CN118356414A - Rasagiline mesylate oral membrane composition, preparation method and application thereof - Google Patents

Rasagiline mesylate oral membrane composition, preparation method and application thereof Download PDF

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CN118356414A
CN118356414A CN202311604333.0A CN202311604333A CN118356414A CN 118356414 A CN118356414 A CN 118356414A CN 202311604333 A CN202311604333 A CN 202311604333A CN 118356414 A CN118356414 A CN 118356414A
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rasagiline mesylate
groups
composition
mass
film
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应述欢
付俊
郭桢
刘俞利
卢鹏程
王婷婷
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Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Yunshengyan Neoplasm Technology Co ltd
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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems

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Abstract

The invention discloses a rasagiline mesylate oral dissolved film composition, a preparation method and application thereof. The invention provides rasagiline mesylate oral film composition comprising an active drug, a film-forming material and a taste masking agent; the active medicine is one or more of N-propargyl-1 (R) -aminoindene mesylate (rasagiline mesylate) and solvate thereof shown in a formula I. The rasagiline mesylate oral solution film composition has the advantages of thin thickness, good taste, stable property, good dissolution rate, no need of drinking water, instant dissolution in the oral cavity, no gritty feel after dissolution in the oral cavity, high oral absorption speed, uniform appearance, good flexibility, simple process, no sedimentation in the film liquid preparation process, satisfactory content uniformity and high drug loading rate. Solves the defects of inconvenient taking, poor patient compliance and the like of the existing preparation, and is particularly suitable for patients with dysphagia.

Description

Rasagiline mesylate oral membrane composition, preparation method and application thereof
The application claims the priority of the prior application of the rasagiline mesylate oral membrane composition, the preparation method and the application thereof, which are filed by the 1 st month 19 of 2023 to the China national intellectual property agency, and have the patent application number 202310059727.6. The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a rasagiline mesylate oral dissolved film composition, a preparation method and application thereof.
Background
Parkinson's Disease (PD) is a common neurodegenerative disease, and is common to the elderly, with average age of onset around 60 years, and rarely seen in young parkinsonism under 40 years. The prevalence of PD in people over 65 years old in China is about 1.7%. Most parkinson's disease patients are sporadic cases, with less than 10% of patients having a family history. The most prominent pathological change in parkinson's disease is the degeneration and death of neurons by midbrain substantia nigra dopamine (dopamine, DA), which causes a significant decrease in striatal DA content to cause disease. The exact etiology leading to this pathological change is still unclear, and genetic factors, environmental factors, age-related aging, oxidative stress, etc. may be involved in the degenerative death process of PD dopaminergic neurons. Existing treatments for parkinson's disease include oral, parenteral, and neurosurgical procedures, depending on the stage and severity of the disease. Various classes of drugs are available for the treatment of this complex neurological disease. There is no definite cure method for parkinsonism, drug treatment is the most important treatment means for parkinsonism, and surgical treatment is an effective supplement to drug treatment. Rehabilitation therapy, psychological therapy and good care can also improve symptoms to a certain extent. The applied treatment means can only improve symptoms, can not prevent the progress of the disease and can not cure the disease, but the effective treatment can obviously improve the life quality of patients. Current drug strategies for controlling symptoms are levodopa, catechol-O-methyltransferase (COMT) inhibitors, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, anticholinergic and amantadine drugs. Despite the variety of drugs for the treatment of parkinsonism, effective relief of the features associated with the disease remains elusive. Long-term treatment of most drugs can lead to several complications and non-athletic performance.
