US 20070269537Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0269537 A1 Gupta (43) Pub. Date: NOV. 22, 2007
(54) SKIN CONDITION IMPROVEMENT Related US. Application Data INCLUDING ACNE, ROSACEA, AND TOPICAL WOUNDS BY ARTEMISIA ANNUA (63) Continuation-in-part of application No. 10/248,691, EXTRACT VIA IRON SIDEROPHORE ?led on Feb. 10, 2003, noW abandoned. TROJAN HORSE DELIVERY SYSTEM Publication Classi?cation
(75) Inventor: Shyam K. Gupta, Scottsdale, AZ (US) (51) Int. Cl. A61K 31/335 (2006.01) A61K 36/282 (2006.01) Correspondence Address: A61P 17/10 (2006.01) SHYAM K. GUPTA (52) U.S. c1...... 424/740;514/450 BIODERM RESEARCH 5221 E. WINDROSE DRIVE (57) ABSTRACT SCOTTSDALE, AZ 85254 (US) This invention relates to certain extracts of Artemisia annua plant, both in their crude and re?ned forms, and certain (73) Assignee: BIODERM RESEARCH, SCOTTS re?ned forms of Artemisia annua plant extracts composed DALE, AZ substantially of Artemisinin and its analogs, Which are chemically classi?ed as sesquiterpenes With an endo-perox ide group [FIG 1]. These are suitable for compositions (21) Appl. No.: 11/615,561 comprising topical application, and for the treatment or improvement of skin condition including acne, rosacea, topical Wounds, age spots, Wrinkles, excess facial oil, and (22) Filed: Jan. 1, 2007 darkened skin.
Artemisinin Patent Application Publication Nov. 22, 2007 Sheet 1 0f 8 US 2007/0269537 A1
Figure1.Artemisinin Patent Application Publication Nov. 22, 2007 Sheet 2 0f 8 US 2007/0269537 A1
wmDImDEwEmwEDEIUDEEwm.Hwm=.__m__"_ Patent Application Publication Nov. 22, 2007 Sheet 3 0f 8 US 2007/0269537 A1
5
I {5} FIGURE3.EHTERUBACTINSIDEHUPHURE Di Patent Application Publication Nov. 22, 2007 Sheet 4 0f 8 US 2007/0269537 A1 Patent Application Publication Nov. 22, 2007 Sheet 5 0f 8 US 2007/0269537 A1
Hubredmcin
- H c " 1,5 H-smrr HFHJ P. Annals
Figure 5. Artemisinin Mechanism of Action
Patent Application Publication Nov. 22, 2007 Sheet 7 0f 8 US 2007/0269537 A1
20own 3?? cammmI u?xhwcéhmEEEETEEL.E3%Péu?._.._lPEME Patent Application Publication Nov. 22, 2007 Sheet 8 0f 8 US 2007/0269537 A1
I320EmFEEHEIn 3EgrudmmmEmEE..mmED?E US 2007/0269537 A1 Nov. 22, 2007
SKIN CONDITION IMPROVEMENT INCLUDING polyamine regulatory proteins. It also markedly inhibits ACNE, ROSACEA, AND TOPICAL WOUNDS BY nucleic acid and protein syntheses. Further, it affects cellular ARTEMISIA ANNUA EXTRACT VIA IRON membrane functions and decreases hepatic cytochrome oxi SIDEROPHORE TROJAN HORSE DELIVERY dase enzyme system activity. Still further, it is virustatic SYSTEM against in?uenza and cidal against three groups of patho genic parasites. [0001] This invention is a continuation-in-part of US. patent application Ser. No. 10/248,691 (?led Feb. 10, 2003), [0008] Known analogs of artemisinin that have higher noW abandoned. solubility in Water are dihydroartemisinin, artemether, arte [0002] This invention relates to certain extracts of Arle sunate, arteether, propylcarbonate dihydroartemisinin and misia annua plant, both in their crude and re?ned forms, and artelinic acid. Dihydroartemisinin has an antimalarial certain re?ned forms of Artemisia annua plant extracts potency that is 60% higher than that of artemisinin. Arte composed substantially of Artemisinin FIG. 1 and its ana mether and artesunate have antimalarial potencies that are 6 logs, Which are chemically classi?ed as sesquiterpenes With times and 5.2 times, respectively, that of artemisinin. In an endo-peroxide group. The above are suitable for topical terms of their ability to inhibit nucleic acid synthesis, application and for the treatment or improvement of skin dihydroartemisinin, artemether, artesunate, arteether, and condition including acne, rosacea, topical Wounds, age propylcarbonate dihydroartemisinin all have 100 times the spots, Wrinkles, excess facial oil, and darkened skin. activity of artemisinin, and protein synthesis is stimulated to an even greater extent by these compounds. Artesunate [0003] FIG. 1. stimulates the immune system at loW doses and inhibits it at [0004] The present invention also discloses a method of high doses. Artelinic acid is the most Water-soluble and the topical application of certain re?ned forms of Artemisia most stable of the group. TWo of the compounds in this annua plant composed substantially of Artemisinin, or its group have been demonstrated to display synergistic activity analogs or derivatives. This method can include a base, a With doxorubicin (a chemotherapeutic agent) and micona carrier, or a delivery system. This method provides a number zole (an antifungal agent) in the in vitro killing of Plasmo of topical bene?ts, Which includes skin Whitening, skin diumfalciparum, the etiologic agent of malaria. Artemisone has recently been disclosed to possess high antimalarial Wrinkles reduction, acne control, rosacea control, and facial oil control. activity [Haynes et al., AngeW. Chem. Int. Ed. Engl., 20, 2082 (2006)]. Secondary metabolites of Artemisia annua [0005] Artemisia annua extracts have been used in ancient extract and their biological activity has been reviewed Chinese medicine (qinqhao) for a number of treatments. [Bhakuni et al., Current Science, 80, 35 (2001)]. Medicinal use of the Chinese herb qinqhao appears in several standard Chinese Materia Medica texts as a treat [0009] The very loW toxicity of these compounds to ment for febrile illnesses. The herb Was speci?cally recom humans is a major bene?t. Artesunate, for example, is tWice mended for fevers in the Zhou Hou Bei ? Fang (The as safe as artemether and only one-?ftieth as toxic as Handbook of Prescriptions for Emergencies) Written by Ge chloroquinine, the most common antimalarial. The ?rst Heng and published in 341 AD. The most detailed descrip manifestation of toxicity of these compounds is generally a tion appears in the “Compendium of Materia MedicaiBen decreased reticulocyte count. Other manifestations include Cao Gang Mu, compiled in 1596, and is still printed in China transient fever, decreased appetite and elevated blood tran today. The antimalarial activity of qinqhao Was rediscovered saminase levels, the latter an indication of hepatotoxicity. in China in 1972, and the antimalarial active principal of [0010] US. Pat. No. 4,978,676 discloses the use of arte qinqhao Was named “qinghaosu”. The Western name for the misinin and artemisinin analogs in the treatment of skin compound is artemisinin. Recently, hoWever, this extract has conditions such as psoriasis, blistering skin diseases, viral been used for the treatment of malaria. Distribution of Warts, and hemorrhoids. artemisinin in Artemisia annua has been revieWed [Ferreira et al., Progress in NeW Crops, J. Janick (ed.), ASHS Press [0011] US. Pat. No. 5,219,880 discloses the use of arte 579 (1996)]. misinin and artemisinin analogs in the treatment of Warts, molluscum contagiosum and hemorrhoids. [0006] Moreover, it has been disclosed that artemisinin FIG. 1 is the active agent that delivers the antimalarial [0012] US. Pat. No. 5,225,427 discloses certain 10-sub bene?ts of Artemisia annua extracts. Only orally adminis stituted ether derivatives of dihydroartemisinin alleged to tered compositions seem to provide antimalarial or other exhibit antimalarial and antiprotozoal activity. bene?ts. [0013] Artemisinin alone has been shoWn to be toxic to [0007] Artemisinin (Qinghaosu) and its analogs are the cancer cells in vitro at 20 to 180 .mu.M range (Sun et al., treatments of choice for cerebral or chloroquine resistant “Antitumor Activities of 4 Derivatives of Artemisic Acid malaria or for patients With chloroquine allergy. Artemisinin and Artemisinin B in vitro,” Chung-Kuo-Yao-Li-Hsuch-Pao is a naturally occurring substance, obtained by puri?cation 13:541-543 (1992)). The effect Was found to be more from sWeet Wormwood, Artemisia annua. Artemisinin and effective for hepatoma and embryonic lung cells than against its analogs are sesquiterpene lactones With a peroxide human gastric cancer cells. In another study (Woerdenbag et bridge, and are characterized by very loW toxicity and poor al., “Cytotoxicity of Artemisinin-related Endoperoxides to Water solubility. Artemisinin is knoWn as a humoral immu Erich Ascots Tumor Cells,” J. Nat. Prod. 56(6): 849-856 nosuppressive agent that is less active than cyclophospha (1993)), artemisinin Was shoWn to have an lC.sub.50 value mide, the latter being one of the major chemotherapeutic of 29.8 .mu.M on Ehrlich ascots tumor cells. Several deriva agents for carcinomas. Artemisinin stimulates cell-mediated tives of dihydroartemisinin (artemether, arteether, sodium immunity, and yet decreases abnormally elevated levels of artesunate, artelinic acid, and sodium artelinate) had US 2007/0269537 A1 Nov. 22, 2007
