that the target concentration of lithium in the skin is 0.01 to 0.05 ⁇ , 0.05 to 0.1 ⁇ , 0.1 to 0.5 ⁇ , 0.1 to 1 ⁇ , 0.5 to 1.0 ⁇ , 1.0 to 1.5 ⁇ , 1 to 2.5 ⁇ , 1 to 5 ⁇ , 5 to 10 ⁇ , 10 to 50 ⁇ , 50 to 100 ⁇ , 100 to 150 ⁇ , 150 to 200 ⁇ , 250 to 300 ⁇ , 100 to 250 ⁇ , 100 to 500 ⁇ , 200 to 400 ⁇ , 500 to 1000 ⁇ , 1 to 10 mM, 1 to 5 mM, 5 to 10 mM, 10 to 100 mM, 100 to 200 mM, or 500 to 1000 mM.
  • the concentration of lithium achieved in the skin is greater than 0.1 mM.
  • the concentration of lithium achieved in the skin is greater than 1.0 mM.
  • the concentration of lithium achieved in the skin is greater than 1.0 mM.
  • concentration of lithium achieved in the skin is greater than 1.5 mM.
  • the amount of lithium achieved in the skin is approximately 1 mM to 5 mM. In one embodiment, the amount of lithium achieved in the skin is approximately 5 mM to 10 mM. In one embodiment, the amount of lithium achieved in the skin is approximately 100 to 200 mM. In one embodiment, the amount of lithium achieved in the skin does not exceed 5 mM. In one embodiment, the amount of lithium achieved in the skin does not exceed 10 mM. In one embodiment, the amount of lithium achieved in the skin does not exceed 50 mM.
  • an amount of lithium is administered such that the concentration of lithium delivered to the stratum corneum is 0.1 to 0.5 mM, 0.5 to 1 mM, 1 to 10 mM, 10 to 100 mM, 100 to 200 mM, or 500 to 1000 mM. In some embodiments, the concentration of lithium delivered to the stratum corneum is greater than 1.5 mM. In one embodiment, the amount of lithium achieved in the stratum corneum is approximately 100 to 200 mM. In one embodiment, the amount of lithium achieved in the stratum corneum does not exceed 5 mM. In one embodiment, the amount of lithium achieved in the stratum corneum does not exceed 10 mM.
  • lithium concentrations in skin using techniques known in the art, for example, mass spectroscopy, e.g., inductively coupled plasma mass spectroscopy (ICP-MS).
  • mass spectroscopy e.g., inductively coupled plasma mass spectroscopy (ICP-MS).
  • ICP-MS inductively coupled plasma mass spectroscopy
  • concentration of lithium in skin can be measured using the method provided in the example of Section 6 below or equivalent methods.
  • the lithium concentration is measured in the hair shaft using techniques known in the art, e.g., Tsanaclis & Wicks, 2007, Forensic Science Intl. 176: 19-22, which is incorporated by reference herein in its entirety.
  • lithium can be applied topically, e.g. , as a cream, gel, ointment, or other form for topical administration as described in Section 5.2 supra.
  • Topical lithium may be administered to wounded or unwounded skin.
  • the lithium formulation for topical administration ⁇ e.g., gel, cream, ointment, salve, etc.
  • a monovalent lithium salt ⁇ e.g., lithium gluconate, lithium chloride, lithium stearate, lithium orotate, etc.
  • a divalent lithium salt ⁇ e.g., in some embodiments, lithium succinate, lithium carbonate
  • a trivalent lithium salt ⁇ e.g., in some embodiments, lithium citrate), refers to a salt form of lithium in which there are three lithium cations for each anion of the salt.
  • a lithium formulation comprising lithium (or monovalent lithium salt) at a concentration in the range of 50 mM to 200 mM is chosen for use in the embodiments described herein.
  • a lithium formulation comprising lithium (or monovalent lithium salt) at a concentration in the range of 200 mM to 400 mM is used.
  • a lithium formulation comprising lithium (or monovalent lithium salt) at a concentration in the range of 400 mM to 600 mM is used.
  • a lithium formulation comprising lithium (or monovalent lithium salt) at a concentration in the range of 600 mM to 800 mM is used.
  • concentration of lithium in a particular topical lithium formulation to deliver the intended dose of lithium will depend on the release properties of the lithium ion, the hydrophobicity of the lithium salt form, the partition coefficient of the lithium salt form, etc.
  • Lithium formulations comprising the foregoing lithium (or monovalent lithium salt) concentrations may be achieved using, for example, a formulation comprising, w/w, lithium ions at a concentration of 0.10% lithium, 0.15% lithium, 0.20% lithium, 0.25% lithium, 0.30% lithium, 0.35% lithium, 0.40% lithium, 0.45% lithium, 0.50% lithium, 0.55% lithium, 0.60% lithium, 0.65% lithium, 0.70% lithium, 0.75% lithium, 0.80% lithium, 0.85% lithium, 0.90% lithium, 0.95% lithium.
  • the form of lithium for topical administration comprises, w/w, 0.1 % to 0.5%> lithium ions, 0.2%> to 0.5%> lithium ions, 0.5%> to 1% lithium ions, or more.
  • the amount of a salt form of lithium to generate a topical lithium formulation with one of the aforementioned concentrations of lithium ion is readily deducible by one of ordinary skill in the art, and depends upon several factors including, e.g., the valency of the salt form, the stability of the salt form, the ability of the salt form to release the lithium ion, the hydrophobicity or hydrophilicity, etc.
  • Lithioderm (Labcatal) comprises 8% lithium gluconate, which corresponds to 0.275%) lithium ion ⁇ i.e., 274.8 mg Li+/100 g gel).
  • a formulation of topical 8% lithium gluconate, w/w contains approximately 80 mg/ml lithium gluconate, which is approximately 400 mM lithium gluconate (and, thus, 400 mM lithium ion).
  • a formulation for topical administration comprises a salt form of lithium ⁇ e.g. , lithium carbonate or other form described in Section 5.1 above) at a concentration, w/w, of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 16%, 18%, 20%, or more.
  • a salt form of lithium for topical administration comprises, w/w, 1% to 2% lithium salt ⁇ e.g., lithium carbonate or other form described in Section 5.1 above), 2% to 5% lithium salt, 5% to 10% lithium salt, 10% to 15% lithium salt, 15% to 20% lithium salt, 20% to 25% lithium salt, or 25% to 50% lithium salt.
  • the form of lithium for topical administration is 1% to 20% w/w lithium salt.
  • a formulation for topical administration comprises lithium carbonate at a concentration of 1.46% w/w. In another embodiment, a formulation for topical administration comprises lithium carbonate at a concentration of 2.91% w/w. In yet another embodiment, a formulation for topical administration comprises lithium carbonate at a concentration of 5.66% w/w.
  • a topical formulation of lithium comprises 0.25%-0.75%, 0.75%- 1.5%, or 1.5%-3%, 3%-6%, or 8%-16%, or more lithium carbonate (w/w).
  • a topical formulation of lithium comprises l%-4% lithium gluconate (w/w).
  • a topical formulation of lithium comprises 4%-8% lithium gluconate (w/w).
  • a topical formulation of lithium comprises 8%-16% or more lithium gluconate (w/w).
  • a topical formulation of lithium comprises 0.2%)- 1%), or l%>-5%>, or more lithium chloride (w/w).
  • a topical formulation of lithium comprises 0.5%>-2%>, or 2%>-4%>, or 4%-8%, or 8%>-16, or more lithium succinate (w/w). In some embodiments, a topical formulation of lithium comprises 0.5%>-6%>, 6%>-12%>, or 12%>-25%>, or more lithium stearate (w/w). In some embodiments, a topical formulation of lithium comprises l%-4%, 4%-8%, or 8%-16%, or more lithium orotate (w/w).
  • the topical lithium formulation comprises 0.10%- 0.25%, 0.25%-0.75%, 0.75%-1.5%, 1.5%-3%, 3%-4.5%, or 4.5-6%, or more lithium carbonate (w/w).
  • a topical formulation of lithium comprises 0.25%- 1.5%, 1.5%-3.0%, or 3%-6%, or more 8% lithium citrate (w/w).
  • a 50 kg patient is administered a single droplet - approximately 0.1 ml - of 8% (w/w) lithium gluconate at 3 sites, twice daily. This corresponds to approximately 8 mg lithium gluconate (0.274 mg Li+) per site, i.e., 0.16 mg/kg lithium gluconate (0.005 mg/kg Li+) per site. Over three sites twice daily, this corresponds to approximately 0.96 mg/kg lithium gluconate (0.033 mg/kg Li+) per day.
  • a patient e.g., a 50 kg patient
  • a patient is administered about 30-50 mg, about 50-75 mg, or about 75-100 mg topical lithium gluconate/day, which is equivalent to about 1-1.7 mg, 1.7-2.2 mg, or 2.2-3.5 mg, respectively, Li+/day.
  • a patient is administered topical lithium carbonate that is equivalent to about 2.74 mg, 5.48 mg, 10.73 mg, or 20 mg respectively, Li+/gram. In some embodiments, a patient is administered topical lithium carbonate that is equivalent to about 1- 3 mg, 1.5-3 mg, 2-3 mg, 2.4-2.8 mg, 2.6-2.8, mg or 2.65-2.75 mg Li+/gram. In some embodiments, a patient is administered topical lithium carbonate that is equivalent to about 2- 8 mg, 3-7 mg, 4-6 mg, 5-6 mg, 5.2-5.6, mg, 5.3-5.5 mg, or 5.4-5.5 mg Li+/gram.
  • a patient is administered topical lithium carbonate that is equivalent to about 8- 12 mg, 9-11 mg, 10-11 mg, 10.2-10.9 mg, 10.3-10.8, mg, 10.5-10.75 mg, or 10.70-10.76 mg Li+/gram.
  • a patient is administered topical lithium carbonate that is equivalent to about 18-22 mg, 19-21 mg, 1.9.5-20.5 mg, 19.6-20.4 mg, 19.7-20.3, mg, 19.8- 20.2 mg, or 19.9-20.1 mg Li+/gram.
  • a topical lithium formulation is administered once daily. In some embodiments, a topical lithium formulation is administered twice daily. In some embodiments of a twice daily treatment regimen, doses are administered 6 hours apart, or 7 hours apart, or 8 hours apart, or 9 hours apart, or 10 hours apart, or 11 hours apart, or 12 hours apart. In a particular embodiment, the doses are administered 7 to 8 hours apart.
  • an amount of lithium is administered such that the peak lithium concentration in skin is between 0.01 mM and 0.05 mM, 0.05 mM and 0.1 mM, 0.1 mM and 0.5 mM or between 0.5 mM and 10 mM, for example, between 0.1 and 0.5 mM, 0.5 mM and 1 mM, 1 mM and 2 mM, between 2 mM and 5 mM, 5 mM to 10 mM, or 10 mM to 50 mM.
  • the peak lithium concentration in blood may be one or more orders of magnitude lower than the peak concentration in skin (for example, 0.001 mM to 0.01 mM, 0.01 mM to 0.1 mM, or 0.1 mM to 0.5 mM, 0.5 mM to 1.0 mM, or 1.0 mM to 10 mM).
  • the steady state blood concentration of lithium should not exceed a maximum of 1.5 mM to 2 mM.
  • a formulation of lithium described herein (by non-limiting e.g., lithium carbonate, lithium gluconate, lithium chloride, lithium succinate, lithium citrate, lithium stearate, lithium orotate, etc.) is administered subcutaneously, to either wounded or unwounded skin.
  • the form of lithium for subcutaneous administration is administered at a dose comprising 0.001 mg lithium ion per kg of patient weight.
  • the dose is 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/ kg, 0.020 mg/kg, 0.025 mg/kg, 0.050 mg/kg, 0.075 mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.40 mg/kg, 0.50 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg
  • the dose does not exceed 50 mg/kg.
  • the lower ranges of dosages may be preferably used for bolus dosing.
  • the maximum dosage that may be administered at any one time may vary depending on the release kinetics of the lithium and the concentration of efficacy of the formulation.
  • concentration of a salt form of lithium required to generate a subcutaneously administered formulation that delivers lithium ions at one of the aforementioned dosages is readily deducible by one of ordinary skill in the art, and depends upon several factors including, e.g., the valency of the salt form, the stability of the salt form, the ability of the salt form to release the lithium ion, the hydrophobicity or hydrophilicity, etc.
