97.8%! Another breakthrough for China's ceramide source factory

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In the prelude to life, when a baby first comes into the world, they are covered by a delicate layer of white fetal fat. This seemingly insignificant protective film contains the initial miracle of life - ceramides. This is not only the first barrier of a baby's skin, but also the secret of their first close contact with the world.

The name ceramide comes from its Latin description - “cera” meaning wax and “amide” meaning amide, which together mean “wax-like amide”. This molecule exists as if it were nature's natural armor for human skin. In Chinese, the word “nervine” was added because of their wide distribution throughout the body, and their earliest discovery in the nervous system, which gave them this name.

In ancient legends, having healthy and smooth skin is regarded as a gift from heaven, and ceramides are known as “God's bricks” because of their ability to repair damaged skin barriers, as if they were brick walls built by God's own hands, and they silently guard our skin, maintaining its balance and health.

In the cosmetic industry, the certification of ceramides' beneficial effects on the skin comes from the 2014 Journal of American Academy of Dermatology (JAAD): Structure, Function, and Importance of Ceramides in the Skin and Their Therapeutic Uses in Skin Care Products.

01

Structural mysteries: the dance of fatty acids with sphingomyelins

The structure of a ceramide consists of two basic components: fatty acids and sphingosine.

Fatty acids: Fatty acids are one end of the ceramide spectrum, and they come in three different forms:

1. esterified omega-hydroxy fatty acids (EO-)

2. alpha-hydroxy fatty acids (A-)

3. non-hydroxy fatty acids (N-)

Sphingosine: At the other end of the ceramide spectrum is sphingosine, which comes in four different variants, each of which contributes to the diversity and functionality of the ceramide:

1. 6-hydroxy sphingosine (-H)

2. phytosphingosine (-P)

3. (Neuro)sphingosine (-S)

4. Dihydroxy sphingosine (-DS)

When these fatty acids and different variants of sphingosine combine with each other, they can form 12 different types of ceramides - together playing a symphony of skin health.

It is also because of its complex structure and wide variety of ceramides that the global ceramide market has long been monopolized by multinational giants, with companies from Germany, Japan, and South Korea, in particular, dominating in terms of technological leadership and market share.

In the Chinese market, despite the strong consumer demand for skin care products, high-quality ceramide raw materials have been dependent on imports. This phenomenon not only raises production costs, but also puts domestic skincare companies at a disadvantage in international market competition.

In recent years, with the advancement of biotechnology and consumers' trust in domestic brands, domestic enterprises have gradually begun to focus on the independent research and development and production of ceramides in an attempt to break this monopoly pattern.
 

02

A journey of discovery starting from strains

There are three main methods for the preparation of ceramides: natural extraction, chemical synthesis and microbial fermentation. Among them, microbial fermentation is gaining more and more attention in the production of ceramides due to its high efficiency, sustainability and environmental protection.

In 2015, an “obscure” domestic biopharmaceutical company aimed at the synthetic biology track, chose ceramide domestic self-research for technological research, and later developed into the source factory of ceramide in China - Chongqing Zhihe Biopharmaceutical Co. Ltd. (hereinafter referred to as Zhihe Bio), the source factory of ceramide in China.

Zhihe's ceramide research began with the introduction of the original strain. The team collected a wide range of microbial resources, covering ecological environments potentially rich in tetraacetyl phytosphingosine (TAPS) strains, including samples from extreme environments, traditional fermented foods, and inter-root soils of medicinal plants. After bioinformatics analysis and high-throughput screening techniques, candidate strains capable of synthesizing TAPS were finally screened from the inter-root soil of rainforest plants.

Tetraacetyl phytosphingosine strains are essential for the preparation of ceramides by microbial fermentation, because phytosphingosine, obtained by deacetylation after fermentation to obtain tetraacetyl phytosphingosine under certain environments, is the precursor of ceramides.