IC.sub.50 values ranged from 12.2 to 19.9 .mu.M. An ether [0016] Golenser et al. [Int. J. Parasitol., Sep. 12, 2006] dimer of dihydroartemisinin Was found to have an IC.sub.50 report Artemisinin derivatives are the most recent single of 1.4 .mu.M. However, the toxicity of the dimer to normal drugs approved and introduced for public antimalarial treat cells Was not tested. The authors of the latter paper con ment. Although their recommended use is for treatment of cluded that, “The artemisinin-related endoperoxides shoWed Plasmodium falciparum infection, these drugs also act cytotoxicity to Ehrlich ascites tumor cells at higher concen against other parasites, as Well as against tumor cells. The trations than those needed for in vitro antimalarial activity, mechanisms of action attributed to artemisinin include inter as reported in the literature.” HoWever, serum concentra ference With parasite transport proteins, disruption of para tions at the levels reported by the tWo papers cannot be site mitochondrial function, modulation of host immune reached in vivo. function and inhibition of angiogenesis. Artemisinin com [0014] Artemisinin is a relatively safe drug With little bination therapies are currently the preferred treatment for side-effects even at high doses. Oral dose of 70 mg/kg/day malaria. for 6 days has been used in humans for malaria treatment. [0017] Meshnick [Int. J. Parasitol., 32, 1655 (2002); Furthermore, more potent analogs of this and similar com Microbiological RevieWs, 301 (1996)] report Artemisinin pounds are also available. Higher ef?cacy of artemisinin and its derivatives are Widely used throughout the World. action also can be achieved by other means. For example, The mechanism of action of these compounds appears to artemisinin is more reactive With heme than free iron (Hong, involve the heme-mediated decomposition of the endoper et al. “The Interaction of Artemisinin With Malarial Hemo oxide bridge to produce carbon-centered free radicals. The Zoin,” Mol. Biochem. Parasit. 63:121-128 (1974)). Heme involvement of heme explains Why the drugs are selectively can be introduced into cells using transferrin (Stout, D. L., toxic to malaria parasites. The resulting carbon-centered free “The Role of Transferrin in Heme Transport,” Biochim. radicals are alkylate heme and proteins, one of Which is the Biophy. Res. Comm. 189:765-770 (1992)) or the heme translationally controlled tumor protein. The mechanism of carrying compound hemoplexin (Smith et al., “Expression action of artemisinin thus appears to involve tWo steps. In of Haemopexin-Transport System in Cultured Mouse the ?rst step, activation, intra-parasitic iron catalyses the Hepatoma Cells,” Biochem. J. 256:941-950 (1988); Smith et cleavage of the endoperoxide bridge and the generation of al., “Hemopexin Joins Transferrin as Representative Mem free radicals. In the second step, alkylation, the artemisinin bers of a Distinct Class of Receptor-Mediated Endocytic derived free radical forms covalent bonds With parasite Transport System,” Europ. J. Cell Biol. 53:234-245 (1990)). proteins. The effectiveness of artemisinin also can be enhanced by increasing oxygen tension, decreasing intake of antioxi [0018] The topical applications of Artemisia annua dants, and blockade of peroxidase and catalase by drugs extracts or artemisinin for the skin condition improvement such as miconaZole (Meshnick et al., “Activated Oxygen such as acne, rosacea, and dark spots are not knoWn in the Mediates the Antimalarial Activity of Qinghaosu,” Prog. prior art. Clin. Biol. Res. 313:95-104 (1989); Krungkrai et al., “The [0019] Goldstein et al. (US. patent application Ser. No. Antimalarial Action on Plasmodium falciparum of Qing 20050147631) disclose certain cosmetic compositions and haosu and Ar‘tesunate in Combination With Agents Which methods for retarding hair groWth comprising a combination Modulate Oxidant Stress,” Tran. Roy. Soc. Trop. Med. Hyg. of an ornithine decarboxylase inhibitor, an anti-angiogenic 81:710-714 (1989); Levander et al., “Qinghaosu, Dietary active and an anti-in?ammatory. Said compositions can Vitamin E, Selenium, and Cod Liver Oil: Effect on the include artemisinin. Susceptibility of Mice to the Malarial Parasite Plasmodium yoelii,” Am. J. Clin. Ntr. 50:346-352 (1989)). [0020] DisbroW et al. [Cancer Research, 65,10854 (2005)] report dihydroartemisinin and other artemisinin derivatives [0015] The endoperoxide moiety of artemisinin and its may be useful for the topical treatment of epithelial papil analogs has been found to be necessary for antimalarial lomavirus lesions, including those that have progressed to activity, and analogs lacking this group have been found to the neoplastic state. be inactive. In the presence of heme, the Endoperoxide Bridge undergoes reductive decomposition to form a free [0021] MaZZio et al. (US. patent application Ser. No. radical and electrophilic intermediates. Accordingly, endop 20040185123) disclose a topical herbal formulation for eroxide bearing compounds other than artemisinin and its preventing and/or treating dyshidrosis (pompholyx), non analogs have been found to have antimalarial activity. For responsive to topical steroids. The formulation may also be example, arte?ene (Biirgen et al., A NeW Effective Antima used to treat contact dermatitis, ecZema, palmoplantar pus larial: Chemical Structure and Biological Activity, Sixth tulosis and skin infections incurred by invasive pathogens International Congress for Infectious Diseases, Abst. 427, p. such as mold, fungus and bacteria. The formulation is 152, April 1994, Prague), and the 1,2,4-trioxanes, such as comprised of plant extracts and niacin, that When combined the fenoZans (Peters et al., “The Chemotherapy of Rodent yield an effective multi-faceted pharmaceutical approach to Malaria. XLIX). The Activities of Some Synthetic 1,2,4 treating dry skin disorders. The active ingredients Within the Trioxanes Against Chloroquinine-Sensitive and Chloroqui formula include a combination of dry, aqueous, acid and nine-Resistant Parasites. Part 2: Structure-Activity Studies alcohol extracts of black Walnut hull (Juglans Ni gra), Worm on cis-fused Cyclopenteno-1,2,4-Trioxane (FenoZans) Wood (Arlemisia Absinlhium), tumeric rhiZome (Curcuma Against Drug-Sensitive and Drug-Resistant Lines of Plas Longa), garlic (Allium salivum), chamomile (Malricaria modium berghei and R yoelii spp. NS In Vivo,” Annals of Chamomile), licorice root (Glycyrrhiza Glabra), St Johns Tropical Medicine and Parasitology, 87(1):9-16 (1993)), and Wort (Hypericum perforalum), aloe vera, niacin and herbal the 1,2,4,5-tetraoxanes [Vennerstrom et al., “Dispiro-1,2,4, anti-bacterial agents. It is to be noted that Arlemisia extract 5-tetraoxanes: A NeW Class of Antimalarial Peroxides,” J. of or artemisinin alone Were not disclosed as a topical treat Medicinal Chemistry, 35(16):3023-3027 (1992)]. ment agent. US 2007/0269537 A1 Nov. 22, 2007
[0022] Lai et al. (U.S. Pat. No. 5,578,637) disclose com [0028] Remberg et al. (US. Pat. No. 7,118,770) discloseA pounds having an endoperoxide moiety that is reactive With method of obtaining extract from Arlemisia plant, said heme that are administered under conditions that enhance method comprising the steps of: (i) distilling fresh, neWly intracellular iron concentrations. Representative endoperox harvested plants selected from the group consisting of ide compounds include endoperoxide bearing sesquiterpene Artemisia abrolanum, Arlemisia pallens, Arlemisia ler compounds such as artemisinin and its analogs, arte?ene and chinia, Arlemisia Zhuscula, Arlemisia rehan, Arlemisia per its analogs, 1,2,4-trioxanes and 1,2,4,5-tetraoxanes. Intrac sica, Arlemisia glabella, Arlemisia rupeslris, Lanlana ellular iron concentrations may be enhanced by the admin camara and Tanacelum vulgare by boiling to obtain an istration of iron salts or complexes. It is to be noted that essential oil comprising davanon and 1,8-cineol and a Arlemisia extract or artemisinin alone Were not disclosed as remaining residual green mass of plant material; (ii) heating a topical treatment agent for the skin condition improvement the residual green mass of step (i) in Water to hydrolyZe the such as acne, rosacea, and dark spots. ?avonol glycosides therein to free ?avonols and sugar; (iii) drying the residual green mass and extracting the green mass [0023] Zhao et al [Yao. Xue Xue Bao, 24, 813 (1989)] With alcohol to obtain an alcoholic extract of said residual report Qinghaosu, also knoWn as artemisinin and arteannuin, is a neW type of antimalarial drug isolated from Arlemisa green mass containing free ?avonols; and (iv) combining the alcoholic extract of residual green mass containing free annua. Its loW solubility in Water and oil limited its Wide ?avonols of step (iii) With the essential oil comprising spread clinical use. Artesunate (sodium dihydroqinghaosu hydrogen hemisuccinate monoester) is easily soluble in davanon and 1,8-cineol obtained in step (i) to obtain the extract. These are useful for making a preparation having Water and is used in the treatment of acute cerebral and malignant malaria via intravenous injection. HoWever, arte effect against allergic symptoms, more particularly a prepa ration Which has proved to be effective for therapeutic and sunate Was shoWn to have a very short half-life When given prophylactic relief or prevention of symptoms associated iv in animals as Well as in human beings. A transdermal With allergic rhinitis, asthmatic conditions and other allergic dosage form of artesunic acid had been prepared and Was reported to have reliable suppressing and killing effects on conditions, such as allergic conjunctivitis, urticaria, or insect plasmobium berghei in mice. or plant stings [0029] FeW publications disclosed the use of artemisinin [0024] Hoang (U.S. patent application Ser. No. or artemisinin analogs as an anti-bacterial agent. U.S. Pat. 20050096369) discloses compositions and methods for treating patients suffering from a proliferation disorder char No. 6,127,405 disclosed that .alpha.-arteether inhibits the acteriZed by an increased voltage gated ion-channel uptake groWth of E. coli strains defective in DNA-gyrase enzyme Whereas the Wild type of E. coli having intact DNA gyrase are described. Included are compositions comprised of a compound selected from the group consisting of matrine, genes Were not sensitive to said .alpha.-arteethers. Shoeb et oxymatrine, artemisinin, agmatine, and vinpocetine. HoW al. (. Chemotherapy, 2, 362-367,1990) disclosed that arte misinin possesses an anti-microbial activity against anaero ever, Hoang did not disclose topical applications of Artemi bic bacteria. None of these publications disclose or suggest sia annua extracts or artemisinin for the skin condition that artemisinin or its analogs may be used as an anti improvement such as acne, rosacea, and dark spots. bacterial agent against oxic or anoxic bacteria in general or [0025] Avery et al. (U.S. patent application Ser. No. speci?cally against acne and rosacea or treat topical Wounds. 