  • a formulation comprising lithium carbonate may be subcutaneously administered at a dosage of approximately 10 mg lithium carbonate per kg of patient weight (mg/kg), 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, or 1000 mg/kg.
  • the formulation for subcutaneous administration contains a dose of 10 mg/kg to 50 mg/kg, 50 mg/kg to 100 mg/kg, 100 mg/kg to 200 mg/kg, 200 mg/kg to 400 mg/kg, 400 mg/kg to 600 mg/kg, or 100 mg/kg to 600 mg/kg of lithium carbonate.
  • the formulation for subcutaneous administration contains a dose in the range of 30 mg/kg to 150 mg/kg lithium carbonate.
  • the formulation for subcutaneous administration contains a dose in the range of about 30 mg/kg to 300 mg/kg lithium carbonate.
  • the dose for subcutaneous administration does not exceed 300 mg/kg lithium carbonate.
  • the dose for subcutaneous administration does not exceed 600 mg/kg lithium carbonate.
  • the lower ranges of dosages may be preferably used for bolus dosing.
  • a controlled release e.g., a delayed release or a sustained release
  • the maximum dosage that may be administered at any one time may vary depending on the release kinetics of the lithium and the concentration of efficacy of the formulation.
  • the lithium formulation is administered subcutaneously once daily. In some embodiments, the lithium formulation is administered subcutaneously twice daily. In some embodiments of a twice daily treatment regimen, doses are administered 6 hours apart, or 7 hours apart, or 8 hours apart, or 9 hours apart, or 10 hours apart, or 11 hours apart, or 12 hours apart. In a particular embodiment, the doses are administered 7 to 8 hours apart.
  • an amount of lithium is administered such that the peak lithium concentration in skin is between 0.1 ⁇ and 0.2 ⁇ , 0.2 ⁇ and 0.5 ⁇ , 0.5 and 1 ⁇ , 1 ⁇ and 2 ⁇ , 2 ⁇ to 10 ⁇ , 10 ⁇ to 100 ⁇ , 100 ⁇ to 500 ⁇ , 500 ⁇ to 1000 ⁇ .
  • peak values will depend on the lithium release properties of the formulation, the hydrophobicity of the lithium salt form, the partition coefficient of the lithium salt form, etc.
  • the concentration in skin is 0.2 ⁇ to 1.5 ⁇ lithium. In some embodiments, the peak concentration in skin should not exceed 1 ⁇ or 1.5 ⁇ lithium. In some embodiments, the peak concentration in skin is 10 ⁇ to 100 ⁇ lithium. In some embodiments, the peak concentration in skin is 100 ⁇ to 1000 ⁇ lithium. In some such embodiments, the peak lithium concentration in blood may be several orders of magnitude higher, for example, 0.1 mM to 0.5 mM, or 0.5 mM to 1.1 mM, 1.1 to 1.5 mM, 1.5 mM to 5 mM, 5 mM to 10 mM, 10 mM to 50 mM, or 50 mM to 100 mM.
  • the steady state blood concentration of lithium should not exceed a maximum of 1.5 mM to 2 mM.
  • a formulation of lithium described herein (by non-limiting e.g., lithium gluconate, lithium chloride, lithium succinate, lithium carbonate, lithium citrate, lithium stearate, lithium orotate, etc.) is administered orally, for example, once daily, or twice daily as determined by the medical practitioner and in accordance with Section 5.4 above.
  • an oral formulation comprising of 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1 mM, 1.1 mM, 1.2 mM, 1.3 mM, 1.4 mM, 1.5 mM, 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, or more, but preferably less than 10 mM, of lithium ions (or monovalent lithium salt) is administered.
  • an oral formulation comprising lithium ions or a monovalent lithium salt in the range of 0.1 to 0.5 mM, 0.4 to 0.6 mM, 0.5 to 1 mM, 0.6 to 1.2 mM, or 1 to 1.5 mM, is administered.
  • Administration of the foregoing amounts of lithium may be achieved by oral administration of a lithium formulation at a dosage comprising 0.001 mg lithium ion per kg of patient weight.
  • the dose is 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/ kg, 0.020 mg/kg, 0.025 mg/kg, 0.050 mg/kg, 0.075 mg/kg, 0.10 mg/kg, 0.15 mg/kg, 0.20 mg/kg, 0.25 mg/kg, 0.30 mg/kg, 0.40 mg/kg, 0.50 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/
  • the dose does not exceed 50 mg/kg Li+.
  • the maximum dosage that may be administered at any one time may vary depending on the release kinetics of the lithium and the concentration of efficacy of the formulation.
  • concentration of a salt form of lithium required to generate an orally administered formulation that delivers lithium ions at one of the aforementioned dosages is readily deducible by one of ordinary skill in the art, and depends upon several factors including, e.g., the valency of the salt form, the stability of the salt form, the ability of the salt form to release the lithium ion, the hydrophobicity or hydrophilicity, etc.
  • a formulation comprising lithium carbonate which is a divalent lithium salt (e.g., trade names Eskalith CR, Eskalith, Lithobid) may be orally administered at a dosage of approximately 2 mg lithium carbonate per kg of patient weight (mg/kg), 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, or 250 mg/kg or more is administered.
  • divalent lithium salt e.g., trade names Eskalith CR, Eskalith, Lithobid
  • the oral formulation contains a dose of 2 mg/kg to 10 mg/kg, 10 mg/kg to 25 mg/kg, 25 mg/kg to 50 mg/kg, 50 mg/kg to 100 mg/kg, 100 mg/kg to 200 mg/kg, or 200 mg/kg to 500 mg/kg of lithium carbonate. In one embodiment, the oral formulation contains a dose in the range of 5 mg/kg to 100 mg/kg lithium carbonate. In one embodiment, the oral formulation contains a dose in the range of about 5 mg/kg to 50 mg/kg lithium carbonate. In one embodiment, the oral formulation contains a dose in the range of about 10 mg/kg to 100 mg/kg lithium carbonate. In one embodiment, the oral formulation contains a dose that does not exceed 300 mg/kg lithium carbonate.
  • the maximum dosage that may be administered at any one time may vary depending on the release kinetics of the lithium and the concentration of efficacy of the formulation.
  • an amount of lithium compound is administered such that the peak lithium concentration in skin is between 0.1 ⁇ and 0.2 ⁇ , 0.2 ⁇ and 0.5 ⁇ , 0.5 and 1 ⁇ , 1 ⁇ and 2 ⁇ , 2 ⁇ to 10 ⁇ , 10 ⁇ to 100 ⁇ , 100 ⁇ to 500 ⁇ , 500 ⁇ to 1000 ⁇ .
  • peak values will depend on the lithium release properties of the formulation, the hydrophobicity of the lithium salt form, the partition coefficient of the lithium salt form, etc.
  • the peak concentration in skin is 0.2 ⁇ to 1.5 ⁇ lithium.
  • the peak concentration in skin should not exceed 1 ⁇ or 1.5 ⁇ lithium. In some embodiments, the peak concentration in skin is 10 ⁇ to 100 ⁇ lithium. In some embodiments, the peak concentration in skin is 100 ⁇ to 1000 ⁇ lithium. In some such embodiments, the peak lithium concentration in blood may be several orders of magnitude higher, for example, 0.1 mM to 0.5 mM, or 0.5 mM to 1.1 mM, 1.1 to 1.5 mM, 1.5 mM to 5 mM, 5 mM to 10 mM, 10 mM to 50 mM, or 50 mM to 100 mM.
  • the steady state blood concentration of lithium should not exceed a maximum of 1.5 mM to 2 mM.
  • a pulse lithium treatment can be administered one time, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. For example, in the treatment of bipolar disorder, therapeutically useful amounts of lithium ( ⁇ 0.4 to 1.2 mM) are only slightly lower than toxic amounts (>1.5 mM), so the skilled practitioner knows that the blood levels of lithium must be carefully monitored during treatment to avoid toxicity.
  • a pulse lithium treatment is administered at the time of integumental perturbation. In some embodiments, a pulse lithium treatment is administered following integumental perturbation. In some embodiments, a pulse lithium treatment is administered immediately following integumental perturbation. In one embodiment, a pulse lithium treatment is begun 1 week prior to wound closure ⁇ e.g. , day 4-7 following
  • integumental perturbation in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered before scab formation. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered during scab formation. In one embodiment, in which a pulse lithium treatment is administered following an
  • the pulse lithium treatment is administered periscab detachment. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered immediately after scab detachment. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered 1 hour after scab detachment. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered up to 6 hours after scab detachment.
  • the pulse lithium treatment in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered 6- 12 hours after scab detachment. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered 12-18 hours after scab detachment. In one
  • a pulse lithium treatment in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered 18- 24 hours after scab detachment. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered 1 day after scab detachment. In one embodiment, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered 2 days after scab detachment.
  • the pulse lithium treatment in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, is administered 3 days after scab detachment. In some embodiments, in which a pulse lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the pulse lithium treatment is administered within 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11, days, 12 days, 13 days, 2 weeks, or 3 weeks after integumental perturbation.
  • the pulse lithium treatment is administered at the time of integumental perturbation, or immediately after, and then maintained for 3 or 4 or 5 or 6 or 7 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, a pulse lithium treatment is administered as soon as the scab falls of and maintained for 3 or 4 or 5 or 6 or 7 days. In one embodiment, the pulse lithium treatment is administered at the time of integumental perturbation and then maintained for 7 or 10 or 12 or 14 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, a pulse lithium treatment is administered as soon as the scab falls of and maintained for 7 or 10 or 12 or 14 days.
  • the pulse lithium treatment is administered at the time of integumental perturbation and then maintained for 19 or 21 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, a pulse lithium treatment is administered as soon as the scab falls of and maintained for 19 or 21 days. In some embodiments, the pulse lithium treatment is administered in order to modulate the neoepidermis that forms underneath the scab. In some such embodiments, the pulse lithium treatment is administered at the time of integumental perturbation and is maintained up to some time after scab falls off, for example, between 5 - 14 days or more (e.g., up to 2 weeks, or 3 weeks, or 4 weeks or more) following integumental perturbation.
  • the pulse lithium treatment is administered beginning 1 week prior to wound closure (e.g., 4- 7 days after integumental perturbation), and continued for 5 - 14 days or more. In some embodiments, the pulse lithium treatment is administered beginning at the time the scab falls off (e.g., 1 1-14 days after integumental perturbation), for 5 - 14 days or more.
  • the course of treatment with lithium is short, for example, limited to a few days just following scab detachment, or even continued only for as long as the scab is still attached. In some embodiments, the course of treatment with lithium is longer, for example, exceeding 2 weeks.
  • the timing of integumental perturbation and lithium administration is preferably monitored and adjusted so that optimal results are achieved.
  • a pulse treatment is combined with a form of integumental perturbation that does not lead to formation of a scab.
  • the pulse lithium treatment is administered at the time of integumental perturbation.
  • a pulse lithium treatment is administered following integumental perturbation.
  • the pulse lithium treatment is administered following an integumental perturbation that does not lead to formation of a scab
  • the pulse lithium treatment is administered within 15 minutes of, or 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, or 3 weeks after integumental perturbation.
  • An intermittent lithium treatment can be administered one time (e.g. , using a controlled release formulation), or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • lithium can be administered daily (e.g. , once, twice or three times daily) for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days; and in some embodiments not more than 14 or 15 days, or not more than 3 weeks, or not more than 4 weeks.
  • lithium can be administered daily (e.g., once, twice or three times daily) for at least 12 days, 14 days, at least 16 days, at least 19 days, or at least 21 days; in some embodiments not more than 21 days.
  • Holidays can be interspersed for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days; and in some embodiments not more than 14 or 15 days., or not more than 3 weeks, or not more than 4 weeks. In some embodiments, holidays are interspersed for at least 14 days, 21 days, 28 days, or longer.
  • an intermittent lithium treatment is begun at the time of integumental perturbation. In some embodiments, an intermittent lithium treatment is begun following integumental perturbation. In some embodiments, an intermittent lithium treatment is begun immediately following integumental perturbation. In one embodiment, in which an intermittent lithium treatment is begun following an integumental perturbation that leads to formation of a scab, the intermittent lithium treatment is begun before scab formation. In one embodiment, in which an intermittent lithium treatment is begun following an integumental perturbation that leads to formation of a scab, the intermittent lithium treatment is begun during scab formation.
  • the first administration of lithium in the intermittent lithium treatment is periscab detachment. In one embodiment, in which the intermittent lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the first administration of lithium is immediately after scab detachment. In one embodiment, in which the intermittent lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the first administration of lithium is up to 6 hours after scab detachment.
