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Risperidone is a classic antipsychotic drug with over 20 years of clinical use. The drug was first launched in the UK in 1992 and in the US in 1993. From 1993 to 2014, the conventional formulations of risperidone (Risperdal: oral tablets, oral solution, orally disintegrating tablets) generated at least 30 billion USD in sales revenue for Johnson & Johnson.With the arrival of the patent cliff for conventional formulations, Johnson & Johnson upgraded Risperidone — Long-actingInjectable Risperidone Microspheres(Risperdal Consta), this extended-release microsphere formulation is a white to off-white powder, available in 12.5 mg, 25 mg, 37.5 mg, or 50 mg. The microsphere excipient is 7525 polylactic-hydroxycaproic acid (PLG), with each gram of microspheres containing 381 milligrams of risperidone. The composition of the diluent includes:Anhydrous Citric Acid1mg/mL, disodium hydrogen phosphate dihydrate 1.27 mg/mL, polysorbate 20. 1mg/mL, sodium carboxymethyl cellulose 22.5 mg/mL, sodium chloride 6mg/mL, sodium hydroxide 0.54 mg/mL, water for injection. The microspheres are suspended in the diluent prior to injection. Advantages: Intramuscular injection every two weeks significantly improves patient clinical compliance, but after the first injection, oral risperidone is required for three weeks to maintain blood drug concentration. Since Risperdal Consta was approved by the U.S. FDA for marketing in 2003, its sales experienced ten years of rapid growth, especially peaking in 2011 (approximately $1.6 billion) after the patent for oral risperidone expired in 2009. Sales have slowly declined since then, with revenue in 2021 reaching $592 million. In 2007, it entered the Chinese market under the trade name Hengde®.In July 2018, Indivior PLC's risperidone extended-release injectable suspension (brand name Perseris) received FDA approval for subcutaneous injection to treat adult schizophrenia. The available dosages are 90mg and 120mg. The formulation includes D,L-lactide copolymer (lactide to glycolide ratio of 80:20).N-Methylpyrrolidone。Advantages: Subcutaneous injection once a month, administered in the abdomen or posterior upper arm. The blood concentration reaches its peak for the first time 4-6 hours after injection. There is no need to combine it with oral risperidone, but it must be confirmed before use that the patient tolerates risperidone well. However, patients currently taking oral risperidone at doses of <3mg/day or >4mg/day may not be suitable for switching to Perseris due to difficulty in dose conversion.In 2021, the domestic company GreenLeaf Pharmaceuticals' Risperidone Microspheres for Injection (2-week formulation) was registered and marketed under Category 2.2, with the trade name Rixience®. The specifications are 25mg, 37.5mg, and 50mg. The formulation consists of risperidone, mannitol (5.38 mg/100 mg risperidone), poly(lactic-co-glycolic acid) (PLGA) 5050 (24.2 mg/100 mg risperidone), and poly(lactic-co-glycolic acid) (PLGA) 7525 (96.7 mg/100 mg risperidone). The diluent contains: citric acid monohydrate 1.10 mg/mL, anhydrous disodium phosphate 1.02 mg/mL, polysorbate 80 0.6 mg/mL, sodium carboxymethyl cellulose 6 mg/mL, sodium chloride 6 mg/mL, sodium hydroxide 0.54 mg/mL, and water.Advantages: By improving the drug release method, Rysinor® shortens the initial drug release lag period, eliminating the need for oral supplementation after the first injection. Effective blood concentration required for efficacy is directly achieved after injection, further enhancing the convenience of clinical treatment. For patients experiencing acute episodes with poor compliance and cooperation, Rysinor® can quickly control disease symptoms. Additionally, after discontinuation of Rysinor®, the drug concentration stays in the body for a significantly shorter time compared to Risperdal Consta, allowing doctors to adjust the dosage according to the condition at any time. At the end of 2021, Rysinor was included in the National Medical Insurance Catalog, and sales began to increase starting from 2022. On January 15, 2023, the English trade name Rykindo® for Rysinor® officially received FDA approval for marketing, used for treating adult patients with schizophrenia, as well as for maintenance treatment of Type I bipolar disorder in adults as monotherapy or as an adjunct to lithium or valproate.In April 2023, MedinCell andTevaThe extended-release injectable suspension of risperidone (TV46000, trade name Uzedy), co-developed, has been approved by the FDA for subcutaneous injection to treat adult schizophrenia. The frequency is once a month (corresponding specifications: 50mg, 75mg, 100mg, 