20050240034) disclose synthesis, bioassay, and utility of [0030] In the present invention it is thus both surprising neW C-9 and C-10 substituted artemisinin derivatives With and unexpected that Artemisia annua extracts, both in their easily functionaliZable groups attached to the artemisinin crude and re?ned forms, and certain re?ned forms of Arle skeleton through carbon chain or heteroatoms. Described also is the demonstration of this class of compounds for their misia annua plant composed substantially of Artemisinin, broad-spectrum anti-parasitic activity. Certain of these ana cause an improvement of skin condition such as acne and rosacea, and dark spots and topical Wounds. Although arte logs possess noticeable cytotoxicity deliberately focused on misinin has been disclosed to have antibacterial bene?ts, it treatment of cancerous diseases. is also Well knoWn that there are thousands of other anti [0026] Marash et al. (U.S. patent application Ser. No. bacterial agents knoWn to science all of Which do not also 20060258716) disclose methods and compositions for treat cause a treatment or improvement of skin condition such as ing or preventing pathological conditions associated With acne, or rosacea, or dark spots, or topical Wounds. Thus, ferrous-dependent bacteria, such as, Helicobacler pylori in merely being an antibacterial agent does not cause an Which high intracellular ferrous iron concentration is ingredient or composition to also cause a treatment or required for survival and pathogenesis. The compositions of improvement of skin condition such as acne, rosacea, dark the invention comprise endoperoxide bridge-containing spots, or topical Wounds. compounds that speci?cally inhibit the groWth of the fer [0031] Moreover, the inclusion of iron, especially in a rous-dependent bacteria and preferably promote the eradi complexed form, further increases the ef?cacy of the com cation of the bacteria. The compositions, typically also positions of the present invention. This is contrary to tradi include at least one active agent for treating Helicobacler tionally practiced antibiotic treatments’, such as tetracycline sp-related gastrointestinal disorders, such as a proton pump and macrolide antibiotics, Which must not be administered inhibitor, an H2 blocker or a bismuth-containing compound. in the presence of heavy metals such as iron, as said metals [0027] O’Neill et al. (US. patent application Ser. No. diminish the activity or ef?cacy of said antibiotic treatments. 20050256184) disclose certain substituted 1,2,4-trioxanes [0032] Acne, Rosacea, and Facial Oil Control Bene?ts. and 1,2,4-trioxepanes useful as anti-malarial and/or antican cer agents, and an improved method for their preparation. [0033] Acne is caused by a combination of several factors. These are structural analogs of artemisinin. In a previous disclosure (U .S. patent application Ser. No. US 2007/0269537 A1 Nov. 22, 2007
10/248,691; ?led Feb. 10, 2003; noW abandoned) the present sebum blockade. With this blockage, the number of resident inventor has discussed that acne is a group of diseases Whose follicular ?ora increases dramatically. These bacteria pro initial pathology is the comedo and includes acne vulgaris, duce in?ammatory products, Which permeate through thin neonatal acne, infantile acne, and pomade acne. There are Walls of dilated sebum-?lled duct. Once in the perifollicular approximately 45 million people who suffer from acne in dermis, they trigger the body’s oWn immune defenses (both America alone. The disease is so common in youth at their acute and granulaomatous) to produce the characteristic puberty that it often has been termed physiological. in?ammatory papules, pustules and nodules characteristic of Although acne stops appearing for most people by the age of in?ammatory acne. The term “acne” is used herein as a 25, some people, the majority of them are Women, experi general term to include in?ammatory diseases of the pilose ence the disease Well into their adult life. This “adult acne” baceous unit. In the medical ?eld, the speci?c type of acne differs from teenage acne in location and that it tends to be is usually indicated by a modifying term, although the term more in?ammatory With feWer comedones. As the human acne is frequently used alone to designate common acne or concern for facial beauty continues to receive heightened acne vulgaris. marketing attention, the cure for various forms of acne has [0036] Thus, there are four factors that are believed to be received much attention, as evidenced by the number of patents and patent applications that have appeared recently. the contributors of acne: (1) The patent literature abounds With acne treatments. From [0037] Increased sebum production; (2) Comedo forma January 2001 to January 2003 time period over 900 patent tion, in Which the follicular infundibulum hypercorni?es, applications Were published in Us. patent applications hyperkeratiniZes, and hypodesquamates; (3) ColoniZation of computer database search that related to acne. From 1975 to the follicule by anaerobic Propionibaclerium, mainly R January 2003, there Were over 9000 patents issued by the acnes; and (4) The host’s in?ammatory response. The above Us. Patents O?ice that had some reference to acne. From four factors are interrelated to each other. Sebum is come these data, it Would become obvious that a suitable solution dogenic and causes in?ammation by itself. Propionibacle to this problem has eluded past efforts. rium acnes is a relatively sloW groWing, (typically) obligate [0034] The disease of acne is characteriZed by a great anaerobe gram positive bacterium that is linked to the skin variety of clinical lesions. Although one type of lesion may condition acne. An anaerobic organism or anaerobe is any be predominant (typically the comedo), close observation organism that does not require oxygen for groWth. Obligate usually reveals the presence of several types of lesions anaerobes Will die When exposed to atmospheric levels of (comedones, pustules, papules, and/or nodules). The lesions oxygen. can be either non-in?ammatory or, more typically, in?am [0038] The Propionibaclerium has high lipolytic activity matory. In addition to lesions, patients may have, as the and liberates free fatty acids from sebum lipids. The free result of lesions, scars of varying siZe. The fully developed, fatty acids have been shoWn to cause marked in?ammation. open comedo (i.e., a plug of dried sebum in a skin pore) is The microorganisms also produce other extracellular not usually the site of in?ammatory changes, unless the enZymes such as proteases and hyaluronidases, and chemo patient traumatiZes it. The developing microcomedo and the tactic factors, Which may be important in the in?ammatory closed comedo are the major sites for the development of process. It Would thus be advantageous to provide relief in?ammatory lesions. Because the skin is alWays trying to from all of the above four principal causes of acne. repair itself, sheaths of cells Will groW out from the epider mis (forming appendageal structures) in an attempt to encap [0039] Rosacea is a common facial dermatitis that cur sulate the in?ammatory reaction. This encapsulation is often rently affects an estimated 13 million Americans. It is a incomplete and further rupture of the lesion typically occurs, chronic and progressive cutaneous vascular disorder, prima leading to multi-channeled tracts as can be seen in many rily involving the malar and nasal areas of the face. Rosacea acne scars. is characterized by ?ushing, erythema, papules, pustules, telangiectasia, facial edema, ocular lesions, and, in its most [0035] In general, there are four major principles presently advanced and severe form, hyperplasia of tissue and seba governing the therapy of acne: (i) correction of the altered ceous glands leading to rhinophyma. Rhinophyma, a ?orid pattern of follicular keratiniZation; (ii) decrease sebaceous overgroWth of the tip of the nose With hypervascularity and gland activity; (iii) decrease the follicular bacterial popula modularity, is an unusual progression of rosacea of unknoWn tion (especially R acnes) and inhibit the production of extra cause. Ocular lesions are common, including mild conjunc cellular in?ammatory products through the inhibition of tivitis, burning, and grittiness. Blepharitis, the most common these microorganisms; and (iv) produce an anti-in?amma ocular manifestation, is a nonulcerative condition of the lid tory e?‘ect. Acne is a chronic in?ammatory disease affecting margins. Rosacea most commonly occurs betWeen the ages the sebaceous glands. Acne lesions primarily involve the of 30 to 60, and may be seen in Women experiencing sebaceous glands located on the face, neck, chest and back. hormonal changes associated With menopause. Women are Both closed comedones (blackheads) and open comedones more frequently affected than men; the most severe cases, (Whiteheads) are caused by hyperkeratiniZation of the hoWever, are seen in men. Fair complexioned individuals of infundibulum of the sebaceous duct. These keratinous plugs Northern European descent are most likely to be at risk for block the ?oW of sebum. These dilated ducts abound With rosacea; most appear to be pre-disposed to ?ushing and the colonies of Priopionibacterium acnes and other fat blushing. splitting organisms. The clinically evident open and closed comedones and the microscopic microcomedo are the signal [0040] The cause of rosacea is poorly understood, numer lesions of acne. The acne process results from a cascade of ous theories have been offered. Hypotheses have included events. First, at puberty a spike in androgen production gastrointestinal, psychological, infectious, climatic, and heralds an increase in sebum production and begins the immunological causes, although scienti?c evidence has not hyperkeratiniZation process causing microcomedones and substantiated any of these as primary. Controlled studies US 2007/0269537 A1 Nov. 22, 2007