  • the first administration of lithium is 6-12 hours after scab detachment. In one embodiment, in which the intermittent lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the first administration of lithium is 12-18 hours after scab detachment. In one embodiment, in which the intermittent lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the first administration of lithium is 18-24 hours after scab detachment.
  • the first administration of lithium is 1 day after scab detachment. In one embodiment, in which the intermittent lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the first administration of lithium is 2 days after scab detachment. In one embodiment, in which the intermittent lithium treatment is administered following an integumental perturbation that leads to formation of a scab, the first administration of lithium is 3 days after scab detachment.
  • the first administration of lithium is administered immediately after scab detachment (e.g., 1 1-14 days after integumental perturbation), followed by another administration each day for several days to 1 week, or two 2 weeks or more.
  • the pulse lithium treatment is begun within 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, or 3 weeks after integumental perturbation.
  • the intermittent lithium treatment is begun at the time of integumental perturbation, or immediately after, and then administered daily (or twice daily) for 3 or 4 or 5 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, the intermittent lithium treatment is begun as soon as the scab falls off, and administered daily for 3 or 4 or 5 days. In one embodiment, the intermittent lithium treatment is begun at the time of integumental perturbation, or immediately after, and then administered daily (or twice daily) for 7 days thereafter (in some embodiments, a scab forms during this time).
  • the intermittent lithium treatment is begun at the time of integumental perturbation and then maintained for 7 or 10 or 12 or 14 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, an intermittent lithium treatment is begun as soon as the scab falls of and maintained for 7 or 10 or 12 or 14 days. In some embodiments, the intermittent lithium treatment is begun at the time of integumental perturbation and then maintained for 19 or 21 days thereafter (in some embodiments, a scab forms during this time). In some embodiments, an intermittent lithium treatment is begun as soon as the scab falls of and maintained for 19 or 21 days. In some embodiments, the intermittent lithium treatment is begun as soon as the scab falls off, and administered daily for 7 days.
  • the intermittent lithium treatment is begun at the time of integumental perturbation, or immediately after, and then administered daily (or twice daily) for 14 or 15 days thereafter (in some embodiments, a scab forms during this time).
  • the intermittent lithium treatment is begun 1 week prior to wound closure (e.g., day 4-7 following integumental perturbation), and continued for 5 - 14 days or more.
  • the intermittent lithium treatment is begun as soon as the scab falls off, and administered daily for 14 or 15 days.
  • the intermittent lithium treatment is to modulate the neoepidermis that forms underneath the scab.
  • the intermittent lithium treatment is begun at the time of integumental perturbation and is continued with daily dosing up to some time after scab falls off, for example, between 5 - 14 days following integumental perturbation.
  • the course of treatment with lithium is short, for example, limited to daily doses for a few days just following scab detachment, or even continued only for as long as the scab is still attached.
  • the course of treatment with lithium is longer, for example, exceeding 2 weeks or 3 weeks or one month or more.
  • the timing of integumental perturbation and lithium administration is preferably monitored and adjusted so that optimal results are achieved.
  • an intermittent lithium treatment is combined with a form of integumental perturbation that does not lead to formation of a scab.
  • the intermittent lithium treatment is begun at the time of integumental perturbation.
  • an intermittent lithium treatment is begun following integumental perturbation.
  • the intermittent lithium treatment is begun following an integumental perturbation that does not lead to formation of a scab
  • the intermittent lithium treatment is begun within 15 minutes of, or 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, or 3 weeks after integumental perturbation.
  • the lithium treatments described herein may be in combination with other methods, including conventional methods, for treating, reducing or preventing microbial infections or microbial colonizations.
  • the effect that each drug offers could be an additive or synergistic improvement, or a combination of two different pharmacologically defined effects, to achieve the desired end result.
  • the combined modality of treatment could involve alternating treatment of each dosage form or concurrent or simultaneous treatment.
  • Synergism occurs when the combination has an effect that is more than would be expected from merely the additive effect of each element in the combination.
  • the lithium treatments described herein may be in combination with other methods, including conventional methods, for wound healing or scar revision.
  • the effect that each modality (e.g., drug or integumental perturbation method) offers could be an additive or synergistic improvement, or a combination of two different (e.g. , pharmacologically defined effects), to achieve the desired end result.
  • the combined modality of treatment could involve alternating each treatment or concurrent or simultaneous treatment. Synergism occurs when the combination has an effect that is more than would be expected from merely the additive effect of each element in the combination.
  • a lithium treatment described herein may be in combination with other methods, including conventional methods, for (i) treating, reducing or preventing microbial infections or microbial colonizations; and (ii) wounding healing or scar revision.
  • the lithium treatments described herein may be in combination with any additional treatment(s) described or incorporated by reference herein or determined to be appropriate by the medical practitioner.
  • the amount of an additional treatment(s) will depend on the desired effect and the additional compound or treatment method that is selected. Dosages and regimens for administering such additional treatment(s) are the dosages and regimens commonly in use, which can be easily determined by consulting, for example, product labels or physicians' guides, such as the Physicians' Desk Reference (“PDR”) (e.g., 63rd edition, 2009, Montvale, NJ: Physicians' Desk Reference). Specific examples of treatments for use in combination with the lithium treatments described herein follow.
  • the combination treatment comprises lithium and an additional compound(s) formulated together.
  • the lithium in such formulations may be released concurrently with or separately from the additional compound(s), or may be released and/or delivered to the tissue site with different pharmacokinetics.
  • one or more of the compounds in the formulation undergoes controlled release, whereas one or more of the other compounds does not.
  • one or more of the compounds in the formulation undergoes sustained release whereas one or more of the other compounds undergoes delayed release.
  • the combination treatment comprises lithium and an additional compound(s) formulated separately.
  • the separate formulations may be
  • the lithium compound may be administered sequentially, or concurrently with another compound to achieve the desired effect of improved wound healing or scar revision.
  • the combination treatment comprises lithium and mupirocin.
  • the combination treatment comprises lithium carbonate and mupirocin.
  • a detailed description of a combination treatment comprising lithium carbonate and mupirocin is provided below.
  • lithium carbonate can be substituted with any other lithium compound, including but not limited to lithium gluconate, lithium succinate, lithium chloride, lithium citrate, a lithium salt of mupirocin, and lithium hydroxide.
  • a method for treating a microbial infection or microbial colonization comprising (a) administering a lithium carbonate composition that delivers an effective amount of lithium ions to a human subject in need thereof; and (b) administering mupirocin to the human subject in need thereof.
  • a combination of lithium carbonate and mupirocin for use in treating a microbial infection or a microbial colonization.
  • the microbial infection is a bacterial infection.
  • the bacterial infection is caused by Methicillin-resistant Staphylococcus aureus.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to treat or ameliorate one or more of the following symptoms caused by Methicillin-resistant Staphylococcus aureus: boils, abscesses, a sty, carbuncles, impetigo, a rash, fever, chills, low blood pressure, joint pains, furunculosis, septic arthritis, headaches, and shortness of breath.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to treat or ameliorate the symptoms of one or more of the following conditions caused by Methicillin-resistant
  • Staphylococcus aureus cellulitis, necrotizing fasciitis, osteomyelitis, sepsis, pyomyositis, necrotizing pneumonia, infective endocarditis, bone infections and joint infections.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to treat or ameliorate one or more of the following symptoms caused by Staphylococcus aureus and/or Streptococcus pyogenes: secondarily infected traumatic skin lesions, skin and soft tissue infections, and impetigo.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to treat, reduce, or prevent a microbial biofilm.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to treat, reduce, or prevent a microbial biofilm comprising Methicillin-resistant Staphylococcus aureus.
  • the combination treatment comprising lithium carbonate and mupirocin results in 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% reduction of a biofilm.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes.
  • colonization refers to presence, growth, and multiplication of an organism without observable clinical symptoms or immune reaction.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization in or on one or more of the following: nares, anterior nares, axillae, chronic wounds, decubitus ulcer surface, perineum, around gastrostomy sites, around tracheostomy sites, in sputum, in urine, or in the bowel.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to a subject to prevent, reduce, or eradicate nasal colonization.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes in order to reduce the risk of developing a subsequent infection in that subject.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes, including but limited to Staphylococcus aureus, methicillin-resistant
  • a combination treatment comprising lithium carbonate and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization in order to reduce the risk of developing a subsequent infection by of one or more microbes, including but not limited to Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Enterococci, and drug-resistant Enterococci.
  • colonization that can be prevented or reduced using a combination treatment comprising lithium carbonate and mupirocin is colonization with methicillin-resistant Staphylococcus aureus in the nares, axillae, chronic wounds or decubitus ulcer surface, perineum, around gastrostomy and tracheostomy sites, in the sputum or urine.
  • colonization that can be prevented or reduced using a combination treatment comprising lithium carbonate and mupirocin is colonization with Enterococci in the bowel and the female genital tract.
  • colonization that can be prevented or reduced using a combination treatment comprising lithium carbonate and mupirocin is colonization with drug-resistant Enterococci in the bowel.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to subjects at high risk of methicillin-resistant Staphylococcus aureus infection, such as adult patients and health care workers, to prevent infection or reduce the risk of infection with methicillin-resistant Staphylococcus aureus.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to adult patients and health care workers for the reduction or eradication of nasal colonization with methicillin-resistant S. aureus in a as part of a comprehensive infection control program to reduce the risk of spreading colonization or infection among patients and heath care workers and those they come into contact with at high risk of methicillin-resistant S.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to adult patients and health care workers for the reduction or eradication of nasal colonization with methicillin-resistant S. aureus in a as part of a comprehensive infection control program to reduce the risk of spreading colonization or infection among patients, heath care workers, and those they come into contact with at high risk of methicillin-resistant S. aureus infection or colonization during community outbreaks of infections with this pathogen (for example, Community-Acquired MRSA).
  • a topical formulation of a combination treatment comprising lithium carbonate and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection or colonization by bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidi
  • a topical formulation of a combination treatment comprising lithium carbonate and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection or colonization by fungi.
  • topical formulations of the lithium treatments described herein are administered as a skin sanitizer and/or hand sanitizer to prevent infection or colonization by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • the combination treatment comprises separate administration of lithium carbonate and mupirocin.
  • lithium carbonate and mupirocin are formulated separately.
  • the separate formulations of lithium carbonate and mupirocin may be administered concurrently, sequentially, or in alternating sequence.
  • the administration regimens for lithium carbonate and mupirocin can be overlapping or offset.
  • lithium carbonate is administered to a subject at reasonably the same time as the mupirocin.
  • This method provides that the two administrations are performed within a time frame of less than one minute to about five minutes, or up to about sixty minutes from each other, for example, at the same doctor's visit.
  • the two administrations are performed within a time frame of less than one minute to about five minutes, or up to about sixty minutes from each other, for example, at the same doctor's visit.
  • lithium carbonate and mupirocin are administered at exactly the same time.
  • lithium carbonate and mupirocin are administered in a sequence and within a time interval such that lithium treatment and the other treatment can act together to provide an increased benefit than if they were administered alone.
  • mupirocin is administered twice daily for 10 days and lithium carbonate is also administered twice daily for 10 days.
  • mupirocin is administered before lithium carbonate.
  • lithium carbonate is administered before mupirocin.
  • the combination of lithium carbonate and mupirocin can be administered according to any of the regimens for combination treatments described in Section 5.5.
  • a combination treatment described herein contains 0.01% mupirocin, 0.02% mupirocin, 0.03%> mupirocin, 0.04% mupirocin, 0.05%> mupirocin, 0.06%> mupirocin, 0.07%> mupirocin, 0.08%> mupirocin 0.09%> mupirocin, 0.1 % mupirocin, 0.2% mupirocin, 0.3%> mupirocin, 0.4% mupirocin, 0.5%> mupirocin, 0.6%> mupirocin, 0.7%> mupirocin, 0.8%> mupirocin 0.9%> mupirocin, 1.0% mupirocin, 1.1% mupirocin, 1.2% mupirocin, 1.3% mupirocin, 1.4% mupirocin, 1.5% mupirocin, 1.5% mupirocin,
  • a combination treatment described herein contains 0.5% - 2.5%, 0.75% - 2.75%, 1.0% - 3%, 1.25% - 3.25 %, 1.5% - 3.5 %, 1.75% - 3.75%, or 0.1% - 5% mupirocin.
