Azeco Cosmeceuticals

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Ingredient information file

Ingredient information file Azeco Cosmeceuticals

When quality and reliability come first

INGREDIENT INFORMATION FILE AZECO COSMECEUTICALS

Version 1.00

February 2020

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

Index of Change

Version number Description

Date

1.00

Original Ingredient Information File

02-2020

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

Summary

Index of Change

3 5 5 5 5 5 6 7 7 7 8 8 8 9 9

1. Active ingredient

1.1 Company

1.2 General Information

1.2.1 Nomenclature

1.2.2 Azelaic acid and chemical and cosmetic inventories

1.2.3 Structure

1.2.4 General Properties

1.2.5 Origin

1.2.6 Manufacture

1.2.7 Ingredient

1.2.7.1 Specification

1.3 KOSHER and HALAL status of Azepur99®

1.4 Azepur99® and the standard ISO16128

1.5 Shelf life, storage stability and retest date of Azepur99®

2. Azepur99® as a cosmetic ingredient

10 10 10 11 13 17 17 19 22 24 29

2.1 Compliance of Azepur99® with the 1223/2009 EC regulations

2.2 Azelaic acid in skin care products

2.2.1 Azelaic acid in anti-acne products

2.2.2 Anti-acne preparation, Asian and European formulas

2.2.3 Efficacy testing on skin with some disorders

2.2.4 Azelaic acid in whitening / lightening creams

2.3 Azelaic acid in hair care products

2.4 Percutaneous absorption

3. Container closure system

4. References

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

1. Active ingredient

Azelaic Acid (cosmetic grade, purity > 99%)

1.1 Company • Azeco Cosmeceuticals BV ; hereinafter Azeco • Mussenberg 1, 6049 GZ Roermond • The Netherlands • Phone: 0031475 782540 • Mail: service@azeco-cosmeceuticals.com • Website: www.azeco-cosmeceuticals.com

1.2 General Information Information on the nomenclature, structure and general properties is presented on the following pages.

1.2.1 Nomenclature INCI, other non-proprietary names and chemical names are presented below along with compendial name together CAS registry number and other registration numbers.

International Nomenclature of Cosmetic Ingredients (INCI):

Azelaic acid Azelaic acid

International Non-Proprietary Name (INN):

Chemical name:

Nonanedioic acid

US Approved Name (USAN): British Approved Name (BAN):

Azelaic acid Azelaic acid Azelaic acid

Indian Pharmacopoeia:

Chemical Abstracts Registry Number (CAS No):

123-99-9

Product Name Azeco Cosmeceuticals

Azepur99®

1.2.2 Azelaic acid and chemical and cosmetic inventories Azeco’s Azelaic acid is listed / not listed in the following national lists/inventories:

Country / Inventory

Number / Name (when applicable)

Canada - Domestic Substances List (DSL)

Listed

Canada - Non-Domestic Substances List (NDSL)

Not listed

Japan - Existing and New Chemical Substances Inventory (ENCS)

Listed; 2-878 (MITI number)

Japan - Japanese Standards of Cosmetic Ingredients (JSCI)

Listed; Azelaic Acid

Australia - Australian Inventory of Chemical Substances (AICS)

Listed

Korea - Existing Chemicals List (ECL)

Listed; N° KE-26092

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

Korea - Designated existing substances List (First Batch)

Not listed

Korea - K-REACH registration exemption substances list

Not listed

Korea - K-REACH CMR substances list by MOE

Not listed

Korea - K-REACH Priority control substances 1 & 2

Not listed

China - Inventory of Existing Chemical Substances in China (IECSC)

Listed; N°28095; nonanedioic acid

China - Catalog of Hazardous Chemicals (2015)

Not listed

China - List of Toxic Chemicals Restricted to be Imported / Exported

Not listed

China - Inventory of Prohibited Chemicals

Not listed

China - List of Hazardous Chemicals for Priority Management- SAWS

Not listed

China - Catalogue of Precursors and Chemicals used in Production of Narcotic Drugs and Psychotropic Substances

Not listed

China - New Psychoactive Substance list

Not listed

China - Inventory of Existing Cosmetic Ingredients in China (IECIC)

Listed; Azelaic acid

Europe - (EINECS, REACH)

Listed; 204-669-1; 01-2119557891-28-xxxx

Europe - COSmetic INGredient database (COSING)

Listed; Azelaic acid

New Zealand Inventory (NZIoC)

Listed

Philippine Inventory of Chemicals and Chemical Substance (PICCS)

Listed

Switzerland

Listed

Taiwan Chemical Substance Inventory (TSCI)

Listed

USA - Toxic Substances Control Act Inventory (TSCA)

Listed

USA - International Cosmetic Ingredient Dictionary and Handbook (CTFA)

Listed; Azelaic acid

1.2.3 Structure The structure, molecular formula and molecular weight of azelaic acid are given below.

Structural formula

Molecular Formula Molecular Weight

C9H16O4

188.22

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

1.2.4 General Properties General properties of Azelaic acid are given below.

Description White to off-white crystalline powder.

Solubility Soluble in glycols, glycerin and alcohols.

Potential isomerism There is no potential for either optical and/or geometrical isomerism since Azelaic acid contains neither chiral centers nor olefinic bonds respectively. 1.2.5 Origin Azepur99® is a unique product obtained from renewable feedstocks having European origin and respecting local biodiversity (100% from European vegetable oils).