have not demonstrated consistent preponderance of gas only, the gel is usually applied once nightly. Side effects trointestinal symptoms in rosacea patients. Similarly, neither include frequent scaling, burning, redness and dryness. a distinct psychological abnormality nor one pharmacologi Improvement is delayed and is not evident for 4-8 Weeks. cal mechanism has been isolated in rosacea patients. Perhaps Sodium sulfacetamide 10%/sulfur 5% (Sulfacet-R) is also the most commonly touted of the etiologic theories is based available by prescription only. It is a lotion With antibacterial on the presence of Demodex folliculorum mites in patients and comedolytic action. As With tretinoin, improvement is With rosacea; the organism feeds on sebum, and in some seen in 4-8 Weeks. Salicylic acid 2% is an over the counter cases treatment of demodex infestation has noted improve product that exhibits mild comedolytic activity. ment in the rosacea; hoWever, in a revieW of 79 biopsies in 1969, Demodex folliculorum Was noted in only 19% of the [0044] The only products that have anti-sebum activity are specimens. A bacterial cause for the disease has been estrogens and 13 cis-retinoic acid (isotretinoin) and these hypothesized, but no consistent ?ndings of one bacterium must be used systemically to be effective. Isotretinoin have been demonstrated. Climate, speci?cally exposure to (Accutane) is a metabolite of Vitamin A available by pre extremes of sun and cold, may have an effect on the course scription only. Isotretinoin is used to treat only severe cystic of the disease, but the role of climate in What appears to be or conglobate acne. Because of its teratogenic properties, a connective tissue disorder is not clear. An autoimmune birth defects can occur. Isotretinoin is a poWerful drug and process has been suggested, and tissue ?xed immunoglobu can elevate triglycerides, total cholesterol and decrease lins have been reported in patients With chronic in?amma high-density lipoproteins (HDL). Other side effects include tion of rosacea, but no other evidence has been found. Other dry skin, dry eyes, itching, headaches, nosebleed, and pho experimental evidence has suggested this disease may rep tosensitivity. It is generally taken for 4-5 months to see resent a type of hypersensitivity reaction. No single hypoth improvement. Recently, one brand of oral contraceptive has esis appears to adequately explain both the vascular changes been approved for the treatment of acne for patients Who and the in?ammatory reaction seen in rosacea, leaving the request birth control. pathogenesis unclear. More recently, certain investigators [0045] A number of topical and systemic agents are used have suggested a connection betWeen rosacea and H. pylori, to loWer the number of bacteria that coloniZe the follicular bacteria shoWn to cause certain gastrointestinal ulcers, duct. These include benZoyl peroxide (BP), BP 5%/eryth because symptoms seem to have abated in some ulcer romycin 3% (BenZamycin). BP has antibacterial activity and patients also suffering rosacea. Nevertheless, the connection drying effects and is available over the counter or by betWeen H. pylori and rosacea has been questioned. H. Herr, prescription. Moreover, it has been recently reported that J. Korean Med Sci Oct. 15, 2000; (5):551-4; R. Boni, benZoyl peroxide seems to induce free radical production SchWeiZ Med Wochenschr Sep. 16, 2000; 130(37): 1305-8). that can produce skin changes that qualitatively resemble [0041] Kang et al. (US. Patent Application 20020183399) ultraviolet B damage, e.g., increases in epidermal thickness, have recently concluded that rosacea and acne have many and deleterious changes in elastin and glycosaminoglycans common features in their onset and cure. The topical com content (Ibbotson, S. H., et al., J. Inves. Derm., 1999, 112: position for treating rosacea, Which comprises a combina 933-938). In addition, BenZoyl peroxide is highly reactive, tion of an antimicrobial and at least one of (a) an anti and is thus di?icult to stabiliZe in practical compositions. BP in?ammatory and (b) a non-retinoid inhibitor, are very is applied once or tWice daily for 1-2 months. BP can similar for treating acne, according to Kang, for example. It produce erythema and peeling of skin. BP is often tried ?rst Would thus appear logical to develop broad-spectrum com for both non-in?ammatory and mild in?ammatory acne. positions that can treat both acne and rosacea, although such Other topical antibiotics include clindamycin and erythro compositions are still unknown, until noW. mycin. These are used as solutions, lotions or gels by prescription only. Usually they are applied once or tWice [0042] Most acne treatments are directed at preventing daily and results are seen in 1-2 months. AZelaic acid 20% in?ammatory lesions, particularly the larger nodulo-cystic (AZelex) also has mild antibacterial effects. Systemic anti lesions that tend to be destructive and lead to permanent biotics include tetracycline and its analogs, Which are used scarring. In general, visible comedones are the only minor in loW doses for years or until the end of the acne prone cosmetic nuisances and do not lead to in?ammatory lesions. years. Most patients With mild in?ammatory acne receive a Most acne treatment is directed to four areas: (1) Keratinous combination of topical antibiotics and tretinoin or other plugs in sebaceous ducts; (2) Large sebaceous glands pro retinoid. Bacterial resistance does occur so antibiotics may ducing excess sebum; (3) Increased numbers of resident be changed or BP is substituted since resistance does not follicular bacteria; and (4) In?ammatory response to chemi occur With BP. More severe acne requires systemic antibi cal mediators passing through the follicular Wall. otics and topical retinoid. The most severe must receive oral [0043] Topical products used to remove comedones are isotretinoin for 4-5 months. knoWn as comedolytics, the most effective being tretinoin, [0046] There are no drugs that directly affect the in?am marketed as a prescription product (Retin A) and by several matory acne. The retinoids do have some anti-in?ammatory generic companies. Tretinoin or all-trans retinoic acid is the properties, but these are poorly described. Topical steroid naturally occurring metabolite of Vitamin A. Tretinoin and even systemic steroids have been used to abort a severe increases epidermal cell turnover, thus causing comedolysis ?are of fulminant acne, but these are limited uses because of and most importantly prevents the formation of neW kera the side effects. BenZoyl peroxide gels are sometimes used tinous plugs. Applications of tretinoin are normally once a as ?rst aid on acne lesions. These function as a “draWing day at bedtime. Dryness, stinging and redness sometimes poultice”, but data supporting this use is not available. accompany the applications. Importantly, improvement is usually not seen for 6-8 Weeks. Adapalene 0.1% (Di?‘erin) is [0047] The treatment for acne centers on opening the pore, a topical retinoid like tretinoin. Available by prescription killing R acnes, reducing sebum production and regulating US 2007/0269537 A1 Nov. 22, 2007
in?ammatory responses. Retinoids are the agents to reduce topical bioavailability and anti-acne e?icacy of salicylic acid sebum production and open the pore. As a topical agent, With a reduction in its irritation causing side effects. Di?‘erin (adapalene) or Retin-A (tretinoin) is used for mild and moderate acne. lsotretinoin, an oral drug, is very effec [0053] The prior art literature abounds With acne and tive but reserved for the severe and resistant acne because of rosacea treatments. From January 2001 to January 2003 time its teratogenicity, hepatotoxicity, elevating triglyceride level period over 900 patent applications Were listed in US. and other side effects. patent applications computer database search that related to acne. From 1975 to January 2003, there Were over 9000 [0048] For topical applications, the Food & Drug Admin patents issued by the US. Patents Office that had some istration (FDA) has approved the folloWing ingredients for reference to acne. In the same period, there Were over 400 marketing topical acne products in the USA (Code of patents that had a reference to rosacea. It may also be Federal Regulations, 21CFR333.310); (1) Resorcinol (2%, appreciated that the study and treatment of rosacea has been in combination only); (2) Resorcinol monoacetate (3%, in a long-time concern of the medical community. For combination only); (3) Salicylic acid 0.5 to 2 percent, and example, about 1,000 medical papers have been published (4) Sulfur 3 to 10 percent. on this subject. From these data, it Would become obvious [0049] Salicylic acid has been used to treat acne for some that a suitable solution to acne and rosacea problems has not time. Salicylic acid dries the skin, Which helps in acne yet been found. A discussion of the patents and patent management, but it also causes skin irritation in perilesional applications most pertinent to the present invention folloWs. skin areas of acne patients, especially patients With sensitive US. Patent Application 20030021855 (Perricone) discloses skin, and in some cases the erythema is extreme. Salicylic acne prevention by the topical application