MAO-B inhibitors have been used in the treatment of Parkinson's disease, both in early monotherapy and in combination therapy in patients with advanced disease. MAO-B inhibitors, also known as monoamine oxidase type B inhibitors, are a first-line drug of antiparkinsonian drugs; such drugs include selegiline and rasagiline. The mechanism of treating parkinson's disease includes two aspects: protecting nerves and improving symptoms. Studies prove that MAO-B inhibitors protect neurons through antioxidation stress, inhibition of synuclein aggregation, reduction of apoptosis, neurotrophic effect and the like, and part of clinical experiments show that the medicine can delay the progress of parkinsonism. Rasagiline is currently the primary MAO-B inhibitor in clinical treatment of parkinson's disease, first on the market in color in month 3, in the united kingdom in month 6, in irish in month 9, in the united states in 2006, and formally in china in 2017. Compared with selegiline, it has many advantages such as 5-10 times the potency of selegiline, its selectivity is dose-dependent, adverse effects are small, and it is not metabolized to amphetamine derivatives, etc. A double blind, known as ADAGIO, with respect to rasagiline, delayed medication test showed that: rasagiline treatment at 1mg/d shortened the average time to the daily "off" state and improved parkinsonism symptoms in patients with motor fluctuations treated with L-dopa. Several studies have shown that rasagiline may have neuroprotective and disease modifying (disease modifying) effects. Oral rasagiline is rapidly absorbed from the gastrointestinal tract and reaches maximum plasma concentrations within one hour. Among the existing MAO-B inhibitors approved for treatment, rasagiline is one of the most widely used for the treatment of Parkinson's disease. In europe, rasagiline (Azilect) was approved by the European Medicines Agency (EMA) for the treatment of idiopathic parkinson's disease, either as monotherapy (without levodopa) or as adjunctive therapy (with levodopa) to treat end-stage patient dose fluctuations in 2005. Azilect provides only a 1mg standard immediate release conventional film coated tablet, which should be taken once daily, depending on the approved dosage, whether or not levodopa is to be taken. In japan, azilect was approved in 2018, 3, providing only immediate release conventional film coated tablets of 0.5mg and 1mg gauge, the indications being the same as europe.
Rasagiline has a high hepatic first pass metabolism and an oral bioavailability of about 36%. For the elderly patients with dysphagia, the medicine in the dosage form is not suitable for taking, and the medicine can not be conveniently taken by patients without water. Furthermore, pharmaceutical dosage forms comprising rasagiline are known to produce dry mouth and if they are absorbed from the oral cavity, it may lead to local numbness.
Therefore, the search for rasagiline preparations with stable properties, quick effect, convenient administration and good patient compliance is a technical problem which needs to be solved urgently at present.
Disclosure of Invention
The invention aims to solve the technical problems of poor stability, poor patient compliance and the like of rasagiline mesylate oral dissolved film composition in the prior art, and a preparation method and application thereof.
The invention provides a rasagiline mesylate oral solution film composition, which comprises an active drug, a film forming material and a taste masking agent; the active medicine is one or more of N-propargyl-1 (R) -aminoindene mesylate (rasagiline mesylate) and solvate thereof shown in a formula I;
According to an embodiment of the invention, the active agent is present in an amount of 1.0% to 40.0%, for example 1.6%, 3.9%, 6.5%, 10%, 15.6%, 20%, 25%, 30%, 31.2% or 35% by mass, the mass percentage being the mass of the active agent relative to the total mass of the rasagiline mesylate oromembrane composition.
According to an embodiment of the invention, the active agent has a particle size D 90 of less than 200 μm.
According to an embodiment of the invention, the film-forming material is a carrier for a drug, preferably one or more of xanthan gum, guar gum, pectin, gelatin, shellac, acacia, starch, dextrin (e.g. maltodextrin), agar, sodium alginate, zein, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymers, polylactic acid and silicone rubber.
In some embodiments, the film-forming material is one or more of polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, dextrin (e.g., maltodextrin), and polyethylene glycol (e.g., polyethylene glycol 6000).
In some embodiments, the film-forming material is selected from a mixture of a first film-forming material selected from one or more of polyvinyl alcohol, hypromellose, and hypromellose and a second film-forming material selected from one or more of dextrin (e.g., maltodextrin) and polyethylene glycol (e.g., polyethylene glycol 6000);
Preferably, the mass percentage of the first film forming material is greater than the mass percentage of the second film forming material, for example, the mass ratio of the first film forming material to the second film forming material is not less than 2:1, such as (2-40): 1, and also such as (3-30): 1, and exemplary are 3:1, 6:1, 7:1, 10:1, 15:1, 20:1, and 25:1.