It is manufactured in plants using a world-first proprietary technology. In particular, through an oxidative scission reaction, with a low environmental impact, the vegetable oils are processed into azelaic acid, pelargonic acid and glycerin.

Product Name

Starting Feedstock

Country origin of the used feedstock

Country origin of the product

% of renewable Carbon in the product

Azepur99®

High Oleic Vegetable Oil

Europe (EU)

100 (from Vegetable source)

1.2.6 Manufacture

Flow scheme of the production process

Route of Synthesis – Azelaic acid Azelaic acid is obtained by oxidative cleavage of the double bond of oleic acid, according the following reaction:

R=H, azelaic acid

pelargonic acid

R = H, alkyl group

The production of Azelaic acid is based on a proprietary process using food grade high oleic vegetable oil as feedstock and consis- ting.

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

1.2.7 Ingredient

1.2.7.1 Specification The specification of the active ingredient is shown in the table below. More information on the used methods are reported in the next pages.

Testing parameter

Unit

Limit

Analytical method

Azelaic acid content

min. 99.0

Dicarboxylic acids < C9

Max. 0.5

GC (see the method reported in the paragraph 1.1.8.2)

Dicarboxylic acids > C9

Max. 0.5

Monocarboxylic acids

Max. 0.25

Water content

Max. 0.5

Karl Fisher (see the method reported in the paragraph 1.1.8.3)

Acid Value

mg KOH/g

590 - 605

(see the method reported in the paragraph 1.1.8.4)

Melting Point

°C

105 - 110

(see the method reported in the paragraph 1.1.8.5)

Colour

Apha

100

Gardner (see the method reported in the paragraph 1.1.8.6)

Residual Solvents***

ppm

Max. 7

GC (see the method reported in the paragraph 1.1.8.7)

10 Heavy Metals

ppm

ICP – AES (see the method reported in the paragraph 1.1.8.8)

ppm

0,2

*** 2,3,4-trimethylpentane (CAS 565-75-3)

ppm

GC (see the method reported in the paragraph 1.1.8.7)

*** 2,3-dimethylexane (CAS 584-94-1)

ppm

Aerobic mesophylic micro-organism count

CFU/mL

100

(see the method reported in the paragraph 1.1.8.9)

1.3 KOSHER and HALAL status of Azepur99® Azepur99® is made starting from Kosher and Halal certified raw materials (vegetable oil) and other reagents in compliance with these standards. It is then in compliance with both the standards. It can be assured that: 1. This product is from a synthetic manufacturing process fully based on raw materials of vegetable origin. 2. It does not contain any ingredient of animal origin and ingredients of animal origin have not been used in the manufacturing process. 3. The product does not contain ethanol (alcohol) and ethanol has not been used in the manufacturing process. 4. The equipment used in the manufacturing of this product does not get in contact with materials of animal origin or ethanol.

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

1.4 Azepur99® and the standard ISO16128 Azepur99® is completely obtained from a vegetable raw material (High Oleic Sunflower oil) with a new proprietary chemical process in agreement with the “green chemistry” principles (https://www.epa.gov/greenchemistry ). According to the standard ISO 16128 and its two parts: 1) Part 1 - ingredient characterization; 2) Part 2 - approaches to determine indexes that apply to the ingredient categories defined in Part 1. Framework to determi - ne the natural, natural origin, organic and organic origin content of products based on the ingredient characterization. 1.5 Shelf life, storage stability and retest date of Azepur99® Azepur99® is stable for at least 3 years if maintained closed in the original packing (see the paragraph 5) as supplied. This shelf has been evaluated according to the ICH (Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products. The stability tests have been carried out at room temperature at also at 40 °C (accelerated testing, up to 12 months). The accelerated testing, in addition to long-term stability studies, can be used to assess longer term chemical effects at nonaccelerated conditions and to evaluate the effect of short-term excursions outside the label storage conditions such as might occur during shipping. In particular three primary batches of Azepur99® representative of the quality of the material to be made on a production scale have been tested using the same container closure system of the packaging proposed for storage and distribution. Considering the proposed containers are impermeable to moisture and solvents, the sensitivity to moisture or potential for solvent loss is not a concern for Azepur99®. Thus, the stability studies were conducted under any controlled or ambient humi- dity condition. The table herein below contains the obtained data. According to them the Retest Date, the date after which samples of the active ingredient should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given finished cosmetic product, has been fixed after 36 months of its manufacturing date and its Retest period, the period of time during which the active ingredient is expected to remain within its specification and, therefore, can be used in the manufacture of a given cosmetic product, provided that the active ingredient has been stored under the recom- mended conditions, is then fixed at 36 months. After this period, a batch of the active ingredient, destined for use in the manufacture of a cosmetic product should be retested for compliance with the specification and then used immediately. A batch of the active ingredient can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. Azepur99® can be defined as a derived natural ingredient with 100% of renewable carbon content.

