Technology name
In-situ Microimplants
Developer(s)
Sponsor(s)
Not specified
Type of technology
Polymer-based in-situ implant
Administration route
Intramuscular
Development state and regulatory approval
Risperidone
Phase III
Approved by the EMA under the brand name OKEDI on 14/02/2022 and approved by the FDA under the brand name RISVAN on 02 April 2024.
Description
Insitu implant (ISM) technology addresses common limitations associated with traditional prolonged-release oral and injectable formulations. This innovative approach utilizes a solid, biodegradable polymer composed of L-lactide and glycolide monomers. By employing a polymeric matrix, ISM addresses several critical limitations, including complex administration procedures, low encapsulation efficiency, and compromised stability of active substances. Furthermore, this technology enables precise control over the initial release of the drug, resulting in consistent therapeutic efficacy.
Developer(s)
Laboratorios Farmacéuticos ROVI, founded in 1946 in Madrid, Spain, is a prominent global player in the pharmaceutical industry. Initially established as a domestic company, ROVI has evolved into an international leader in the research, development, manufacturing, and commercialization of both small molecules and biologics using in situ microimplants.
Technology highlight
The in situ implant is a monthly intramuscular injectable no-particulate solid implant composed of a biodegradable copolymer matrix of dimethylaminomethacrylate and other acrylate monomers, exhibiting enhanced encapsulation efficiency and improved stability of the API. The molecular weight of the copolymers exceeds 15 kDa, contributing to the controlled degradation and release profile. Upon injection, the formulation forms a solid depot at the site, enabling the gradual and sustained drug release over several weeks to months. The API particles are maintained within a size range of 10 to 225 microns, optimizing the balance between immediate and sustained release kinetics.
Illustration(s)
Technology main components
(i) Biocompatible polymer ( Copolymer of poly ( lactic acid ) and poly ( lactic acid - co - glycolic acid ) (ii) Water miscible solvent ( Dipole moment is in between 3.5-4.5D) (iii) API dissolved in a miscible solvent
The price of OKEDI (Risperidone ISM) is £222.64/vial in the United Kingdom and its equivalent in EU states.
Delivery device(s)
No delivery device
APIs compatibility profile
Min: 1
Max: 2
Unit: mg/mL
Drug hereby includes the API and/or a metabolite or a prodrug thereof
Targeted drugs for ISM formulation are water-soluble antipsychotic drugs including but not limited to paliperidone, risperidone, olanzapine, opioids like fentanyl, and aromatase inhibitors including but not limited to letrozole and anastrozole.
The water-miscible solvent utilized for dissolving the active pharmaceutical ingredient (API) should exhibit a dipole moment in the range of approximately 3.7 to 4.5 Debye (D) and a dielectric constant between 30 and 50.
The viscosity of the ISM is targeted to fall within the range of 0.50 to 4.0 Pascal-seconds (Pa·s).
30-50 wt%
1 single API :
Min: -1
Max: 3
Only hydrophilic and partial hydrophilic drugs are suitable
Scale-up and manufacturing prospects
ROVI Farmaceuticos has expanded its injectable manufacturing capacity with three new plants, producing 250 million syringes and 160 million vials annually.
Not provided
ISM manufacturing unit is in accordance with ISO 140001:2015 for the production of pharmaceutical specialties and health products in low-volume injectable forms and suppositories. The manufacturing process for these products involves the following steps: 1) Mixing lactic acid and glycolic acid monomeric polymers at a range from 48:52 to 100:0. 2) Mixing the mixture with API dissolved in a water-miscible solvent. 3) Expose the mixture to Beta-radiation (5 - 23 KGy). 4) Sterilize the solvent by filtering it through a medium having a pore size of 0.22 microns or less. 5) Reconstitution process.
Not provided
Excipients
No proprietary excipient used
No novel excipient or existing excipient used
No residual solvent used
Additional features
- Biodegradable
- Drug-eluting
- Monolithic
- Removable
- At least 1 year shelf life
- Needs insertion kit
ISM provides a sustained release of API and achieves therapeutic plasma levels within the first day after a single dose of API. The ISM provides a sustained release throughout the 4-week dosing period over multiple intramuscular injections.
Intramuscular ISM injections are prefilled injections with 20G and 21G needles. The injection kit contains a powder-prefilled syringe, a solvent-prefilled syringe, and two sterile safety hypodermic needles: a 20G needle (for gluteus muscle) and a 21G needle (deltoid muscle). Phase I studies revealed a 15% incidence of injection site erythema and a 7.5% incidence of injection site induration, which healthcare professionals should carefully consider.
