[go: up one dir, main page]

WO2025243901A1 - Préparation d'injection - Google Patents

Préparation d'injection

Info

Publication number
WO2025243901A1
WO2025243901A1 PCT/JP2025/017460 JP2025017460W WO2025243901A1 WO 2025243901 A1 WO2025243901 A1 WO 2025243901A1 JP 2025017460 W JP2025017460 W JP 2025017460W WO 2025243901 A1 WO2025243901 A1 WO 2025243901A1
Authority
WO
WIPO (PCT)
Prior art keywords
microparticles
dopamine receptor
receptor agonist
rotigotine
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2025/017460
Other languages
English (en)
Japanese (ja)
Inventor
功明 佐方
亮 ▲高▼畠
百香 縄司
甲子郎 藤本
綾乃 金城
弘晃 岡田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sentan Pharma
Sentan Pharma Inc
Original Assignee
Sentan Pharma
Sentan Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sentan Pharma, Sentan Pharma Inc filed Critical Sentan Pharma
Publication of WO2025243901A1 publication Critical patent/WO2025243901A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to an injectable formulation.
  • Dopamine receptor agonists include pramipexole, ropinirole, and rotigotine.
  • the commercially available oral formulations of pramipexole and ropinirole are Bi-Sifrol (registered trademark) and Requip (registered trademark), respectively. Oral administration is subject to the first-pass effect, resulting in low bioavailability, and high doses are unavoidable to achieve sufficient efficacy.
  • Transdermal formulations currently on the market include Neupro® Patch, a sustained-release formulation of rotigotine, and Haruropi® Tape, a sustained-release formulation of ropinirole.
  • the sustained-release period for these transdermal formulations is only one day. This is because transdermal formulations typically have low bioavailability due to low permeability through the skin, and to avoid skin disorders such as rashes that may occur if the formulation is applied for more than one day.
  • Transdermal formulations are highly non-invasive for patients, but there are concerns about reduced medication compliance in patients with severe Parkinson's disease, such as forgetting to apply or remove the transdermal formulation due to memory decline, or unintentional removal of the transdermal formulation due to movement disorders, etc.
  • Injectable formulations which can avoid the first-pass effect that occurs with oral administration, have relatively high bioavailability and can be expected to provide high efficacy at lower doses. Furthermore, with injectable formulations, medication administration is managed by a physician, which is expected to improve medication compliance, a concern with transdermal formulations.
  • microparticle formulations that release rotigotine for extended periods of time, from two weeks to one month, are known.
  • Patent Document 2 discloses that when a pharmaceutical composition containing rotigotine behenate, in which rotigotine is bound to a linear saturated fatty acid, was injected intramuscularly into rats, rotigotine was detected in the blood for 42 days.
  • the microparticle formulation disclosed in Patent Document 1 has a maximum sustained release time of rotigotine of one month, but experiments using beagle dogs have shown that the blood drug concentration is relatively low and hardly meets the blood drug concentration requirement (>0.5 ng/mL) for the treatment of Parkinson's disease, particularly during the evaluation period. Furthermore, the microparticle formulation disclosed in Non-Patent Document 1 can only sustain release rotigotine for two weeks, which is hardly long enough. No microparticle formulation is known yet that can sustain the release of a dopamine receptor agonist for more than one to two months and maintain the required blood drug concentration.
  • microparticle formulations disclosed in Patent Document 1 and Non-Patent Document 1 have an average particle diameter of 70 ⁇ m to 90 ⁇ m. Therefore, when administering these microparticle formulations via intramuscular or subcutaneous injection, it is necessary to select an injection needle with a large diameter, which causes pain during administration and may require anesthesia, placing an unavoidable burden on the patient.
  • the present invention was made in consideration of the above circumstances, and aims to provide an injectable formulation that sustainably releases a dopamine receptor agonist over a longer period of time and reduces the burden on the recipient.
  • the injectable formulation for treating Parkinson's disease or restless legs syndrome comprises:
  • the present invention comprises microparticles containing a free dopamine receptor agonist and a biodegradable polymer,
  • the volume average particle diameter D50 of the microparticles is 50 ⁇ m or less,
  • the concentration of the dopamine receptor agonist in the plasma of the administered subject is maintained for one month or longer.
  • the volume average particle diameter D50 of the microparticles is 1 to 50 ⁇ m. This may also be the case.
  • the maintenance period is 2 months. This may also be the case.
  • the dopamine receptor agonist is rotigotine free base or ropinil free base,
  • the content of the dopamine receptor agonist in the microparticles is 5 to 50% by weight. This may also be the case.
