WO2014120026A1 - Traitement et prévention de l'acné - Google Patents

Traitement et prévention de l'acné Download PDF

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Publication number
WO2014120026A1
WO2014120026A1 PCT/PH2013/000006 PH2013000006W WO2014120026A1 WO 2014120026 A1 WO2014120026 A1 WO 2014120026A1 PH 2013000006 W PH2013000006 W PH 2013000006W WO 2014120026 A1 WO2014120026 A1 WO 2014120026A1
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WO
WIPO (PCT)
Prior art keywords
lactoferrin
whey
acne
zinc
vitamin
Prior art date
Application number
PCT/PH2013/000006
Other languages
English (en)
Inventor
Joyce Bedelia B. SANTOS
Kennie U. Dee
Original Assignee
Santos Joyce Bedelia B
Dee Kennie U
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santos Joyce Bedelia B, Dee Kennie U filed Critical Santos Joyce Bedelia B
Priority to PCT/PH2013/000006 priority Critical patent/WO2014120026A1/fr
Priority to CN201380075300.XA priority patent/CN105283197B/zh
Priority to SG11201505909WA priority patent/SG11201505909WA/en
Publication of WO2014120026A1 publication Critical patent/WO2014120026A1/fr
Priority to PH12015500468A priority patent/PH12015500468A1/en
Priority to HK16108566.9A priority patent/HK1220396A1/zh