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

2. Azepur99® as a cosmetic ingredient

2.1 Compliance of Azepur99® with the 1223/2009 EC regulations In consideration of the used process and raw materials, and of the done analytical evaluation on the finished product, Azepur99® does not contain any substance classified as CMR (Carcinogenic, Mutagenic and Reprotoxic substances 1a, 1b, 2) according to the 1272/2008 EC regulation. In addition, it has vegetal (synthetically modified) origin, and does not contain any animal or cell culture derived materials, it is not produced using, or does not come into contact with animal origin materials at any stage of the manufacturing steps. Moreover, no animal origin materials are used for other products in direct contact with production equipment used to manufacture Azepur99®. This high pure grade of Azelaic acid is then TSE (Transmissible Spongiform Encephalopathy) / BSE (Bovine Spongiform Encephalopa- thy) free. The starting vegetable used oil is a highly refined oil (Highly refined oils are intended to signify refined, bleached, deodorized (RBD) oils). These oils described in studies as “highly refined” do not demonstrate a significant hazard to allergic individuals, as shown in studies using the “gold standard” for food allergy diagnosis, the double-blind placebo-controlled food challenge any ingredient deri- ved from such highly refined oil.” This is due to the very low content of residual proteins of these oils. Azepur99® does not contain any ingredient classified as nanomaterial or nanoparticles as defined in the Article 2 of Regulation No 1223/2009 and/or in the Commission recommendation of 18 October 2011 (2011/696/EU) and/or in the French decree 2011/0673 and it has not been tested on animals for cosmetics purposes. 2.2 Azelaic acid in skin care products Azelaic acid is a naturally occurring straight-chained saturated dicarboxylic acid present in rye, wheat, and barley. A single mechanism of action has not been identified to explain the effects of azelaic acid on the skin. It helps scavenge reactive oxygen species, redu - ces expression of kallikrein-5 (KLK-5) and pro-inflammatory cathelicidins such as LL-37, as well as inhibits toll-like receptor 2 (TLR-2) (1,2). In fact, azelaic acid has been demonstrated to be effective for the treatment of rosacea. It is available as a 20% cream or a 15% hydrogel. It reduces inflammatory lesions and erythema in rosacea patients and also inhibits neutrophilic ROS (Reactive Oxygen Spe - cies). In the neutrophil system azelaic acid inhibits the ROS formation in a dose-dependent manner, markedly decreasing the number of free radicals. Azelaic acid is probably the only non-pharmaceutical ingredient that has been demonstrated to exhibit good activity for the treatment of rosacea, without side effects. In addition, it inhibits the pigment producing enzyme tyrosinase (3), has comedoly- tic properties, and may reduce epidermal hyperkeratinization. It has been shown to be effective in the treatment of hyperpigmen- tary disorders such as chloasma and lentigo maligna, and to have a cytotoxic effect on the human malignant melanocyte (4). While treating cases of chloasma with topical application of an azelaic acid cream, it was observed, and confirmed by patients, that lesions of acne within the areas being treated showed significant improvement. This acid is then used to treat bacterial-related acne breakouts by attacking the infected pores to help in reducing inflammation and lowering the production of keratin which creates clumps of dead skin cells that trap sebum in skin pores causing more breakouts. With that said, as azelaic acid was more commonly used to treat acne related problems, doctors noticed it had side effects to it which were related to skin lightening. Hyperpigmentation is a skin disturbance affecting many people all over the world. In 1978, the tyrosi- nase-inhibiting activity of certain lipid fractions, mainly C9–C11 dicarboxylic acids, was demonstrated for the first time in vitro.