  • the biodegradable polymer is a lactic acid polymer or a lactic acid/glycolic acid copolymer having a molecular weight of 5,000 to 150,000. This may also be the case.
  • the present invention enables the sustained release of dopamine receptor agonists over a longer period of time, reducing the burden on the recipient.
  • FIG. 1 shows the particle size distribution of Formulation 1.
  • FIG. 1 shows the particle size distribution of Formulation 2.
  • FIG. 1 shows the particle size distribution of formulation 3.
  • FIG. 1 shows the particle size distribution of formulation 4.
  • FIG. 1 shows the particle size distribution of formulation 5.
  • FIG. 1 shows the particle size distribution of formulation 6.
  • FIG. 1 shows scanning electron microscope images of Formulations 1 to 6.
  • FIG. 1 shows the time course of the subcutaneous residual rate of rotigotine in rats administered subcutaneously with either Preparation 1 or Preparations 3 to 6 in Test Example 1.
  • FIG. 1 shows the time course of plasma rotigotine concentration in rats subcutaneously administered with an injection formulation of Formulation 2 in Test Example 2.
  • the injectable formulation of this embodiment is used to treat Parkinson's disease or restless legs syndrome.
  • the injectable formulation may be a therapeutic agent for Parkinson's disease or restless legs syndrome.
  • the injectable formulation comprises microparticles containing a free-form dopamine receptor agonist and a biodegradable polymer.
  • the dopamine receptor agonist is not particularly limited and can be any substance that agonizes or activates dopamine receptors.
  • Free-form refers to the free form of a dopamine receptor agonist that is not a salt form and can take the form of a physiologically acceptable salt. Examples of free-form dopamine receptor agonists include the free base of a dopamine receptor agonist when the dopamine receptor agonist is a basic dopamine receptor agonist, and the free acid of a dopamine receptor agonist when the dopamine receptor agonist is an acidic dopamine receptor agonist.
  • the injectable formulation contains the free base of rotigotine or the free base of ropinil as the dopamine receptor agonist.
  • a biodegradable polymer can be any polymer that has biodegradable properties.
  • a biodegradable polymer is a polymer that is low in irritation and toxicity to the living body and is broken down and metabolized after administration. After administration, a biodegradable polymer remains in the body, hydrates and swells, and gradually releases the dopamine receptor agonist as hydrolysis progresses.
  • a biodegradable polymer is, for example, a biodegradable polymer.
  • Biodegradable polymers can be produced from biodegradable polyesters.
  • Biodegradable polyesters are polyesters synthesized by copolymerizing one or more monomers or dimers selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolic acid, glycolide, ⁇ -caprolactone, ⁇ -hydrohexanoic acid, ⁇ -butyrolactone, ⁇ -hydroxybutyric acid, ⁇ -valerolactone, ⁇ -hydroxyvaleric acid, hydroxybutyric acid, malic acid, etc.
  • Biodegradable polymers may also be obtained by mixing and polymerizing the above monomers or dimers in appropriate ratios.
  • the biodegradable polymer is lactic acid polymer (PLA) or lactic acid-glycolic acid copolymer (PLGA).
  • the polymerization ratio of PLGA is not particularly limited.
  • the polymerization ratio of PLGA is, for example, 1:99 (lactic acid:glycolic acid) to 99:1.
  • the molecular weight of PLA and PLGA is, for example, 5,000 to 150,000. More preferably, the molecular weight of PLA and PLGA is 8,000 to 100,000.
  • PLA and PLGA can be synthesized from monomers or dimers by common methods such as dehydration condensation and ring-opening polymerization.
  • the particle diameter of the microparticles is 1 to 50 ⁇ m, more preferably 10 to 40 ⁇ m. If the particle diameter of the microparticles is too small, the ratio of surface area to volume increases, which can increase the adhesion and cohesion of the powder and deteriorate dispersibility and flowability. On the other hand, microparticles larger than 50 ⁇ m require a large-diameter needle when injected intramuscularly or subcutaneously, and in some cases the patient may be forced to receive the injection under anesthesia. Therefore, the particle diameter range of the microparticles is particularly set to be within the range (10 to 40 ⁇ m) that allows the use of a thin needle of approximately 23 to 26 G that does not require local anesthesia, and ensures sustained release.
  • the particle size of microparticles can be measured by sieving, sedimentation, microscopy, light scattering, laser diffraction/scattering, electrical resistance testing, observation with a transmission electron microscope, observation with a scanning electron microscope, etc.
  • the particle size of microparticles can be expressed as a Stokes equivalent diameter, circle equivalent diameter, sphere equivalent diameter, etc. depending on the measurement method.