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
    • 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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • Acne Vulgaris is a common skin condition affecting all ages, races, and genders. Prevalence peaks at 80-90 percent in adolescents, but continues beyond the teenage years especially in women. Acne develops due to a blockage of the hair follicles. Hyperkeratinization and formation of a plug of keratin and sebum, called microcomedo, is the earliest change. The microcomedo may enlarge to form an open comedone (blackhead) or closed comedone (whitehead). In these conditions, the largely commensal bacterium Propionibacterium acnes can cause inflammation leading to inflammatory lesions (papules and pustules).
  • Glanal activity such as puberty and menstrual cycles, which increases sebum production, may contribute to the formation of acne.
  • Current treatments for acne include topical benzoyl peroxide, topical and oral retinoids, topical and oral antibiotics, and oral hormones for women.
  • adverse events are associated with these treatments varying from dryness, redness and irritation of the skin when using topical retinoids, to antibiotic resistance when using antibiotics, to birth defects when using oral retinoids, and to weight gain and thrombosis when using hormones. There is therefore a need for a safer alternative to current treatment protocols.
  • Lactoferrin is a protein that occurs naturally in cow's milk. Lactoferrin is classified as GRAS (Generally Regarded as Safe) by the US Food and Drug Administration and European Food Safety Authority, for use as an ingredient in functional foods. Lactoferrin exhibits antimicrobial, antioxidant and anti-inflammatory properties.
  • Bovine lactoferrin is obtained commercially from skim milk or from cheese whey. It is important to understand the difference between lactoferrin isolated from skim milk and cheese whey to understand the prior art. Bovine milk protein is broadly classified into casein and whey. Bovine milk protein is 80% casein, which is a name for a family of related phosphoproteins (asl, as2, ⁇ , ⁇ ) with an isoelectric point of 4.6. Casein is relatively hydrophobic, making it poorly soluble in water. Casein is found in milk as a suspension of particles called casein micelles, wrapped in soluble ⁇ -casein molecules. Casein carries a negative charge at the pH of milk of about 6.6-6.8.
  • Bovine milk protein is 20% whey protein, which is a collection of globular proteins that are soluble independent of pH. Whey proteins include ⁇ - lactoglobulin, a-lactalbumin, and serum albumin. These whey proteins have isoelectric points below 6.6 - the pH of milk - which means that they are present as negatively charged proteins in milk. There are two minor proteins in bovine milk that have isoelectric points above 6.8. One is lactoferrin, which is an 80-kda protein with a reported isoelectric point of 7.8-8.7, and lactoperoxidase with an isoelectric point of 9.6. Lactoferrin can be isolated directly from skim milk. First, fat is removed from whole milk by centrifugation to produce skim milk.
  • Skim milk at a natural pH of 6.6-6.8 is filtered and applied to a cationic-exchange chromatography, such as carboxymethyl (CM)-Sephadex, which removes the positively charged proteins lactoferrin and lactoperoxidase.
  • CM carboxymethyl
  • the column is washed with a low concentration (1.6%) NaCl solution, which elutes lactoperoxidase.
  • lactoferrin is eluted with a high concentration (5%) NaCl solution.
  • the lactoferrin is concentrated by ultrafiltration and is separated from NaCl by diafiltration. After low heat treatment, lactoferrin is freeze-dried to make a powder. Lactoferrin produced from skim milk is substantially free of other whey proteins.
  • lactoferrin derived directly from skim milk as "skim milk-derived lactoferrin”.
  • Lactoferrin can also be isolated from cheese whey, which is the waste material from cheese making.
  • Hard cheeses such as cheddar cheese, are produced by adding to whole milk lactic acid-producing bacteria for acidification, and rennet. The combined action of acidification and rennet coagulates milk into solid (curds) and liquid (whey).
  • the curd is mainly fat and casein protein.
  • Lactoferrin ends up in the whey. Rennet is a complex of enzymes obtained from calf stomach. Rennet contains many enzymes including the protease enzymes chymosin and pepsin, and lipases.
  • Chymosin is an aspartic protease that specifically hydrolyzes the peptide bond in Phel05-106Met of -casein, removing the hydrophilic portion of ⁇ -casein that stabilizes the casein micelles, causing the casein to coagulate.
  • the hydrophilic portion of ⁇ -casein is a protein with 64 amino acids called glycomacropeptide that ends up with the whey. Glycomacropeptide has been reported to be antibacterial, antiviral, and antiinflammatory. Treatment with the lactic acid bacteria and rennet during cheese making also produces a group of proteins, collectively called proteose peptones, derived from proteolysis and hydrolysis of casein and whey proteins.
  • proteose peptones are heat-stable and acid-soluble proteins that end up in the whey during cheese making. Lactoferrin from whey is purified essentially by the same process described above for skim milk-derived lactoferrin. Because of the additional basic proteins generated from proteolysis and hydrolysis, purification may be more difficult and may require additional steps.
  • PRIOR ART US 8,147,875B2 discloses a method for the treatment of acne by oral administration of a whey protein fraction containing lactoferrin, and preferably containing further specific whey proteins.
  • proteins and peptides as glycomacropeptide, and proteose peptones, which originate from the casein of the milk are also called whey protein”.
  • the other whey proteins are basic, i.e. they elute from an acidic ion exchange resin, and have isoelectric points above 6, especially above 7. It is also preferred that the other whey proteins have a molecular weight between 10 kD and 60 kD".
  • lactoferrin which is not obtained from whey can be used to treat and prevent acne, preferably in combination with Vitamin E and zinc, therefore there is no reason to believe that bovine lactoferrin cannot be replaced with other sources of lactoferrin that are not isolated from whey.