In some embodiments, the film-forming material is selected from the group consisting of polyvinyl alcohol, hypromellose, a mixture of hypromellose and polyethylene glycol (e.g., polyethylene glycol 6000), a mixture of polyvinyl alcohol and dextrin (e.g., maltodextrin), and a mixture of hypromellose and dextrin (e.g., maltodextrin).
According to an embodiment of the invention, the film-forming material comprises, by mass, 30.0% to 80.0%, for example 35%, 38.2%, 40%, 45%, 50.0%, 44.4%, 51.8%, 53.5%, 58.0%, 59.7%, 60%, 67.3%, 70% or 75%, the mass percentage being the mass of the film-forming material relative to the total mass of the rasagiline mesylate oromembrane composition.
According to an embodiment of the present invention, the taste masking agent is a substance for masking bad taste of an active drug, reducing oral absorption of the active drug, preferably one or more of sodium polystyrene sulfonate, potassium polycosaline and polacrilin resin.
According to an embodiment of the invention, the taste masking agent comprises 10.0% -50.0% by mass, for example 10.0%, 15.0%, 20.0%, 21.5%, 21.9%, 25.0%, 25.9%, 30.0%, 35%, 41.7% or 45% by mass, the mass percentage being the percentage of the mass of the taste masking agent to the total mass of the rasagiline mesylate oromembrane composition.
According to embodiments of the present invention, the rasagiline mesylate oral film composition may further comprise one or more of a disintegrant, a plasticizer, a flavoring agent, a filler, and a colorant.
According to an embodiment of the present invention, the disintegrant refers to an auxiliary material which promotes rapid disintegration of the drug into small particles in the gastrointestinal tract, preferably one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium and sodium carboxymethyl starch.
According to an embodiment of the invention, the content of the disintegrant is 0 to 5.0% by mass, for example 0, 2.0% or 3.0% by mass, the content of the disintegrant being the percentage of the total mass of the rasagiline mesylate oromembrane composition.
According to an embodiment of the present invention, the plasticizer means a substance for lowering the glass transition temperature of a film, increasing plasticity and toughness, and increasing elongation; the plasticizer is preferably one or more of glycerin, propylene glycol, silicone oil, polypropylene glycol and hexylene glycol.
According to an embodiment of the present invention, the plasticizer is preferably present in an amount of 0 to 20.0% by mass, for example 0, 6.0%, 7.0%, 10.0%, 15.0% or 20.0% by mass, the mass percentage being the mass of plasticizer relative to the total mass of the rasagiline mesylate oromembrane composition.
According to an embodiment of the present invention, the flavoring agent refers to a substance that plays a flavoring role in a film, preferably one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, spice, menthol, sodium chloride, saccharin and saccharin sodium.
According to an embodiment of the invention, the flavoring agent is preferably 0-5.0% by mass, for example 0, 2.4%, 2.6%, 2.8%, 3.0% or 4.0% by mass, the weight percentage being the percentage of the weight of the flavoring agent to the total weight of the rasagiline mesylate oromembrane composition.
According to an embodiment of the present invention, the filler is a solid substance added to the material to improve the properties of the material, or to increase the capacity and weight of the material and reduce the cost of the material, and preferably one or more of mannitol, starch, microcrystalline cellulose, pregelatinized starch, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.
According to an embodiment of the invention, the filler is preferably present in an amount of 0 to 30.0%, such as 0, 10.0% or 26.0% by mass, the mass percentage being the percentage of the mass of filler in the total mass of the rasagiline mesylate oromembrane composition.
According to embodiments of the present invention, the colorant is a substance, preferably one or more of titanium dioxide, pigment and lake, that improves the apparent color of the formulation, and can be used to identify the concentration of the formulation, differentiate the method of application and reduce the patient's perceived averse to the medication.