  • a combination treatment described herein contains 0.10%-0.25%, 0.25%-0.75%, 0.75%-1.5%, 1.5%-3%, 3%-4.5%, 4.5%-6%, 6%-8% or 8%- 16% lithium carbonate.
  • a combination treatment described herein contains 0.5% - 2.5%, 0.75% - 2.75%, 1.0% - 3%, 1.25% - 3.25 %, 1.5% - 3.5 %, 1.75% - 3.75%, or 0.1% - 5% mupirocin and 0.10%-0.25%, 0.25%-0.75%, 0.75%-1.5%, 1.5%-3%, 3%-4.5%, or 4.5%- 6%, 6%-8% or 8%-16% lithium carbonate.
  • a combination treatment described herein contains 2.0% mupirocin and 0.10%-0.25%, 0.25%-0.75%, 0.75%- 1.5%, 1.5%-3%, 3%-4.5%, or 4.5%-6%, 6%-8% or 8%-16% lithium carbonate. In some embodiments, a combination treatment described herein contains 1.0% mupirocin and 0.10%-0.25%, 0.25%-0.75%, 0.75%- 1.5%,
  • a combination treatment described herein comprises 1.46% w/w lithium carbonate (2.74 mg Li+/g), 5.66%> w/w lithium carbonate (10.64 mg Li+/g), or
  • a combination treatment described herein comprises 1.46% w/w lithium carbonate (2.74 mg Li+/g) and 0.5% - 2.5%, 0.75% - 2.75%, 1.0% - 3%, 1.25% - 3.25 %, 1.5% - 3.5 %, 1.75% - 3.75%, or 0.1% - 5% mupirocin.
  • a combination treatment described herein comprises 5.66% w/w lithium carbonate (2.74 mg Li+/g) and 0.5% - 2.5%, 0.75% - 2.75%, 1.0% - 3%, 1.25% - 3.25 %, 1.5% - 3.5 %>, 1.75%) - 3.75%), or 0.1 % - 5% mupirocin.
  • a combination treatment described herein comprises 11.5% w/w lithium carbonate (2.74 mg Li+/g) and 0.5% - 2.5%, 0.75% - 2.75%, 1.0% - 3%, 1.25% - 3.25 %, 1.5% - 3.5 %, 1.75% - 3.75%, or 0.1% - 5% mupirocin.
  • a combination treatment described herein comprises 1.46% w/w lithium carbonate (2.74 mg Li+/g) and 2% mupirocin. In another specific embodiment, a combination treatment described herein comprises 5.66% w/w lithium carbonate (2.74 mg Li+/g) and 2% mupirocin. In another specific embodiment, a combination treatment described herein comprises 11.5% w/w lithium carbonate (2.74 mg Li+/g) and 2% mupirocin.
  • lithium carbonate and mupirocin for use in treating a microbial infection prepared to be administered as 5.66% w/w lithium carbonate (2.74 mg Li+/g) and 2% mupirocin.
  • a combination of lithium carbonate and mupirocin for use in treating a microbial infection or a microbial colonization prepared to be administered as
  • compositions formulated for topical administration comprising lithium carbonate, mupirocin, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is formulated as a hydrogel comprising 0.18%-1 1.5% w/w lithium carbonate, 2% mupirocin, glycerol, carboxymethyl cellulose, allantoin, sodium alginate, methyl paraben, and propyl paraben.
  • the pharmaceutical composition is formulated as a cream comprising 0.18%-11.5 % w/w lithium carbonate, 2% mupirocin Citric Acid, Carbopol 980, Tween 20, Cetearyl Alcohol, Silicon 350 CSt, Silicon 12,500 CSt, Span 80, Lanolin Alcohol, and Emulsifier 10.
  • the pharmaceutical is formulated as a cream comprising 0.18%-11.5 % w/w lithium carbonate, Citric Acid, Carbopol 980, Tween 20, Cetearyl Alcohol, D350 Mineral Oil, Span 80, Lanolin Alcohol, and Emulsifier 10.
  • the pharmaceutical composition is formulated as a cream comprising 0.18%-11.5 % w/w lithium carbonate, 2% mupirocin, Citric Acid, Carbopol 980, Tween 20, Lecithin, Silicon 350 CSt, D350 Mineral Oil, Span 80, Lanolin Alcohol, and Emulsifier.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid,
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1 % alginate, 5% glycerol, 5% citric acid, distilled water, 2% mupirocin and 1.46% lithium carbonate.
  • Concentrations of citric acid may be varied from 5%-10% w/w.
  • Concentrations of lithium carbonate can be varied from 1%-15%.
  • Concentrations of glycerol may be varied from 1%-10%.
  • Boric acid may be used instead of citric acid, in concentrations 5-10% w/w.
  • Hydrochloric acid may be used in conjunction with citric acid or boric acid, for the purpose of adjusting pH to a physiologically acceptable formulation for wounds.
  • Hyaluronic acid at concentrations 0.1-2% may be used instead of carboxymethylcellulose (CMC).
  • CMC carboxymethylcellulose
  • Other polymers to be used instead of CMC may be hydroxyethyl cellulose (0.1-2%), hydroxypropylmethyl cellulose (0.1%>), Xanthan Gum (0.1- 1%), Guar Gum (0.1-1%).
  • the pharmaceutical composition is formulated as a hydrogel comprising carbomethylcellulose, allantoin, alginate, glycerol, citric acid, distilled water, mupirocin and lithium carbonate.
  • the pharmaceutical compisitoin is formulated as a hydrogel comprising 0.5% to 3% mupirocin
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 0.5% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 0.5% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 1% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid,
  • composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1%
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin, and 11.5% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid, distilled water, 3% mupirocin and 5.66% lithium carbonate.
  • the pharmaceutical composition is formulated as a hydrogel comprising 1% carbomethylcellulose, 0.1% allantoin, 0.1% alginate, 5% glycerol, 5% citric acid,
  • composition is formulated as a hydrogel comprising 1%
  • composition is formulated as a hydrogel comprising 1%
  • the combination treatment is formulated as an "immediate release" formulation, i.e., releases 90-100% of Li+ within the first day of administration.
  • a combination treatment is formulated as an immediate release formulation as described in greater detail in Section 6.12.1 infra.
  • the combination treatment is formulated as a "Sustained Release" formulation, i.e., releases 90-100% of Li+ within 3 to 7 days of administration.
  • a combination treatment is formulated as a sustained release formulation as described in greater detail in Section 6.12.3 infra.
  • the combination treatment comprises administering immediate release mupirocin and immediate release lithium carbonate. In another embodiment, the combination treatment comprises administering sustained release mupirocin and sustained release lithium carbonate. In another embodiment, the combination treatment comprises administering sustained release mupirocin and immediate release lithium carbonate. In another embodiment, the combination treatment comprises administering immediate release mupirocin and sustained release lithium carbonate.
  • the combination treatment comprises administering both sustained release and immediate release lithium carbonate and immediate release mupirocin. In an embodiment, the combination treatment comprises administering both sustained release and immediate release lithium carbonate and sustained release mupirocin. In an embodiment, the combination treatment comprises administering both sustained release and immediate release mupirocin and immediate release lithium carbonate. In an embodiment, the combination treatment comprises administering both sustained release and immediate release mupirocin and sustained release lithium carbonate. In an embodiment, the combination treatment comprises administering both sustained release and immediate release mupirocin and both sustained release and immediate release lithium carbonate.
  • the combination treatment comprising lithium carbonate and mupirocin is bactericidal.
  • the combination treatment comprising lithium carbonate and mupirocin causes a decrease in bacterial load by at least 10%, 20%>, 30%>, 40%>, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
  • the combination treatment comprising lithium carbonate and mupirocin inhibits tRNA synthetase activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
  • the combination treatment comprising lithium carbonate and mupirocin inhibits protein synthesis by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. In another embodiment, the combination treatment comprising lithium carbonate and mupirocin inhibits DNA synthesis by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. In another embodiment, the combination treatment comprising lithium carbonate and mupirocin inhibits cell wall synthesis by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
  • the combination treatment comprising lithium carbonate and mupirocin does not inhibit R A synthesis, more specifically R A synthesis is inhibited by at most 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
  • the combination treatment comprising lithium carbonate and mupirocin inhibits tRNA synthetase, protein synthesis, lipid synthesis, DNA synthesis, and cell wall synthesis by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.
  • the combination treatment comprising lithium carbonate and mupirocin inhibits lipid synthesis by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%. or 100%.
  • the combination treatment comprising lithium carbonate and mupirocin causes a decrease in bacterial load 10%>, 20%>, 30%>, 40%>, 50%>, 60%>, 70%>, 80%, 90%, 95%, or 99% faster than 2% mupirocin alone.
  • the combination treatment comprising lithium carbonate and mupirocin causes a decrease in bacterial load 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% faster than 11.5% lithium carbonate alone.
  • the combination treatment comprising lithium carbonate and mupirocin causes a decrease in bacterial load in pathogens selected from the following: gram-positive pathogens, including but not limited to Staphylococcus aureus, methicillin resistant Staphylococcus aureus, Streptococcus pyogenes, and gram-negative bacteria including but not limited to Haemophilus influenzae, Neisseria spp., and Bordetella pertussis.
  • pathogens selected from the following: gram-positive pathogens, including but not limited to Staphylococcus aureus, methicillin resistant Staphylococcus aureus, Streptococcus pyogenes, and gram-negative bacteria including but not limited to Haemophilus influenzae, Neisseria spp., and Bordetella pertussis.
  • An article of manufacture comprises a combination of lithium carbonate and mupirocin described herein formulated as wound dressings, which can be in the form of barriers, membranes, or films.
  • a combination of lithium carbonate and mupirocin is added to dressing backings, such as barriers, membranes, or films.
  • a barrier, membrane, or film can be supplied in a variety of standard sizes, which can be further cut and sized to the area being treated.
  • the backing can be a conventional dressing material, such as a bandage or gauze to which lithium carbonate and mupirocin described herein is added or coated on, prior to application to the patient.
  • a combination of lithium carbonate and mupirocin can be formulated as a nasal spray to treat or reduce nasal colonization.
  • a combination of lithium carbonate and mupirocin can be formulated as a barrier, membrane, or film made out of strings, microbeads, microspheres, or microfibrils, or the composition can be formulated as a barrier- forming mat.
  • a combination of lithium carbonate and mupirocin can be formulated as a spray that can be sprayed on to skin or a wound to treat infection, and reduce or eradicate colonization (see Section 5.11 for a detailed description of a spray delivery system).
  • a combination of lithium carbonate and mupirocin can be formulated as a spray that can be sprayed on to skin or a wound as a protective layer (see Section 5.11 for a detailed description of a spray delivery system).
  • a combination of lithium carbonate and mupirocin can also be formulated as a component of a wipe or spray to disinfect surfaces.
  • the combination treatment comprises lithium carbonate and a tRNA synthetase inhibitor selected from the following: mupirocin, L-tryptophan, indolmycin, chuangxinmycin, borrelidin, granaticin, furanomycin, ochratoxin A, and cispentacin.
  • mupirocin and lithium carbonate are co-mixed as a simple cream.
  • a combination treatment comprising a lithium compound described herein and chlorhexidine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination of a lithium compound described herein and chlorhexidine can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a combination treatment comprising a lithium compound described herein, chlorhexidine, and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination of a lithium compound described herein, chlorhexidine, and mupirocin can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a topical formulation of a combination treatment comprising a lithium compound described herein and chlorhexidine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to,
  • Escherichia coli Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • a topical formulation of a combination treatment comprising a lithium compound described herein and chlorhexidine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • chlorhexidine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • a topical formulation of a combination treatment comprising a lithium compound described herein, chlorhexidine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to,
  • Escherichia coli Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • a topical formulation of a combination treatment comprising a lithium compound described herein, chlorhexidine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • topical formulations of a combination treatment comprising a lithium compound described herein, chlorhexidine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • a combination treatment comprising a lithium compound described herein and iodine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination of a lithium compound described herein and iodine can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a combination treatment comprising a lithium compound described herein, iodine, and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination of a lithium compound described herein, iodine, and mupirocin can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a topical formulation of a combination treatment comprising a lithium compound described herein and iodine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidi
  • a topical formulation of a combination treatment comprising a lithium compound described herein and iodine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • topical formulations of a combination treatment comprising a lithium compound described herein and iodine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • a topical formulation of a combination treatment comprising a lithium compound described herein, iodine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to,
  • Escherichia coli Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • a topical formulation of a combination treatment comprising a lithium compound described herein, iodine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • topical formulations of a combination treatment comprising a lithium compound described herein, iodine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • a combination treatment comprising a lithium compound described herein and povidone -iodine is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination of a lithium compound described herein and povidone-iodine can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a combination treatment comprising a lithium compound described herein, povidone-iodine, and mupirocin is administered to a subject to prevent, reduce, or eradicate colonization of methicillin resistant Staphylococcus aureus.