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

The interest in azelaic acid, which is a C9-dicarboxylic acid, for treating pigmented lesions thus ensued (5). This acid is produced naturally by a yeast, Malassezia furfur. Its inhibitory activity against tyrosinase is reflected in the appearance of depigmented maculae on the skin of subjects suffering from a mycosis, Pityriasis versicolor. This fungus produces lipoxygenases that are capable of acting on the unsaturated fatty acids present on the skin surface. In culture, this fungus is capable of oxidizing oleic acid into azelaic acid (6). There is unanimous agreement regarding its efficacy and absence of undesirable effects of note. A placebo-controlled clinical study conducted on 52 women with dark or pigmented skin (phototypes IV to VI) suffering from melas- ma demonstrated the superiority of a cream containing 20% azelaic acid. The women found that their skin was smoother and were thus satisfied overall (7). It seems that the preparations containing 20% azelaic acid and 4% hydroquinone are equivalent in vivo (5). The anti-inflammatory, anti-keratinizing and bacteriostatic activity of azelaic acid justifies its use in treating diseases such as rosacea or acne (8, 9). Over the treatment (of melasma) period the azelaic acid cream, compared to the hydroquinone one, yielded good or excellent results; no significant treatment differences were observed with regard to overall rating, reduction in lesion size, and pig - mentary intensity. Severe side effects such as allergic sensitization or exogenous ochronosis were not observed with azelaic acid (10). Azelaic acid is then today considered as the rising star for anti-acne OTC products. In fact, for the medical treatment of acne vulgaris a variety of preparations are commercially offered with a concentration of azelaic acid of 10-20%. Azelaic acid may be used in the personal care & cosmetic products, in medical devices and in pharmaceutical products of many countries without concentration limitations. It shows no significant side effects, it has no cytotoxic properties and does not exhibit CMR properties. The major constraint for the use of azelaic acid is its solubility. However, the solubility problem of azelaic acid can be solved using particular solvent systems or using smart formulation techniques. Because of the poor solubility the bio-availability is also limited, but that problem may simultaneously be solved while tuning the solubility. Commercial personal care preparations contain 8-12% azelaic acid, enabling to better control undesired side reactions. 2.2.1 Azelaic acid in anti-acne products The word acne comes from the Ancient Greek “acme”, meaning ‘top’ blossom or “highlight”. The word not only relates to the fact that pimples and blemishes occur as small mountain tops protruding above the skin, but also that the disease occurs primarily in peo- ple in the ‘flowering’ of their lives. In 1935, the word acne was record-ed as a new Latin medical term, taken from a misspelling of the word acme by a 6th century physician Aetius. Acne vulgaris is one of the most common skin conditions in children and adolescents. Acne is a skin disorder associated with Propionibacterium acnes (abbreviated as P.acnes). This is a slow growing gram-positive anaero- bic rod-shaped bacterium, reasonably tolerant to oxygen. It clinically manifests itself by the formation of closed and open comedones (white- or blackheads), papules (red bumps), pustules and nodules. P.acnes affects many young adults and adolescents undermining their self-esteem. Sebaceous glands may become a growth matrix for P.acnes. It feeds itself on the lipids produced in the sebaceous glands, acquiring water from the blood stream and obtaining its amino acids by destruction of the wall of the sebaceous glands. P.acnes may become opportunistic if the conditions for growth are optimal, mostly by blocking the sebaceous glands due to exces- sive sebum production that also has a higher viscosity relative to standard. The result is the formation of closed comedones. P.acnes produces enzymes that break down the wall of sebaceous glands. This leads to folliculitis which may advance to skin breakage and scarring. In some cases these scars may also get infected. In extreme cases P.acnes may be responsible for endocarditis. The conse- quences of acne may be quite severe indeed. A variety of treatments are available to resolve acne, but basically all treatments use harsh ingredients such as benzoyl peroxide, salicylic acid, elementary sulphur, zinc compounds, antibiotics (e.g. clindamycin, doxycycline) or tretinoin. Most of these products are strictly forbidden in personal care & cosmetic products, and are made available only as prescription drugs. The side effects are certainly not to be ignored, as these ingredients not only resolve acne but also affect the native microflora present on the skin.

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

This includes beneficial bacteria that live with us in harmony. Long term use of these ingredients will result in premature skin ageing, semi-permanent skin dehydration and a complete disruption of the skin’s microflora. The ultimate result is an attack on the overall immune system with all consequences. Several of these frequently used anti-acne ingredients have outspoken CMR proper-ties (Carci- nogenicity-Mutagenicity-Reprotoxicity). The FDA have placed in January 2014 an inquiry for surveillance for adverse drug effects for anti-acne products containing benzoyl peroxide, salicylic acid, or both, on its latest quarterly list of products to monitor because of potential signals of hyper-sensitivity and anaphylactic reactions. Reference is made to:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm376571.htm.

Azelaic acid is able to assist in normalisation of the microflora on the skin. Organisms that have become opportunistic are normalised to their normal level, including P.acnes, and it thus assists in many cases in clearing and preventing acne. Azelaic acid is prescribed mostly in cream form and works well in mild to moderate outbreaks of acne; it does not work for forms of acne that have a different origin. It takes 1-2 months before azelaic acid starts to show its performance and the acne lesions to start disappearing. The mode of action has not been fully elucidated, but in numerous preclinical and clinical studies it has been demonstrated that aze- laic acid displays three pharmacological properties: 1. It normalizes the disturbed follicular keratinization that leads to the formation of comedones in acne patients. The reduction in the count of comedones has subsequently been demonstrated in various clinical studies. 2. Azelaic acid has a significant antibacterial effect on the follicular Propionibacterium acnes and Staphylococcus epidermidis (in vitro). This effect is primarily bactericidal but may in vivo be modified to a bacteriostatic one. Studies have shown that in acne patients two or three months of topical treatment with azelaic acid reduces the intra-follicular microbial colonization by more than 97.7%. Whereas P.acnes is frequently resistant against topical antibiotics such as erythromycin and/or clindamycin, there are no indications that P.acnes may become resistant against azelaic acid. 3. In addition it has been shown that azelaic acid is effective in inhibiting the growth of antibiotic resistant P.acnes. 4. In addition to an indirect effect on inflammation by reducing the growth and activity of P.acnes, azelaic acid also reveals direct anti-inflammatory activities by reducing the production and release of reactive oxygen species from neutrophils. This direct anti-in - flammatory property is considered to be the basis for the clinical effect of azelaic acid in treating rosacea. Azelaic acid is not restricted in use in personal care and cosmetic products in the European Union. It shall nonetheless be emphasized that EU Legislation does not allow the claim “prevents” or “cures” acne vulgaris. A semantic approach is required to present anti-ac- ne products containing azelaic acid, such as “suppresses the occurrence of pimples” and similar statements.