  • Preferred sources of lactoferrin of our instant invention includes bovine lactoferrin isolated directly from skim milk, and recombinant lactoferrin (bovine, human, or others) produced in animals, plants, bacteria, fungi, and mold. In the case of recombinant lactoferrin, there is no concept of "whey protein" or "whey protein fraction" because only the lactoferrin gene is introduced into the host.
  • the whey protein fraction used in the clinical studies described in Example 1 of US 8,147,875B2 was derived from cheddar whey and contains about 80% lactoferrin, the balance being other whey proteins.
  • lactoferrin for treatment of acne used this crude whey protein fraction containing about 20% other whey proteins.
  • oral lactoferrin treatment will work unless it is a component of a whey protein fraction, i.e. unless other whey proteins generated from lactic acid bacteria and rennet proteolysis and hydrolysis are present.
  • lactoferrin obtained directly from skim milk without the additional whey proteins, especially basic whey proteins, generated from the lactic acid bacteria and rennet proteolysis/hydrolysis of milk proteins during cheese making, can be used for the oral treatment and prevention of acne.
  • the lactoferrin of this instant invention is combined with Vitamin E and Zinc.
  • lactoferrin which is not obtained from whey can be used to treat and prevent acne, preferably in combination with Vitamin E and zinc, therefore there is no reason to believe that bovine lactoferrin cannot be replaced with other sources of lactoferrin, as long as they are not isolated from whey.
  • Preferred sources of lactoferrin of this instant invention includes bovine lactoferrin isolated directly from skim milk, and recombinant lactoferrin (bovine, human, or others) produced in animals, plants, bacteria, fungi, and mold.
  • the lactoferrin of this instant invention can be formulated as a tablet, capsule or a liquid for oral administration.
  • the preferred daily dose of lactoferrin of this instant invention is 100 mg to 500 mg, most preferably 100-300 mg.
  • Vitamin E is an integral part of the skin's antioxidant defenses, primarily providing protection against UV radiation and other free radicals that may come in contact with the skin. Deficiency of Vitamin E is associated with acne (Thiele et al., Molecular Aspects of Medicine, 2007, 28:646-667). However, it is not known if supplementation with Vitamin E, alone or in combination with lactoferrin and zinc, can be used to treat and prevent acne.
  • the Vitamin E or its analogues can be selected from, but not limited to, d-a- tocopherol; dl-a-tocopherol; d-a-tocopheryl esters; dl-a-tocopheryl esters; natural mixed tocopherols comprising a isomer, ⁇ isomer, ⁇ isomer, and ⁇ isomer; and tocotrienols and tocotrienol esters comprising a isomer, ⁇ isomer, ⁇ isomer, and ⁇ isomer.
  • the daily dose of vitamin E, in combination with lactoferrin and zinc of this instant invention is preferably less than 100 IU, most preferably less than 50 IU.
  • Zinc deficiency has also been demonstrated to provoke flare-up of existing acne.
  • the therapeutic role of zinc in acne vulgaris is based on its antiinflammatory activity and its role in androgen metabolism.
  • Zinc inhibits the enzyme 5-a-reductase, responsible for converting testosterone to its biologically active metabolite dehydrotestosterone, which mediates stimulation of sebaceous gland activity. Reduction of sebum secretion is known to result from zinc exposure.
  • Zinc may also have direct activity, inhibiting bacterial lipases from converting serum triglycerides to fatty acids, which are more potent mediators of acne (Amer et al., International Journal of Dermatology, 1982, 21 :81-484).
  • the zinc salt of this instant invention can be selected from, but not limited to, zinc sulfate, zinc gluconate, and zinc citrate.
  • the daily dose of zinc, in combination with Vitamin E and lactoferrin of this instant invention is preferably less than 50 mg, most preferably less than 25 mg.
  • Skim milk-derived lactoferrin was obtained commercially.
  • the lactoferrin content was more than 97%.
  • the purity of this skim milk-derived lactoferrin was assessed using essentially the same procedure used in Example 1 of US 8,147,875 B2 for the preparation of crude whey protein fraction containing 79.6% lactoferrin from Cheddar Whey. Briefly, the skim milk-derived lactoferrin was dissolved in phosphate buffer solution pH 6.8, then passed over a CM-Sephadex Fast Flow column. The column was then washed with water, followed by 0.3M NaCl, and finally with 1M NaCl to elute lactoferrin.
  • the 0.3M NaCl and 1M NaCl eluates were analyzed using SDS-PAGE.
  • the 0.3M NaCl eluate was clean, and the lM NaCl eluate only showed lactoferrin with no other contaminating proteins.
  • the whey protein f action of Example 1 of US 8,147,875B2 showed other basic proteins. This is to be expected since the skim milk- derived lactoferrin should not contain other "whey proteins", especially basic whey proteins, generated from the proteolytic and hydrolytic action of the lactic-acid bacteria and rennet.
  • magnesium stearate All the ingredients excluding magnesium stearate were mixed in a sigma blender for 15 minutes. Magnesium stearate was then added, and mixed for 1 minute. The final blend was filled into size 1 gelatin capsule using a GKF 400 encapsulating machine (Bosch, Germany).
  • Example 2 A containing only skim milk-derived lactoferrin.
  • the subjects were evaluated by a dermatologist at 0, 2, 4, 8, and 12 weeks. The total number of blackheads, whiteheads, papules, and pustules were counted. The results are given in Table 2:
  • Example 2B containing 100 mg of skim milk-derived lactoferrin, 8 IU of Vitamin E, and 2.5 mg of Zinc.
  • the subjects were evaluated by a dermatologist at 0, 1, 2, 4, 8, and 12 weeks. The total number of blackheads, whiteheads, papules, and pustules were counted. The results are given in Table 3 :
  • Example 2C containing 100 mg of skim milk- derived lactoferrin, 11 IU of Vitamin E, and 5 mg of Zinc.
  • the subjects were evaluated by a dermatologist at 0, 1, 2, 4, 6, 8, 10, and 12 weeks.
  • the study period of 12 weeks included at least three menstrual cycles. Menstrual acne, a flare-up of blemishes every month that coincides with menstruation, is fairly common.
  • lactoferrin which is not part of a whey protein fraction, combined with Vitamin E and Zinc, can be given orally to treat and prevent acne.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Immunology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