  • a combination of a lithium compound described herein, povidone-iodine, and mupirocin can be formulated as a hand or body wash, a wound dressing, which can be in the form of barriers, membranes, or films, a gel, a lotion, a cream, an ointment, a surgical scrub, or a spray that can be sprayed on to skin or a wound as a protective layer.
  • a topical formulation of a combination treatment comprising a lithium compound described herein and povidone-iodine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to,
  • Escherichia coli Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • a topical formulation of a combination treatment comprising a lithium compound described herein and povidone-iodine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • topical formulations of a combination treatment comprising a lithium compound described herein and povidone- iodine is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • a topical formulation of a combination treatment comprising a lithium compound described herein, povidone-iodine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram-positive aerobes, and Bacteroides fragilis.
  • bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acne
  • a topical formulation of a combination treatment comprising a lithium compound described herein, povidone-iodine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • topical formulations of a combination treatment comprising a lithium compound described herein, povidone-iodine, and mupirocin is administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • the combination treatment comprises lithium and an antibacterial agent selected from, e.g., benzyl alcohol, methyl paraben ethanol, isopropanol, glutaraldehyde, formaldehyde, chlorine compounds, iodine compounds, hydrogen peroxide, peracetic acid, ethylene oxide, triclocarban, chlorhexidine, alexidine, triclosan,
  • an antibacterial agent selected from, e.g., benzyl alcohol, methyl paraben ethanol, isopropanol, glutaraldehyde, formaldehyde, chlorine compounds, iodine compounds, hydrogen peroxide, peracetic acid, ethylene oxide, triclocarban, chlorhexidine, alexidine, triclosan,
  • hexachlorophene polymeric biguanides, aminoglycoside antibiotics, glycopeptides, amphenicol antibiotics, ansamycin antibiotics, cephalosporins, cephamycins oxazolidinones, penicillins, quinolones, streptogamins, tetracyclins and analogs thereof, ampicillin, amoxicillin, ciprofloxacin, gentamycin, kanamycin, neomycin, penicillin G, streptomycin, sulfanilamide, and vancomycin, azithromycin, cefonicid, cefotetan, cephalothin, cephamycin, chlortetracycline, clarithromycin, clindamycin, cycloserine, dalfopristin, doxycycline, erythromycin, linezolid, mupirocin, oxytetracycline, quinupristin, rifampin, spectinomycin, and
  • bacampicillin benzylpenicillinic acid, benzylpenicillin sodium, epicillin, fenbenicillin, floxacillin, penamccillin, penethamate hydriodide, penicillin o benethamine, penicillin 0, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, and phencihicillin potassium), quinolones and analogs thereof (e.g., cinoxacin, ciprofloxacin, clinafloxacin, flumequine, grepagloxacin, levofloxacin, and moxifloxacin), streptogramins (e.g., quinupristin and dalfopristin), sulfonamides (e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide, phthalylsulfacetamide,
  • Additional examples include cycloserine, mupirocin, tuberin amphomycin, bacitracin, capreomycin, colistin, enduracidin, enviomycin, and 2,4 diaminopyrimidines (e.g., brodimoprim), isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, erythromycin, azithromycin,
  • 2,4 diaminopyrimidines e.g., brodimoprim
  • isoniazid isoniazid
  • rifampin pyrazinamide
  • streptomycin erythromycin
  • azithromycin azithromycin
  • the combination treatment comprises lithium and an antifungal agent selected from, e.g., 5-fluorocytosine, Abafungin, Acrisorcin, Amorolfme, Albaconazole, Albendazole, Amorolfme, Anidulafungin, Arasertaconazole, Azithromycin, Becliconazole, Benzodithiazole, Bifonazole, Butenafme, Butoconazole, Calbistrin, Caspofungin, Chloroxine, Chlorphenesin, Ciclopiroxolamine, Ciclopirox, Cioteronel, Clotrimazole, Croconazole, Cytoporins, Deoxymulundocandin, Eberconazole, Econazole, Efungumab, Fenticonazole, Flavanoid glycosides, Fluconazole, Flutrimazole, Flucytosine, Fosfluconazole, Genacon
  • an antifungal agent selected from
  • Tafenoquine Terconazole, Tioconazole, Tolnaftate, Voriconazole
  • the combination treatment comprises lithium treatment in combination with one or more treatments selected from, e.g., cell therapy (such as a stem cell), a formulation for gene therapy (such as, e.g., a virus, virus-like particle, virosome), an antibody or antigen-binding fragment thereof, an herb, a vitamin (e.g., a form of vitamin E, a vitamin A derivative, such as, e.g. , all-trans retinoic acid (ATRA), a B vitamin, such as, e.g.
  • cell therapy such as a stem cell
  • a formulation for gene therapy such as, e.g., a virus, virus-like particle, virosome
  • an antibody or antigen-binding fragment thereof an herb
  • a vitamin e.g., a form of vitamin E, a vitamin A derivative, such as, e.g. , all-trans retinoic acid (ATRA)
  • a B vitamin such as, e.g.
  • a shampoo ingredient e.g., ammonium chloride, ammonium lauryl sulfate, glycol, sodium laureth sulfate, sodium lauryl sulfate, ketoconazole, zinc pyrithione, selenium sulfide, coal tar, a salicylate derivative, dimethicone, or plant extracts or oils
  • a conditioning agent e.g., a soap product, a moisturizer, a sunscreen, a waterproofing agent, a powder, talc, or silica, an oil-control agent, alpha- hydroxy acids, beta-hydroxy acids (e.g., salicylic acid), poly-hydroxy acids, benzoyl peroxide, antiperspirant ingredients, such as astringent salts (e.g. , zinc salts, such
  • chlorohydrex PEG aluminum chlorohydrex PG, aluminum dichlorohydrate, aluminum dichlorohydrex PEG, aluminum dichlorohydrex PG, aluminum sesquichlorohydrate, aluminum sesquichlorohydrex PEG, aluminum sesquichlorohydrex PG, aluminum sulfate, aluminum zirconium octachlorohydrate, aluminum zirconium octachlorohydrex GLY
  • a massage agent e.g., an exfoliant, an anti-itch agent, a pro-inflammatory agent, an immunostimulant (e.g., interferon, cytokines, agonists or antagonists of various ligands, receptors and signal transduction molecules of the immune system, immunostimulatory nucleic acids, an adjuvant that stimulates the immune response and/or which causes a depot effect).
  • an immunostimulant e.g., interferon, cytokines, agonists or antagonists of various ligands, receptors and signal transduction molecules of the immune system, immunostimulatory nucleic acids, an adjuvant that stimulates the immune response and/or which causes a depot effect.
  • adjuvants and/or other stimulators of local cytokines are used in conjunction with the intermittent lithium treatment or pulse lithium treatment.
  • one rationale for administering adjuvants and/or other stimulators of local cytokines in conjunction with the lithium treatment is that the production of local cytokines may induce changes in an infected wound and recruit new stem cells to the wound.
  • compositions of the invention are used in combination with one or more adjuvants.
  • the adjuvant(s) can be administered separately or present in a pharmaceutical composition in admixture with pharmaceutical compositions of the invention of the invention.
  • a systemic adjuvant is an adjuvant that can be delivered parenterally.
  • Systemic adjuvants include adjuvants that creates a depot effect, adjuvants that stimulate the immune system and adjuvants that do both.
  • An adjuvant that creates a depot effect as used herein is an adjuvant that causes the antigen to be slowly released in the body, thus prolonging the exposure of immune cells to the antigen.
  • This class of adjuvants includes but is not limited to alum (e.g., aluminum hydroxide, aluminum phosphate); or emulsion-based formulations including mineral oil, non-mineral oil, water-in- oil or oil-in-water-in oil emulsion, oil-in-water emulsions such as Seppic ISA series of Montanide adjuvants (e.g., Montanide ISA 720, AirLiquide, Paris, France); MF-59 (a squalene-in-water emulsion stabilized with Span 85 and Tween 80; Chiron Corporation, Emeryville, Calif; and PRO VAX (an oil-in-water emulsion containing a stabilizing detergent and a micelle-forming agent; IDEC, Pharmaceuticals Corporation, San Diego, Calif).
  • alum e.g., aluminum hydroxide, aluminum phosphate
  • emulsion-based formulations including mineral oil, non-mineral oil, water-in- oil or oil-in-water
  • adjuvants stimulate the immune system, for instance, cause an immune cell to produce and secrete cytokines or IgG.
  • This class of adjuvants includes but is not limited to immunostimulatory nucleic acids, such as CpG oligonucleotides; saponins purified from the bark of the Q. saponaria tree, such as QS21 (Antigenics, MA); derivatives of
  • LPS lipopolysaccharides
  • MPL monophosphoryl lipid A
  • MDP muramyl dipeptide
  • t-MDP threonyl-muramyl dipeptide
  • systemic adjuvants are adjuvants that create a depot effect and stimulate the immune system. These compounds are those compounds which have both of the above- identified functions of systemic adjuvants.
  • This class of adjuvants includes but is not limited to ISCOMs (Immunostimulating complexes which contain mixed saponins, lipids and form virus-sized particles with pores that can hold antigen; CSL, Melbourne, Australia); AS01B (Glaxo SmithKline adjuvant system) which is a liposome based formulation containing MPL and QS21 ; AS02A (Glaxo SmithKline adjuvant system) which is an oil-in-water-based formulation containing MPL and QS21 , and AS 15 (Glaxo SmithKline adjuvant system) which is a formulation containing QS21 , CpG oligonucleotides and MPL.
  • the mucosal adjuvants useful according to the invention are adjuvants that are capable of inducing a mucosal immune response in a subject when administered to a mucosal surface in conjunction with a pharmaceutical composition of the invention.
  • Mucosal adjuvants include but are not limited to CpG nucleic acids (e.g. International Publication No. WO 99/61056) and Bacterial toxins: e.g., Cholera toxin (CT).
  • the combination treatment comprises lithium in
  • a hormonal agonist e.g., flutamide, bicalutamide, tamoxifen, raloxifene, leuprolide acetate (LUPRON), LH-RH antagonists
  • a steroid e.g., a steroid
  • aspirin, ibuprofen, diclofenac, and COX-2 inhibitors pain relievers, leukotreine antagonists (e.g., montelukast, methyl xanthines, zafirlukast, and zileuton), beta2-agonists (e.g.
  • hexylresorcinol methylbenzethonium chloride, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, glycerin, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium proprionate, sorbic acid, and thiomersal (thimerosal)).
  • the combination treatment comprises lithium treatment in combination with one or more narcotic analgesics, selected from the group of, e.g., alfentanil, benzylmorphine, codeine, codeine methyl bromide; codeine phosphate, codeine sulfate, desomorphine, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, ethylmorphine, hydrocodone, hydromorphone, methadone hydrochloride, morphine, morphine hydrochloride, morphine sulfate, nicomorphine, normethadone, normorphine, opium, oxycodone, oxymorphone, phenoperidine, and propiram.
  • one or more narcotic analgesics selected from the group of, e.g., alfentanil, benzylmorphine, codeine, codeine methyl bromide; codeine phosphate, codeine sulfate,
  • the combination treatment comprises intermittent lithium treatment or a pulse lithium treatment in combination with one or more non-narcotic analgesics, selected from the group of, e.g., aceclofenac, acetaminophen, acetanilide, acetylsalicylsalicylic acid; aspirin, carbamazepine, dihydroxyaluminum acetylsalicylate, fenoprofen, fluproquazone, ibufenac, indomethacin, ketorolac, magnesium acetylsalicylate, morpholine salicylate, naproxen, phenacetin, phenyl salicylate, salacetamide, salicin, salicylamide, sodium salicylate, and tolfenamic acid.
  • Other pain treatments that may be used in combination with the lithium treatments described herein include nerve blocks or non-traditional pain medications, such as, e.g., Lyrica (pregabalin) or Neuront
  • a combination treatment comprises a lithium treatment in combination with an agent that also modulates wound healing, including any treatment known in the art to modulate wound healing, including any treatment describe in
  • the lithium treatment is administered in combination with a treatment that enhances one or more of the steps of wound healing discussed above, including any treatment described herein or known in the art to enhance wound healing.