125mg) or once every two months (corresponding specifications: 100mg, 150mg, 200mg, 250mg).Prescribing Information: UZEDY is a sterile, white to off-white opaque viscous injectable suspension for subcutaneous administration in the abdomen or posterior upper arm, containing risperidone (and deliverable volume per single-dose pre-filled syringe): 50 mg (0.14 mL), 75 mg (0.21 mL), 100 mg (0.28 mL), 125 mg (0.35 mL), 150 mg (0.42 mL), 200 mg (0.56 mL), and 250 mg (0.7 mL). Excipients include dimethyl sulfoxide (45% w/w), methoxy polyethylene glycol-co-(D, L-lactide) (15% w/w), and poly(D, L-lactide)-co-polyethylene glycol-co-(D, L-lactide) (10% w/w).Advantages: Uzedy adopts MedinCell's BEPO copolymer technology. According to MedinCell, its patented BEPO technology can control and ensure the regular administration of drugs at optimal therapeutic doses over several days, weeks, or months. Upon injection, the BEPO technology forms a polymer deposit of a few millimeters under the skin, exerting systemic or localized targeted effects. Functioning like an injectable and bioabsorbable miniature pump, the deposit releases the active ingredient through absorption over the required period. The therapeutic blood concentration is reached within 6-24 hours after a single dose, without the need for concomitant oral risperidone. However, prior to use, it is necessary to confirm that the patient tolerates risperidone well.In addition, Uzedy overcomes the limitations of Perseris, which has a single dosing frequency and few optional specifications, by providing up to seven different specifications corresponding to oral risperidone 2-5 mg/day, with flexible interchangeability between once-monthly and once-every-two-months formulations.In terms of packaging, Uzedy uses a pre-filled syringe with a 21-gauge needle for administration. The needle is shorter than the commonly used 22-gauge and 23-gauge needles for intramuscular long-acting injections, and thinner than a 20-gauge needle, causing less psychological stress to patients during the injection process. This further improves patient compliance with medication.Insight 1: After a drug is marketed, developing improved new drugs plays a positive role in maintaining the product life cycle.Patent CliffBefore the arrival, advance technological upgrades and patent layouts are essential to maintaining a leading position. For example, Johnson & Johnson laid out patents for Risperdal Consta and Invega (risperidone microspheres) before the expiration of its conventional formulation patents. It also continuously launched new products such as Invega (paliperidone extended-release tablets, the main metabolite of risperidone), Invega Sustenna (paliperidone palmitate injectable), and Invega Trinza (ultra-long-acting paliperidone palmitate injectable).Revelation 2: The development of long-acting formulations should be based on unmet clinical needs. Risperidone formulations have evolved from Risperdal Consta, administered once every two weeks, to Uzedy, administered once every two months; from Risperdal Consta requiring supplementary oral administration to subsequent products that eliminate the need for combination with oral medications, significantly improving clinical compliance. However, with the intensification of competition among similar products, while meeting clinical needs, it is also necessary to consider the unique advantages of the product. For example, on July 10, 2024, Indivior announced it would cease sales of its schizophrenia treatment drug Perseris (risperidone) and lay off approximately 130 employees due to increased competition and changes in Medicaid coverage as the company grapples with market pressures and lowers its full-year forecast.Insight 3: The formation of a distinctive platform facilitates the faster and better development of similar formulations, enabling the company to enter a new growth phase. For example, Medincell's Uzedy (Risperidone Extended-Release Injectable Suspension), developed using BEPO technology, received FDA approval in April 2023. On April 16, 2024, Medincell announced a collaboration with AbbVie to jointly develop and commercialize up to six therapeutic products across multiple therapeutic areas and indications using its long-acting injectable technology platform. It is believed that the launch of these drugs will not only benefit patients but also bring substantial rewards to the company.- 1. The Evolution of Risperidone: A Model for Global Reformulated New Drugs https://www.sohu.com/
- 2. $1.9 Billion: AbbVie Bets on MedinCell’s Long-Acting Injection Technology https://www.vbdata.cn/
- 3. Instructions for Each Product
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