Frost & Sullivan releases the 'Current Industry Status and Future Development Report on Active Vitamin D (Calcitriol)' (with full text available for download)

Vitamin D is a fat-soluble steroid substance, mainly composed of vitamin D3 and vitamin D2. Vitamin D3 is an endogenous substance that the human body can synthesize naturally through sunlight exposure; whereas vitamin D2 can usually only be obtained from food or supplements. After metabolism in the human body, vitamin D not only participates in maintaining the normal function of the skeletal neuromuscular system; but recent extensive research has confirmed that vitamin D also has extroskeletal health effects, participating in the differentiation, proliferation, and active regulation of tissue cells, and has a regulatory effect on the body's immune function. It plays a crucial role in the normal operation of various bodily functions.

Due to limited pathways for vitamin D synthesis and acquisition, many factors can lead to insufficient vitamin D levels in the human body. Among these, diet and sunlight exposure are the most important.

The Report details the importance of vitamin D for the human body, risk factors for vitamin D deficiency, and epidemiological analysis. For more detailed content, please refer to the full version of the report.

Vitamin D3 itself does not possess physiological activity and needs to be hydroxylated in the human body by 25-hydroxylase to form 25(OH)D, also known as calcidiol, which is then further hydroxylated by 1&alpha-hydroxylase in the kidneys to form 1,25-(OH).₂D₃Calcitriol, also known as calcidiol, is the active form that can exert physiological regulatory functions. Therefore, calcidiol and calcitriol are referred to as the active forms of vitamin D, that is, active vitamin D. The metabolic principle of vitamin D2 is the same. Compared to oral conventional vitamin D, active vitamin can reach cells in the intestinal wall or other tissues and act directly on them.

Source: Literature search, Frost & Sullivan analysis

Currently, there are about ten active vitamin D products approved for marketing in different countries or regions around the world, mainly divided into two categories: natural active vitamin D and new active vitamin D. The difference lies in that natural active vitamin D is a chemical substance that can be naturally produced after vitamin D is metabolized by the human body; whereas new active vitamin D is an active substance obtained through the modification of the chemical structure of natural active vitamin D by pharmaceutical chemists.

The Report details the development history, metabolic mechanisms, natural and novel active vitamin D products, as well as their application fields. For more detailed content, please refer to the full version of the report.

In terms of sales volume, although the global sales of active vitamin D formulations have fluctuated slightly due to COVID-19 over the past five years, the overall performance has been relatively stable. In 2022, global sales of active vitamin D were still concentrated in the Japanese, Chinese, and American markets, accounting for more than 56% of the market share. In other countries around the world, the distribution of sales of active vitamin D formulations is more dispersed.

Source: IMS Pharmaceutical Database, Frost & Sullivan analysis

Currently, there are six varieties of active vitamin D products in sales status in China: calcitriol, alfacalcidol, calcipotriol, tacalcitol, paricalcitol, and edetate. Although affected by COVID-19 in 2020 and 2022, the market for active vitamin D fluctuated slightly over these two years. Overall, the Chinese active vitamin D market showed an increasing trend from 2018 to 2022, with the market size exceeding 6 billion yuan in 2022.

Source: Analysis by Frost & Sullivan

The Report analyzes the global, Japanese, and Chinese active vitamin D market overview, listed products and market size in China, clinical research pipelines for vitamin D receptors, and future development trends. For more detailed content, please refer to the full report.

Source: Literature search, Frost & Sullivan analysis

Osteoporosis is a chronic metabolic disease characterized by an increase in bone fragility due to the loss of calcium and minerals from the patient's bones, leading to damage to the microstructure of bone tissue or a decrease in bone strength. It is a prevalent condition, with the latest data indicating that the global number of people living with osteoporosis has reached 200 million, accounting for a prevalence rate of 18.3%.

Source: Literature search, Frost & Sullivan analysis

Currently, there are three active vitamin D products available globally for the treatment of osteoporosis, including calcitriol, alfacalcidol, and idocrin. The original drugs of these three products have now entered China, and corresponding generic drugs have been launched and sold. Among these three types of active vitamin D, calcitriol and alfacalcidol have a long history of use in China; although idocrin was launched in Japan over 10 years ago, it has not been widely marketed globally (especially in Europe and America), with China being the second country to market and apply it.