Phase I studies of Risperidone ISM demonstrated that the most frequent adverse event was hyperprolactinemia, occurring in 54% of participants. A total of 13 serious adverse events (SAEs) were reported, including dystonia.
The ISM has a non-degradable/ non-erodible that provides structural stability for the device regardless of the pH of a surrounding aqueous environment.
Not provided
Therapeutic area(s)
- Oncology
- Mental health
Not provided
Potential associated API(s)
- Paliperidone
- Risperidone
- letrozole
Use of technology
- Administered by a community health worker
- Administered by a nurse
- Administered by a specialty health worker
Weekly, Monthly
Not provided
Targeted user groups
- Adults
- Older Adults
- All
Unspecified
Unspecified
No
Not provided
Type D2 Dopamine receptor antagonist
Pre-clinical
Not provided
Schizophrenia
Not provided
Not provided
Not provided
Risperidone
alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptor antagonist
Phase III
NCT03160521
Schizophrenia
18-65 aged adults with Schizophrenia
Once monthly
Approved by the EMA under the brand name OKEDI on 14/02/2022 and approved by the FDA under the brand name RISVAN on 02 April 2024.
letrozole
Aromatase Inhibitors
Phase I
NCT03401320; NCT06315205
Breast Cancer
Post Menopausal women
Not provided
Not provided
Antipsychotic injectable depot composition
The present invention is directed to a composition that can be used to deliver an antipsychotic drug such as risperidone as an injectable in-situ forming biodegradable implant for extended release providing therapeutic plasma levels from the first day. The composition is in the form of drug suspension on a biodegradable and biocompatible copolymer or copolymers solution using water miscible solvents that is administered in liquid form. Once the composition contacts the body fluids, the polymer matrix hardens retaining the drug, forming a solid or semisolid implant that releases the drug in a continuous manner. Therapeutic plasma levels of the drug can be achieved since the first day up to at least 14 days or more even up to at least four weeks.
US10182982B2
Composition of the formulation
Laboratorios Farmaceuticos Rovi SA
Not provided
May 31, 2031
Active
Methods for the Preparation of Injectable Depot Compositions
Injectable depot compositions, comprising a biocompatible polymer which is a polymer or copolymer based on lactic acid and/or lactic acid plus glycolic acid having a monomer ratio of lactic to glycolic acid in the range from 48:52 to 100:0, a water-miscible solvent having a dipole moment of about 3.7-4.5 D and a dielectric constant of between 30 and 50, and a drug, were found suitable for forming in-situ biodegradable implants which can evoke therapeutic drug plasma levels from the first day and for at least 14 days.
US20180318208A1
Not provided
Laboratorios Farmaceuticos Rovi SA
Not provided
May 31, 2024
Active
Risperidone or paliperidone implant formulation
The present invention is directed to an injectable intramuscular depot composition suitable for forming an in situ solid implant in a body, comprising a drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination, a biocompatible copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid of about 50:50 and DMSO solvent, wherein the composition releases the drug with an immediate onset of action and continuously for at least 4 weeks and wherein the composition has a pharmacokinetic profile in vivo that makes it suitable to be administered each 4 weeks or even longer periods.
US11007139B2
Formulation
Laboratorios Farmaceuticos Rovi SA
Not provided
May 31, 2031
Active
Injectable composition with aromatase inhibitor
The present invention provides a composition suitable for forming an intramuscular implant. It comprises a biodegradable thermoplastic polymer of polylactic acid (PLA), DMSO and an aromatase inhibitor compound. The invention also provides a kit suitable for the in situ formation of the composition and its use as a medicine for treating cancer, especially breast cancer.
US11918682B2
Composition of the formulation
Laboratorios Farmaceuticos Rovi SA
Not provided
April 16, 2032
Active
Procedure for the filling of solids in pharmaceutical containers and the sealing thereof under sterile conditions
A sterile procedure for the filing of solids into pharmaceutical containers and the sealing thereof under sterile conditions is provided. Exemplary containers include syringes, vials, capsules, ampoules, single-dose devices or cartridges. The containers can be filled with powder, granules, nanoparticles or microparticles. After sealing, the containers are airtight. More specifically, the procedure minimizes adherence of those solids to the interior surfaces of the containers during the filling and sealing steps, thus ensuring airtightness of the seal and precision of the weight of the solid dispensed into the containers.