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

2.2.2 Anti-acne preparation, Asian and European formulas

European Formula INCI Name

Trade Name / Other name

% by weight

Function

A Aqua

Water

56.45

Solvent

Betaine

Betafin BP20 [1]

5.00

Emulsifier

Glycerine

Pricerine 9083 [2]

2.00

Humectant

Aqua, Sodium Hydroxyde

Sodium Hydroxide, 18% Aqueous Solution

1.50

Neutralizer

B Azelaic acid

Azepur99®

Active ingredient

Cetearyl Isononanoate

Cetiol SN [4]

5.00

Emollient

Cetearyl Alcohol

Lanette O [4]

4.00

Body agent

PEG-20 Glyceryl Stearate

Cutina E24 [4]

4.00

Emulsifier

Isopropyl Myristate

Crodamol IPM [2]

3.00

Emollient

Steareth-2

Brij 72 [2]

3.00

Emulsifier

Steareth-21

Brij 721 [2]

3.00

Emulsifier

Crodamol DOA

Diethylhexyl Adipate [2]

2.00

Emollient

C Phenoxyethanol, Methylparaben, Ethylparaben, Butylparaben, Propylparaben, Isobutylparaben

Phenonip [3]

0.90

Preservative

D Parfum

EVA – RV 66404A [5]

0.15

Fragrance

Suppliers:

1) Dupont / Danisco Finnfeeds Oy 2) Croda Oleochemicals 3) Clariant / Nipa Preservatives 4) BASF / Cognis 5) Fragrance Resources

Cream Specifications:

Appearance

Soft cream

Color Odour

White

Characteristic 4,9 – 5,6 Typical: 5,21

Brookfield Viscosity (S4, 20 rpm, 25° C

3,500 – 4,200 cPs Typical: 3,650 cPs

Microbiology

< 10 CFU/g

Microbiological Purity

Pathogens absent

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

Test on preservative efficacy / Challenge test (Ph.Eur.5.1.3): The following data were obtained as the log-reduction, with a starting inoculation of 106 CFU/g:

t=0

t=2d t=7d t=14d

t=28d

Staphylococcus aureus

6,0

1,5

1,0

Pseudomonas aeruginosa

6,0

1,2

1,0

Candida albicans

6,0

2,4

1,0

Aspergillus brasiliensis

6,0

5,2

1,0

The results satisfy the Ph.Eur.5.1.3. requirements.

Manufacturing instructions: 1. The equipment is sterilised using peracetic acid and/or ethanol (non-denatured). The ATP count shall be below 100 for the rinse liquid at the outlet of the reactor. If this boundary condition is not met, the sterilisation procedure shall be repeated.

2. The water phase (Phase A) is prepared by combining the ingredients. The water phase shall be alkaline as to (partially) neutralise azelaic acid present in the oil phase. Ignoring to do so will inhibit emulsion formation. The water phase is heated to 70-75°C.

3. The oil phase (Phase B) is made by combining the ingredients and heating to 70-75°C. The oil phase shall be completely clear and has a slight yellowish colour.

4. The oil phase is added to the water phase at 70-75°C while stirring with a planetary mixer. The mixture, that is still unstable, is stirred during 5 minutes (on a laboratory scale). Subsequently the mixture is homogenised using a high velocity rotor-stator mixer at maximum capacity. The pre-emulsion is cooled to 40-45°C and re-homogenised adding the preservative (Phase C). The obtain- ed emulsion is white and is still low viscous. Upon further cooling the viscosity will continue to increase. At 25°C the fragrance is added (Phase D); stirring is continued during 15 minutes. 5. The pH is adjusted to the specifications with an 18% aqueous sodium hydroxide solution. The lotion is kept in quarantine for 5 days and committed for microbiological analysis. After 5 days the analytical data of the lotion may be adjusted to the specifications, if required. After the quarantine period the lotion may be committed for confectioning or transferred to bulk storage, provided it satisfies the specifications. INCI list: Ingredients: Aqua, Azelaic Acid, Betaine, Cetearyl Isononanoate, Cetearyl Alcohol, PEG-20 Glyceryl Stearate, Isopropyl Myristate, Steareth-2, Steareth-21, Diethylhexyl Adipate, Glycerin, Parfum, Phenoxyethanol, Methylparaben, Ethylparaben, Butylparaben, Pro- pylparaben, Isobutylparaben. Shelf life: 3 years after production, 12 months after opening. Store at ambient temperature, out of direct sun light. Preferred packaging: tube, 30 ml.

Mussenberg 1 • 6049 GZ Roermond • The Netherlands

European Formula INCI Name

Trade Name / Other name

% by weight

Function

A Aqua

Water

45.45

Solvent

Betaine

Betafin BP20 [1]

5.00

Emulsifier

Glycerine

Pricerine 9083 [2]

5.00

Humectant

Aqua, Sodium Hydroxyde

Sodium Hydroxide, 18% Aqueous Solution

1.50

Neutralizer

B Azelaic acid

Azepur99®

Active ingredient

Cetearyl Isononanoate

Myritol 318 [4]

12.00

Emollient

Cetearyl Alcohol

Lanette O [4]

2.00

Body agent

PEG-20 Glyceryl Stearate

Cutina E24 [4]

3.00

Emulsifier

Isopropyl Myristate

Crodamol IPM [2]

3.00

Emollient

Glyceryl Stearate, Ceteareth-12, Ceteareth-20, Cetearyl Alcohol, Cetyl Palmitate

Emulgade SE [2]

10.00

Emulsifier

Crodamol DOA

Diethylhexyl Adipate [2]