Secondary hyperparathyroidism (SHPT) refers to a condition in which patients with chronic kidney disease, under the long-term stimulation of high blood phosphorus or low blood calcium caused by various factors, secrete excessive parathyroid hormone (PTH). More than 85% of patients with end-stage chronic kidney disease suffer from this condition, which is associated with many complications and poor nutritional status. Once adverse events such as cardiovascular and cerebrovascular accidents or sepsis occur, the prognosis is poor.

Currently, there are seven drugs approved globally for the treatment of secondary hyperparathyroidism, which are active vitamin D and its derivatives. Among them, only calcitriol, alfacalcidol, and paricalcitol are available in China, while the rest are in clinical trial or preclinical stages in China. Calcitriol is the most classic drug used for treating SHPT. In addition, due to the higher safety profile of new active vitamin D drugs, they have a wide patient base both domestically and internationally.

Psoriasis, commonly known as 'psoriasis vulgaris', is a chronic inflammatory skin disease that causes patches of skin to appear and form scales. It is most commonly found on the knees, elbows, trunk, and scalp, and often worsens in winter. Currently, more than 125 million people worldwide are affected by psoriasis. The prevalence rate of psoriasis in China has stabilized between 0.86% and 3.29%.

Local application of active vitamin D and its derivative preparations can promote epidermal proliferation or differentiation and are currently the first-line treatment method for patients with psoriasis. Currently, the main active vitamin D derivatives approved globally for the treatment of psoriasis include tacalcitol, calcipotriol, and mescaline calcipotriol trihydrate.

The Report details four application scenarios of active vitamin D, and analyzes the pathogenic factors, disease classification, disease staging, epidemiology, disease burden, treatment methods, and comparative application of active vitamin D drugs in each scenario. For more detailed content, please refer to the full report.

Due to the conjugated double bond structure in the steroidal backbone of active vitamin D and its derivatives, this structure is unstable under light, heat, and oxygen conditions, making it prone to chemical changes that produce impurities. This complicates purification and poses significant difficulties in the upstream synthesis and downstream purification and separation steps of industrial production of active vitamin D.

The Report details the upstream synthesis barriers of active vitamin D, the difficulties in downstream purification and separation, and the advantages of SFC supercritical fluid chromatography. For more detailed content, please refer to the full report.

Currently, the dosage forms of active vitamin D that have been marketed include oral solid preparations, injections, and semi-solid topical preparations, with corresponding products available on the market. However, these preparations all have their own production challenges in terms of technology.

Among them, the preparation of low-dose oral solid preparations is particularly noteworthy. Since active vitamin D can easily cause side effects such as hypercalcemia, the content of active vitamin D in single-dose products usually does not exceed 1 mg or the loading dose <0.01% (w/w). Compared to conventional oral dosage forms, low-dose preparations often suffer from issues such as low potency and poor stability due to uneven mixing of active pharmaceutical ingredients with pharmaceutical excipients.

The Report details the preparation difficulties, processes, patents, and advantages of the twin-screw wet granulation process for low-dose oral solid preparations. For more detailed content, please refer to the full report.

For active vitamin D preparations, given their low-dose pharmaceutical formulation nature, in addition to prescription research, process development, and scaled-up production, the establishment of quality control methods and analytical techniques for these preparations is more challenging than for conventional formulations. The main quality control inspection items for active vitamin D preparations include content uniformity that reflects its homogeneity, related substances (impurities) and content that characterize its stability, dissolution tests that reflect possible changes in crystal form, etc. These key quality attributes directly affect the safety, efficacy, and quality controllability of the drug.

The Report details the three major challenges in quality control of active vitamin D preparations. For more detailed content, please refer to the full report.