  • a treatment that enhances one or more of the steps of wound healing discussed above including any treatment described herein or known in the art to enhance wound healing.
  • enhancement of a step of wound healing or enhancement of wound healing is meant the hastening of healing, improvement of healing, or reduction of scarring, etc.
  • the lithium treatment is administered in combination with a wound dressing or skin replacement, such as, for example, gauze, calcium-alginates, impregnated gauzes, films, foams, hydrogels, hydrocolloids, adsorptive powders and pastes, silicone, mechanical vacuum, dermal matrix replacements, dermal living replacements, or skin living replacements, a collagen dressing, cadaveric skin, or other matrix useful to promote healing of the wound such as described herein or known in the art. See, e.g., Table 10.3 in Lorenz & Longaker, which is incorporated by reference herein in its entirety.
  • the lithium treatment is administered in combination with a pain reliever, antibiotic and anti-bacterial use or other anti-infectives (such as, e.g., tea tree oil), debridement, drainage of wound fluid, mechanical removal of bacteria, removal of devitalized tissue (such as, e.g., by surgery or maggot therapy), irrigation (e.g., by pulsed lavage), vacuum-assisted closure (otherwise referred to as negative pressure wound therapy), warming, oxygenation (e.g., using hyperbaric oxygen therapy), antioxidant therapy, revascularization therapy, moist wound healing, removing mechanical stress, use of elastase inhibitors, or adding cells or other materials to secrete or enhance levels of healing factors.
  • a pain reliever such as, e.g., tea tree oil
  • debridement such as, e.g., tea tree oil
  • debridement such as, e.g., tea tree oil
  • drainage of wound fluid such as, e.g., by surgery or maggot therapy
  • irrigation
  • the lithium treatment is administered in combination with the upregulation of endogenous growth factors or exogenous application of growth factors, which may accelerate normal healing and improve healing efficacy.
  • growth factors include, but are not limited to, vascular endothelial growth factor (VEGF), insulin-like growth factor 1-2 (IGF), PDGF, transforming growth factor- ⁇ (TGF- ⁇ ), epidermal growth factor (EGF), EGF-receptor, members of the FGF family, and others described herein and listed in, e.g., Table 10.2 in Lorenz & Longaker, which is incorporated by reference herein in its entirety.
  • Such growth factors can be applied exogenously or may be applied by spreading onto the wound a gel of the patient's own platelets, implanting cultured keratinocytes into the wound, or treating the wound with artificial skin substitutes that have fibroblasts and keratinocytes in a matrix of collagen.
  • the lithium treatment is administered in combination with a treatment that reduces the time it takes for an infected wound to heal or that reduces the extent of the wound.
  • treatments include, for example, periodic rotation of the patient or wounded tissue or use of an air mattress, use of a lower pressure cast or relieving excessive suture tension, cleansing of the wound, debridement of tissue, particularly necrotic tissue, improvement of circulation and oxygen delivery to the tissue by, e.g., hyperbaric oxygen therapy or other oxygen administration, whirlpool therapy, ultrasound therapy, electrical stimulation, magnetic therapy have been utilized to aid the body in healing wounds coverage of wound with vascularized tissue, revascularization of the wounded tissue, treatment of circulatory obstruction or other treatment that improves circulation, treatment of ischemia, edema, or hypoxia, or improvement of the hematocrit (e.g., to at least 15%).
  • Treatment of tissue necrosis e.g., with antibiotics such as povidone -iodine, chlorhexidine gluconate, hexachlorophene, or silver sulfadiazine and others described herein (particularly for burn wound care), irrigation (e.g., with saline), and/or debridement), improvement of nutrition (e.g., increasing intake of vitamins, e.g., vitamin A, C, Bl, B2, B5, or B6, or trace metals, such as, e.g., zinc and copper, amino acids such as arginine, glutamine, or Bromelain, Curcumin, etc.), herbal supplements (e.g., Aloe Vera, Centella), diabetes treatment (for example, to improve vascular conditions, or by administering glucose), skin graft, treatment with hormones (such as estrogen) or treatment with growth factors (e.g., epidermal growth
  • the lithium treatment is administered in combination with a treatment that slows the natural adult wound healing process.
  • such combination treatments are used in the presence of a sterile wound dressing that obviates the need to heal the wound quickly (for example, in natural wound healing, the wound heals quickly in order to avoid infection).
  • the lithium treatment is administered in combination with a treatment that causes the postnatal wound healing process to resemble the fetal wound healing process. In some embodiments, this is accomplished by placing the wounded skin into a womb-like environment, for example, using a dressing and/or heat.
  • the lithium treatment is administered in combination with an agent that reduces or inhibits the inflammatory phase of wound healing, using, e.g., an antiinflammatory agent such as a NSAID or a topical glucocorticoids, an anti-androgen, or an antagonist of TNFa, TGFp, NFkB, IL-1, IL-6, IL-8, IL-10, IL-18, or an antagonist of one or more other proinflammatory cytokines.
  • the lithium treatment is administered in combination with an agent that slows the wound healing process by extending the inflammatory phase, e.g., an androgen (see, e.g., Gilliver et al, 2007, Clin. Dermatol. 25:56-62).
  • the treatment is administered in combination with an agent that suppresses the proliferative phase of wound healing, or the maturation and remodeling phase of wound healing.
  • the treatment is administered in combination with an agent that slows or interferes with fibrin deposition, clotting caused by fibrin, or fibrin-induced immunity.
  • the treatment is administered in combination with a treatment that inhibits the activity of fibrinogen.
  • the treatment is administered in combination with an agent that decreases the activity of myofibroblasts.
  • the treatment is administered in combination with a treatment that reduces collagen synthesis, deposition, or accumulation, for example, collagenases.
  • the treatment is administered in combination with a treatment that maintains the wound in an open state for a longer than normal period of time.
  • a treatment is administered in combination with rapamycin or corticosteroids.
  • a biocompatible, synthetic skin substitute is placed on the wound, especially if the wound is deep, covers large area, and is bulk ablated. This process can help minimize or prevent the rapid wound contraction that occurs after loss of a large area of tissue, frequently culminating in scar tissue formation and loss of skin function.
  • the biocompatible synthetic skin substitute is impregnated with depots of a slow releasing lithium formulation described herein. This method of treatment may enable treating a large area in one session at the treatment clinic.
  • other molecules are also co-eluted at the site through the skin substitute, such as, e.g. , anesthetics and antibiotics, to prevent further pain and minimization of infection, or any other compound described herein.
  • the skin substitute in the presence or absence of a lithium compound and/or other compounds described herein, may also be pre-cooled and applied to the wound to provide a feeling of comfort to the patient. This mode of lithium or other compound application may prevent the lithium or other compound from being cleared away from the wound site as the wound heals.
  • a lithium treatment is administered in combination with a treatment that also reduces the appearance or extent of scarring, including any treatment known in the art to modulate wound healing, including any treatment described in
  • a lithium treatment is administered in combination with a treatment that improves the appearance and/or function of scarred skin, including any such treatment described herein or known in the art.
  • a lithium treatment is administered in combination with a treatment for scar revision or a treatment that improves the texture or appearance of skin, such as skin graft, serial expansion of surrounding skin, laser treatment, or
  • a pulse lithium treatment is administered in combination with re-excision with subsequent healing by primary intention, treatment with steroids (e.g., corticosteroid injection), silicone scar treatments ⁇ e.g., dimethicone silicone gel or silicone sheeting), use of porcine fillers or other cosmetic fillers ⁇ e.g., inserted under atrophic scars), ribosomal 6 kinase (RSK) antagonists, antagonists of pro-inflammatory cytokines, such as TGFP2 or TNF, osteopontin antagonists, the use of pressure garments, needling, dermabrasion, collagen injections, low-dose radiotherapy, or vitamins ⁇ e.g., vitamin E or vitamin C or its esters).
  • steroids e.g., corticosteroid injection
  • silicone scar treatments ⁇ e.g., dimethicone silicone gel or silicone sheeting
  • porcine fillers or other cosmetic fillers ⁇ e.g., inserted under atrophic scars
  • RSK ribosomal 6
  • a lithium treatment is administered in combination with a treatment that also reduces surgical scarring, e.g., by placement of elective incisions parallel to the natural lines of skin tension (Langer's lines) or by applying sutures in a "zigzag" pattern.
  • the lithium treatment is administered in combination with a treatment of wounds that also minimizes scarring, by, for example, administering physical therapy to a subject (e.g., range-of-motion exercises), reducing separation of wound edges, minimizing collagen synthesis, deposition, or accumulation or otherwise causing the process of healing by secondary intention to better resemble healing by primary intention.
  • the lithium treatments described herein may be administered in combination with methods of integumental perturbation.
  • a lithium treatment described herein is used together with a method for integumental perturbation in order to improve the skin, for example, to promote wound healing or scar revision
  • a lithium treatment described herein is administered in combination with a method of scar revision (which involves wounding), for example, serial expansion, surgical excision of the wound and surrounding normal tissue (e.g., in which a jagged surgical incision is created so that the lines of tension of the skin are parallel to the incisions), dermabrasion to remove epidermis and papillary dermis, needling, subcision, or laser, such as pulsed dye laser or nonablative fractional laser.
  • enhancement of wound healing or scar revision is accomplished by lithium treatment alone, for example, in acutely wounded skin or skin affected by a chronic non-healing wound, i.e., skin already subjected to integumental perturbation.
  • enhancement of wound healing or scar revision is accomplished by a combination of integumental perturbation and a lithium treatment.
  • Integumental perturbation can be used to induce, for example, a burn, excision,
  • dermabrasion dermabrasion, full-thickness excision, or other form of abrasion or wound.
  • Mechanical means of integumental perturbation include, for example, use of sandpaper, a felt wheel, ultrasound, supersonically accelerated mixture of saline and oxygen, tape-stripping, spiky patch, or peels.
  • Chemical means of integumental perturbation can be achieved, for example, using phenol, trichloroacetic acid, or ascorbic acid.
  • Electromagnetic means of integumental perturbation include, for example, use of a laser (e.g., using lasers, such as those that deliver ablative, non-ablative, fractional, non-fractional, superficial or deep treatment, and/or are C0 2 -based, or Erbium- YAG-based, neodymium:yttrium aluminum garnet (Nd:YAG) laser, etc.).
  • Integumental perturbation can also be achieved through, for example, the use of visible, infrared, ultraviolet, radio, or X-ray irradiation.
  • integumental perturbation is by light energy, such as described in Leavitt et al, 2009, Clin. Drug. Invest. 29:283-292.
  • Integumental perturbation can also be achieved through surgery, for example, a biopsy, a skin transplant, skin graft, follicular unit extraction, hair transplant, cosmetic surgery, open-heart surgery, etc.
  • integumental perturbation is by laser treatment.
  • Exemplary laser treatments for integumental perturbation include Fraxel, laser abrasion, Erbium- YAG laser, Ultrapulse C0 2 fractional laser, Ultrapulse C0 2 ablative laser, Smooth Peel Full-ablation Erbium laser (Candela).
  • integumental perturbation by laser treatment is by a fractional laser.
  • a fractional laser treatment is treatment with an Erbium- YAG laser at around 1540 nm or around 1550 nm (for example, using a Fraxel® laser (Solta Medical)).
  • Another example is a C0 2 laser at 10,600 nm.
  • the laser treatment is ablative and fractional.
  • fractional tissue ablation can be achieved using a C0 2 laser at 10,600 nm or an Erbium- YAG laser at 2940 nm (e.g., the Lux 2940 laser, Pixel laser, or Profractional laser).
  • the mode of laser treatment is non-ablative.
  • Lasers that are non-ablative include the pulsed dye laser (vascular)(at, e.g., 585-595 nm), the 1064 Nd:YAG laser, or the Erbium- YAG laser at 1540 nm or 1550 nm (e.g., the Fraxel® laser).
  • the mode of laser treatment is fractional and non-ablative, which can be accomplished, e.g., using the Erbium- YAG laser with an emission at or around 1540 nm or 1550 nm.
  • integumental perturbation is by dermabrasion (also referred to herein as "DA").
  • Dermabrasion may be carried out using any technique known in the art or as described herein, for example, using the novel dermabrasion tip described herein.
