In the field of pharmaceutical preparations, create a new blue ocean

Formulation definition

Preparation refers to a drug that is prepared in accordance with the requirements of a certain dosage form to meet the needs of treatment or prevention and can be finally provided to the drug object. The so-called drug preparation, in a narrow sense, is a specific drug product prepared in accordance with a certain form, such as amoxicillin capsules.

Pharmaceutical preparation industry analysis

Pharmaceutical preparation is an important branch of pharmaceutical manufacturing industry, and the demand for pharmaceutical preparation products has a certain rigidity, which is related to national health, social stability and economic development. Pharmaceutical preparation is the first pillar industry in the domestic pharmaceutical industry. With the obvious aging trend of the population, the improvement of residents' living standards, the strengthening of health awareness, the continuous improvement of the social security system and the continuous development of medical science and technology, the human demand for pharmaceutical preparations will continue to increase, and the market size of the pharmaceutical preparations industry will continue to grow.

The long-term development model of "heavy apis, light preparations" in China's pharmaceutical industry has led to the strong position of apis, while the preparation industry is very weak. At present, the market of new preparations, new excipients and new preparations technology in China is almost monopolized by foreign companies, which directly leads to the abnormal development of China's pharmaceutical industry.

The varieties of preparations in China do not match the varieties of raw materials. China is already a major producer of raw material drugs in the world, but it is difficult to enter the international market because of insufficient research and development of drug preparation technology, low level of preparation, and low quality of most preparation products. On average, a raw material in China can only be made into three preparations, while a foreign raw material can be made into a dozen or even dozens of preparations. The preparation technology is backward and the quality stability of the preparation products is not high.

The continuous development of the pharmaceutical industry is mainly driven by technological innovation and capital investment. In the international pharmaceutical market, large multinational pharmaceutical enterprises rely on their strong capital strength and strong research and development force, constantly improve the development of innovative drugs, and through the continuous launch of innovative drugs and market expansion, so as to obtain monopoly income of patented drugs. This model requires a lot of research and development investment, high resource investment, is currently mainly used by pharmaceutical companies in developed countries. At present, most domestic enterprises adopt the generic drug model, that is, pharmaceutical enterprises obtain market development space through imitation patent protection expired patent drugs. In order to improve market competitiveness, some enterprises have gradually increased investment in new drug research and development, gradually converted to the new drug innovation model, and introduced new drugs with independent intellectual property rights to the market.

The global pharmaceutical technology development in the past 70 years and the future prospects of the pharmaceutical pharmaceutical market

In 1952, Smith Kline Beecham successfully developed the first oral sustained-release formulation of D-amphetamine 12h, which greatly improved patient compliance. In the 1970s, the theory of basic slow release transport system was gradually established. At the same time, the first transdermal patch, Scop®, was marketed in 1979.

Into the 1980s, liposomes, nanoparticles, and microspheres were locked as research and development hotspots, and drug precision delivery was required to be higher. In the 21st century, with the development of computer technology, 3D printing, digital drugs, chip insertion drugs and other preparation technology will be further refined.

As of 2019, the FDA has approved 38,117 drugs (9820 new drugs and 28,297 generic drugs), including 112 new routes of delivery and 172 new dosage forms.

In recent years, with the in-depth exploration of diseases and the progress and development of related basic disciplines, the research level of new preparations has been continuously improved. Over the past decade, the global compound annual growth rate of new formulations has reached more than 10%, which is ahead of the average growth level of the pharmaceutical industry. At present, the utilization rate of new preparations in China is less than 5%, which is far lower than the global average level, and the development prospects of the industry are broad. With the upgrading of pharmaceutical consumption, the use of new preparations is an inevitable trend, and China's new preparations market will show explosive development.

China's pharmaceutical preparation industry currently presents the following characteristics

The first is highly technical. With the development of high and new technology, modern pharmaceutical technology from manufacturing process to pharmaceutical ingredients requires the support of advanced technology, precision equipment and instruments, cutting-edge technical talents and sufficient research and development funds. Pharmacy has become a representative discipline with the cross-penetration of various disciplines and the integration of cutting-edge technologies. For example, biopharmaceutics, physical pharmacy, industrial pharmacy and other sub-disciplines continue to emerge, the research level from the organ level, tissue level to the molecular cell and other micro level, the dosage form from the traditional tablet, capsule, ointment development to new targeted preparations, intelligent slow release preparations, nano drug delivery system. Innovative technology is not only the main driving force to promote the rapid development of the industry, but also an important means for pharmaceutical enterprises to enhance their core competitiveness.