  • the particle size of microparticles shown here may also be expressed as an average particle size, particularly a volume average particle size or mass average particle size, calculated as an average from the number distribution based on measurements such as laser diffraction/scattering, using multiple particles as the measurement subject.
  • the particle diameter of the microparticles may be an average particle diameter calculated from a volume distribution based on measurements by a laser diffraction/scattering method. Specifically, when a cumulative curve is calculated assuming the total volume of a particle population to be 100%, the particle diameter may be the volume average particle diameter (50% diameter; D 50 ), which is the particle diameter at the point where the cumulative curve reaches 50%.
  • the cumulative curve and D 50 can be determined using a commercially available particle size distribution analyzer.
  • An example of a particle size distribution analyzer is the Microtrac particle size distribution/particle shape analyzer Sync Analyzer (manufactured by Microtrac BEL).
  • the D 50 of the microparticles is 50 ⁇ m or less.
  • the D 50 of the microparticles is 1 to 50 ⁇ m, more preferably 10 to 40 ⁇ m.
  • the span value of the microparticles is preferably 3.5 or less.
  • the span value is calculated by ( D90 - D10 )/ D50 .
  • D90 is the 90% particle diameter at the point where the cumulative curve is 90%.
  • D10 is the 10% particle diameter at the point where the cumulative curve is 10%.
  • D90 and D10 can also be calculated using a commercially available particle size distribution analyzer. More preferably, the span value of the microparticles is 3.0 or less.
  • the dopamine receptor agonist content in the microparticles is not particularly limited, but is preferably 5 to 50% by weight, and more preferably 5 to 30% by weight. If the dopamine receptor agonist content is less than 5% by weight, an effective plasma dopamine receptor agonist concentration cannot be ensured, while if the content is more than 50% by weight, the release of the dopamine receptor agonist will be unstable, which may lead to side effects.
  • the injectable formulation of this embodiment may further contain an excipient to improve redispersibility during use and stability during storage.
  • an excipient can be used.
  • the excipient is a sugar or an amino acid. More specifically, examples of excipients include lactose, mannitol, trehalose, inositol, erythritol, sucrose, pullulan, sorbitol, starches, dextrin, dextran, sodium alginate, crystalline cellulose, methylcellulose, carmellose sodium, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), natural polymers, synthetic polymers, glycine, leucine, isoleucine, arginine, histidine, etc.
  • the excipient is mannitol.
  • Any known production method such as a phase separation method or an oil-in-water (O/W) emulsion method, can be used to produce the microparticles contained in the injectable formulation.
  • the O/W emulsion method uses two types of solvents: a good solvent that can simultaneously dissolve the free dopamine receptor agonist and the biodegradable polymer, and a poor solvent that does not dissolve at least the biodegradable polymer.
  • a good solvent that can simultaneously dissolve the free dopamine receptor agonist and the biodegradable polymer
  • a poor solvent that does not dissolve at least the biodegradable polymer.
  • an organic solvent that dissolves the biodegradable polymer and is miscible with the poor solvent can also be used as the good solvent.
  • Good solvents include organic solvents that have a boiling point lower than that of water and are poorly water-soluble, such as dichloromethane, chloroform, halogenated alkanes, ethyl acetate, diethyl ether, hexane, and cyclohexane.
  • Dichloromethane and chloroform are preferred because they are easy to emulsify, have a low boiling point, and can easily reduce the amount of residual solvent.
  • a small amount of a solvent such as methanol, ethanol, or acetone may be added to the good solvent to increase the solubility of the dopamine receptor agonist in the good solvent.
  • An example of a poor solvent is water, to which a dispersant may be added.
  • the dispersant is removed by washing during the preparation process.
  • a dispersant may not be required.
  • Dispersants include surfactants, polyethylene glycol, polyvinyl alcohol (PVA), polyvinylpyrrolidone, hydroxymethylcellulose, hydroxypropylcellulose, glycerin, fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, polyglycerin fatty acid esters, polysorbates, etc. Dispersants have both hydrophilic and hydrophobic functional groups and may function as protective colloids or surfactants.
  • a mixture of a dopamine receptor agonist and a biodegradable polymer dissolved in a good solvent is first added dropwise to a stirred poor solvent, causing the good solvent in the mixture to rapidly diffuse into the poor solvent.
  • the good solvent emulsifies in the poor solvent, forming emulsion droplets of the good solvent.
  • the solubility of the dopamine receptor agonist and biodegradable polymer within the emulsion droplets decreases. Further, by continuing to promote the diffusion and evaporation of the organic solvent through stirring under normal pressure, microparticles of biodegradable polymer containing the dopamine receptor agonist are eventually produced. Subsequently, the emulsion can be washed to remove the dispersant, redispersed in water, and subjected to freeze-drying or other procedures to obtain redispersible microparticles.
