Azelaic acid as a multi-action active as hair thicker and hair growing agent for cosmetic products

Abstract

Azelaic acid is an organic substance belonging to the dicarboxylic acid family. It is naturally occurring and found on skin, whole grains, rye, barley, animal products and other natural sources.
For humans, azelaic acid helps to fight infections and functions as an antibacterial, antioxidant, pore- blockage fighter, skin blemish treatment and as anti-inflammatory agent. In other words, from azelaic acid, it is possible to get a lot of benefits for both skin and hair.

Thanks to these characteristics, azelaic acid is commonly used to treat acne and rosacea, two inflammatory skin conditions, but these same properties with its strong ability to inhibit 5-α-reductase together with a very good toxicological profile make azelaic acid the ideal active ingredient for hair grow/thickening cosmetic products. An innovative formulation for hair grow, based on an ultrapure azelaic acid easy to be dispersed and containing other active ingredients (Zinc and Vitamine B6), according to the Stamatiadis studies (5), has been developed.

Introduction

In humans, hair has an aesthetic function influencing our appearance. For centuries, decoration and styling of the scalp hair have been means of social communication as well as display of social identity and status. Today, it also has social, psychological, and sexual significance. Any change in the pattern of the hair, such as hair loss, hair overgrowth, or color change, may negatively affect the self- esteem of individuals and has emotional consequences. In addition, hair serves as an aid in camouflage and protection from the sun and provides sensory, tactile information about the environment.

As a consequence, the hair care market is one of the largest personal care markets all over the world. In the past, the main aim of using hair care products was to clean them by removing soilage and dirt. Today, hair care products are desired to provide additional benefits, such as beautifying the hair, making it easy to handle, or repairing damages, to treat dandruff and also certain hair problems, such as hair thinning and loss.

Hair structure

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):

1. 1)  The anagen stage: this is known as the growth stage of the hair. Growth starts in the papilla.Hairs stay several years in the anagen stage. The majority of hairs is in the anagenstage.
2. 2)  The catagen stage: it follows the anagen stage. During the catagen stage the melanin formation comes to a full stop because of apoptosis of the follicular melanocytes. The catagen stage duration is about 2-3 weeks. The blood supply to the papilla comes to a full stop, andconsequently the hair is not nourished anymore.
3. 3)  The telogen stage: follows the catagen stage and is also named the resting stage. The follicleremains 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.

In practice there is a fragile equilibrium between the anagen, catagen and telogen stage.
Each hair undergoes repeated cycles of active growth and rest; the relative duration of each cycle

varies with the age of the individual and the region of the body where the hair grows. The length of the cycle is often modified by a variety of physiologic and pathologic factors. The balding process is a conversion of the follicles so that they produce vellus hairs rather than terminal hairs.
The hair follicle contains stem cells, dispersed in the basal layer of the outer root sheath and in an area called the bulge. From this reservoir stem cells migrate to the hair matrix and start to divide and differentiate. Their behavior is largely controlled by cytokines (signaling proteins that enable cells to communicate) that are produced by cells of the dermal papilla. Dermal papilla cells, and some cells of the inner and outer sheaths of the follicle, have androgen receptors in their cytoplasm and nucleus, and are androgen dependent. Androgens indirectly control hair growth by influencing the synthesis and release of cytokines from the dermal papilla cells.

Androgens are steroid hormones that stimulate or control the development and maintenance of male characteristics by binding to androgen receptors. The primary and most well-known androgens are testosterone, dihydrotestosterone (DHT) and androstenedi

Androgens bind to their receptors both in the cytoplasm and the nuclei of dermal papilla cells and some cells of the sheaths of the follicle, but only if the hair is in the anagen or telogen stage. Upon the formation of the complex of the androgen and the receptor cytokines are produced that are essential for hair growth. When the formation of the complex is inhibited or made impossible, cytokine production will also be inhibited and thus hair growth is put to a full stop. Retinoic acid (vitamin A), if used for a long time, may reduce the number of active androgen receptors by 30-40 %, while pyridoxine (vitamin B6) reduces cytokine production by 40-50%.

So 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.

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), also particular fungal infections (ringworm) caused by Trichophyton rubrum and related organisms may result in hair loss.

The most dramatic influence on dermal papilla cells is induced by dihydrotestosterone, and this the major cause for hair loss. It is produced in an equilibrium reaction from testosterone, catalysed by the enzyme 5-α-reductase. Sportsman using testosterone supplements to increase their muscle volume will automatically also increase the concentration dihydrotestosterone, and that results in baldness. There are two forms of 5-α-reductase. Type 1 (259 amino acids) resides mainly in sebocytes but also in epidermal and follicular keratinocytes, dermal papilla cells and sweat glands. Sebocytes are highly specialized, sebum-producing epithelial cells that release their content by rupture of the cell membrane and cellular degradation (holocrine secretion). Type 2 (254 amino acids) is located mainly in the epididymis, seminal vesicles, prostate and fetal genital skin as well as in the inner root sheath of the hair follicle. In particular substrates that selectively bind to type 1 5-α- reductase may be considered for the treatment of androgenetic alopecia.