of compositions acid is also pH-sensitive, as in neutraliZed forms, such as containing an alkanolamine such as dimethylaminoethanol, sodium salicylate or triethanolamine salicylate, there is a in combination With tyrosine and a sulfur ingredient such as loss of e?icacy due to poor bioavailability. In free acid form, lipoic acid or glutathione. Such alkanolamines have strong salicylic acid is absorbed rapidly and transported into blood amine odor that is objectionable to consumers for applica stream. This is the reason for its irritation-causing problems. tion on face. Moreover, several such alkanolamines have a It Would thus be advantageous if salicylic acid can be high pH that can cause irritation. US. Patent Application provided in a form that is sloW to absorb into deeper layers 20030021816 (Kang) discloses an immunosuppressant com of skin for its maximum topical bioavailability and anti-acne pound, a second active ingredient selected from the group e?icacy. consisting of comedolytics, antibacterials, anti-in?amma tory, retinoids, glucocorticoids, and mixtures thereof, and a [0050] Topical and oral antibiotics (especially tetracy dermatologically acceptable carrier for acne treatment. Such cline, erythromycin, and clindamycin) are sometimes pre immunosuppresants are not readily available for common scribed for patients With in?ammatory papules and pustules, use. US. Patent Application 20020192298 (Burrell) relates but, in addition to the undesirability of antibiotic overuse in to the use of antimicrobial metals, preferably silver for the general, Which can lead to enhanced susceptibility to infec treatment of an acne. It is preferred that the use of any tion, disadvantages to such treatments include phototoxicity antimicrobial agents for acne treatment be minimized or and interactions With other medications. Other factors that eliminated due to development of resistant bacteria. US. play a role in exacerbating acne, including oil-based cos Patent Application 20020172672 (Sieberg) is directed to the metics and some drugs (e.g., androgenic hormones, high use of serine proteases, either alone or in combination With progestin birth control pills, systemic corticosteroids, and a retinoid compound in a pharmaceutical or cosmetic com iodide- and bromide-containing agents) are often minimiZed position for acne treatment. Such enZyme preparations can during acne treatment. Besides the side effects of the anti cause serious skin allergy in some humans. US. Patent microbial agents, development of resistant microorganisms Application 20020155180 (Goodman) discloses treatment has become an important issue noWadays. The number of of acne that comprises topically applying an effective patients harboring resistant R acnes has been shoWn to be amount of a saW palmetto berry extract and one or more groWing. For this reason, it Would be advantageous to constituents that enhance penetration of the extract into hair exclude antibiotics and antibacterial agents from topical follicle sebaceous glands. This disclosure is speci?c to one preparations for acne. ingredient, hence of limited application. US. Patent Appli [0051] For e?icacious topical treatments, it Would thus be cation 20020151527 (Wiegand) discloses a method for advantageous to include the folloWing six-prong provisions reducing the number and severity of acne lesions comprising to control fundamental elements that can provide control of administering a sensory regimen to doWn regulate the activ both acne and rosacea in a single composition: (1) Control ity of the hypothalamus-pituitary-adrenal axis, in combina of excess sebum production; (2) Control of undesirable tion With the administration of a topical anti-acne compo bacteria and mites; (3) Control of in?ammation; (4) sition comprising an anti-acne agent selected from salicylic Enhanced desquamation of follicular infundibulum cells; (5) acid, sulfur, lactic acid, glycolic acid, pyruvic acid, urea, Reduction of irritation from anti-acne and anti-rosacea com resorcinol, N-acetylcysteine, retinoic acid, benZoyl perox positions themselves; and (6) An enhancement of the topical ide, octopirox, triclosan, aZelaic acid, phenoxyethanol, phe bioavailability of anti-acne and anti-rosacea compositions. noxypropanol, ?avinoids, derivatives thereof, and mixtures thereof. The problems of salicylic acid irritation and loW [0052] Since the resistance to bacteria is becoming a topical bioavailability and the use of antibacterials are still problem, it Would be advantageous to control bacteria With not eliminated by Wiegand. US. Patent Application out using an antibacterial agent. Also, salicylic acid is being 20010056071 (Pelicchia) discloses the application of anti one of the most favored and inexpensive ingredients to oxidant resveratrol for acne treatment. US. Pat. No. 6,451, control acne, albeit its irritation causing side effects, it Would 773 (Oester et al.) discloses a combination of chitosan With be advantageous to devise methodologies to increase both aZelaic acid, benZoyl peroxide, retinoic acid, salicylic acid, US 2007/0269537 A1 Nov. 22, 2007
or mixtures thereof, for the treatment of acne. Chitosan is panied by seborrhea or enhancement of feeling of heat on the used as a ?lm-forming agent for topical application of other face due to emotional stress or change of environmental active ingredients for better adhesion to skin surface. While temperature. Thus, these symptoms give a patient mental topical bioavailability is enhanced, the skin irritation and and physical suffering. For the time being, the real cause of other problems of salicylic acid and aZelaic acid use are not rosacea is unknoWn (Hifuka Chirya Handbook, pp. 380-381, reduced. US. Pat. No. 6,440,994 (Sanders) discloses acne NanZando (1987) and Gerd PleWing, Albert M. Kligman, treatment using a mixture of antihistamines and anti-in?am ACNE and ROSACEA, 2nd, Completely Revised and matory agents. This does not provide a multifaceted treat Enlarged Edition, pp. 431-454, Springer-Verlag (1993)). ment objective. US. Pat. No. 6,436,417 (Singh) discloses Rosacea is apt to be confused With acne. Rosacea, Which can solubiliZed forms of salicylic acid for acne treatment. Such coexist With acne, essentially differs from acne. It is char solubiliZed forms absorb more quickly, reaching blood acteriZed by facial ?ush due to vasculariZation and proceeds stream at a faster rate. Both the topical anti-acne ef?cacy With acne rosacea and tumor on apex nasi. The etiology of may be loWer and skin irritation may be higher for such rosacea is not fully knoWn, hoWever, at least four factors or compositions. US. Pat. No. 6,433,024 (Popp et al.) discloses co-factors have been suggested. The ?rst of these is endo topical anti-acne compositions based on benZoyl peroxide, crine in that the disease occurs most frequently in Women an alpha hydroxy acid, a moisturizer, an isosorbide and a betWeen the ages of thirty and ?fty. As such, one de?nite detergent. These compositions contain several skin irritating type of rosacea is believed to have a hormonal basis. A ingredients. US. Pat. No. 6,365,623 (Perricone) discloses second factor is vasomotor liability, believed to have some one preferred embodiment that contains a combination of connection With menopause, Which brings about an impair lipoic acid, an .alpha.-hydroxy acid, and dimethylaminoal ment of normal or consistent How of blood to the face and cohol. Lipoic acid is also claimed to cure rosacea (US. Pat. its capillaries. Therein, excessive How of blood to the face, No. 6,472,432; Perricone). US. Pat. No. 6,262,117 (Sefton) i.e., the Well-knoWn “hot ?ashes” of menopause, is believed discloses acne treatment based on a combination of benZoyl to constitute a factor in the disease and its pathogenesis. peroxide and aZelaic acid. The poor stability of benZoyl More particularly, it has been proven that increased skin peroxide and the skin irritation of either benZoyl peroxide or temperature, as occurs in facial ?ushing, increases suscep aZelaic acid are still unsolved in Sefton disclosure. US. Pat. tibility to the condition. Rosacea has also been observed as No. 6,168,798 (O’Halloran et al.) discloses an alcoholic a side effect or immune response to the use of certain solution of salicylic acid and salicylates for acne treatment. cortisone products, Which can bring about a severe form of The rapid absorption of such clear solutions into skin Would the condition. Finally, pathology analysis of the expressed reduce the topical bioavailability of the active ingredients in contents of in?amed pustule follicle of the nose in acute such compositions. US. Pat. No. 5,989,523 (FitZjarrell et rosacea has demonstrated the existence of demodices, Which al.) discloses a topical spray comprising niacinamide, Aloe is a signature of the ectoparasite demodex folliculorum. Vera extract and NaPCA in a Water carrier base. US. Pat. Accordingly, in such cases, a speci?c external pathogenic No. 5,910,312 (Fried) discloses an anti-acne composition factor is evident. This factor is not present in other forms of comprising benZoyl peroxide, salicylic acid, and a vasocon acne, e.g., acne vulgaris. strictor in an inert carrier. BenZoyl peroxide has been [0055] HoWever, the information available so far does suggested for treating acne vulgaris. (See US. Pat. No. establish that both acne and rosacea are interrelated, and 4,387,107.) For many years, benZoyl peroxide has been hence a common treatment for both Would be highly desir proven to be a particularly poWerful keratolytic and anti able. seborrhic agent, as Well as being endoWed With antibacterial properties. Topical benZoyl peroxide compositions, includ [0056] Relative to rosacea treatment compositions, US. ing a vehicle to enhance the ef?cacy