  • microparticles may be produced using the W/O/W emulsion method.
  • a W/O emulsion is prepared with an aqueous solution of the dopamine receptor agonist dissolved therein as the internal phase, and then the W/O emulsion is injected into a stirred aqueous phase to produce a W/O/W emulsion.
  • the injectable formulation of this embodiment may contain other pharmaceutically acceptable ingredients in addition to the microparticles, as needed.
  • other ingredients include carriers, lubricants, binders, disintegrants, solvents, solubilizers, suspending agents, isotonicity agents, buffers, preservatives, antioxidants, and colorants.
  • the injectable formulation of this embodiment is administered to humans and non-human animals.
  • Non-human animals are preferably mammals, such as dogs, cats, cows, pigs, horses, sheep, and deer.
  • the administration route of the injectable formulation in this embodiment is intramuscular, subcutaneous, intradermal, intraperitoneal, etc.
  • the administration route of the injectable formulation is preferably intramuscular or subcutaneous injection.
  • the dosage of the injectable formulation of this embodiment is determined appropriately based on the age, sex, weight, symptoms, etc. of the recipient so that the dopamine receptor agonist is an effective amount.
  • an effective amount is the amount necessary to treat Parkinson's disease or restless legs syndrome, or to prevent, delay, or inhibit the progression of the condition.
  • the dopamine receptor agonist concentration in the plasma of the administered subject is maintained for a period of one month or more, for example, two months.
  • the administration interval of the injectable formulation of this embodiment is determined appropriately so as to maintain a certain level of plasma drug concentration or higher.
  • the on-off phenomenon which is one of the symptoms that occurs during continuous drug treatment for Parkinson's disease, is a symptom that interferes with the daily or social life of Parkinson's disease patients and requires early treatment.
  • a wearing-off phenomenon in which the efficacy of the drug gradually decreases, is known to occur in the treatment of Parkinson's disease.
  • microparticles for the manufacture of an injectable preparation for treating Parkinson's disease or restless legs syndrome.
  • a method for treating Parkinson's disease or restless legs syndrome comprising the step of administering the microparticles to a subject.
  • the microparticles for use in treating Parkinson's disease or restless legs syndrome comprising the step of administering the microparticles to a subject.
  • Microparticles containing rotigotine and PLA or PLGA as a biodegradable polymer were prepared by the above-mentioned O/W emulsion method as follows.
  • the preparation conditions for the oil phase of the microparticle formulations are shown in Table 1. Note that in the following, PLA is represented as PLA-m, where m represents the weight-average molecular weight of PLA, and PLGA is represented as PLGA(x/y)-z, where x/y represents the polymerization ratio of lactic acid/glycolic acid, and z represents the weight-average molecular weight of the polymer.
  • the temperature of an oil phase solution containing rotigotine and a biodegradable polymer dissolved in dichloromethane was adjusted to 18°C.
  • the solution was then poured into 1.0 L of 0.1% PVA aqueous solution over approximately 1 minute while vigorously stirring (room temperature, 6000 rpm) in a Clearmix (M Technique Co., Ltd.). Vigorous stirring continued for 3 minutes after the injection to emulsify the solution.
  • the organic solvent was then removed by gentle stirring (room temperature, 1000 rpm, 3 hours).
  • the resulting suspension was sieved through a 75 ⁇ m mesh sieve and centrifuged (4°C, 350 ⁇ g, 5 minutes) to recover the microparticles.
  • the particle size distribution of the obtained microparticle formulations was measured using a Microtrac particle size distribution and particle shape analyzer, Sync Analyzer (Microtrac BEL).
  • the particle size distributions of Formulations 1, 2, 3, 4, 5, and 6 are shown in Figures 1, 2, 3, 4, 5, and 6, respectively. D50 was determined as the particle size here.
  • microparticle formulations were observed using a tabletop microscope, Miniscope TM4000PlusII (Hitachi High-Technologies Corporation), and scanning electron microscope photographs of Formulations 1 to 6 are shown in Figure 7.
  • HPLC high-performance liquid chromatography
  • HPLC analysis conditions Equipment: 1260 Infinity II (Agilent) Column: TSKgel ODS-100V 5 ⁇ m (manufactured by Tosoh Corporation) Column size: 4.6 mm I.D. x 15 cm Column temperature: 40°C HPLC mobile phase: acetonitrile-0.3% aqueous phosphoric acid solution (50:50, v/v) Flow rate: 1.000mL/min Injection volume: 10.00 ⁇ L Detection: UV 241 nm Measurement time: 10.00 minutes