According to an embodiment of the invention, the colorant is preferably present in an amount of 0 to 1.0%, for example 0, 0.1% or 0.2%, by mass, based on the total mass of the rasagiline mesylate oromembrane composition.
According to embodiments of the present invention, the rasagiline mesylate oromembrane composition may be any of the following formulations:
Prescription 1:31.2% of rasagiline mesylate, 50.0% of polyvinyl alcohol, 6.0% of glycerin, 10.0% of potassium polycosalicylic and 2.8% of sucralose, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral dissolving film composition;
prescription 2:15.6% rasagiline mesylate, 50.0% hypromellose, 10.0% glycerol, 10.0% sodium polystyrene sulfonate, 2.4% steviol glycoside, 2.0% sodium carboxymethyl starch and 10.0% pregelatinized starch, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral film composition;
prescription 3:15.6% of rasagiline mesylate, 44.4% of polyvinyl alcohol, 10.0% of glycerol and 30.0% of potassium polycosalicyline, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution composition;
Prescription 4:3.9% of rasagiline mesylate, 58.0% of hypromellose, 20.0% of glycerol, 15.0% of potassium polycleirine, 2.5% of stevioside, 0.3% of menthol, 0.2% of essence and 0.1% of lake, wherein the mass percentages of the components account for the total mass of the rasagiline mesylate oral solution composition;
Prescription 5:3.9% of rasagiline mesylate, 40.5% of hypromellose, 13.0% of polyethylene glycol 6000, 15.0% of glycerol, 25.0% of potassium polycosaponate, 2.5% of sucralose and 0.1% of essence, wherein the mass percentages of the components account for the total mass of the rasagiline mesylate oromembrane composition;
Prescription 6: rasagiline mesylate, 38.2% polyvinyl alcohol, 7.0% glycerol, 20.0% sodium polystyrene sulfonate, 2.0% sucralose, 1.0% menthol, 1.0% essence, 0.1% lake, 0.1% titanium dioxide, 3.0% sodium carboxymethyl starch, 16.0% pregelatinized starch and 10.0% microcrystalline cellulose, wherein the mass percentages of the components are the total mass of the rasagiline mesylate oral film composition;
Prescription 7:6.5% of rasagiline mesylate, 50.0% of polyvinyl alcohol, 1.8% of polyethylene glycol 6000 and 41.7% of potassium polycosamide, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution composition;
Prescription 8:4.0% of rasagiline mesylate, 51.9% of hypromellose, 7.8% of maltodextrin, 10.4% of glycerol and 25.9% of sodium polystyrene sulfonate, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution film composition;
Prescription 9:3.4% of rasagiline mesylate, 65.9% of hydroxypropyl cellulose, 6.6% of maltodextrin, 2.2% of titanium dioxide and 21.9% of sodium polystyrene sulfonate, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution composition;
Prescription 10:3.4% of rasagiline mesylate, 64.4% of hydroxypropyl cellulose, 10.7% of maltodextrin and 21.5% of sodium polystyrene sulfonate, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution film composition.
The invention also provides a preparation method of the rasagiline mesylate oral dissolved film composition, which comprises the following steps:
1) Preparing an active drug aqueous solution;
2) Adding a taste masking agent into the active medicine aqueous solution obtained in the step 1), and stirring to obtain a sample;
3) Centrifuging the sample obtained in the step 2), removing part of supernatant fluid, and enabling the mass of the rest lower layer material to be 10-15 times that of the active medicine to obtain medicine carrying resin;
4) Dissolving the film-forming material in water, mixing with a flavoring agent (optionally one or more of a plasticizer, a colorant and a filler), and stirring uniformly to obtain a glue solution;
5) Transferring the drug-loaded resin obtained in the step 3) into the glue solution obtained in the step 4), fully stirring to obtain uniform glue solution, and after stirring, removing bubbles from the glue solution in vacuum, coating, drying and cutting to obtain the rasagiline mesylate oral solution preparation;
6) And 5) uniformly coating the medicine-containing glue solution obtained in the step 5) on a release film by using a coating machine, heating, drying and cutting to obtain the rasagiline mesylate oral solution film composition.