Second, the internal differentiation of the pharmaceutical preparation industry has intensified. In the past two years, under the baptism of new policies such as medical insurance cost control, volume procurement and generic drug consistency evaluation, the overall profit growth of China's chemical pharmaceutical industry has slowed down, the operating pressure of some low-end generic drug manufacturers has increased, and the market demand for high-end generic drugs has gradually expanded, and it is expected that the internal differentiation of the chemical pharmaceutical industry will continue in the future, and the internal structural transformation and upgrading and adjustment of the industry are the main.

Third, innovative drug preparations have high benefits and high risks. New drug research and development costs are high, the cycle is long, and the risk of uncertainty is high. According to research data from the School of Pharmacy of Tsinghua University, the average success rate of new drug research and development projects in the world is only 4.1%, and the whole process takes 10 to 20 years, excluding early research and development and management costs after the drug is launched, the average cost is as high as 873 million US dollars. However, opportunities and risks coexist, and the success of new drug development under high risks will also bring high returns. At present, the patent protection period of new drugs in China is 20 years, if it can pass clinical trials and drug registration, pharmaceutical companies will gain an innovation premium for a long time.

Precisely because pharmaceutical preparations are highly technical and innovative drugs have high return attributes, many companies will increase their research and development investment in pharmaceutical preparations, and gradually transform to innovative drug models to improve domestic and even global market competitiveness. In the field of pharmaceutical preparation processing, research and development companies will combine modern preparation technology with polymer materials or polymers to disperse drugs in special structures, resulting in innovative preparations that are different from traditional delivery routes.

Several new preparation processing technologies

Oral slow-controlled release technique

Oral slow and controlled release system is a new type of drug delivery system which develops rapidly in modern pharmacy and is widely used in clinic. Based on conventional dosage forms, the system uses slow control preparation technology to delay and control drug release speed, reduce drug toxicity, improve efficacy and reduce adverse reactions. Generally speaking, the release of oral slow-controlled release preparations is mainly completed by diffusion, corrosion, dissolution and penetration, and the dosage forms mainly include skeleton type, membrane control type, osmotic pump type and double slow-release type. For example, membrane controlled release technology is to treat tablets, particles, capsules, etc., with one or more packaging materials, so as to achieve the purpose of controlling the dissolution or diffusion rate of drugs. At present, the research on oral sustained-release drug preparations has become an important direction in the development of drug preparations. The 2020 edition of Chinese Pharmacopoeia also gives the latest guidelines for oral sustained-release, controlled-release and delayed release preparations.

Carrier drug delivery technique

Carrier drug delivery technology includes the research and development of long-acting injection microspheres (particles), nanoparticles, liposomes, implants and related pharmaceutical excipients. Among them, microsphere technology is to attach the drug in the polymer, forming a small spherical solid, with the function of preservation and stability of the drug effect, more convenient for patients to take medicine or injection anytime and anywhere, but the production process of microsphere technology is complex, the cost is high, and it is also the bottleneck that needs to be broken through. Polymer nanotechnology is a kind of synthetic and degradable polymer material. The drug carrier produced by this material is not only small in size, easy to take, but also has a non-volatile effect, which reduces side effects and improves bioavailability effectively. Liposome refers to bilayer spherical vesicles composed of phospholipids and other lipids. It encloses drugs in bilayer to form a miniature drug-carrying system, which can also reduce drug toxicity and improve the targeting and therapeutic stability of the preparation, and has broad application prospects.

Transdermal drug delivery techniques

Transdermal drug delivery (TDDS) or transdermal absorption (TTS) technology is the application of drugs on the skin, the drug components through the skin cuticle, into the dermis and subcutaneous fat to achieve the purpose of local treatment, or by the capillaries and lymphatic vessels absorbed into the human circulation, producing systemic therapeutic effects.

Solid dispersion technique

Solid dispersion system refers to the dispersion system in which the drug is uniformly dispersed in a solid carrier substance in the state of molecule, colloidal state and microcrystal.