Inhibition of 5-α-reductase type 1 is therefore an answer to androgenic alopecia. This may be done using pharmaceutically active products such as dutasteride, finasteride or Minoxidil®; a major consideration is that these products (all three are alpha blockers) only enable to produce vellus hair and to some extent intermediate hairs. These products are in any case not allowed in cosmetic preparations because of the possible very sincere side effects. These side effects originate from the fact that these products are also used to treat benign prostatic hyperplasia (BPH) in men with an enlarged prostate.

There is only a limited number of cosmetically allowed 5-α-reductase inhibitors available. Saw palmetto, alfalfa, Japanese pagoda tree, red clover and the often praised Indian mulberry (noni fruit) have been reported to exhibit 5-α-reductase inhibition properties. It has been suggested that the aromatase activity (2) is responsible for these effects (3, 4).

Azelaic acid is a very potent 5-α-reductase inhibitor (type 1). According to Stamatiadis (5) 5-α- reductase inhibition is already detectable at an azelaic acid concentration as low as 0,2 mMol/l. Inhibition is complete at a concentration of 3 mMol/l, equivalent to ~0,6 mg/l. Stamatiadis also studied the inhibitory effects of zinc sulphate (3-9 mMol/l) using an in vitro assay with 1,2[3H]-testosterone as substrate; also zinc sulphate showed to be a potent 5-α-reductase inhibitor. An additive effect of these two inhibitors was observed. Pyridoxine (vitamin B6) potentiated the inhibitory effect of zinc sulphate, but not of azelaic acid. This observation suggests that different mechanisms are involved. Simultaneous use of the three products showed to be already effective for the treatment of androgenic alopecia, indicative for a powerful synergy.

Many individuals suffer from hair loss (alopecia), both males and females and virtually everybody will face sooner or later involutional alopecia (old age hair loss) and this can only be delayed by providing the hair follicles with a frequent shot of essential nutrients (e.g., B vitamins and some metal ions). A low-protein diet or severely calorie-restricted 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 grow with increasing intensity (pregnant woman frequently have thicker hair) but after the 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 completely 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 again obtained using azelaic acid, without the unwanted side effects of sulfasalazine and/or anthralin7 (1,8-dihydroxyanthron) (6).

In this study 31 subjects were recruited with patchy alopecia areata. The researchers then randomly assigned the patients into one of two groups. The first group applied 20% azelaic acid cream to the affected portion of the scalp daily for 12 consecutive weeks. The second group applied, with the same conditions, 0.5% anthralin cream. Afterward, there was an 8-week follow-up during which patients applied no cream. The goal of this follow-up was to see whether the patients could maintain their treatment results. At the end of this 20 week period, a clinical examination on each participant was done. Each of the subject’s scalps was awarded a Terminal Hair Regrowth Score on a scale from 0 to 2, where 0 indicated an inadequate response, 1 a partial response, and 2 a complete response. At week 20, the Average Terminal Hair Re-growth Scores indicated that azelaic acid based cream showed the same results of the one based on anthralin.

The powerful combination {azelaic acid + zinc sulphate + vitamin B6} for the treatment of androgenic alopecia is cosmetically suitable contrary to the steroidal and non-steroidal pharmaceutical preparations. In addition, azelaic acid has a superior toxicological profile. Side effects of azelaic acid boil down to the particular cosmetic properties: skin lightening at the site of application, a slight risk of hypertrichosis, and [seldom] slight skin irritation.

Combinations of minoxidil and azelaic acid are commercially available, despite the unwanted side effects of minoxidil. Both products work on the basis of different mechanisms of action in preventing baldness. The combination of the two would work more effectively than either alone. Commercial products contain up to 15% azelaic acid and 5% minoxidil. These high concentrations are explained because of the poor bioavailability of especially minoxidil.

So azelaic acid seems very reliable for cosmetic grade product to be used for hair health and grow, and we feel it’s a great alternative to other types of actives, here’s why:

1. First and foremost, it’s much safer of the main part of the available alternative products;
2. Azelaic acid is an antimicrobial agent. Considering fungal infections can have an important

role in hair loss, being this active able to work against these types of infections, azelaic acid could be able to prevent hair loss due to them.