  • the ratio of the calculated mass of rotigotine to the mass of the microparticle formulation was taken as the content, and the ratio of the calculated mass of rotigotine to the amount of rotigotine charged shown in Table 1 was taken as the encapsulation rate.
  • Test Example 1 In vivo release test of microparticle formulation Ten mg of each of Formulations 1 and 3 to 6 was suspended in 0.2 mL of a dispersion medium containing 5% mannitol, 0.5% carboxymethylcellulose sodium salt, and 0.1% polysorbate 80 to prepare an injectable formulation. Healthy male Crl:CD (SD) rats (Charles River) aged 6 weeks, weighing between 175 and 200 g, and maintained with free access to food and water, were administered the injectable formulation. Specifically, the injectable formulation was subcutaneously injected into the occipital region of the SD rat under isoflurane inhalation anesthesia using a 1 mL Terumo syringe equipped with a 23G needle. Immediately after subcutaneous administration, the puncture site was sealed with medical soft tissue adhesive to confirm that the injectable formulation did not leak out of the body.
  • the measurement sample was thawed, and 20 mL of the above-mentioned HPLC mobile phase was added.
  • the sample was homogenized twice (10,000 rpm, 2 minutes) using a Hiscotron NS-56S (Microtec Nition) equipped with a generator shaft (NS-10).
  • the suspension containing the disrupted tissue fragments was irradiated with ultrasound for 10 minutes in an ultrasonic cleaner.
  • the suspension was then centrifuged (room temperature, 1640 x g, 10 minutes). The supernatant was collected and filtered through a 0.2 ⁇ m syringe filter to prepare the sample for HPLC analysis.
  • Rotigotine was quantified in the same manner as for preparing samples for HPLC analysis, and this was taken as the amount of rotigotine injected (100%) at the start of release (0 hours).
  • Figure 8 shows the time course of the subcutaneous rotigotine retention rate in rats administered subcutaneously with Formulation 1, or any of Formulations 3 to 6. While there were slight differences in the in vivo rotigotine release rate between Formulations 1, 3, and 4, with the initial release one day after administration ranging from 12.6% to 24.7%, there were no significant differences in the release trends up to six weeks after administration, with 78.3% to 83.0% of rotigotine released by six weeks after administration. Formulations 1, 3, and 4 all demonstrated release over six weeks associated with the hydration rate of the biodegradable polymer and changes in the physical properties of the polymer due to biodegradation. These results demonstrate that Formulations 1, 3, and 4 provide continuous sustained release of rotigotine over a period of at least six weeks.
  • Test Example 2 Measurement of drug concentration in plasma of rats administered with a microparticle formulation
  • the injection preparation was subcutaneously administered to SD rats in the same manner as in Test Example 1. The dose was determined based on the average body weight of SD rats, and an injection preparation prepared by suspending 84 mg (7.8 mg as rotigotine) of Preparation 2 in 0.2 mL of the dispersion medium was administered.
  • a heparinized syringe was used to collect 0.7 mL to 1.0 mL of blood from the jugular vein, and the plasma components were centrifuged (4°C, 1100 x g, 10 minutes) to obtain plasma samples. Samples were stored in a -80°C deep freezer until they were prepared for analysis by a high-performance liquid chromatograph triple quadrupole mass spectrometer (LC/MS).
  • Figure 9 shows the time course of rotigotine plasma concentrations in SD rats administered Formulation 2 subcutaneously. No initial burst was observed on day 1 after administration, and plasma rotigotine concentrations increased bimodally up to 3 weeks after administration (peaks of 8.3 ng/mL and 8.6 ng/mL), followed by a gradual decrease from 4 to 6 weeks after administration.
  • the bimodal increase in plasma rotigotine concentrations is due to the release of rotigotine localized on the surface of the microparticles and the release of rotigotine associated with swelling of the biodegradable polymer and subsequent hydrolysis. Therefore, it was demonstrated that the injectable formulation of this example maintains plasma rotigotine concentrations for at least 8 weeks, which is thought to depend on the biodegradability of the biodegradable polymer.
  • the present invention is useful for sustained-release injectable formulations.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychology (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation d'injection pour le traitement de la maladie de Parkinson ou du syndrome des jambes sans repos, la préparation d'injection comprenant des microparticules contenant chacune un agoniste du récepteur de la dopamine libre et un polymère biodégradable. Le diamètre de particule moyen en volume D50 des microparticules est inférieur ou égal à 50 µm, et la concentration de l'agoniste du récepteur de la dopamine dans le plasma d'un patient auquel la préparation d'injection a été administrée est conservée pendant au moins 1 mois.
PCT/JP2025/017460 2024-05-21 2025-05-14 Préparation d'injection Pending WO2025243901A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2024082281 2024-05-21
JP2024-082281 2024-05-21