  • dermabrasion may be carried out using standard DA with aluminum oxide crystals using the Aseptico Econo-Dermabrader, Advance Microderm DX system, or M2-T system; standard DA with Bell Hand Engine with diamond fraize; etc.
  • DA is carried out using an abrasive wheel.
  • DA with an abrasive wheel is used in order to achieve pinpoint bleeding.
  • DA may be carried out using an abrasive wheel to achieve larger globules of bleeding and frayed collagen.
  • non-powered devices such as abrasive cloths can also be used to achieve the DA, with the optional achievement of the same endpoint(s).
  • DA is accomplished using a device typically used for microdermabrasion.
  • DA is accomplished by removal of surface skin by particle bombardment (also referred to herein as "particle mediated dermabrasion" (“PMDA”)), for example, with alumina-, ice- or silica-based particles.
  • particle bombardment also referred to herein as "particle mediated dermabrasion” (“PMDA)
  • PMDA particle mediated dermabrasion
  • micron- sized particles are propelled toward the surface of the skin via short strokes of a handpiece, such as a particle gun, as known in the art.
  • the velocity of particles is controlled through positive or negative pressure.
  • the depth of skin removed by particle bombardment DA (e.g., PMDA) is a function of the volume of particles impacting the skin, the suction or positive pressure, the speed of movement of the handpiece, and the number of passes per area of the skin.
  • integumental perturbation by one or more of the aforementioned methods achieves removal of part or all of the epidermis. In some embodiments, integumental perturbation by one or more of the aforementioned methods achieves removal of part of the epidermis. In some embodiments, integumental perturbation removes the entire epidermis. In some embodiments, integumental perturbation disrupts the papillary dermis. In some embodiments, integumental perturbation removes the papillary dermis. In some embodiments, integumental perturbation removes the reticular dermis. The depth of integumental perturbation depends on the thickness of the skin at a particular treatment area.
  • the skin of the eyelid is significantly thinner than that of the scalp.
  • the occurrence of pinpoint bleeding indicates that the epidermis and portions of the dermis have been removed. Deeper penetration can results in much more bleeding, and the perturbation can go as deeps as the hypodermis.
  • integumental perturbation by one or more of the aforementioned methods is to a skin depth of 60 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 60-100 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 100 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 150 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 100-500 ⁇ . In some embodiments, integumental perturbation is to a skin depth of less than 500 ⁇ . In some embodiments, integumental perturbation is to a skin depth of 500- 1000 ⁇ .
  • integumental perturbation is to a skin depth of 1 mm or more. In some embodiments, integumental perturbation is to a skin depth of 1 mm to 3 mm. In some embodiments, integumental perturbation is to a skin depth of 1 mm to 5 mm.
  • the approaches described herein permit wound healing and scar revision under sterile and controlled conditions that recreates and harnesses the fetal skin's plastic and regenerative capacity.
  • the present invention is based, in part, on the
  • hair follicles play a role in wound healing. Inducing the formation of new hair follicles in wounds, or enhancing the entry of hair follicles into wounds (for example, by transplanting hair follicles into wounds) may harness their regenerative capacity and provide a transformational approach to scar revision and the management of wounds.
  • the invention is based in part on the discovery that there is a correlation between the extent of wound contraction and the deposition of adnexal structures, such as new hair follicles, in wounded areas.
  • adnexal structures such as new hair follicles
  • lithium treatments may promote wound healing and scar revision by, at least in part, promoting the entry of hair follicles into the wound as it heals. This may occur by inducing the generation of new hair follicles and/or promoting migration of hair follicles into the wound site.
  • wounded skin which may be wounded as part of the process of scar revision
  • proper hair patterning in the skin e.g., scalp, arm, leg, chest, etc.
  • a lithium treatment described herein may be in combination with a method for enhancing hair growth or preventing or delaying hair loss.
  • the lithium treatments e.g., a pulse or intermittent lithium treatment, described herein can be administered concurrently or alternating sequentially with one or more of the following treatments that prevent follicle senescence, for example, anti-oxidants such as glutathione, ascorbic acid, tocopherol, uric acid, or polyphenol antioxidants); inhibitors of reactive oxygen species (ROS) generation, such as superoxide dismutase inhibitors;
  • ROS reactive oxygen species
  • ROS breakdown such as selenium
  • mTOR inhibitors such as rapamycin
  • sirtuins or activators thereof such as resveratrol, or other SIRT1, SIRT3 activators, or nicotinamide inhibitors.
  • the lithium treatments e.g., an intermittent lithium treatments or a pulse lithium treatment, provided herein can also be administered concurrently or alternating sequentially with one or more of the following treatments that promote hair growth: minoxidil, kopexil (for example, the product KeraniqueTM), finasteride, bimatoprost (Latisse), CaCl 2 , or adenosine, or techniques of integumental perturbation such as, e.g.
  • a laser such as one that delivers ablative, non-ablative, non-fractional, superficial, or deep treatment, and/or are C0 2 -based, or Erbium- YAG-based, or neodymium:yttrium aluminum garnet (Nd:YAG) laser, etc.
  • irradiation irradiation, radio frequency (RF) ablation, or surgical procedures (e.g. , hair transplantation, strip harvesting, follicular unit extraction (FUE), scalp reduction, etc.).
  • RF radio frequency
  • Treatments that promote hair growth, or, alternatively, treatments that prevent hair growth may also be used in combination with a lithium treatment, e.g. , an intermittent lithium treatment or a pulse lithium treatment, described herein in order to promote the establishment of desired hair patterning in the healed wound or revised scar, thereby improving the appearance of the treated skin.
  • a lithium treatment e.g. , an intermittent lithium treatment or a pulse lithium treatment, described herein in order to promote the establishment of desired hair patterning in the healed wound or revised scar, thereby improving the appearance of the treated skin.
  • treatments that regulate gender- specific specialized human hair follicles including those under the influence of sex-steroid regulation, or that regulate the differentiation of stem cells into gender-specific specialized human hair follicles, possibly resulting in follicles having features that are different from natural follicles in the target location of skin (e.g.
  • normal sized follicles with terminal hair where previously miniaturized follicles with vellus hair were present may be administered.
  • treatment of grafted skin with a combination of lithium and a modulator of specific hair patterning may reduce donor dominance and enhance the ability of the graft to acquire properties of the recipient site.
  • a lithium treatment e.g., an intermittent lithium treatment or a pulse lithium treatment
  • a treatment that enhances hair growth (described above) or a cytotoxic drug
  • a hair growth retardant such as eflornithine HC1 (Vaniqa), 5-fluorouracil (5-FU) (e.g., Efudex 5% cream)
  • other epilation or depilation methods to prevent or reduce hair growth.
  • aforementioned methods and agents improves the effectiveness of these methods, making the treatment more effective, efficient, cost-effective, pain-free, and/or user friendly. For example, fewer treatments may be required.
  • a conventional antimicrobial, wound healing, or scar revision treatment on its own is not cosmetically satisfactory, does not adequately restore function of the skin, or the benefits are too shortlived.
  • the treated skin area may be more cosmetically satisfactory, the effects of the treatment longer lasting, or skin function is restored.
  • the lithium treatment can be administered prior to, concurrently with, or subsequent to the administration of a second (or third, or more) treatment.
  • the lithium treatment is administered to a subject at reasonably the same time as the other treatment.
  • This method provides that the two administrations are performed within a time frame of less than one minute to about five minutes, or up to about sixty minutes from each other, for example, at the same doctor's visit.
  • the lithium treatment and other treatment are lithium treatment and other treatment.
  • the lithium treatment and the other treatment are administered in a sequence and within a time interval such that lithium treatment and the other treatment can act together to provide an increased benefit than if they were
  • the lithium treatment and other treatment are administered sufficiently close in time so as to provide the desired outcome.
  • Each can be administered simultaneously or separately, in any appropriate form and by any suitable route.
  • the lithium treatment and the other treatment are administered by different routes of administration.
  • each is administered by the same route of administration.
  • the lithium treatment can be administered at the same or different sites of the subject's body. When administered simultaneously, the lithium treatment and the other treatment may or may not be administered in admixture or at the same site of administration by the same route of administration.
  • the lithium treatment and the other treatment are administered less than 1 hour apart, at about 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the lithium treatment and other treatment are administered 2 to 4 days apart, 4 to 6 days apart, 1 week apart, 1 to 2 weeks apart, 2 to 4 weeks apart, one month apart, 1 to 2 months apart, 2 to 3 months apart, 3 to 4 months apart, 6 months apart, or one year or more apart.
  • the lithium treatment and the other treatment are administered in a time frame where both are still active. One skilled in the art would be able to determine such a time frame by determining the half life of each administered component.
  • the lithium treatment and the other treatment are administered within the same patient visit. In one embodiment, the lithium treatment is administered prior to the administration of the other treatment. In an alternate embodiment, the lithium treatment is administered subsequent to the administration of the other treatment.
  • the lithium treatment and the other treatment are cyclically administered to a subject.
  • Cycling treatment involves the administration of the lithium treatment for a period of time, followed by the administration of the other treatment for a period of time and repeating this sequential administration.
  • the first treatment may be with the lithium treatment or with the other treatment, depending on the subject's prior treatment history and the intended outcome.
  • cycling treatment can also reduce the development of resistance to one or more of the treatments, avoid or reduce the side effects of one of the treatments, and/or improve the efficacy of the treatment.
  • alternating administration of the lithium treatment may be followed by the administration of another treatment (or vice versa) 1 year later, 6 months later, 3 months later, 1 month later, 3 weeks later, 2 weeks later, 1 week later, 4 to 6 days later, 2 to 4 days later, or 1 to 2 days later, wherein such a cycle may be repeated as many times as desired.
  • the lithium treatment and the other treatment are alternately administered in a cycle of 3 weeks or less, once every two weeks, once every 10 days or once every week.
  • Such time frames can be extended or reduced depending on whether a controlled release formulation of either the lithium compound or the other treatment formulation is used, and/or depending on the progress of the treatment course. See the examples in Section 6 to 9 for specific treatment variations.
  • an area of skin that was pre-treated with lithium is used as a source for transplanted skin or follicles.
  • Treatment with lithium at the wound(s) from which transplanted tissue was obtained and/or the site of implantation is initiated for one week, and then discontinued and optionally followed by another treatment.
  • a pharmaceutical composition which comprises a lithium compound described herein is administered to treat a subject with a microbial infection, i.e., a bacterial infection, a fungal infection, a yeast infection, or a parasitic infection.
  • a microbial infection i.e., a bacterial infection, a fungal infection, a yeast infection, or a parasitic infection.
  • “treatment” or “treating” refers to an amelioration of a microbial infection, or at least one discernible symptom thereof.
  • “treatment” or “treating” refers to an amelioration of at least one measurable physical parameter associated with a microbial infection, not necessarily discernible by the subject.
  • “treatment” or “treating” refers to inhibiting the progression of a microbial infection, either physically, e.g. , stabilization of a discernible symptom, physiologically, e.g. , stabilization of a physical parameter, or both.
  • the pharmaceutical compositions of the present invention are administered to a subject as a preventative measure against such microbial infections.
  • prevention or “preventing” refers to a reduction of the risk of acquiring a given microbial infection.
  • the pharmaceutical compositions of the present invention are administered as a preventative measure to a subject having a genetic predisposition to a microbial infection.
  • administration of a pharmaceutical composition of the invention leads to an inhibition or reduction of infectious agents by at least 99%, at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, at least 50%, at least 45%, at least 40%, at least 45%, at least 35%, at least 30%, at least 25%, at least 20%, or at least 10% relative to the growth in absence of said
  • the lithium treatments described herein can be administered to any subject who may benefit from such treatment.
  • the subject is preferably a human subject, including male, female, intermediate/ambiguous (e.g., XO), and transsexual subjects.
  • intermediate/ambiguous e.g., XO
  • transsexual subjects e.g., XO, and transsexual subjects.
  • the subject is a Caucasian subject. In certain embodiments, the subject is an African subject or an African-American subject. In certain embodiments, the subject is a human infant. In certain embodiments, the subject is a human child. In certain embodiments, the subject is a human adolescent. In certain embodiments, the subject is undergoing puberty. In certain embodiments, the subject is a young adult. In certain embodiment, the subject is a middle-aged adult. In certain embodiments, the subject is a premenopausal adult. In certain embodiments, the subject is undergoing menopause. In certain embodiments, the subject is postmenopausal. In certain embodiments, the subject is elderly.