thereof, are knoWn (See Pat. Nos. 6,352,724 and 5,654,013 (Taylor et al.) discloses US. Pat. No. 4,411,893). Topical compositions of benZoyl rubbing common salt (Sodium chloride). Sodium chloride is peroxide combination With antibiotics are also knoWn. (See the subject of additional disclosures for the treatment of both US. Pat. Nos. 4,407,794; 4,692,329 and 4,387,107). The acne and rosacea (US. Pat. No. 4,443,442 to Skillern; US. problems of skin irritation from benZoyl peroxide or sali Pat. No. 3,867,522 to Kligman). HoWever, such treatments cylic acid, and the chemical instability and reactivity of only Work by a single biochemical mechanism, that of benZoyl peroxide are still not solved, although complex, abrasion and debridement of the affected skin. Also, once the dual-chamber delivery systems (such as US. Pat. No. 6,462, debridement is completed, the affected skin Will feel pain, 025; V1shnupad and US. Pat. No. 6,448,233; LaFevre et al.) since it Will be equivalent to “adding salt to injury”. US. Pat. have been disclosed. Such delivery systems are usually No. 6,174,534 (Richard et al.) provides a composition that expensive, not convenient, and not precise in delivering contains long chain fatty acids for rosacea treatment. product quantity. Although such composition may be suitable for rosacea, such fatty acids may actually exacerbate acne due to excess [0054] Rosacea is, While rare among colored races, com sebum-like activity from such fatty acids. US. Pat. No. mon among races With a light-colored skin, especially 6,136,806 (Hittel) discloses certain synthetic organic mol among White races, and many cases occur among them. It is ecules for rosacea treatment that are not commonly avail divided according to the symptoms into the ?rst degree able, or available by prescription only in certain countries. (telangiectatic rosacea on the forehead, cheeks, dorsum US. Pat. Nos. 6,133,310 (Parks) and 5,952,372 (McDaniel) nasi), the second degree (acne rosacea, coexistence of fol disclose the application of lnvermectin in the treatment of licular papules and pustules), and the third degree (rhino rosacea. This ingredient has also been used frequently for phyma, dark red tumor and dilated pore on apex nasi). It the treatment of acne. lnvermectin, hoWever, provides relief starts With facial ?ush (redness) and eventually involves by a single biochemical mechanism, not a six-prong serious impairment of appearance, developing papules, pus approach. Moreover, lnvermectin is not commonly avail tules, rhinophyma and tumor on apex nasi, it is also accom able. US Pat. No. 5,972,993 (Ptchelintsev) discloses the US 2007/0269537 A1 Nov. 22, 2007
application of certain antioxidants for the treatment of transport has been extensively studies in the prior art, for rosacea. This treatment is thus based only on a single example Nielands et al. [Adv. Inotg. Biochem., 5, 137 approach of anti-in?ammatory action of such antioxidants. (1983); Struct. Bonding (Berlin), 58, 1 (1984)]. The agents US. Pat. No. 5,667,790 (Sellers) discloses the application of responsible for iron transport into and Within bacteria have aluminum salts for acne and rosacea treatment. Such alu been extensively studied, and many structural and chemical minum salts only block the exudation of sebum and provide details have been ?rmly established. The problem is that iron relief probably by astringent action. Their long-term use can is not spontaneously available to oxic (aerobic) organisms in actually cause additional in?ammatory response. US. Pat. an aqueous environment because of the very loW solubility No. 5,885,595 (Corey) discloses esters of retinal for acne of ferric hydroxide (pK ~38). Thus Fe3+ ions at a pH of ~7 and rosacea treatment. US. Patent Application have a molar concentration of only ~10(—18), and simple 20020013361 (Perricone) claims the use of lipoic acid. diffusion into cells could never suf?ce to supply their needs. Since lipoic acid is an antioxidant, it probably Works by Indeed, simple inWard diffusion Would not occur, since iron anti-in?ammatory biochemical mechanism, thus constitut is already more concentrated than this in the living cell. ing just one-prong treatment. US. patent applications Therefore special chelating agents called “siderophores” are 20020172719, 20020054918, and 20020041901 (Murad) produced by bacteria and ejected into their environment to disclose pharmaceutical composition and methods for the gather iron and transport it through the cell Wall into the cell. cleansing of skin to facilitate the prevention, treatment, and In some cases it appears that iron is released by the chelator management of skin conditions that include rosacea and at the cell Wall and it passes through alone, Whereas in others acne by a composition that includes a hydroxy acid or tannic the entire complex enters the cell. acid to exfoliate a portion of the skin, stabiliZed hydrogen peroxide to facilitate cleansing of the skin, and an antimi [0061] The siderophores are rather diverse chemically but crobial agent to inhibit or reduce microorganisms on the have in common the use of chelating, oxygen-donor type skin. Since the overuse of antimicrobial agents can cause ligands. A very large number of siderophores that have been further problems, as mentioned earlier, Murad inventions are characterized employ hydroxamate moieties, 4COiNi thus of limited application, or even to be possibly avoided O(—), as the ligands. The structure of a siderophore, called for any long-term rosacea and acne treatment regimen. a “ferrichrome” consists of a cyclic hexapeptide in Which three successive amino acid residues have side chains end [0057] It is thus both surprising and unexpected that the ing in hydroxamate groups. These hydroxamate groups bind compositions of the present invention relieve the symptoms iron by forming a tris-chelate octahedral complex FIG. 2. of acne and also rosacea. The exact mechanism of this action is not Well understood at this time. HoWever, this does not [0062] FIG. 2. reduce the signi?cance or utility of the present invention for [0063] Another type of siderophore, especially common in consumer applications. prokaryotes such as enteric bacteria is called an “enterobac [0058] Topical application of artemisinin for the treatment tin”; the ligating units are catecholate anions that also of viral tumors/diseases, hemorrhoids, and bullous skin chelate very effectively [Raymond et al., J. Am. Chem. Soc., diseases has been disclosed by Thornfeldt (US. Pat. No. 107, 6920 (1985)]. 4,978,676). No treatment of acne or rosacea Was reported by [0064] FIG. 3. Thornfeldt. [0065] Iron-Sulfur proteins are relatively loW molecular [0059] MaZZio et al (US. patent application Ser. No. Weight compounds consisting of peptide chains bound 2004185123) disclose a topical herbal formulation for pre though cysteine sulfur atoms to redox centers that consist venting and/or treating dyshidrosis (pompholyx), non-re either of one iron atom or a cluster of iron and sulfur atoms, sponsive to topical steroids. The formulation may also be the latter often being called “inorganic” sulfur atoms to used to treat contact dermatitis, ecZema, palmoplantar pus distinguish them from the sulfur atoms of the cysteine tulosis and skin infections incurred by invasive pathogens residues. The term “rubredoxin” is used for those With one such as mold, fungus and bacteria. The formulation is iron atom, While those containing clusters are called “ferre comprised of plant extracts and niacin, that When combined doxins”FIG. 4. yield an effective multi-faceted pharmaceutical approach to treating dry skin disorders. The active ingredients Within the [0066] FIG. 4. formula include a combination of dry, aqueous, acid and alcohol extracts of black Walnut hull (Ouglans Nigra), [0067] Rubredoxins are found in anoxic (anaerobic) bac WormWood (Arlemisia Absinlhium), tumeric rhiZome (Cur teria Where they are believed to participate in biological cuma Longa), garlic (Allium salivum), chamomile (Matri redox reactions. They are relatively loW molecular Weight caria Chamomile), licorice root (Glycyrrhiza Glabra), St. proteins (~6000 amu) containing only one iron atom. In the Johns Wort (Hypericum perforalum), aloe vera, niacin and best-characterized rubredoxin, from the bacterium herbal anti-bacterial agents. These authors do not disclose Closlridium paslurianum, the iron atom, Which is normally anti-acne or anti-rosaces properties of Arlemisia, either in the III oxidation state, is surrounded by a distorted alone or in combination With other agents. tetrahedron of cysteinyl sulfur atoms. The FeiS distances range from 2.24 to 2.33 Angstroms (A), and the SiFeiS [0060] The present inventor hypothesiZes possible mecha angles from 104 to 114 degrees. When the Fe (III) is reduced nism(s) for anti-acne activity of the present invention. Acne to Fe (II) there is a slight (0.05 A) increase in the FeiS is caused, among other factors, by Propionibaclerium acnes. distances. HoWever, Mossbauer spectroscopy shoWs that Fe Most bacteria are greatly dependent on iron (in Fe3+ state) is actually present both in (III) and (II) oxidation states. for their metabolic activity. This Fe demand is greater that Fe Ferredoxins are also relatively small proteins (~6000-12000 requirements of normal human cells. The bacterial iron amu) in Which the redox centers, clusters of tWo, three, or US 2007/0269537 A1 Nov. 22, 2007
