Huashan Is Not the Only Road: A Brief Discussion on the Development Opportunities of Pharmaceutical Dosage Form Improvement

It's difficult to create innovative drugs with high thresholds, and generics are highly competitive with few barriers, leading to excessive competition. This phenomenon has caused more and more companies to turn their attention to the market for modified new drugs, creating a new path between complete innovation and imitation. Due to the characteristics of lower R&D risks, shorter development cycles and higher returns, this niche market of modified new drugs is gradually drawing people's attention. Although the development of modified new drugs in China started relatively late, they have benefited from better safety, effectiveness, and compliance. Driven by factors such as the national policy's emphasis on clinical value and the upgrading of novel preparation technology, the market size of modified new drugs has rapidly grown. Improving the original dosage forms to address unmet clinical needs and extend the product life cycle is a major R&D approach for modified new drugs at present. 

The recent approval of several new dosage forms of blockbuster drugs has confirmed this point to some extent. Last month, FDA officially approved a new dosage form (Entresto sprinkle) of Novartis's blockbuster cardiovascular product Entresto (Sacubitril Valsartan Sodium, Entresto). Entresto Sprinkle is supplied in the form of capsules with film-coated oral granules inside for oral administration. It is approved in two specifications, containing 6mg sacubitril and 6mg valsartan; or containing 15mg sacubitril and 16mg valsartan. It is worth noting that Entresto achieved a staggering sales volume of USD 6.035 billion globally last year. Similarly, FDA also approved Abbvie's new oral solution dosage form of Upadacitinib (Rinvoq) this month, with the brand name Rinvoq LQ. Last year, the global sales volume of Upadacitinib also reached USD 3.969 billion. 

After considering the approval of the new dosage form of Sacubitril Valsartan Sodium and Upadacitinib, we can find that original manufacturers are making efforts to extend the product life cycle. When the patents on key compounds of the two drugs expire in recent years, the approval of new dosage forms will deepen the protection of the products and delay the speed of market segmentation by generics. 

Throughout history, whether it is Risperidone and paliperidone palmitate that shine in the field of psychiatry or the classic drug Paclitaxel in the field of tumor, they have all ushered in a new engine of growth after continuous dosage form upgrades. And with the continuous development of preparation technology platforms such as slow release control, microspheres, liposomes, and inhalation preparations, more possibilities are added to the dosage form improvement. Pharmaceutical dosage form improvement has been on the fast track of high-speed development, whether it is driven by products or preparation technology. 

01 Differentiation benchmark 

Opening the global drug sales data for 2023, it is not difficult to find that all good times don't last long. The former king of medicine Humira saw a sharp decline in sales volume under the impact of patent cliff, and Keytruda took over as the new king of medicine. Meanwhile, several blockbuster products including Lenalidomide, Etanercept, and Ibrutinib have continued to decline under the erosion of generics after their patents expired. Modifying the original dosage forms is currently a strategy for many drugs to extend their product life cycle. Both changing Keytruda into subcutaneous preparation and changing semaglutide into oral preparation reflect the wisdom of the original drug manufacturers. 

Among numerous modified dosage forms, the long-acting injectable suspensions of paliperidone palmitate undoubtedly stands out as the most impressive one, achieving an astonishing global sales volume of USD 4.115 billion in 2023. Paliperidone is a kind of atypical antipsychotics that is the primary metabolic product of Risperidone. INVEGA, a daily oral preparation, was approved in the United States in 2006. INVEGA SUSTENNA, a monthly preparation, was approved in the United States in 2009. INVEGA TRINZA, a three-month preparation, was approved in the United States in 2015. INVEGA HAFYERA, a six-month preparation, was approved in the United States in 2021. 

The commercial success of the long-acting injectable suspensions of paliperidone palmitate is attributed to two major reasons. Firstly, it really addresses the unmet clinical needs. The treatment of schizophrenia is relatively long, and some patients have poor medication compliance, they may have a tendency to spit out the medication or refuse to swallow it. Some special injections can achieve the purpose of long-acting or attenuated toxicity. As the only antipsychotics currently available that can extend the medication interval to once every six months, the long-acting injectable suspensions of paliperidone palmitate not only guarantees corresponding therapeutic effects, but also greatly reduces the times of hospital visits for patients, saving time and improving the efficiency of medical resource utilization. 

Secondly, in the past few decades of rapid development of preparation technology, paliperidone palmitate has taken advantage of nanocrystal technology and used nanocrystal wet milling technology to make fine drug particles. With the increase of the surface area of drug particles, the water solubility of the drug is improved, thus forming the water suspension preparation that can be used for intramuscular injection, and also increasing the absorption rate and bioavailability of the drug. After administration, paliperidone palmitate dissolved slowly, with smaller particles dissolving first and larger particles dissolving later. The dissolved paliperidone palmitate is then completely hydrolyzed into Paliperidone by esterases. Through the improvement of dosage forms, paliperidone palmitate has met clinical needs, which is conducive to maintaining long-term therapeutic effects and reducing recurrence rates. It has significant clinical application value and also extends the product's life cycle. 

