Looking at the secret of prolonging the life cycle of pharmaceutical products from "the nth spring of risperidone"

505 (b) (2) contemplation < br / > in recent years, there has been a great deal of innovation in medicineNo matter the successful domestic market of PD-1 antibody, or the approval of BTK inhibitor zebotinib in the United States, it has gained a lot of traffic and praiseHowever, innovative drug R & D investment is large, time-consuming and high-risk, at the same time, it also faces the risk of future marketing failureIt is a hot topic to turn to generic drugsConsistency evaluation, two vote system and 4 + 7 centralized purchase have made the prices of generic drugs drop sharply, and the trend of generic drug companies returning to the corporate attributes of manufacturing industry has been overwhelming< br / > Where is the new growth point of pharmaceutical enterprises? Where are the acceptable cost inputs, relatively controllable R & D risk projects and high commercial value projects? 505 (b) (2) project provides a new ideaIn 1984, the U.SCongress passed the Hatch-Waxman AmendmentPart 505 of the revised federal food, drug and Cosmetic Act provides three channels for the application for the registration of improved new drugsThe specific categories and the general situation of approval are shown in Figure 1< br / > Fig1.505 (b) (2) approved general situation chart < br / > most nce or NME use 505 (b) (1) application path, and the main purpose of registration application through 505 (b) (2) channel is to increase the indications and improve the approved indicationsIn the development history of 505 (b) (2) drugs, the development examples of aripitan nanocrystals, leuprorelin long-acting injection microspheres, edaravone in the treatment of amyotrophic lateral sclerosis all shine with the wisdom of medical peopleFrom the trend chart of the number of chemical drugs 505 (b) (1) and 505 (b) (2) approved in recent 10 years, 505 (b) (2) has a tendency to get rid of 505 (b) (1)Among these drugs approved through 505b (2), risperidone's post marketing improvement process is an excellent interpretation of the basis and ideas for the commercial success of drug 505b (2)This is a very good reference for the application of class 2 new drugs in China< br / > Figure 2 Trend chart of 505 (1) and (2) NDA approved number in recent 10 years < br / > risperidone improvement in the first spring < br / > risperidone was developed by Janssen (a subsidiary of Johnson & Johnson) and approved for marketing by the US Food and Drug Administration (FDA) on December 29, 1993, under the trade name risperidal ® Acute manic episodes and mixed episodes of schizophrenia and bipolar disorder were treated with oral tablets < br / > during the clinical treatment of senile schizophrenia, it was found that the traditional tablets and capsules of antipsychotics caused poor drug compliance of patients The oral liquid has the following advantages, as shown in Figure 3 According to statistics, 50% of patients are not satisfied with the prescription preparation; 30% of patients feel that tablets and capsules are difficult to swallow or have swallowing difficulties, especially the elderly and children [1] It is very difficult for the patients with mental diseases, especially the acute patients to take ordinary tablets Oral liquid can be more convenient to be used in the dark medication, and can reduce the burden of patients' nursing work [2] On June 10, 1996, Johnson risperidone oral liquid was successfully approved for marketing < br / > Figure 3 Summary of advantages of oral liquid for schizophrenia < br / > risperidone improved in the second spring < br / > on April 2, 2003, risperidone orally disintegrating tablet was approved by FDA The basis for submitting this NDA is based on the fact that orally disintegrating tablets can improve compliance in patients with treatment resistance (e.g., vomiting) or oral dysphagia Johnson & Johnson has carried out clinical taste, safety, bioavailability, bioequivalence research, and no new clinical effectiveness research [3] < br / > Figure 4 Summary of the advantages of orally disintegrating tablets in schizophrenic patients < br / > risperidone improved the third spring < br / > although the wide application of antipsychotic drugs has achieved good results, the relapse of schizophrenia has long plagued clinicians and patients, a major factor of relapse is poor drug compliance The research shows that good treatment compliance and long-term use of maintenance drugs have positive significance in controlling the disease and reducing recurrence In real life, after the mental symptoms of the patients are relieved, the patients and their families may think that they have recovered, and then they will reduce and stop the medication by themselves Patients may also refuse to take medicine due to adverse reactions or discontinue medicine due to incomplete self-knowledge and unsupervised care [4] [5] < br / > on April 2, 2003, risperidone microsphere injection of Johnson & Johnson company was approved for marketing The recommended dose was 25 mg intramuscular injection once every two weeks Some patients may need higher doses, such as 37.5 mg or 50 mg < br / > in the application documents submitted, only animal toxicology study was included in the preclinical study, including the microsphere blank control group The paper also includes single dose and multi dose pharmacokinetics of microspheres, bioequivalence of microspheres and tablets, pharmacokinetics in vivo of schizophrenia patients, dose exploration, safety and effectiveness The results showed that risperidone microsphere had a definite therapeutic effect and the adverse reactions were similar to those of oral tablets While developing risperidone injection microspheres, Johnson & Johnson applied for patent protection for the product The main related patents are shown in Table 1 < br / > Table 1 Main patents of risperidone injection microspheres < br / > sales volume of risperidone injection microspheres in recent 15 years is shown in Figure 5 < br / > Figure 5 Risperdal consta's sales volume in the past 15 years [6] < br / > Risperdal injection microsphere sales volume has increased year by year, reaching a peak sales volume of US $1.58 billion in 2011, after which, although the decline trend is slow year by year, the advantages of Risperdal consta are summarized as follows: < br / > Figure 6 Risperdal injection microsphere advantages summary figure < br / > Risperdal improvement fourth spring < br / > in the process of Risperdal development, It was found that 9-hydroxyrisperidone, the metabolite of risperidone in vivo, also has certain pharmacological activity Johnson started the development of 9-hydroxyrisperidone after risperidone was listed on the market Finally, on December 19, 2006, palipex was approved by FDA