  • the subject is a newbon human, a human of 1 year old or less, 2 years old or less, 2 years old, 5 years old, 5 to 10 years old, 10 to 15 years old, e.g., 12 years old, 15 to 20 years old, 20 to 25 years old, 25 to 30 years old, 30 years old or older, 30 to 35 years old, 35 years old or older, 35 to 40 years old, 40 years old or older, 40 to 45 years old, 45 to 50 years old, 50 years old or older, 50 to 55 years old, 55 to 60 years old, 60 years old or older, 60 to 65 years old, e.g., 65 years old, 65 to 70 years old, 70 to 75 years old, 75 to 80 years old, 80 to 85 years old, 85 to 90 years old, 90 to 95 years old or 95 years old or older or older.
  • a newbon human a human of 1 year old or less, 2 years old or less, 2 years old, 5 years old, 5 to 10 years old, 10 to 15 years old, e.g., 12 years old, 15 to
  • the subject is a male 20 to 50 years old. In some embodiments, the subject is a male or female 12 to 40 years old. In some embodiments, the subject is not a female subject. In some embodiments, the subject is not pregnant or expecting to become pregnant. In some embodiments, the subject is not a pregnant female in the first trimester of pregnancy. In some embodiments, the subject is not breastfeeding.
  • the lithium treatments described herein can be any lithium treatments described herein.
  • a patient preferably a mammal, most preferably a human, who has been diagnosed with a microbial infection, i.e., an infection caused by bacteria, fungi, yeast, or a parasite.
  • the lithium treatments described herein can be administered to a patient, preferably a mammal, most preferably a human, who is suffering from a disorder associated with, characterized by or caused by a microbial infection, i.e., an infection caused by bacteria, fungi, yeast, or a parasite.
  • Such subjects may or may not have been previously treated for the microbial infection or may have failed treatment.
  • the patient can have a genetic predisposition to a microbial infection or a disorder associated with, characterized by or caused by a microbial infection, such as a family history of the microbial infection or the disorder, or a non-genetic predisposition to the microbial infection or a disorder associated with, characterized by or caused by a microbial infection.
  • the lithium compositions of the present invention are administered to humans in need of inhibition of microbial cells, e.g., bacterial cells, fungal cells, parasitic cells. In certain embodiments, the growth of such cells is inhibited.
  • the lithium treatments described herein are administered to a subject that is at risk of having a microbial infection. In certain embodiments, the lithium treatments described herein are administered to a subject that has or is at risk of developing a cutaneous microbial infection, e.g., a cutaneous bacterial infection or a cutaneous fungal infection. In certain embodiments, the lithium treatments described herein are administered to a subject that has or is at risk of developing an infected wound, e.g., a bacterial-infected wound or a fungal-infected wound.
  • the lithium treatments described herein are administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes.
  • colonization refers to presence, growth, and multiplication of an organism without observable clinical symptoms or immune reaction.
  • the lithium treatments described herein are administered to a subject to prevent, reduce, or eradicate colonization in or on one or more of the following: nares, anterior nares, axillae, chronic wounds, decubitus ulcer surface, perineum, around gastrostomy sites, around tracheostomy sites, in sputum, in urine, or in the bowel.
  • the lithium treatments described herein are administered to a subject to prevent, reduce, or eradicate nasal colonization. In an embodiment, the lithium treatments described herein are administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes in order to reduce the risk of developing a subsequent infection in that subject. In an embodiment, the lithium treatments described herein are administered to a subject to prevent, reduce, or eradicate colonization of one or more microbes, including but not limited to Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Enterococci, drug-resistant Enterococci.
  • the lithium treatments described herein are administered to a subject to prevent, reduce, or eradicate colonization in order to reduce the risk of developing a subsequent infection by one or more microbes, including but not limited to: Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Enterococci, drug-resistant Enterococci.
  • colonization that can be prevented or reduced using the lithium treatments described herein is colonization with methicillin-resistant Staphylococcus aureus in the nares, axillae, chronic wounds or decubitus ulcer surface, perineum, around gastrostomy and tracheostomy sites, in the sputum or urine.
  • colonization that can be prevented or reduced using the lithium treatments described herein is colonization with Enterococci in the bowel and the female genital tract.
  • colonization that can be prevented or reduced using the lithium treatments described herein is colonization with drug-resistant Enterococci in the bowel.
  • the lithium treatments described herein are administered to subjects at high risk of methicillin-resistant Staphylococcus aureus infection, such as adult patients and health care workers, to prevent infection or reduce the risk of infection with methicillin-resistant Staphylococcus aureus.
  • the lithium treatments described herein are administered to adult patients and health care workers for the reduction or eradication of nasal colonization with methicillin-resistant S. aureus as part of a comprehensive infection control program to reduce the risk of spreading colonization or infection among patients and heath care workers and those they come into contact with at high risk of methicillin-resistant S. aureus infection during institutional outbreaks of infections with this pathogen.
  • a combination treatment comprising lithium carbonate and mupirocin is administered to adult patients and health care workers for the reduction or eradication of nasal colonization with methicillin-resistant S. aureus in a as part of a comprehensive infection control program to reduce the risk of spreading
  • topical formulations of the lithium treatments described herein are administered as a skin sanitizer and/or hand sanitizer to prevent infection by bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter cloacae, Streptococcus pyogenes, corynebacterium species, enterococci, Proteus mirabilis, group D streptococci, other gram- positive aerobes, and Bacteroides fragilis.
  • bacteria including, but not limited to, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Staphylococcus epidermidis, Acinetobacter baumannii, Klebs
  • topical formulations of the lithium treatments described herein are administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi.
  • topical formulations of the lithium treatments described herein are administered as a skin sanitizer and/or hand sanitizer to prevent infection by fungi and bacteria.
  • the skin sanitizer formulation and/or hand sanitizer formulation is aqueous based or glycerol based.
  • the skin sanitizer and/or hand sanitizer can be formulated as a cream or an ointment.
  • the lithium treatments described herein are
  • the lithium treatments described herein are administered directly to a wound to prevent the development of a microbial infection or a microbial colonization in or around said wound.
  • the lithium treatments described herein are used to treat chronic microbial infections and colonizations or chronic disorders associated with, characterized by or caused by microbial infections and colonizations.
  • the lithium treatments described herein are used to threat chronic cutaneous microbial infections and colonizations or disorders associated with, characterized by or caused by cutaneous microbial infections or colonizations.
  • the lithium treatments described herein are used to treat chronic microbial wound infections and colonizations or chronic disorders associated with, characterized by or caused by microbial wound infections and colonizations.
  • the subject with a chronic microbial infection may, e.g., have a suppressed immune system (e.g., post-operative patients, chemotherapy patients, and patients with immunodeficiency disease), have an impaired renal or liver function, be elderly, be a child, be an infant, have a neuropsychiatric disorder, take a psychotropic drug, have a history of seizures, or be on medication that would negatively interact with the anti-microbial therapies.
  • a suppressed immune system e.g., post-operative patients, chemotherapy patients, and patients with immunodeficiency disease
  • have an impaired renal or liver function be elderly, be a child, be an infant
  • have a neuropsychiatric disorder take a psychotropic drug
  • have a history of seizures or be on medication that would negatively interact with the anti-microbial therapies.
  • a lithium treatment described herein is administered to a patient who has been diagnosed with a disease caused by infection or colonization with a bacteria, e.g., the patient has been infected by E. coli, Klebsiella (e.g.., Klebsiella
  • Staphylococcus e.g., Staphylococcus aureus
  • Staphylococcus epidermidis
  • Streptococcus e.g., Streptococcus pneumoniae
  • Haemophilus influenzae e.g., Neisseria gonorrhoeae
  • Pseudomonas e.g., Pseudomonas aeruginosa

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Abstract

L'invention concerne des traitements au lithium pour le traitement d'infections microbiennes chez des sujets humains. L'invention concerne des utilisations de compositions contenant des composés qui libèrent des ions lithium, ainsi que des adjuvants et des dispositifs pour l'administration. Le ou les traitements au lithium peuvent être utilisés en combinaison avec d'autres traitements, tels que la mupirocine, pour traiter des infections microbiennes. Le ou les traitements combinés peuvent être administrés simultanément, ou avant et/ou après le traitement au lithium. L'invention concerne également des traitements au lithium pour la révision de cicatrice et la cicatrisation de plaie chez des sujets humains. L'invention concerne également des traitements de dermabrasion pour des états cutanés et de nouvelles pointes de dermabrasion pour l'exécution de tels traitements.
PCT/US2012/029475 2011-03-17 2012-03-16 Traitement au lithium pour infections microbiennes WO2012125941A1 (fr)

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US201161453746P 2011-03-17 2011-03-17
US201161453895P 2011-03-17 2011-03-17
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US201161453848P 2011-03-17 2011-03-17
US61/453,848 2011-03-17
US61/453,895 2011-03-17
US61/453,746 2011-03-17
US61/453,902 2011-03-17
US201161513906P 2011-08-01 2011-08-01
US61/513,906 2011-08-01
US201161525589P 2011-08-19 2011-08-19
US61/525,589 2011-08-19
US201161534156P 2011-09-13 2011-09-13
US61/534,156 2011-09-13
US201261590937P 2012-01-26 2012-01-26
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EP3189829A1 (fr) * 2016-01-11 2017-07-12 Justus-Liebig-Universität Gießen Moyen a effet antimycosique
WO2020257650A1 (fr) * 2019-06-19 2020-12-24 Ganio Carl Formulations utilisant du lithium pour traiter l'arthropathie de la goutte
CN113325185A (zh) * 2021-07-09 2021-08-31 重庆鼎润医疗器械有限责任公司 多水平质控品及其制备方法和在血栓弹力图检测上的应用
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CN114481392A (zh) * 2022-01-06 2022-05-13 西安工程大学 一种纳米纤维包覆纱及其制备方法、纳米纤维包覆纱股线及其应用
US11850259B2 (en) 2020-10-05 2023-12-26 The United States Government As Represented By The Department Of Veterans Affairs Methods of treating viral infections affecting the respiratory tract using topically administered lithium agents

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Cited By (16)

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Publication number Priority date Publication date Assignee Title
US11207511B2 (en) 2010-12-06 2021-12-28 Follica, Inc. Methods for treating baldness and promoting hair growth
US10123988B2 (en) 2013-03-15 2018-11-13 Allergan, Inc. Compositions including encapsulated isotretinoin and methods for use thereof
WO2014151769A1 (fr) * 2013-03-15 2014-09-25 Allergan, Inc. Composition comprenant de l'isotrétinoïne encapsulée et leurs procédés d'utilisation
WO2016100307A1 (fr) * 2014-12-17 2016-06-23 Mower Morton M Procédé et appareil pour cicatrisation améliorée
KR20170094220A (ko) 2014-12-17 2017-08-17 모튼 엠 모워 개선된 상처 치유를 위한 방법 및 장치
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US10238860B2 (en) 2014-12-17 2019-03-26 Morton M. Mower Method and apparatus for improved wound healing
JP2020199271A (ja) * 2014-12-17 2020-12-17 エム．モワー モートン 創傷治癒を改善するための方法及び装置
JP7212013B2 (ja) 2014-12-17 2023-01-24 エム．モワー モートン 創傷治癒を改善するための方法及び装置
EP3189829A1 (fr) * 2016-01-11 2017-07-12 Justus-Liebig-Universität Gießen Moyen a effet antimycosique
WO2020257650A1 (fr) * 2019-06-19 2020-12-24 Ganio Carl Formulations utilisant du lithium pour traiter l'arthropathie de la goutte
AU2020267170B2 (en) * 2019-06-19 2022-09-01 The United States Government As Represented By The Department Of Veterans Affairs Methods and formulations using lithium to treat gout inflammatory arthropathy and pain
US11850259B2 (en) 2020-10-05 2023-12-26 The United States Government As Represented By The Department Of Veterans Affairs Methods of treating viral infections affecting the respiratory tract using topically administered lithium agents
CN113325185A (zh) * 2021-07-09 2021-08-31 重庆鼎润医疗器械有限责任公司 多水平质控品及其制备方法和在血栓弹力图检测上的应用
CN113325185B (zh) * 2021-07-09 2024-04-19 重庆鼎润医疗器械有限责任公司 多水平质控品及其制备方法和在血栓弹力图检测上的应用
CN114481392A (zh) * 2022-01-06 2022-05-13 西安工程大学 一种纳米纤维包覆纱及其制备方法、纳米纤维包覆纱股线及其应用

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