Publications (1)

Publication Number Publication Date
WO2025243901A1 true WO2025243901A1 (fr) 2025-11-27

Family

ID=97795220

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2025/017460 Pending WO2025243901A1 (fr) 2024-05-21 2025-05-14 Préparation d'injection

Country Status (1)

Country Link
WO (1) WO2025243901A1 (fr)

Similar Documents

Publication Publication Date Title
JP7437074B2 (ja) リバスチグミンを含む長期持続型製剤およびその製造方法
CN102316867B (zh) 氨氯地平微球制剂、其制备方法及应用
KR101003204B1 (ko) 약물 전달용 고형 지질 나노입자, 그 제조방법, 및 그나노입자를 포함하는 주사제
JP2016515612A (ja) ドネペジルを含む非経口投与用の医薬組成物
KR20060109816A (ko) 통증 치료용 마취제의 서방성 투여 제형
JP7386967B2 (ja) イカリチンナノミセル製剤、その調製方法及びその応用
Wang et al. Enhanced encapsulation and bioavailability of breviscapine in PLGA microparticles by nanocrystal and water-soluble polymer template techniques
KR101900482B1 (ko) 미립구형 서방출 주사제 및 그의 제조방법
WO2006032202A1 (fr) Formulation à libération lente et prolongée contenant un agoniste du récepteur de la dopamine et son procédé de préparation
US20230062487A1 (en) Sustained-release matrices for adventitial or periadventitial neural ablation and uses thereof
KR20190000325A (ko) 이중 코어-쉘 구조를 가지는 난용성 캄토테신 화합물을 포함하는 입자, 약제학적 조성물 및 이의 제조방법
JP2019533716A (ja) 医薬組成物及びその使用
KR102235011B1 (ko) 약물 함유 plga 미립구 및 그의 제조방법
Park et al. Nanostructured mucoadhesive microparticles to enhance oral drug bioavailability
AU2016373574A1 (en) Pharmaceutical compositions comprising phenylaminopyrimidine derivative
JP7266220B2 (ja) エスシタロプラムを含む微粒球状徐放出注射剤及びその製造方法
WO2017197970A1 (fr) Composition pharmaceutique contenant de la bupivacaïne, et procédé de préparation et utilisation de cette dernière
WO2025243901A1 (fr) Préparation d'injection
US20250114320A1 (en) Microspheres for extended release of fenofibrate
CN109419771B (zh) 十一酸睾酮缓释药物组合物、其制备方法及用途
CN121013711A (zh) 用于治疗关节病诸如骨关节炎的包含秋水仙碱的关节内注射剂型
CN118356401A (zh) 一种注射用依维莫司缓释微球及其制备方法
JP2023122702A (ja) 注射剤及び注射剤の製造のための粒子の使用
JP7580139B2 (ja) デスロレリンを含む徐放性注射用組成物
KR101764004B1 (ko) 골관절염 예방 또는 치료용, 또는 관절 통증 완화용 주사제 조성물