In order to further enhance the production capacity and stability of the strains, CHIH has conducted several rounds of targeted cultivation and successfully obtained several high quality strains with high yield and stable genetic traits.

03

From the laboratory to the factory - to achieve localization and mass production

Since the plant sphingomyelin strains are not genetically engineered, they are strains screened out from nature, and are difficult to be prepared by synthetic methods, the technology breakthrough has always been a “choke point” in China.

The strains researched by Zhihe over the years are not only able to produce TAPS stably under laboratory conditions, but also maintain high efficiency in industrial-scale fermentation production, which lays a solid foundation for Zhihe-Herb's large-scale production.

For the exploration, optimization and validation of the strains alone, the start-up team of Zhihe Bio has been drilling in the lab for several years, and it was not until 2018 that the development of laboratory strains and processes with industrialization value was completed.
 

However, this is still far from enough for realizing the national independent mass production of ceramide, and Zhihe Bio has been on the road from laboratory to factory for another two years.

The industrialization and commercialization of ceramide not only requires high-quality strains for the preparation of high-quality phytosphingosine, but also requires an efficient fatty chain manufacturing process (including fermentation and extraction and self-research and self-production of fatty chains), which is the core of ceramide research and development to improve the quality and reduce costs. Through technological research, Zhihe Bio has realized the self-production of the whole series of fatty acid chain production scale.

In 2019, Zhihe Bio completed pilot scale-up and production process validation.

In 2020, we will be the first company in China to realize the mass production and sales of phytosphingosine and ceramide raw powder.

Until this day, known as “plant soft gold” plant sphingosine, and ceramide NP on the market at the time of 20,000 yuan per kilogram, in the Zhihe biological independent research and development and strain optimization breakthroughs, before the real “price hit down”.

04

From plant to solution - achieving a leap in quality and purity

Zhihe Bio continuously optimized the production process parameters in the process. Through the directed fermentation technology and unique solvent segmentation extraction method, we obtained the fermented extract with less impurity content, which reduced the difficulty of post-synthesis purification and improved the quality of the product.

By optimizing the stirring form of extraction in production, the amount of extraction solvent was reduced by more than 20%; through the optimization of crystallization solvent and process parameters, the yield was increased by more than 10%.

This innovative production method has not only realized the goal of high efficiency and low cost in the production of ceramide, but also reached the international leading level in product quality. The ceramide products produced by Zhihe Bio, especially its flagship product, ceramide NP1, have reached 97.8% purity in commercialized batches, and have strong competitiveness in domestic and international markets.

05

Independent research and development - to build the core technology advantage

Zhihe Bio has always insisted on independent innovation in the research and development of ceramides. Its core technology not only covers the screening and optimization of bacterial strains, but also includes the whole chain of technologies from fermentation to extraction, from purification to productization, and the product line is extremely rich.

The main ceramide subtypes in the skin stratum corneum are NP, NH, AH, NDS, AS, AP, NS, EOS, EOH, ADS, EOP, and EODS, and Zhihe-Herb has already realized the commercial production of all P series products. In the future plan, in order to enrich the product line and provide the industry with a wider range of ceramide series products, it is making every effort to develop S and DS series products.

At the beginning of July 2024, Zhihe Bio has made a breakthrough in the development of laboratory process and sample preparation for ceramide NS, AS and NDS (which have been filed as NG in the cosmetics catalog) in China, and is planning to carry out commercial trial production in September-October 2024, which is the first time for Zhihe Bio to develop ceramide in China.

The exploration and innovation of Zhihe Bio in the field of ceramide raw powder not only demonstrates its excellent ability in strain technology and production process, but also makes an important contribution to the rise and development of the national biomedical science and technology industry.

As the source factory of ceramide in China, Zhihe Bio has promoted the development of the domestic ceramide industry with its independent R&D and innovation ability, and laid a solid foundation for realizing the strategic goal of independent control of ceramide raw materials.