to be listed mainly for the treatment of acute schizophrenia < br / > if pariprasidone is a common tablet, it may attract attention but it is unlikely to become a star However, with the support of OROS technology, the star of pariprasidone will be dazzling and the potential of the star will be revealed The schematic diagram of the dosage form of the sustained-release tablet is shown in Figure 7 < br / > Figure 7 Schematic diagram of risperidone sustained release delivery system [7] < br / > the tablet consists of three layers, the first and second drug layers are composed of different drug concentrations (the first drug layer contains a lower drug concentration), which provides the concentration gradient required for the gradual rise and release of drugs The first layer is the rapid release layer, which avoids the process of dose titration of risperidone in order to test tolerance, and at the same time, shortens the onset time After taking the tablet, the water in the digestive tract quickly erodes the tablet coat and is absorbed through the semipermeable membrane Semipermeable membrane controls the rate of water entering the core through the osmotic activity gradient determined by osmotic excipients When the drug layer becomes hydrated, a colloidal suspension of perrisperidone is formed The water then enters the propulsion layer containing the hydrophilic polymer, which hydrate and expand This volume expansion "pushes" the drug suspension through the outlet into the digestive tract The drug delivery rate is directly proportional to the permeability of the membrane and the concentration of the drug at the port, regardless of the local environmental conditions (pH, agitation) The controlled release rate of perrisperidone resulted in a slower absorption rate, which led to a gradual increase in plasma concentration, with the maximum observed plasma concentration occurring 24 hours after the first administration day On subsequent treatment days, er formulations provided minimal plasma concentration fluctuations The figure of human blood drug concentration is shown in Figure 8 < br / > figure 8 The single dose mean plasma concentration time curve [7] < br / > the advantages of the sustained-release tablets are summarized in Figure 9 < br / > Figure 9 Summary of advantages of palipexone sustained-release tablets < br / > if the development of palipexone is to this end, there is no doubt After all, palipexone sustained-release tablets have been shining, but Johnson & Johnson is not satisfied In cooperation with EDT company, it has developed palipexone palmitate injection by using nano crystal technology, pushing the improvement of risperidone to a new peak On July 31, 2009, palmitone palmitate injection was approved by FDA After the initial dose, maintain the dose once a month In the past six years alone, on May 18, 2015, the 3-month drug treatment interval formulation of palmitone was approved for marketing, which is the peak of risperidone improvement < br / > the blood concentration curve of invega trinza (3-month dosage form) is shown in Figure 10 below Due to the different median pharmacokinetic curves between the two products (invegatrinza ® and invega sutenna ®), we should be careful when directly comparing their pharmacokinetic characteristics [8] < br / > Figure 10 Blood concentration of palmitate and piperidone < br / > in the double-blind phase of the key trial (psy-3012), pp3m was superior to placebo in delaying the recurrence of schizophrenia symptoms in subjects who had achieved satisfactory symptom control during the 29 week openlabel treatment Based on the pre planned mid-term analysis after the 42nd recurrence event, there was a statistically significant difference between the two treatment groups in the recurrence time of schizophrenia symptoms, which was in favor of pp3m The placebo group (23%) experienced three times as many relapses as the pp3m group (7%) Therefore, the test was terminated in advance as specified in the statistical analysis plan In addition, the safety of pp3m seems to be basically the same as that of investga sustenna for 1 month The results are shown in Figure 11 < br / > Figure 11 Results of interim analysis of palmitone palmitate injection (3 months) [9] < br / > sales of palmitone palmitate injection in the interval period of January and March are shown in Figure 12 [10] < br / > Figure 12 Sales trend chart of invega trinza and invega sustenna < br / > advantages summary chart of palmitone injection is shown in Figure 13 below < br / > Figure 13 Summary of advantages of long-term palmitone injection < br / > the fifth spring of risperidone improvement < br / > the trend of long-term palmitone injection is flourishing, and risperidone improvement seems to have come to a successful end, but individual Inc is not satisfied with this It wants to bring new choices for psychiatric patients, and its development focus is on risperidone itself, Johnson risperidone microspheres were injected once every two weeks, and a greater breakthrough was achieved by using slow and controlled release technology On July 27, 2018, the long-acting subcutaneous injection of risperidone once a month was approved for marketing < br / > Personal Inc risperidone long acting injection (perseris Kit) is provided by sterile dual syringe mixing system A syringe is pre filled with a liquid delivery system, which is dissolved in N-methyl-2-pyrrolidone by a biodegradable DL lactide-glyoxylate copolymer (the molar ratio of lactide to glyoxylate is 80:20) N-methyl-2-pyrrolidone is a water-soluble and biocompatible solvent; the delivery system is also known as the atrigel delivery system The second syringe is pre filled with risperidone powder Once the risperidone injection was prepared by mixing the contents of the two syringes, it was injected subcutaneously into the abdomen Risperidone is dissolved and suspended in a polymer solution After injection, the delivery system contacts the body fluid and solidifies, resulting in a biodegradable implant that releases risperidone in a controlled manner over an extended period of time This is in contrast to the microspherical risperidone Lai system, which uses a static flow method to integrate risperidone into the D, l-lactide-glycolide copolymer matrix and degrade within 14 days (by twice monthly injection) [11] [12] < br / > after injection, SQ library was formed when contacting with body fluid There are two absorption peaks, the first one is 4-6 hours after injection, which is due to the initial release of risperidone during the solidification of SQ library Due to the slow release from the SQ warehouse, the second peak occurred between 10 and 14 days after injection The two peaks have similar amplitude The integrated population pharmacokinetic model showed that patients with lower body mass index (BMI) had a higher initial