2.00

Emollient

C Phenoxyethanol, Methylparaben, Ethylparaben, Butylparaben, Propylparaben, Isobutylparaben

Phenonip [3]

0.90

Preservative

D Parfum

Body Fresh, 344.594 [5]

0.15

Fragrance

Suppliers: [1] Dupont / Danisco Finnfeeds Oy [2] Croda Oleochemicals [3] Clariant / Nipa Preservatives

[4] BASF / Cognis [5] Luzi Fragrances

Specifications: Appearance

Soft cream

Color Odour

White

Characteristic 4,9 – 5,6 Typical: 5,13

Brookfield Viscosity (S4, 20 rpm, 25°C

7,200 – 11,200 Typical: 8,050 cPs

Microbiology

< 10 CFU/g

Microbiological Purity

Pathogens absent

Phone : 0031475 782540 • info@azeco-cosmeceuticals.com • www.azeco-cosmeceuticals.com

Test on preservative efficacy (Ph.Eur.5.1.3): The following data were obtained as the log-reduction, with a starting inoculation of 106 CFU/g:

t=0

t=2d t=7d t=14d

t=28d

Staphylococcus aureus

6,0

1,5

1,0

Pseudomonas aeruginosa

6,0

1,2

1,0

Candida albicans

6,0

2,4

1,0

Aspergillus brasiliensis

6,0

5,2

1,0

The results satisfy the Ph.Eur.5.1.3. requirements.

3. The oil phase (Phase B) is made by combining the ingredients and heating to 70-75°C. The oil phase shall be completely clear and has a slight yellowish colour.

4. The oil phase is added to the water phase at 70-75°C while stirring with a planetary mixer. The mixture, that is still unstable, is stirred during 5 minutes (on a laboratory scale). Subsequently the mixture is homogenised using a high velocity rotor-stator mixer at maximum capacity. The pre-emulsion is cooled to 40-45°C and re-homogenised adding the preservative (Phase C). The obtain- ed emulsion is white and is still low viscous. Upon further cooling the viscosity will continue to increase. At 25°C the fragrance is added (Phase D); stirring is continued during 15 minutes. 5. The pH is adjusted to the specifications with an 18% aqueous sodium hydroxide solution. The lotion is kept in quarantine for 5 days and committed for microbiological analysis. After 5 days the analytical data of the lotion may be adjusted to the specifications, if required. After the quarantine period the lotion may be committed for confectioning or transferred to bulk storage, provided it satisfies the specifications. INCI list: Ingredients: Aqua, Caprylic/Capric Triglyceride, Azelaic Acid, Glyceryl Stearate, Betaine, Glycerin, Isopropyl Myristate, PEG-20 Glyce- ryl Stearate, Cetearyl Alcohol, Diethylhexyl Adipate, Ceteareth-20, Ceteareth-12, Cetyl Palmitate, Parfum, Phenoxyethanol, Methylpa- raben, Ethylparaben, Butylparaben, Propylparaben, Isobutylparaben. Shelf life: 3 years after production, 12 months after opening. Store at ambient temperature, out of direct sun light. Preferred packaging: tube, 30 ml.

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2.2.3 Efficacy testing on skin with some disorders The European composition was tested in 8 patients suffering from infected closed comedones. The composition was applied on the affected two times per day for 30 days. The following visual scale was used:

Visual observation rating: 0-1 No improvement 2-3 Clearly noticeable improvement 4-6 Good improvement 7-9 Excellent improvement 10 Complete recovery

Volunteer Gender

Age

Day

Day #0 Day #5 Day #10 Day #15 Day #20 Day #25 Result #30

Female

Positive

Female

Positive

Female

Negative

Female

Positive

Male

Negative

Male

Positive

Male

Positive

Male

Positive

The results are at least promising and observed to be better than with benzoyl peroxide or salicylic acid. The results compare to the results obtained upon treatment with clindamycin or doxycycline.

2.2.4 Azelaic acid in whitening / lightening creams Depigmentation and skin lightening products, which have been in use for ages in Asian countries where skin whiteness is a major esthetic criterion, are now also highly valued by Western populations, who expose themselves excessively to the sun and develop skin spots as a consequence (11). The allure of a pale complexion is nothing new and many doctors have been looking into this subject for some time, proposing diverse and varied recipes for eliminating all unsightly marks (freckles and liver spots were clearly targeted). Pliny the Elder (Natura- lis Historia), Dioscoride (De Universa medicina), Castore Durante (Herbario nuove), and other authors from other time periods have addressed this issue. In the 16th century, Durante proposed diverse plant-based preparations, for example herbal teas prepared from Erythreae centaurium, Chamaeleon root, powdered Gentiana verna root mixed with honey, lemon juice, to name a few (12). In sub-Saharan Africa where the practice is common, herbal teas are still being prepared from local plants (Tephrosia vogelii, Mirabilis jalapa, Phytolacca dodecandra). In Rwanda, about thirty plants are traditionally used to lighten the complexion of girls for certain ceremonies, such as marriage, for instance. The use of preparations to lighten skin tone is referred to as “voluntary depigmentation”. Depending on the African country in question, the procedure may be called “xessal” (Senegal), “tcha-tcho” (Mali), “ambi” (Gabon), “maquillage” (Congo), “kwitukuza”, which literally means “making one’s skin red” (Rwanda) (13). Illegal cosmetics or preparations, in other words ones not regulated by any drug laws or cosmetics laws, may be used to achieve the desired results. Steroids, hydroqui- none and its derivatives, kojic acid, and mercury derivatives are the most commonly used active ingredients. They are far from being harmless. Undesirable effects (hypercorticism) may be observed in subjects using dermocorticoids.

