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1
preface
In the context of the normalization of drug procurement in China, the pharmaceutical industry has developed to the second half of high-end upgrading and differentiated breakthrough, and the investment and risk of innovative drug development are high, and the homogenization competition of some targets is serious.
Compared with ordinary generic drugs, high-end preparation R&D process and market access barriers are high, and there are fewer competing products; Compared with innovative drugs, the R&D cycle of high-end preparations is short, which can effectively save R&D costs
.
Therefore, high-end preparations are a cost-effective direction for the differentiated development of enterprises, and the revenue generated by its products is no less than that of new molecular entities
.
So, what is the current research and development of domestic high-end preparations? Which companies are laying out?
2
Concept and application of high-end preparations
High-end preparations mainly refer to drugs dispersed in a special structure system through special carriers or means, so as to be different from the traditional drug delivery mechanism, which can achieve the purpose
of changing the release speed, achieving precise administration, and reducing the frequency of administration.
Although many drugs that have been marketed have accurate efficacy, they have shortcomings such as large toxic side effects, inconvenient use or poor bioavailability, and high-end preparations can overcome this type of shortcomings and improve the efficacy
of drugs.
The special dosage forms of high-end preparations include liposomes, microspheres, oral dissolved films, micelles, nanoparticles, PEG (polyethylene glycol) and many other slow-release and targeted dosage forms, among which microspheres and liposomes are difficult dosage forms in the field of preparation and have a high threshold for research and development, and have become one of
the mainstream trends in drug development.
Below we understand the layout and progress
of domestic high-end preparations from several mainstream dosage forms such as liposomes, microspheres, oral dissolved films, micelles, and nanoparticles.
1 Liposomal preparation
Liposomes are an ultra-microspherical carrier preparation formed by lipid bilayers, which are typical representatives of
nanodrug delivery systems.
When amphoteric molecules such as phospholipids are dispersed in the aqueous phase, the hydrophobic tails of the molecules gather together and the hydrophilic head is exposed to the aqueous phase, forming closed vesicles
with a bilayered structure.
A variety of drugs
of different polarities can be wrapped in the aqueous phase and bimolecular membranes in the vesicles.
Liposomes as drug delivery vehicles can increase the solubility of encapsulated drugs; Improve the therapeutic effect of the drug and reduce the dosage; Mitigate adverse reactions to drugs; prolongs the internal circulation time of the drug; overcoming drug resistance in tumor cells; Improve the targeting of drug delivery; It has good biocompatibility
.
Liposomes are currently one of
the most widely studied nanocarriers in nanomedicine delivery systems.
Only 3 nanoliposome drugs in China have obtained production approvals, namely paclitaxel liposomes for injection, liposomal doxorubicin hydrochloride, and liposomal
amphotericin B for injection.
At present, in the domestic market, the listed lipid system preparation enterprises include Luye Pharmaceutical, CSPC Pharmaceutical Group, Shanghai Medicine Xinya, Changzhou Jinyuan and Fudan Zhangjiang
.
Among them, paclitaxel liposomes for injection are the leading products of Luye Pharmaceutical, accounting for nearly 60% of the market share; In the sales of liposomal doxorubicin hydrochloride, the CSPC Group accounted for the highest
proportion.
Luye Pharmaceutical
Luye Pharmaceutical pays attention to the research and development and innovation of various high-barrier technologies, and has established a number of technical platforms to promote the development of China's high-end
preparations.
Its paclitaxel liposome for injection is the world's first approved paclitaxel liposome product for the treatment of non-small cell lung cancer, ovarian cancer, and breast cancer
.
In addition, the company has a number of research projects
including ropivacaine hydrochloride liposomal suspension injection.
CSPC Group
Doxorubicin hydrochloride liposome injection (trade name: Domessin) developed by CSPC Group was approved by the NMPA last year and passed the quality and efficacy consistency evaluation
of generic drugs.
Doxorubicin hydrochloride is mainly used for chemotherapy
for multiple myeloma, lymphoma, ovarian cancer and breast cancer.
At present, doxorubicin hydrochloride liposome injection has been approved by 3 generic drug companies in China, namely CSPC Group, Changzhou Jinyuan Pharmaceutical and Fudan Zhangjiang
.