Table 1 Approved long-acting injectable suspensions of paliperidone palmitate

Figure 1: Approved long-acting injectable suspensions of paliperidone palmitate 

Of course, paliperidone palmitate is just one of the outstanding stars among many modified dosage forms. The improvement of pharmaceutical dosage forms cannot be separated from the continuous upgrading of preparation technology, the continuous evolution of excipients, and more importantly, the unmet clinical needs. 

02 Huashan is not the only road 

According to the data from Sullivan Consulting, the number of patients with chronic diseases in China has been continuously increasing, and the demand for modified new drugs has increased accordingly. With the promotion of technological innovation and favorable policies, the market size of China's modified innovative drugs increased from RMB 261.39 billion to RMB 323.99 billion from 2016 to 2020, with a compound annual growth rate of 5.5%. It is estimated that by 2025, the market size of China's modified innovative drugs will reach RMB 561.29 billion, with a compound annual growth rate of 11.6%. And it is expected to reach RMB 795.17 billion by 2030, with a compound annual growth rate of 7.2%. 

Figure 22: Market size of modified innovative drugs in China, 2016-2030E

Figure 2: Market size of China's modified innovative drugs (Source: Sullivan Consulting) 

According to the new classification of drug registration in China, modified new drugs refer to drugs that have been optimized in terms of their structure, dosage form, prescription process, administration route, indications, etc., based on known active ingredients, and have significant clinical advantages. Among them, the modified type of dosage form, prescription process, and administration route under Class 2.2 has accounted for the highest proportion of applications in the past three years, exceeding 50%. In other words, the pharmaceutical dosage form improvement accounts for half of the modified new drugs. In the current situation of involution in generics and overcrowding of innovative drug targets, there are more ways to break the deadlock than just one. The pharmaceutical dosage form improvement is a good approach, which brings new development opportunities for generic drug companies actively undergoing transformation. 

Currently, the pharmaceutical dosage form improvement is mainly focused on oral preparations. Common cases include the development of granules, oral solutions and dry suspensions, based on tablets or capsules, for special populations such as children and individuals with dysphagia. For instance, in recent years, modified drug preparations such as Entecavir granules, Amlodipine Besylate Dry Suspensions, and Sodium Phosphate Powder have been approved. 

Figure 3: Class 2.2 new drugs currently approved in China (Data source: Drugdataexpy) 

At the same time, oral soluble film has gained significant popularity in recent years for dosage form improvement. Among the currently approved Class 2.2 drugs, several varieties such as Aripiprazole Oral Soluble Film, Tadalafil Oral Soluble Film, Olanzapine Oral Soluble Film, Montelukast Sodium Oral Soluble Film, and Memantine Hydrochloride Oral Soluble Film have been approved and launched on the market. The reasons behind this popularity are easy to understand. Firstly, the feature of the oral membrane is the rapid drug absorption. Unlike oral gastrointestinal administration, drugs absorbed through the buccal mucosa enter the internal jugular vein directly and reach the systemic circulation, avoiding the first-pass effect. It has high bioavailability and are convenient to use, making it a promising new dosage form for the treatment of various diseases such as diabetes, migraine, and chemotherapy-induced nausea. In addition, the oral dissolvable film currently on the market can be declared for marketing after completing BE, and the clinical investment is far less than that of other modified dosage forms. 

Oral dosage form improvement has lower technical barriers and R&D costs compared to complex injections, resulting in fewer approved varieties of high-end injectable dosage forms, including microspheres, liposomes, nano-preparations (including albumin), and micelles. Currently, the leaders in this field are concentrated among top pharmaceutical companies such as Luye Pharmaceutical, Hengrui Pharmaceuticals, and CSPC Pharmaceutical Group. In addition, inhalation preparations and topical administration for external use (emulsifiable paste, ointments, gel patches, etc.) are also among the popular directions for dosage form improvement. Inhalation preparations can directly enter the respiratory tract and lungs, where the enzymatic activity is relatively low, and drug absorption through the lungs can avoid the first-pass effect of the liver, making them the primary dosage form for the prevention and treatment of acute and chronic respiratory diseases globally. Meanwhile, external preparations represented by Loxoprofen Sodium Cataplasms and Flurbiprofen Cataplasms are revealing a rapidly growing blue ocean market with their soaring sales volume. Currently, this market is also waiting for clinically advantageous products to seize the opportunity. 

Reference: 

1. Sullivan: Report on the Current Status and Development Trend of the Modified New Drug Industry; 

2. Pharmcube: Top 100 best-selling drugs globally in 2023; 

3. Drug delivery: Detailed explanation of Paliperidone as a marketed complex injection; 

4. Clinical trial of paliperidone palmitate injection and risperidone oral solution in the treatment of acute schizophrenia [J], The Chinese Journal of Clinical Pharmacology, 2017, 33 (4): 308-311.; 

5. Discussion on the pharmaceutical development of generic long-acting injections of paliperidone palmitate, Chin J Clin Pharmacol. 

6. Pharmacodia: Is there a future for the development of chemical dosage form improvement? Summary of the article: the status of domestic applications for modified new drugs.