four iron atoms, each With an equal number of sulfur atoms conversion of 5,6-dihydroxyindole-2-carboxylic acid are held in place by bonds from cysteine sulfur atoms to iron. (DHICA) to indole-5,6-quinone-2-carboxylic acid; and TRP-2, Which is the melanogenic enZyme DOPAchrome [0068] From the above discussion it can be seen that a tautomerase [EC:5.3.3.12] that catalyZes the conversion of distortion of rubredoxin, ferredoxin, ferrichrome sidero DOPAchrome to DHICA. TRP-2 differs from tyrosinases phore, and enterobactin siderophore can cause a disruption and TRP-l in that it binds tWo Zinc ions instead of copper. of bacterial metabolism. Thus, the bacteria may not be killed The proposed structure of Cu4Cu tyrosinase active site is via the antibacterial action, but their multiplication by cell division may be hampered for their further groWth. shoWn in FIG. 8. [0079] FIG. 8. [0069] In an unexpected and surprising discovery it has noW been found that the compositions of the present inven [0080] The inhibition of melanin synthesis can thus be tion bind With rubredoxin moiety of Prionionibacterium achieved via several pathWays, including the inhibition of acnes. When this bound form of rubredoxin enters the acne tyrosine transaminase (inhibition of amination of hydrox bacterium the cellular redox functions are inhibited FIG. 5. yphenyl Pyruvate or phenyl Pyruvate (Step [7] and/or [4], This causes the acne bacterium to cease its metabolic FIG. 6), Which leads to eventual inhibition of tyrosine activity. HoWever, this is only one mechanism for anti acne biosynthesis. The melanin synthesis can also be blocked by activity of the present invention. There are several other the inhibition of monophenyl monooxygenase (EC possible modes of anti-acne action, as mentioned above, 1 .14. l 8. 1), Which converts tyrosine into dopaquinone via the Which are yet unknoWn for the bene?ts rendered by the intermediacy of dopa FIG. 6. In a surprising and unexpected present invention. As stated before, this should not preclude discovery, the compositions of the present invention inhibit the utility of this invention. both tyrosine transaminase and monophenyl monooxyge nase. The precise mechanism of this inhibition is not knoWn [0070] FIG. 5. at this time, but it is hypothesized that the compositions of [0071] Control of Dark Spots. Inhibition of phenylalanine the present invention bind With Fe in the active-site of hydroxylase and Phenylalanine Transaminase. monophenyl monooxygenase. Regardless of the actual bio chemical mechanism the importance of this invention [0072] The biosynthetic pathWays from shikimic acid remains unexpected and novel. leading to the formation of melanin are summarized in FIG. 6 that Will be used as a reference for subsequent discussions. [0081] Skin Brightening and AntiWrinkle-Antiaging Applications. [0073] FIG. 6. [0082] The compositions of the present invention provide [0074] Phenylalanine hydroxylase is responsible for the an unexpected inhibition of MMP, tyrosinase, and tyrosine ?rst step in the conversion of phenylalanine into tyrosine. biosynthesis enZymes. The doWn-regulation of MMP leads Tyrosine is required for the production of melanin, Which to reduced degradation of connective issue such as collagen gives color to hair and skin. Phenylalanine hydroxylase must and ?brin. This results in increased suppleness of skin, Work in combination With tetrahydrobiopterin to perform leading to reduced visible skin Wrinkles from aging. The this function. Phenylalanine hydroxylase contains iron in its decreased biosynthesis of tyrosine and dopa, and inhibition active site, and tetrahydrobiopterin is required in proximity of Tyrosinase and tyrosine precursor enZymes leads to skin to this active site, as shoWn in FIG. 7. brightening elfects, all of Which are both surprising and [0075] FIG. 7. unexpected When taken as a group of such desirable bene?ts. In normal practice, such group of desirable bene?ts is [0076] It is both surprising and unexpected that composi usually achievable only from a combination of several tions of the present invention inhibit phenylalanine hydroxy ingredients. It is thus unexpected and surprising that just one lase. Although the mechanism of this inhibition is not fully ingredient, such as an Ni[(Hydroxyaryl)alkylidene]amino clear at this time, it is theoriZed that the binding of iron metal acid, can provide multiple desirable topical bene?ts. The at the active site of Phenylalanine hydroxylase (Reaction exact biochemical mechanism for these unexpected bene?ts Step 8, FIG. 6) and/or binding With Fe at tetrahydrobiopterin is not yet knoWn. could be the cause for this e?cect. [0083] Wound Healing Applications. [0077] Control of Dark Spots. Inhibition of tyrosine tran saminase and Monophenol Monooxygenase (Tyrosinase). [0084] The compositions of the present invention provide an unexpected Wound healing bene?t With little scar tissue [0078] Tyrosinase [EC:l.l4.l8.l] is a complex group of formation or skin pigment discoloration. copper monooxygenases that catalyses the hydroxylation of monophenols and the oxidation of ortho-diphenols to ortho [0085] The entire Wound healing process is a complex quinones. This enZyme, found in prokaryotes and eukary series of events that begins at the moment of injury and can continue for months to years. This overvieW Will help in otes, is involved in the formation of pigments such as melanins and other polyphenolic compounds. Tyrosinase identifying the various stages of Wound healing. binds tWo copper ions (CuA and CuB). Each of the tWo [0086] I. In?ammatory Phase. A) Immediate to 2-5 copper ions has been shoWn to be bound by three conserved days; B) Hemostasis, (i) Vasoconstriction, (ii) Platelet histidine residues. The regions around these copper-binding aggregation, and (iii) Thromboplastin makes clot; C) ligands are Well conserved and also shared by some In?ammation, (i) Vasodilation, (ii) Phagocytosis. hemocyanins, Which are copper-containing oxugen carriers [0087] II. Proliferative Phase. A) 2 days to 3 Weeks; B) from the hemolymph of many mollusks and arthropods. At Granulation, (i) Fibroblasts lay bed of collagen, (ii) least tWo peoteins related to tyrosinase are knoWn to exist in Fills defect and produces neW capillaries; C) Contrac mammals, and include TRP-l, Which is responsible for the tion, US 2007/0269537 A1 Nov. 22, 2007 10
[0088] (i) Wound edges pull together to reduce over-expression of MMP-13 should be controlled from the defect; D) EpithelialiZation, (i) Crosses moist sur onset of Wound healing process to avoid apoptosis of neWly face, (ii) Cell travel about 3 cm from point of origin formed connective tissue. Both connective tissue forming in all directions. agents and anti-in?ammatory agents are bene?cial during the later stages of Wound healing. [0089] III. Remodeling Phase. A) 3 Weeks to 2 years; B) NeW collagen forms Which increases tensile strength to [0093] The exact mechanism of topical Wound healing by Wounds; C) Scar tissue is only 80 percent as strong as the compositions of the present invention is believed to be original tissue. due to the inhibition of Heme Oxidase, the exact nature if Which is not yet knoWn. HoWever, this should not preclude [0090] Wound healing, or Wound repair, is the body’s the practical utility of the present invention in topical Wound natural process of regenerating dermal and epidermal tissue. healing applications. When an individual is Wounded, a set of events takes place in a predictable fashion to repair the damage. These events [0094] The present invention discloses a composition overlap in time and must be arti?cially categoriZed into comprising a sesquiterpene endoperoxide for skin condition separate steps: the in?ammatory, proliferative, and matura improvement. tion phases. In the in?ammatory phase, bacteria and debris are phagocytiZed and removed and factors are released that [0095] The present invention also discloses a method of cause the migration and division of cells involved in the topical application for skin condition improvement compris proliferative phase. The proliferative phase is characteriZed ing a sesquiterpene endoperoxide composition, and subse by angiogenesis, collagen deposition, granulation tissue quent complexation of said sesquiterpene endoperoxide With formation, epithelialiZation, and Wound contraction. In an iron siderophore released by an organism on skin surface angiogenesis, neW blood vessels groW from endothelial to form a “Trojan Horse” complex, and Wherein said “Trojan cells. In ?broplasia and granulation tissue formation, ?bro Horse” complex further enters the cell of said iron sidero blasts groW and form a neW, provisional extracellular matrix phore releasing organism and binds With the protein of said (ECM) by excreting collagen and ?bronectin. In epithelial organism, and Wherein said binding deactivates the skin iZation, epithelial cells craWl across the Wound bed to cover condition causing effects of said organism. it. In contraction, the Wound is made smaller by the action [0096] In the present invention, sesquiterpene endoperox of myo?broblasts, Which establish a grip on the Wound ide is selected from the group consisting of artemisinin, edges and contract themselves using a mechanism similar to dihydroartemisinin, artemether, arteether, arte?ene, artesu that in smooth muscle cells. When the cells’ roles are close nate, dihydroxydihydroartemisinin, artelinic acid, artemisi to complete, unneeded cells undergo apoptosis. In the matu none, dihydroartemisinin propyl carbonate, sesquiterpene ration and remodeling phase, collagen is remodeled and endo-peroxide lactones and alcohols, carbonates, esters, realigned along tension lines and cells that are no longer ethers sulfonates and pharmaceutically acceptable salts needed are removed by apoptosis. thereof, trioxolanes, byciclo endoperoxides, trioxanes, tet [0091] In the in?ammatory phase, clotting takes place in raoxanes, terpenes, and substituted terpenes. The sesquiter order to obtain hemostasis, or stop blood loss, and various pene endoperoxide of choice comprises of artemisinin, or factors are released