According to an embodiment of the invention, in step 1), said water is preferably purified water.
According to an embodiment of the present invention, in step 2), the stirring time is preferably 1 hour or more.
According to an embodiment of the invention, in step 3), said centrifugation is preferably performed in a centrifuge; the centrifuge may be a tabletop centrifuge and the centrifuge may be a low-speed centrifuge.
According to an embodiment of the invention, the rasagiline mesylate oral film composition has a thickness of 10 μm to 300 μm, for example 10 μm to 100 μm.
According to an embodiment of the invention, the rasagiline mesylate oromembrane composition is capable of complete disintegration in 900mL of simulated saliva at 37±1 ℃ for 2 min.
The invention also provides application of the rasagiline mesylate oral dissolved film composition in preparing medicines for single medicine treatment for treating and/or preventing primary parkinsonism and combined treatment for patients with end-of-dose fluctuation.
According to an embodiment of the invention, the rasagiline mesylate oral film composition is a pharmaceutical formulation. The dosage form of the pharmaceutical preparation can be an oral film.
The invention also provides a method of treating primary parkinson's disease and patients with end-of-dose fluctuations, comprising administering to a patient in need thereof a therapeutically effective amount of the rasagiline mesylate oromembrane composition.
Unless otherwise indicated, the definitions of terms set forth in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, specific definitions in the examples, and the like, may be arbitrarily combined and combined with each other. Such combinations and combinations are intended to be within the scope of the present disclosure.
The term "therapeutically effective amount" refers to an amount of a pharmaceutically active agent of the present invention sufficient to achieve the intended use, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount may vary depending on the following factors: the intended use (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular active agent selected, the regimen based on, whether to administer in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the beneficial effects that: the rasagiline mesylate oral solution film composition has the advantages of thin thickness, good taste, stable property, good dissolution rate, no need of drinking water, instant dissolution in the oral cavity, no gritty feel after dissolution in the oral cavity, high oral absorption speed, uniform appearance, good flexibility, simple process, no sedimentation in the film liquid preparation process, satisfactory content uniformity and high drug loading rate. Solves the defects of inconvenient taking, poor patient compliance and the like of the existing preparation, and is particularly suitable for patients with dysphagia.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Examples 1 to 10: the prescription is shown as follows
* Indicating removal during the process;
* Represents the weight of the raw and auxiliary materials after water removal.
The preparation method comprises the following steps:
1) Mixing the active medicine with purified water to obtain an active medicine water solution;
2) Adding a taste masking agent into the aqueous solution of the active drug obtained in the step 1), and stirring (2-3 hours) to obtain a sample;
3) Centrifuging the sample obtained in the step 2) (a low-speed centrifuge can be used), discarding part of supernatant fluid, and enabling the mass of the residual lower layer material to be 10-15 times that of the active medicine, thus obtaining medicine carrying resin;
4) Dissolving film-forming material in water, mixing with correctant (one or more of plasticizer, colorant and filler according to prescription), and stirring to obtain glue solution;
5) Transferring the drug-loaded resin obtained in the step 3) into the glue solution obtained in the step 4), fully stirring to obtain uniform glue solution, and after stirring, removing bubbles from the glue solution in vacuum, coating, drying and cutting to obtain the rasagiline mesylate oral solution preparation;
6) And 5) uniformly coating the medicine-containing glue solution obtained in the step 5) on a release film by using a coating machine, heating, drying and cutting to obtain the rasagiline mesylate oral solution film composition.
1. Disintegration time test
According to the formulations of examples 1 to 10, rasagiline mesylate orosol film formulations were prepared and tested for disintegration time using the preparation method provided by the invention, the specific test method being as follows:
the film 6 tablets obtained in each example were taken, 1 tablet was taken each time, gently placed in 900ml of artificial saliva at 37.+ -. 1 ℃ and the time for complete disintegration of the product was observed in a stationary state, and the results are shown in Table 2.
TABLE 2
2. