Polypeptide drug is a huge family, which is one of the more promising development directions. Peptide drugs have the advantages of high biological activity, strong specificity and small side effects. In 2015, the global sales of peptide drugs reached 22 billion US dollars, which is one of the fastest growing drug fields. In recent years, with the development of small molecular drugs becoming more and more difficult, people pay more and more attention to peptide drugs.

At present, there are hundreds of peptide drugs in the research and development stage, and the development field also extends to various indications. The common fields are anti infection, anti-tumor, physiological regulation, pain, heart failure, osteoporosis, diabetes, vaccines, etc.

However, most peptide drugs have the characteristics of direct oral ineffectiveness, short biological half-life and long treatment cycle. Therefore, to improve the compliance of patients, it is also a very meaningful thing to re develop the existing peptide drugs.

Looking at the domestic peptide market, many enterprises have production lines, but they complain that the peptide industry is weak because the products are primary and they don't make money. However, the data of sample hospitals show that in 2015, the amount of peptide drugs used in China was nearly 9 billion yuan, and the market after amplification was over 30 billion yuan, even close to 40 billion yuan. The growth rates in 2014 and 2015 were 16.13% and 6.82%, respectively.

The reason for this situation is that there are many manufacturers, primary products, low technology added value, and most of the market of many products are occupied by multinational pharmaceutical companies. Therefore, it is necessary to upgrade the existing finished products.
At present, the idea of improving polypeptide drugs in foreign countries is long-term injection products, such as the preparation of polypeptide liposomes, polypeptide microspheres, polyethylene glycol modification, fusion protein or subcutaneous implantation, and the second is bypass injection, oral administration, transdermal administration and inhalation administration. In this paper, brick and jade are thrown here for reference and reference by the majority of friends.

Long term effect of polypeptide injection

1PLGA microspheres

PLGA microsphere is the most ideal sustained-release injection carrier, which can achieve sustained release for days to months. PLGA microsphere is also one of the best means for the secondary development of peptide drugs. At present, there are many products on the market, including exenatide microsphere, octreotide microsphere, pareptide microsphere, leuprorelin microsphere and triptoreline microsphere. The market effect of these products is no less than new Molecular entity. The author hereby recommends the medisorb technology of alkermers, whose representative products are naltrexone, risperidone and exenatide.

Medisorb is a kind of emulsification technology, which can change the emulsification process according to different drugs. Medisorb technology is also a very worthy technology to be introduced and imitated. After all, China's peptide drug market is huge. Once successfully imitated or introduced, not only multiple peptide products can be upgraded, but also some psychiatric drugs, such as risperidone, palipexone, naltrexone, can be upgraded.

In this respect, Beijing Bonte and Lizhu pharmaceutical have tasted the sweetness. In 2015, the sales volume of liangprorelin microspheres of Beijing Bonte and Lizhu reached 260 million and 310 million respectively. Later, green leaf kept up with them, and several microsphere products have been declared.

2 liposomes

Mepact and glutathione liposomes have been developed abroad, and the liposome influenza vaccine has been successfully developed (Inflexal V, Switzerland1997), indicating that the liposome development path of polypeptide drugs can work. The author hereby recommends pacira's depofoam technology. According to pacira's official introduction, depofoam technology can load polypeptide, protein and small molecule drugs to achieve 1-30 days of slow drug release. Although there is no peptide drug using depofoam technology on the market, the success of bupivacaine liposomes shows that depofoam technology is a very potential slow-release injection technology. Once the technology is successfully imitated or introduced, it can not only be used in polypeptides, but also in the research and development of many anticancer drugs and painkillers.

3PEG modification

PEG modification can not only increase the hydrophilicity of the drug, but also reduce the filtering effect of the kidney on the drug. At the same time, it can mask the enzyme sites and reduce the biodegradation rate, so as to achieve the long cycle effect. PEG modification technology has been used for many years in the field of polymer. The most typical ones are PEG modified interferon, PEG modified fegerstin, PEG modified erythropoietin, etc. in the aspect of PEG modified polypeptide, the listed cases are somavert of Pfizer and omontys of Takeda

The average half-life of somavert was 74-172 hours after PEG modification. PEG modified GLP-1 analogues are one of the research and development hotspots of domestic manufacturers. Many manufacturers have layout in this field, and the typical product is GLP-1 analogues. Of course, there are two sides to everything. PEG modification also has its own disadvantages, that is, peg will accumulate in the body, and there is a potential risk of adverse reactions.

4 fusion protein

The fusion of protein molecules with high stability and activity with peptide drugs can effectively improve the stability and activity of peptide drugs.For example, the half-life of hsa-ifn-a fusion protein expressed by yeast in macaque is longer than that of hsa-ifn-a alone

IFN - α extended by about 18

Times. At present, the most typical drugs on the market are abirubitide of GSK and dulaglutide of Lilly, both of which are once a week long-acting Gli-1 analogues. In addition, the fusion protein can also be synchronously matched with PEG modification. The efpglenatide of Korea and the United States is a successful case. The drug delivery cycle is up to 1 time per month. With this product, Korea and the United States reached a cooperation agreement of up to 4.2 billion US dollars with Sanofi.

5 fatty acid acylation

Acylation of fatty acids is one of the main directions of Novo Nordisk. In GLP-1, both lilaluptide and somaluptide have introduced fatty chains. The purpose of introducing fatty chains is to increase the hydrophobicity of drugs, mask the binding site of DPP-4 enzyme, reduce renal excretion and improve the half-life of organisms. Novo Nordisk not only applied this idea to GLP-1 analogues, but also its long-acting insulin products, ditorin and degu insulin, realized sustained-release by acylation and introduction of fat chain to increase hydrophobicity.

6 polymer injection

In 2002, the US FDA approved atrix

Eligard, a long-acting preparation of leuprorelin from lab, is a sustained-release suspension prepared by the technology of atrigel. The main sustained-release material is plgh. After injection, the solid is formed in the body (Huang Shengyan, Shanghai medicine, 2005, Vol. 2, phase 5). Then the drug is slowly controlled for up to 6 months. This product is manufactured by tolmar

Therap, promoted by anstar in Japan, had sales of $162 million in 2015.

Development of implants

In terms of implants, the most representative drugs are goserellin of AstraZeneca, histamine of Endo, leuprorelin of Alza and buserellin of Sanofi,Goserellin is a PLGA implant rod, which can last for up to 12 weeks after implantation. Endo's group amrelin implant uses an in vivo compatible polymer controlled release library, which can last for one year after implantation. Compared with PLGA microspheres, implants can be released continuously for a longer time, but they also have their own disadvantages - some products need to be taken out regularly.

Implant is not only an important direction of the second development of peptide drugs, but also a very potential long-term drug delivery system, which can improve some drugs with small dosage, short half-life and long treatment cycle. In 2015, the main products of several implants had a total sales volume of nearly US $3 billion, but the layout of domestic manufacturers is less, which is worth recommending. Once the implantation technology is successfully imitated or introduced, it can not only upgrade the technology of multiple peptide drugs, but also upgrade the sex hormone products, such as estradiol and testosterone.

Respiratory administration

In May 2015, the FDA approved the glucagon inhaler, indicating a new direction for the inhalation and administration of peptide drugs. In fact, inhaled peptides have been successful for a long time. The most typical one is salmon calcitonin. Respiratory administration includes not only inhalation administration, but also nasal administration. The advantages of respiratory administration system lie in the absence of digestive enzymes, gastric acid damage and liver first pass effect. Compared with injection, nasal and inhalation administration can improve the compliance of patients. Compared with oral administration, it has faster onset and higher bioavailability, so the respiratory administration of peptide drugs is also a direction worthy of attention.

Transdermal drug delivery

It has been reported that transdermal enhancers and iontophoresis are used in combination,It can effectively improve the transdermal absorption of some drugs, especially macromolecular peptides. There are few reports on the delivery of peptide drugs by transdermal delivery system. BMS company has tried to develop exenatide transdermal patch, but no new report has been found in phase 1 clinical practice. In addition, transpharma company is also developing this technology

Medical, the development project is viador-glp1 agonist, which is still in phase 1b. Therefore, the technology for domestic companies, attention is enough.

Oral administration

The realization of oral administration of peptide drugs is the ultimate goal of the second development of peptide drugs. However, there are still many challenges to realize the oral administration of peptide drugs. Peptide drugs are easy to be destroyed by gastric acid and digestive enzymes, so how to avoid the degradation of drugs in the gastrointestinal tract is only the first barrier; the second barrier is how to promote absorption, generally more than 500 molecules, absorption is relatively difficult, and the molecular weight of peptide drugs are mostly thousands;

The third is how to solve the problem of first pass effect. Because of the above problems, the existing oral polypeptide drugs generally have low bioavailability, large individual differences and potential safety risks. Of course, these barriers are not insurmountable. At present, products with molecular weight less than 2000 have been put on the market, such as linalootide, products with molecular weight more than 3000, such as somalutide, which have achieved phase III clinical treatment, and the oral GLP-1 of a domestic company in Shanghai has also applied for ind from CFDA.

epilogue
All in all, China's acceptance of peptide drugs is higher than the global average, and the market is optimistic. However, most of the domestic peptide drug market is "dominated" by imported drugs. Even if some products have been localized, they are also lack of competitiveness due to their "primary" products.

The reason is that most of the polypeptide products on the market need to be injected for a long time, and no one is willing to "inject" every day, or even "inject" many times every day. As soon as the long-term preparations are on the market, the ordinary injection will not be sold, such as triptoreline and leuprorelin. Of course, some products are not included in the medical insurance because the long-term preparations are too expensive, so the ordinary people "hold on" to use the ordinary injection For example, octreotide (the price of microspheres for injection is as high as 10000 yuan). Once the price of long-term preparations is reduced, or the domestic imitation is successful, they will be included in the medical insurance. The "death" of short-term preparations is not far away;

There are also some products, such as exenatide, although the microspheres have not yet entered the domestic market, the international sales data has explained everything. Therefore, many polypeptide products have the value of secondary development. For manufacturers with polypeptide products, we can consider it. After all, it is difficult to develop polypeptide products. While others are still engaged in synthesis research, we have approved production, but we also need to cherish our products. If we do not upgrade, there is only one result, that is, elimination.

For the second development of most peptide drugs, PLGA microspheres are the first choice at present. At present, many domestic manufacturers have made technological breakthroughs. Even if we don't have the strength to break through, we can import from the third party. The cost of import is not much higher than that of independent development.
Preparation innovation is a platform innovation, which can benefit from multiple products. The potential products are upgraded one by one in the form of "according to the gourd ladle". In this regard, the research and development pipeline of microspheres with green leaves is available for reference.

In the era of increasingly fierce competition, we have lost ourselves, following others to do "imitation snatching", following others to do consistency evaluation, even following others to do "Chinese style" NME "development. In all kinds of follow-up, we gradually forget our own characteristics and blur our own advantages. In the end, when the national drug policy changes, everyone can't laugh or cry.

In fact, in this environment, we should give full play to our existing advantages, and the way to win for our small and medium-sized enterprises is to "take the side of the sword". From the upgrading of Zhengda Tianqing to glycyrrhizic acid preparation, to the upgrading of Johnson to risperidone, to the upgrading of Novartis to methylphenidate and diclofenac, we may see that it is a very meaningful and valuable thing to upgrade the preparation of existing products. For some potential varieties, why should we get tangled in the rules and regulations of consistency evaluation? Wouldn't it be better to upgrade direct products as exclusive varieties to occupy the market?

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About Shengnuo

Chengdu Shengnuo Biotechnology Co., Ltd. has "Chengdu polypeptide drug engineering technology research center" in Chengdu, mainly engaged in polypeptide, polypeptide drug and beauty peptide research. Our zero defect has passed the FDA certification, and now it has become the first-class professional peptide drug and product development, technology transfer, technical service and peptide drug industry in the scale production and export of China's parks.