3. Azelaic acid has also inflammatory properties. It’s widely known that inflammation of the hair follicles could be a possible cause of pattern baldness.
4. And finally, it’s a well known 5-alpha reductase inhibitor. As already reported above, 5 alpha reductase is accountable for the conversion to testosterone to dihydrotestosterone or DHT and DHT is well known to be the cause of androgenetic type of hair loss that affects men and women alike.

Azelaic acid may be used in the personal care 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 (Carcinogenic, Mutagenic and Reprotoxic) 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.

Azelaic acid is relatively easy soluble in glycols, preferably 1,3-propanediol (INCI Propanediol), 1,3- butanediol (INCI Butylene Glycol) and 1,2-pentanediol (INCI: Pentylene Glycol) and Diethylene glycol monoethyl ether (INCI: Ethoxydiglycol), and mixtures thereof. Another interesting vehicle for dissolution of azelaic acid is composed of polysorbate 85 (PEG-20 sorbitan trioleate) and poloxamer (6, 7, 8). The micro-emulsion obtained is a superb carrier for azelaic acid, with a good degree of bioavailability. The bioavailability can be further improved using phosphatidylcholine dissolved in a suitable solvent such as isopropyl palmitate or ethylhexyl stearate. To the phosphatidylcholine solution a cold (4°C) aqueous/glycerol (1:1) solution of poloxamer 407 containing azelaic acid is added and homogenized using high shear. The obtained organogel (9) has a very high degree of bioavailability, enabling to significantly reduce the concentration azelaic acid while guaranteeing the full functionality of azelaic acid.

Several commercial personal care preparations containing 5-12% azelaic acid are today available on the market. Today also several grades of azelaic acid are available, some of them are derived from animal sources some other from vegetable sources. AZECO Cosmeceuticals has developed and placed on the market an ultra-pure, micronised cosmetic-grade of azelaic acid with vegetable origin, COSMOS approved.

The table below shows the main characteristics of this grade of azelaic acid.

Azelaic acid is, then, the ideal ingredient for use in a variety of personal care products (also COSMOS / ECOCERT approved) for hair, providing important benefits that consumers desire. Here’s a brief overview:

An example of finished Hair Care Cosmetic Product

To complete the proposal for the hair care application, Azeco Cosmeceuticals has developed some finished formulas based on 10% of its azelaic acid (micronised, then easy to be formulated) to be used daily (once or twice a day) to have more thicker and healthy hair. As an example we report here the data relative to a lotion able to work to reduce excess DHT on the scalp, as well as unclog blocked pores, improving in the mean time blood flow in the scalp and giving hair a healthier general outlook. It’s targeted towards all hair types, for both males and females.

The table below contain the formulation, while just after the tips on how prepare an homogeneous and stable lotion are reported.

Suppliers:

[1] Alcoolital Srl
[2] AVG
[3] Siltech

Manufacturing instructions:

1. Prepare Phase A by combining the ingredients, mix untilhomogeneous
2. Prepare Phase B by combining the ingredients, mix untilhomogeneous.
3. Add the Phase B to the Phase A flushing very slowly and waiting for the final phase to be homogeneous.
4. Add all the ingredients of the phase C to the obtained Phase A+B, mixing until homogeneous.

Conclusions

Azelaic acid, mainly if 100% bio-based and palm oil free, obtained by a sustainable process from a definite vegetable source (sunflower oil) is the perfect choice for high-performing (multi-action way to act) and sustainable cosmetic solutions for the hair care products.
Using only one active, it is possible to obtain a whole series of positive actions on both skin and hair. In fact, topical azelaic acid, having anti-inflammatory and antibacterial properties, in addition to comedolytic action together a competitive inhibition of 5-α-reductase, an enzyme involved in steroid metabolism, may effectively be able to maintain an healthy scalp skin promoting in the mean time hair thinning and growing.

References

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5. D Stamatiadis, Inhibition of 5α-reductase activity in human skin by zinc and azelaic acid. Brit.J.Derm., 119,627,1988.
6. Sasmaz S, Arican O. Comparison of azelaic acid and anthralin for the therapy of patchy alopecia areata: a pilot study. Am J Clin Dermatol. 2005;6(6):403–406.
7. S.Murdan. A review of pluronic lecithin organogel as a topical and transdermal drug delivery system. Hospital Pharmacist 12,267,(2005).
8. R.Kumar, O.M.Katare. Lecithin Organogels as a Potential Phospholipid-Structured System for Topical Drug Delivery: A Review. AAPS Pharm.Sci.Tech., 2005; 6 (2) Article 40.
9. S.Kalepu, M.Manthina, V.Padavala. Oral lipid-based drug delivery systems -an overview. Acta Pharm.Sinica 3,36