Enhanced drug mucosal absorption technology

In the field of mucosal drug delivery technology, many researches at home and abroad include chemical absorption enhancers, biological adhesives, precursor drugs and enzyme inhibitors. Chemical absorption enhancers include various polymer materials, cholate salts, etc., which can improve drug permeability and prolong the mechanism of action of drugs on mucosal surface. Bioadhesives are mainly adsorbed to mucosal surface through the water absorption and swelling or surface wetting of drugs. Their advantages are reflected in that the drug action site can be the epidermal cell mucosa of various lumens, including the mouth, nasal cavity, eyes, etc., and the dosage form can be tablets, film agents, gels, etc. Since the mucosa has the structure of lipid bilayer, drugs with high lipid solubility are more easily absorbed through the mucosa. Researchers often design precursor drugs to promote drug penetration through the mucosa and improve the absorption rate. The principle of enzyme inhibitors is to add various enzyme inhibitors to the drug to prevent the enzyme distributed on the mucosal surface from degrading the drug, so as to promote the normal drug effect.

What are the domestic pharmaceutical companies of high-end preparations

Nanoparticle orientation

There are not many varieties for the registration and declaration of nano-preparations in China. The main products include fenofibrate tablets, progesterone nanocrystalline capsules, vinorelbine tartrate nanoparticle for injection, docetaxena rice granules for injection, amphotericin B complex phospholipid nanoliposomes for injection, alprostadil nanoparticles for injection, hydroxycamptocampin lipid nanoparticles for injection, irinoconor hydrochloride micelles for injection, paclitaxel nanoparticles for injection, etc.

The main distribution of enterprises are: National Nanoscience Center, Institute of Toxicology of the Academy of Military Sciences, Shanghai Medical Engineering Institute, Chongqing Lai Mei Pharmaceutical (more declarations), Jiangsu Hausen, Zhengda Tianqing, etc.

Liposomal orientation

For the registration and declaration of liposome preparations in China, there are relatively many varieties. The main products include oxaliplatin liposome injection, docetaxel (precursor) liposome injection, vinorelbine tartrate liposome injection, ribavirin liposome oral milk, amphotericin B liposome oral milk, vincristine sulfate liposome injection, Econazole nitrate liposome gel, doxorubicin hydrochloride liposome injection, epirubicin hydrochloride liposome injection, doxorubicin hydrochloride liposome injection Statin thermosensitive liposome injection, Irinotecan liposome injection, Indometacin liposome eye drops, Docetaxel liposome for injection, amphotericin B liposome for injection, Alprostil liposome for injection, hydroxycamptocampin liposome for injection, paclitaxel liposome for injection, etc.

The distribution of enterprises is mainly: Aikunwei Pharmaceutical, Changzhou Jinyuan Pharmaceutical (more declarations), Guangzhou Langsheng Pharmaceutical, Guangzhou Wanfangjian Pharmaceutical (more declarations), Jiangsu Aosaikang Pharmaceutical, Jiangsu Hengrui, Nanjing Luye Pharmaceutical, Nanjing Sike Pharmaceutical, Shanghai Fudan Zhangjiang Biological (more declarations), Kangping Pharmaceutical Research Institute of Shi Pharmaceutical Group, Shi Pharmaceutical Euitech Pharmaceutical (more declarations), Shi Pharmaceutical Zhongqi Pharmaceutical (more declarations), Xi 'an Libang Pharmaceutical, Zhejiang Haizheng, China Pharmaceutical University, etc.

Microsphere orientation

In China, for the registration and declaration of microsphere preparations, there are not many varieties on the whole, but the number of single-variety declaration and acceptance number is more. The main varieties are exenatide microsphere injection, vinorelbine tartrate lipid microsphere injection, perfluoropropanoin human blood albumin microsphere injection, octreotide acetate microsphere for injection, leuprelin acetate microsphere for injection, triprerelin acetate microsphere for injection, risperidone microsphere for injection, Rotigotine sustained-release microsphere for injection, etc.

The company distribution is mainly: Astrazeneca (China), Beijing Boant Pharmaceutical, Beijing Novartis, Shanghai Medical Engineering Institute, Institute of Toxicology of the Military Academy, Qilu Pharmaceutical, Shandong Luye (more declaration), Lizon Pharmaceutical, Shenyang Pharmaceutical (more declaration), Tianjin Takeda, Xi 'an Janssen, etc.

In summary, the development process of current pharmaceutical technology, as well as domestic enterprises focusing on high-end preparations and corresponding varieties are introduced. It is not difficult to find that the common feature of the corresponding pharmaceutical enterprises is to concentrate the output varieties on the basis of establishing a good pharmaceutical platform. At present, Shenzhen Ruihua Pharmaceutical has a relatively wide coverage of preparations. The company has an industry-leading and complete iterative delivery technology at home and abroad, and its drug delivery platform can cover >90% of the drugs in the market.