L'invention concerne un procédé pour le traitement et la prévention de l'acné, comprenant l'administration orale de lactoferrine, de préférence combinée à de la vitamine E et du zinc, la lactoferrine n'étant pas isolée du lactosérum.
PCT/PH2013/000006 2013-01-30 2013-01-30 Traitement et prévention de l'acné WO2014120026A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/PH2013/000006 WO2014120026A1 (fr) 2013-01-30 2013-01-30 Traitement et prévention de l'acné
CN201380075300.XA CN105283197B (zh) 2013-01-30 2013-01-30 痤疮的治疗和预防
SG11201505909WA SG11201505909WA (en) 2013-01-30 2013-01-30 Treatment and prevention of acne
PH12015500468A PH12015500468A1 (en) 2013-01-30 2015-03-04 Treatment and prevention of acne
HK16108566.9A HK1220396A1 (zh) 2013-01-30 2016-07-19 痤瘡的治療和預防

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/PH2013/000006 WO2014120026A1 (fr) 2013-01-30 2013-01-30 Traitement et prévention de l'acné

Publications (1)

Publication Number Publication Date
WO2014120026A1 true WO2014120026A1 (fr) 2014-08-07

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ID=51262635

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Application Number Title Priority Date Filing Date
PCT/PH2013/000006 WO2014120026A1 (fr) 2013-01-30 2013-01-30 Traitement et prévention de l'acné

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CN (1) CN105283197B (fr)
HK (1) HK1220396A1 (fr)
PH (1) PH12015500468A1 (fr)
SG (1) SG11201505909WA (fr)
WO (1) WO2014120026A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023087052A1 (fr) * 2021-11-16 2023-05-25 Noumi Limited Procédé de production d'une poudre de lactoferrine et ses utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7074759B2 (en) * 1999-05-28 2006-07-11 Naidu A Satyanarayan Treatment of case-ready food products with immobilized lactoferrin (Im-LF) and the products so produced
WO2009154447A1 (fr) * 2008-06-16 2009-12-23 Campina Nederland Holding B.V. Composition de lactoferrine aqueuse, thermostable, et sa préparation et son utilisation
WO2010123386A1 (fr) * 2009-04-24 2010-10-28 Westland Co-Operative Dairy Company Limited Procédé de préparation d'une lactoferrine à faible teneur en fer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7074759B2 (en) * 1999-05-28 2006-07-11 Naidu A Satyanarayan Treatment of case-ready food products with immobilized lactoferrin (Im-LF) and the products so produced
WO2009154447A1 (fr) * 2008-06-16 2009-12-23 Campina Nederland Holding B.V. Composition de lactoferrine aqueuse, thermostable, et sa préparation et son utilisation
WO2010123386A1 (fr) * 2009-04-24 2010-10-28 Westland Co-Operative Dairy Company Limited Procédé de préparation d'une lactoferrine à faible teneur en fer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOWE ET AL.: "Clinical implications of lipid peroxidation in acne vulgaris: old wine in new bottles", LIPIDS IN HEALTH AND DISEASE, vol. 9, no. 141, 2010, pages 1 - 11 *
DRISCOLL ET AL.: "Nutrition and the deleterious side effects of nutritional supplements", CLINICS IN DERMATOLOGY, vol. 28, no. 4, 2010, pages 371 - 379 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023087052A1 (fr) * 2021-11-16 2023-05-25 Noumi Limited Procédé de production d'une poudre de lactoferrine et ses utilisations

Also Published As

Publication number Publication date
CN105283197B (zh) 2017-12-12
HK1220396A1 (zh) 2017-05-05
PH12015500468B1 (en) 2015-04-20
SG11201505909WA (en) 2015-08-28
CN105283197A (zh) 2016-01-27
PH12015500468A1 (en) 2015-04-20

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