Among them, Fudan Zhangjiang's Libao is the first generic drug, and the stone medicine of Domesin is a second generic drug, but the products of stone medicine have good efficacy, and the company has strong sales capabilities, after continuously seizing market share, the market share has reached 40.
4%, far surpassing Fudan Zhangjiang
.
2 microsphere preparations
Microspheres refer to spherical particles formed by drugs dissolved or dispersed in polymer materials, the particle size range of microspheres is generally 1~500um, the small can be several nanometers, and the large can reach 800um
.
Microsphere preparations can use biodegradable polymers as skeleton materials to wrap the drug to form a preparation that can be administered by the injection route, which can release the drug at a certain rate within a fixed time to maintain the effective blood drug concentration and reduce the number of administrations, while reducing the fluctuation of blood drug concentration to achieve the purpose of
long-acting and sustained release.
Microsphere preparations can better protect drugs from damage, so they are suitable for drugs
with small molecular weight, short biological half-life, high activity, wide therapeutic window and long-term medication.
At present, the relevant slow-release microsphere technology has been relatively mature
.
The main participants in the research and development of domestic microsphere preparations include Lizhu Group, Luye Pharmaceutical, Shengzhao Pharmaceutical, etc.
, of which Lizhu Group is the leader of microsphere preparations in China
.
Lizhu Group
In 2009, Lizhu Group successfully developed and listed China's first slow-release microsphere preparation - leuprolide acetate sustained-release microspheres for injection, which is mainly used for the treatment of endometriosis and uterine fibroids, opening a new chapter
in the field of microspheres in China.
In addition, Lizhu Group also has aripiprazole microspheres for injection (1 month extended-release), leuprolide acetate microspheres for injection (3 months extended-release), triptorelin acetate microspheres for injection (1 month extended-release), octreotide acetate microspheres for injection (1 month extended-release), and triptorelin microspheres for injection (3 months extended-release) are under
development.
Luye Pharmaceutical
In 2021, Luye Pharmaceutical announced that its risperidone microspheres (II) for injection (trade name: Rexinto) have been approved for marketing
by the NMPA.
This is the company's first approved innovative formulation
developed by a long-acting sustained release platform.
Rexinto is a long-acting injection that is injected intramuscularly every
two weeks.
It can significantly improve the adherence to oral antipsychotics in patients with schizophrenia and will simplify the course of treatment for
schizophrenia.
Signage Medicine
The company focuses on two major research directions: targeted preparations and long-acting sustained-release preparations, mainly focusing on microspheres, microcrystals
and liposomes.
The R&D products are mainly aimed at malignant tumors, mental diseases, endometriosis and other serious diseases, and more than a dozen innovative preparations
such as risperidone microspheres, doxorubicin hydrochloride liposome injection and irinotecan hydrochloride liposome injection are under development.
Among them, risperidone microspheres and exenatide microspheres are in the workshop process verification stage, and will soon be produced for clinical samples and BE research, and are expected to be commercialized within
2-3 years.
In addition, domestic pharmaceutical companies also include Changchun Kinsey and Qilu Pharmaceutical are also deploying the research and development of
microsphere preparations.
At present, the microsphere market is in a period of rapid growth in China, although it accounts for a small share of the world, but the scale of China's microsphere market will continue to expand
in the future.
3 mouthfuls of film dissolving preparations
Oral dissolving film is a new type of drug delivery, which has the advantages
of high drug flexibility and high patient drug compliance.
The drug is loaded in the oral lytic membrane, the drug disintegrates in the mouth after taking, and the drug is absorbed through the oral mucosa or gastrointestinal tract, which can make the drug work quickly, and can reduce or avoid the first-pass effect of the drug and improve the bioavailability of the drug
.
Oral dissolved film is convenient for administration, especially suitable for children, mental disorders, elderly patients and emergency use
.
Oral film preparations face many challenges and risks in the development process, such as the optimization of taste masking methods, the screening of film-forming materials and packaging materials, the selection of large-scale production equipment and the selection of industrialization processes
.
At present, a total of 4 oral dissolved membranes have been approved for production
in China.
Among them, Qilu Pharmaceutical has 3 models, namely tadalafil oral lytic film, olanzapine oral lytic film, montelukast sodium oral lytic film; Hengrui's Ondansetron oral dissolution film is the first imitation
.