to attract cells that phagocytiZe debris, Arlemisia annua extract. bacteria, and damaged tissue and release factors that initiate the proliferative phase of Wound healing. When tissue is ?rst [0097] The exact amount of each ingredient, or combina tions thereof, to be used for various applications disclosed in Wounded, blood comes in contact With collagen, triggering blood platelets to begin secreting in?ammatory factors. the present invention is determined separately for each such application. In general, the amounts can vary from about Platelets also express glycoproteins on their cell membranes 0.0001 percent by Weight to about 50 percent by Weight. that alloW them to stick to one another and to aggregate, forming a mass. Fibrin and ?bronectin cross-link together [0098] For the treatment of topical Wounds, the inclusion and form a plug that traps proteins and particles and prevents of a Matrix metalloprotease (MMP) inhibitor is additionally further blood loss. This ?brin-?bronectin plug is also the bene?cial. The said MMP can be selected, among others, main structural support for the Wound until collagen is from those disclosed by the present inventor in Us. patent deposited. Migratory cells use this plug as a matrix to craWl application Ser. No. 10/711,775, ?led Oct. 4, 2004. across, and platelets adhere to it and secrete factors. The clot is eventually lysed and replaced With granulation tissue and [0099] The compositions of the present invention can then later With collagen. Platelets, the cells present in the further include additional pharmaceutical or cosmetic active highest numbers shortly after Wounding, release a number of agent selected from a group of anti-acne agents comprising factors into the blood, including ECM proteins and cytok of salicylic acid, benZoyl peroxide, resorcinol, resorcinol ines, including groWth factors. GroWth factors stimulate monoacetate, sulfur, and combinations thereof. cells to speed their rate of division. Platelets also release other proin?ammatory factors like serotonin, brakykinin, [0100] The compositions of the present invention can prostaglandins, prostacyclin, thromboxane, and histamine, further include additional pharmaceutical or cosmetic active Which serve a number of purposes, including to increase cell agent for topical Wound therapy, Which can be selected, proliferation and migration to the area and to cause blood among others, from Zinc ascorbate, copper Hyaluronate, vessels to become dilated and porous. Zinc Hyaluronate, manganese Hyaluronate, copper Glu cosamine complex, Zinc Glucosamine complex, manganese [0092] Contrary to common belief, the use of any anti Glucosamine complex, copper chondroitin, Zinc chon in?ammatory agents during the early stages of Would droitin, manganese chondroitin, copper chondrosine, Zinc healing process is not desirable. On the same note, the chondrosine, manganese chondrosine, copper oleoresin US 2007/0269537 A1 Nov. 22, 2007
complex, Zinc aloeresin complex, manganese aloeresin com ken seed nut shells, silica, clays, beads, lu?a particles, plex, copper aloe emodin, Zinc aloe emodin, and manganese polyethylene balls, mica, pH adjusters, processing aids, and aloe emodin. combinations thereof. [0101] The compositions of the present invention can be [0106] In another preferred aspect, the cosmetically formulated in various cosmetic and pharmaceutical con acceptable composition further comprises one or more sumer products utilizing a variety of delivery systems and excipient selected from the group consisting of Water, sac carrier bases. Such consumer product forms include the charides, surface active agents, humectants, petrolatum, group consisting of shampoos, aftershaves, sunscreens, body mineral oil, fatty alcohols, fatty ester emollients, Waxes and and hand lotions, skin creams, liquid soaps, bar soaps, bath silicone-containing Waxes, silicone oil, silicone ?uid, sili oil bars, shaving creams, conditioners, permanent Waves, cone surfactants, volatile hydrocarbon oils, quaternary nitro hair relaxers, hair bleaches, hair detangling lotion, styling gen compounds, amine functionaliZed silicones, condition gel, styling glaZes, spray foams, styling creams, styling ing polymers, rheology modi?ers, antioxidants, sunscreen Waxes, styling lotions, mousses, spray gels, pomades, active agents, di-long chain amines from about C.sub.l0 to shoWer gels, bubble baths, hair coloring preparations, con C.sub.22, long chain fatty amines from about C.sub.l0 to ditioners, hair lighteners, coloring and non-coloring hair C.sub.22, fatty alcohols, ethoxylated fatty alcohols and rinses, hair grooming aids, hair tonics, spritZes, styling di-tail phospholipids. Waxes, band-aids, and balms. [0107] Representative saccharides include nonionic or cat ionic saccharides such as agarose, amylopectins, amylases, [0102] In another preferred aspect, the delivery system or arabinans, arabinogalactans, arabinoxylans, carrageenans, a carrier base are selected in the form of a lotion, cream, gel, gum arabic, carboxymethyl guar gum, carboxymethyl(hy spray, thin liquid, body splash, poWder, compressed poWder, droxypropyl) guar gum, hydroxyethyl guar gum, carboxym tooth paste, tooth poWder, mouth spray, paste dentifrice, ethyl cellulose, cationic guar gum, cellulose ethers including clear gel dentifrice, mask, serum, solid cosmetic stick, lip methyl cellulose, chondroitin, chitins, chitosan, chitosan balm, shampoo, liquid soap, bar soap, bath oil, paste, salve, pyrrolidone carboxylate, chitosan glycolate chitosan lactate, collodion, impregnated patch, impregnated strip, skin sur cocodimonium hydroxypropyl oxyethyl cellulose, colo face implant, impregnated or coated diaper, and similar minic acid ([poly-N acetyl-neuraminic acid]), corn starch, delivery or packaging form. curdlan, dermatin sulfate, dextrans, furcellarans, dextrans, [0103] In another preferred aspect, the delivery system can cross-linked dextrans, dextrin, emulsion, ethyl hydroxyethyl be human body or hair deodoriZing solution, deodoriZing cellulose, ?axseed saccharide (acidic), galactoglucoman poWder, deodoriZing gel, deodoriZing spray, deodoriZing nans, galactomannans, glucomannans, glycogens, guar gum, stick, deodoriZing roll-on, deodoriZing paste, deodoriZing hydroxy ethyl starch, hydroxypropyl methyl cellulose, cream, deodoriZing lotion, deodoriZing aerosol, and other hydroxy ethyl cellulose, hydroxy propyl cellulose, hydrox commonly marketed human body and hair deodoriZing ypropyl starch, hydroxypropylated guar gums, gellan gum, compositions, household deodoriZing solution, deodoriZing gellan, gum ghatti, gum karaya, gum tragancanth (tragacan poWder, deodoriZing gel, deodoriZing spray, carpet deodor thin), heparin, hyaluronic acid, inulin, keratin sulfate, konjac iZer, room deodoriZer, and other commonly marketed house mannan, modi?ed starches, laminarans, laurdimonium hold deodoriZing compositions, animals and pets deodoriZ hydroxypropyl oxyethyl cellulose, okra gum, oxidiZed ing solution, deodoriZing poWder, deodoriZing gel, starch, pectic acids, pectin, polydextrose, polyquaternium-4, deodoriZing spray, animals and pets carpet deodoriZer, ani polyquatemium-lO, polyquatemium-28, potato starch, pro mals and pets room deodoriZer, and other commonly mar topectins, psyllium seed gum, pullulan, sodium hyaluronate, keted animal and pet deodoriZing compositions. starch diethylaminoethyl ether, steardimonium hydroxyethyl cellulose, raf?nose, rhamsan, tapioca starch, Whelan, levan, [0104] In another preferred aspect, the delivery system can scleroglucan, sodium alginate, stachylose, succinoglycan, be traditional Water and oil emulsions, suspensions, colloids, Wheat starch, xanthan gum, xylans, xyloglucans, and mix microemulsions, clear solutions, suspensions of nanopar tures thereof. Microbial saccharides can be found in Kirk ticles, emulsions of nanoparticles, or anhydrous composi Othmer Encyclopedia of Chemical Technology, Fourth Edi tions. tion, Vol. 16, John Wiley and Sons, NY pp. 578-611 (1994), Which is incorporated entirely by reference. Complex car [0105] Additional cosmetically or pharmaceutically ben bohydrates found in Kirk-Othmer Encyclopedia of Chemi e?cial ingredients can also be included in the formulated cal Technology, Fourth Edition, Vol. 4, John Wiley and Sons, compositions of the present invention, Which can be selected NY pp. 930-948, 1995 Which is herein incorporated by from, but not limited to skin cleansers, cationic, anionic reference. surfactants, non-ionic surfactants, amphoteric surfactants, and ZWitterionic surfactants, skin and hair conditioning [0108] The cosmetically acceptable composition of this agents, vitamins, hormones, minerals, plant extracts, anti invention may include surface-active agents. Surface-active in?ammatory agents, collagen and elastin synthesis boost agents include surfactants, Which typically provide detersive ers, UVA/UVB sunscreens, concentrates of plant extracts, functionality to a formulation or act simply as Wetting emollients, moisturiZers, skin protectants, humectants, sili agents. Surface-active agents can generally be categoriZed cones, skin soothing ingredients, antimicrobial agents, anti as anionic surface-active agents, cationic surface-active fungal agents, treatment of skin infections and lesions, blood agents, nonionic surface-active agents, amphoteric surface microcirculation improvement, skin redness reduction ben active agents and ZWitterionic surface-active agents, and e?ts, additional moisture absorbents, analgesics, skin pen dispersion polymers. etration enhancers, solubiliZers, moisturizers, emollients, [0109] Anionic surface-active agents useful herein include anesthetics, colorants, perfumes, preservatives, seeds, bro those disclosed in Us. Pat. No. 5,573,709, incorporated