Hairen Pharmaceutical (NQ: 870070) is a pharmaceutical company that adheres to innovation-driven development and competitive differentiation in product research and development. It was established as early as 2013. The company possesses globally leading R&D technologies for active vitamin D derivatives and has developed multiple active vitamin D preparation product pipelines based on this technology, covering new and natural active vitamins such as alfacalcidol and calcitriol. It is currently the largest producer of active vitamins in China. As of the latest update, Hairen Pharmaceutical has applied for 24 patents in the field of active vitamins; 14 have been authorized, including 10 invention patents, 2 utility model patents, and 2 design patents. Hairen Pharmaceutical covers the entire upstream and downstream chain of the active vitamin D industry and is currently the only pharmaceutical company in China that develops a full range of active vitamin D derivative APIs and preparations.

Teijin Pharma Co., Ltd. (abbreviation: Teijin Pharma, English name: Teijin Pharma) was developed from the polymer chemistry business of the Teijin Group (TSE: 3401) in the 1970s and is one of the core subsidiaries of the group. Over the past half century, it has continuously cultivated research and development capabilities, integrating the different technical strengths of the group's materials and IT businesses. It has deepened its comprehensive health care solutions that contribute to the entire medical service cycle, including prevention/promotion of health, treatment, rehabilitation/nursing. The company owns two original research active vitamin D products, namely alfacalcidol tablets and calcitriol ointment.

Leo Pharma, founded in 1908 with its headquarters located in Denmark, is a globally renowned pharmaceutical company. Its products are sold in more than 100 countries around the world. Leo China specializes in skin diseases in China and currently has a portfolio of seven topical drug products for the treatment of psoriasis, atopic dermatitis, and acne. The three active vitamin D preparations developed by the company are single-ingredient and combination formulations for psoriasis respectively.

The Roche Group (English name: Roche) was founded in 1896 and is headquartered in Basel, Switzerland. With a history of 125 years, it is one of the world's leading biotechnology, in vitro diagnostic companies, and industrial producers of original drugs. Currently, Roche Pharmaceuticals has a total of 25 products in China, covering eight therapeutic areas including anti-infection, anti-tumor, hemophilia, rheumatology and immunology, transplantation, osteoporosis, neuroscience, and anemia. The Roche Group and its alliance companies have launched calcitriol soft capsules, idurium calcitriol soft capsules, and idurium calcitriol tablets respectively.

Chengdu Guowei Biopharmaceutical Co., Ltd. (referred to as Guowei Medicine) was established in 2005 and is headquartered in the Chengdu High-tech Zone. It is a comprehensive pharmaceutical enterprise integrating R&D, production, and sales. The company's products mainly focus on cardiovascular and cerebrovascular diseases, digestive system issues, anti-infection, urinary system diseases, and other areas. It has obtained 28 drug production approvals, 3 health product production approvals, holds 41 authorized patents, and has registered 176 trademarks. Guowei Medicine currently has three marketed products, including Idurium Soft Capsules, Calcitriol Soft Capsules, and Paricalcitol Injection.

Zhengda Tianqing Pharmaceutical Group Co., Ltd. (referred to as Zhengda Tianqing) is an innovative pharmaceutical group engaged in medical innovation and the research, development, production, and sales of high-quality drugs. It is one of the core subsidiaries of China Biopharmaceutical (01177.HK), dedicated to providing patients with better health solutions and affordable pharmaceutical resources. The company is well-known domestically for its research and development and production bases of anti-tumor and liver disease drugs. The company has three products in clinical trials, namely Idurium Soft Capsules, Calcitriol Injection, and Calcitriol Soft Capsules.

Zhengda Pharmaceutical (Qingdao) Co., Ltd. (referred to as Zhengda Qingdao) is a wholly foreign-owned new high-tech pharmaceutical enterprise invested and established by the Zhengda Pharmaceutical Group. The company's products are divided into four major categories: marine drugs, traditional Chinese medicine, chemical drugs, and health foods. The company's independently developed national-level new drug - calcitriol (calcitriol soft capsules) - has filled a domestic gap and won the first prize for light industry scientific and technological progress in Shandong Province. Currently, the company owns four marketed products in the field of active vitamin D, including calcitriol soft capsules and oral liquid, alfacalcidol capsules, and paricalcidiol injection.