In addition, SacClone Pharmaceutical (China), Sichuan Kelun, Shanghai Modern Pharmaceutical and other companies have also laid out oral dissolution film tracks
.
4 micellar preparations
Micellar preparations refer to molecules in an aqueous solution where the surfactant reaches a certain concentration, the molecules self-assemble to form an orderly arrangement of thermodynamically stable colloidal aggregates
.
Micelles have the advantages of solubilizing poorly soluble drugs, improving bioavailability, and targeting, and are widely
used in antitumor drugs.
In October 2021, Shanghai Yizhong's paclitaxel micelles were approved for marketing in China for the first-line treatment
of patients with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor gene mutation negative and anaplastic lymphoma kinase-negative and unresectable non-small cell lung cancer.
The clinical value of paclitaxel micelles is mainly to increase the tolerated dose to expand the indications to pancreatic cancer, bladder cancer, ovarian cancer, etc
.
At present, there are not many varieties of micelle preparations registered and declared in China, and there are many
enterprises reporting for paclitaxel polymer micelles for injection and docetaxel polymer micelles for injection.
Paclitaxel and docetaxel are both taxane antineoplastic drugs, and their early marketing preparations need to be solubilized with surfactants, which have more serious adverse reactions, and the development of new pharmaceutical preparations such as liposomes, micelles, albumin-bound types, nanoparticles can solve this problem
.
5 nm particle preparation
Nanoparticles are solid drug-loaded colloidal particles supported by natural or synthetic polymer materials, generally with a particle size of 10-1000nm
.
Nanoparticles have passive targeting of liver, spleen, bone marrow and other parts, can be used as a carrier of anticancer drugs, and can also improve the therapeutic effect
of antibiotics and antiviral drugs.
At present, there are not many
varieties of nano preparations under research in China.
It mainly includes ursolic acid nanoliposomes for injection of Wuhan Liyuanheng Medicine, amphotericin B complex phospholipid nanoliposomes for injection of Changzhou Jinyuan Pharmaceutical, fenofibrate tablets (nanometers) of Beijing Wansheng Pharmaceutical, docetaxel nanoparticles for injection, etc
.
3
epilogue
With high entry barriers, a certain difficulty in exploring the R&D process, fewer competitive products, less impact by the centralized procurement policy, and obvious advantages in R&D economics, high-end preparations have become a golden track favored by capital, and the chase boom has gradually emerged
in the pharmaceutical industry.
According to the forecast of R&D progress, a large number of high-end preparation products will be launched from 2022 to 2023, and this market will usher in an explosive period
.
In addition, China's policy also vigorously supports the research and development
of high-end preparations.
In February 2016, Premier Li presided over the executive meeting of the State Council to promote the innovation and upgrading
of the pharmaceutical industry.
The meeting decided to aim at the urgent needs of the masses, strengthen the research and development and innovation of original drugs, first generic drugs, traditional Chinese medicines, new preparations, new medical devices, etc.
, and accelerate the industrialization of
major drugs for multiple diseases and rare diseases such as tumors, diabetes, cardiovascular and cerebrovascular diseases.
In China's pharmaceutical "Thirteenth Five-Year Plan", the state has proposed to vigorously develop new preparations, including the development of new injection drug delivery systems such as liposomes, lipid microspheres, and nano preparations
.
For pharmaceutical companies, the research and development and application of high-end preparations help improve drug effects, reduce the number of medications, reduce side effects, etc.
, and are undoubtedly the best choice
for drug update iteration.
2.
SUN Huiping,ZHANG Guoxi,CHENG Guang,CHEN Wenzhong,YANG Rong,LI Jianguang.
Preparation method and clinical application of liposome drugs[J].
Chinese Journal of Pharmaceutical Industry,2019,50(10):1160-1171; 3.
Gadekar V, Borade Y, Kannaujia S,et al.
Nanomedicines accessible in the market for clinical interventions[J].
Journal of Controlled Release, 2021, 330:372-397;4.
"Shengzhao Pharmaceutical Full R&D Pipeline: 4 Products Advancing to BE Stage, More Than 10 Under Research", Shengzhao Pharmaceutical, 2022-04-26;5.
"Special Report on Microsphere Liposomes: The General Trend of Preparation Upgrade, Ten Billion Blue Ocean "Micro" Visible", GF Hang Seng, 2018-10-25
。