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Applying high-dosage preparations on large areas of skin can lead to an overall change in the state of health (skin atrophy, arterial hypertension, osteoporosis, diabetes, etc.) of the patient or of a family member; children may become poisoned by proxy (14).

Similar cases can also be seen with mercury. Anorexia, emaciation, arterial hypertension, hyperhidrosis, or intense pruritus manifesting in a child whose mother uses depigmenting preparations should alert the attending doctor (15). It is estimated that 25% to 67% of urban-dwelling women in Africa and 20% of women in metropolitan France are affected by this practice (16). Nor are Asian women immune to the allure of a pale complexion. A study sponsored by Chanel and conducted on around forty Chinese women in 2014 revealed that the “purity of the complexion” had an influence on the presumed age of a person. The Chi - nese women on the panel saw the lightening of skin spots with photograph retouching software as a means of giving the impression that one is four years younger than one’s actual age, versus just two years for wrinkle smoothing (17). Considering these results, the interest of Japanese and Chinese women in depigmentation products becomes more understandable, as they are viewed as veritable anti-aging products. The elite of Caucasian populations were preoccupied with the search for a pale complexion for centuries, until the discovery of tan- ning in the 1930s reversed the situation. However, overexposure to the sun still fuels the demand of Europeans for effective anti-dark spot preparations. Lastly, melasma, a type of skin hyperpigmentation linked to pregnancy, to thyroid disorders, and to certain drug treatments (contraceptives), is yet another reason for using skin lightening cosmetics (18). So hyperpigmentation is a common skin condition that refers to any darkening of the skin. Dark patches form usually on the face and hands or other areas that are commonly exposed to the sun. This darkening of the skin occurs when an excess of melanin, which is a brown pigment that gives our skin its color, forms deposits in our skin. This happens by the melanin absorbing the sun’s harmful ultraviolet rays in order to protect the skin from overexposure. In 1978, the tyrosinase-inhibiting activity of certain lipid fractions, mainly C9–C11 dicarboxylic acids, was demonstrated for the first time in vitro. The interest in azelaic acid, which is a C9-dicarboxylic acid, for treating pigmented lesions thus ensued (19). This acid is produced na- turally by a yeast, Malassezia furfur. Its inhibitory activity against tyrosinase is reflected in the appearance of depigmented maculae on the skin of subjects suffering from a mycosis, Pityriasis versicolor (7). This fungus produces lipoxygenases that are capable of acting on the unsaturated fatty acids present on the skin surface. In culture, this fungus is capable of oxidizing oleic acid into azelaic acid (19). There is unanimous agreement regarding its efficacy and absence of undesirable effects of note. So Azelaic acid is a natural skin bleaching agent and a naturally effective lightener for the skin. It has the advantage of giving a paler skin, naturally. Studies were made to see how powerful this ingredient was to lighten complexion. In South America, a 24-week-long study took place and found that 20% concentration of Azelaic Acid was comparable to 2% hydroquinone in treating the skin disorder, azelaic acid for melasma. Another study was conducted in the Philippines and found that 20% of azelaic acid was stronger than that of hydroquinone. A placebo-controlled clinical study conducted on 52 women with dark or pigmented skin (phototypes IV to VI) suffering from melas- ma demonstrated the superiority of a cream containing 20% azelaic acid. The women found that their skin was smoother and were thus satisfied overall. However, some undesirable effects (burning, tingling) were reported (7). It seems that the preparations con - taining 20% azelaic acid and 4% hydroquinone are equivalent in vivo (19). The anti-inflammatory, anti-keratinizing and bacteriostatic activity of azelaic acid justifies its use in treating diseases such as rosacea or acne (7, 8). Azelaic acid apparently behaves differently, depending on the characteristics of the cells concerned. A cytotoxic effect on human melanocytes and a much higher capacity to pe- netrate abnormal cells than normal cells indicated possibilities for use in treating melanoma at one time. However, these hopes were dashed (20, 21). Considering here are different ways to combat hyperpigmentation, sometimes, It may useful to combine different whitening / lightening active agents in the same cosmetic formulation. This was demonstrated by a study (22) sponsorized by Pierre Fabre Dermocosmetique, based on the use of a combination of Azelaic acid with oligopeptide-68 (Azelawhite®) and glycolic acid, where the efficacy of this active combination in a dermo-cosmetic serum on reducing actinic lentigo and improving photoaging was evaluated.