US11987410B2
Not provided
Laboratorios Farmaceuticos Rovi SA
Not provided
May 23, 2040
Active
Publications
Messer, T., Bernardo, M., Anta, L., & Martínez-González, J. (2024). Risperidone ISM®: review and update of its usefulness in all phases of schizophrenia. Therapeutic advances in psychopharmacology, 14, 20451253241280046. https://doi.org/10.1177/20451253241280046
One of the most important challenges in the management of patients with schizophrenia is to ensure adherence to antipsychotic treatment. The contribution of long-acting injectables (LAI) is undeniable in this matter, but there are still some unmet medical needs not covered by these drugs (e.g. quick onset of action for patients with acute exacerbation of schizophrenia). This article summarises the pharmacokinetics, efficacy and safety of Risperidone ISM (in situ microparticles). The aim of this review is to provide information about the potential uses of this new LAI formulation of risperidone for the treatment of schizophrenia, contextualising and diving into the published evidence. Risperidone ISM shows a rapid release which allows achieving within 12 h risperidone active moiety levels similar to those observed in the steady-state for oral risperidone treatment, achieving a mean average concentration of 38.63 ng/mL. The plasma concentration of active moiety achieved by Risperidone ISM comes with a predictable dopamine D2 receptor occupancy above 65% throughout the 28-day dosing period, which is accepted as a threshold for the efficacy of the antipsychotic treatment. This can be associated with the positive efficacy findings throughout its clinical development. In the short term, it provides an early and progressive reduction of symptoms in adult patients with acute exacerbation of schizophrenia without the need for loading doses or oral risperidone supplementation, which could contribute to reinforcing the therapeutic alliance between the patient and the psychiatrist. In addition, long-term treatment was effective, safe and well tolerated regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM during an acute exacerbation or switched from stable doses of oral risperidone. Improvement and maintenance of personal and social functioning and health-related quality of life were observed in each setting, respectively. All these findings endorse Risperidone ISM as a useful and valuable treatment for the acute and maintenance management of patients with schizophrenia.
Laveille, C., Snoeck, E., Ochoa Díaz de Monasterioguren, L., Martínez-González, J., Llaudó, J., Anta, L., & Gutierro, I. (2024). Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®. British journal of clinical pharmacology, 90(9), 2256–2270. https://doi.org/10.1111/bcp.16115
The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data.
Anta, L., Llaudó, J., Ayani, I., Martínez, J., Litman, R. E., & Gutierro, I. (2018). A phase II study to evaluate the pharmacokinetics, safety, and tolerability of Risperidone ISM multiple intramuscular injections once every 4 weeks in patients with schizophrenia. International clinical psychopharmacology, 33(2), 79–87. https://doi.org/10.1097/YIC.0000000000000203
This study characterized the pharmacokinetics, safety, and tolerability of Risperidone ISM, a new long-acting intramuscular formulation, for monthly administration without oral supplementation. Patients with schizophrenia received multiple intramuscular injections of 75 mg in the gluteal or deltoid muscle at 28-day intervals. Of the 70 randomized patients, 67 received at least one dose of study medication. The mean Cmax of the active moiety was achieved 24-48 h (tmax) after each administration, regardless of injection site. They ranged over four consecutive doses from 39.6 to 53.2 and 54.1 to 61 ng/ml, when given in gluteal or deltoid muscle, respectively. Active moiety achieved therapeutic levels by 2 h after dose, and the levels were maintained throughout the 4-week dosing period. No significant changes across the study were observed on either Positive and Negative Syndrome Scale or Extrapyramidal Symptoms Scale. Overall, 63 (94%) patients experienced at least one treatment-emergent adverse event (TEAE). One serious TEAE (dystonia) was related to study treatment. The most frequently reported TEAEs were hyperprolactinaemia (57.7%) and injection site pain (32.8%). Risperidone ISM achieved therapeutic levels from the first hours after drug administration and provided a sustained release throughout the 4-week dosing period over multiple intramuscular injections and was found to be safe and well tolerated.
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Collaborate for development
Consider on a case by case basis, collaborating on developing long acting products with potential significant public health impact, especially for low- and middle-income countries (LMICs), utilising the referred to long-acting technology
Share technical information for match-making assessment
Provide necessary technical information to a potential partner, under confidentiality agreement, to enable preliminary assessment of whether specific medicines of public health importance in LMICs might be compatible with the referred to long-acting technology to achieve a public health benefit
Work with MPP to expand access in LMICs
In the event that a product using the referred to long-acting technology is successfully developed, the technology IP holder(s) will work with the Medicines Patent Pool towards putting in place the most appropriate strategy for timely and affordable access in low and middle-income countries, including through licensing
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