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The aim of this monocentric open-label clinical study was to assess the clinical and instrumental efficacy and tolerability in use condi - tions of a serum containing Azelawhite® complex (oligopeptide-68 2%, azelaic acid 8%) and glycolic acid (3%) for photo-aged skin during 12 weeks. This association already demonstrated an anti-aging efficacy on human cutaneous explants. 42 Caucasian volunteers (45-70 years old) were included and analyzed. At inclusion (D0), subjects presented peri orbital wrinkles graded 3 to 6 (from 1 to 9 scale) and at least one target facial lentigo. This serum was applied on face and neck twice daily (morning and evening), clinical and instrumental photo-aging signs assessments were performed. The local score for the target lentigo improved significantly after 4, 8 and 12 weeks of serum application (42% of improvement). AEVA assessment showed a significant improvement of the rough structu - res (deep wrinkles) after 4 weeks (p=0.008). So Azelaic Acid seems very reliable for lightening the complexion, and we feel it’s a great alternative to other types of skin lighteners, here’s why: • First and foremost, it’s safer than the main part of the available alternative products; • It’s ability to lighten complexion is also thanks to anti-inflammatory and successful ability in treating various forms of acne. Two advantages in one active ingredient. • It’s safe for all skin complexions, especially those with a deeper and darker skin tone. • It’s effective in bringing life back into dull and aged skin by brightening and evening out the tone of your skin. • Unlike hydroquinone, azelaic acid does not affect the pigments of the skin, but rather tackles abnormal melanocytes (small melanin cells) instead. 2.3 Azelaic acid in hair care products Many individuals suffer from hair loss (alopecia), especially females. One of the conditions leading to thinning hair is known as hereditary hypotrichosis simplex. The responsible gene, APCDD1, has been identified and causes hair follicles to shrink (23). Victims of genetic hairlessness also frequently face the absence of eyelashes and eyebrows. There are sincere indications that the number of people condemned to genetic baldness is limited to less than a hundred individuals worldwide; scant comfort for those with an unwanted naked scull. Virtually all individuals will face sooner or later involutional alopecia (old age hair loss) and that can only be delayed by providing the hair follicles with a frequent shot of essential nutrients (B vitamins and some metal ions). A low-protein diet or severely calorie-res- tricted diet frequently causes temporary hair loss. Alopecia areata (spot baldness) and alopecia universalis (total body hair fall-out, including eyebrows & eye lashes) are auto-immune disorders for which no general treatment is available. With Alopecia areata hair loss is observed resulting in smooth, round patches about the size of a coin or larger. It can, rarely, result in complete loss of scalp and body hair. This disease may affect children or adults of any age. The cause of alopecia areata is unknown, having said that the affected victims are generally in excellent health. In most cases, the hair regrows without intervention. Alopecia areata may also be observed with pregnant woman: during pregnancy the hair will be growing with increasing intensity (pregnant woman frequently have beautiful hair) but after delivery many hairs swiftly enter a dormant stage. Within two to three months, some women will notice large amounts of hair coming out in their brushes and combs. This can last up to half a year, but resolves complete- ly in most cases. In a number of cases sulfasalazine or anthralin (1,8-dihydroxyanthron) offer an effective treatment for alopecia areata, but superior results are obtained using azelaic acid, without the unwanted side effects of sulfasalazine and/or anthralin7 (1,8-dihy- droxyanthron). Male pattern hair loss (MPHL; androgenic alopecia) develops under the influence of androgenic hormones and is probably the most important reason for the development of baldness. Androgenic alopecia is not life-threatening. The research investments in hair growth solutions are quite significant indeed, and comparable to the investments made in research on diabetes, cancer and car - dio-vascular conditions. Investments in hair growth research are justified as the hair follicles are an important scientific model for understanding important aspects of human cell biology, organ system developmental biology, immune response medicine,

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the process of controlled cell regeneration & differentiation, stem cell technology and human genetics (24). Apart from the scientific value of studying hair growth there is also a significant commercial interest, especially in the Asian Pacific Region, Japan & China. Abnormal levels of androgenic hormones are responsible for the majority of cases of hair loss. Other frequently occurring reasons are the use of medicinal products (chemotherapeutics, blood thinning agents, beta-blockers and oral contraceptives). Particular fungal infections (ringworm) caused by Trichophyton rubrum and related organisms may result in hair loss. Hair is made up of keratin, a protein that is made in the hair follicle. Hair grows out of the follicle that is located in the living dermis and reaches skin surface through the epidermis. The hair grows through the shaft of the follicle and becomes visible above the scalp. The hair follicle has the shape of a funnel with the narrowest part on the outer surface of the epidermis and extends down into the living dermis. At the base of the follicle the papilla ifs found, which contains the capillaries (tiny blood vessels that nourish the living cells). The living part of the hair is the very bottom part surrounding the papilla, called the bulb; the remainder of the hair is gradually pushed up to the outside world and is truly dead material. The bulb cells swiftly divide (1-3 days), depending on the location on the skin, but markedly much faster than any other cell in the human body.

Hairs grow in three stages: 1) The anagen stage: this is known as the growth stage of the hair. Growth starts in the papilla. Hairs are a number of years in the anagen stage. The majority of hairs is in the anagen stage. 2) The catagen stage: follows the anagen stage. During the catagen stage the hair follicles regain their strength; the melanin formati- on comes to a full stop because of apoptosis of the follicular melanocytes. The catagen stage lasts for approximately 2-3 weeks. The blood supply to the papilla comes to a full stop, and consequently the hair is not nourished anymore. 3) The telogen stage: follows the catagen stage and is also named the resting stage. The follicle remains dormant for 2-6 months. After this period the follicle starts to grow again and a new hair shaft will be formed. The old hair is detached and shed off, and the anagen stage is entered again.

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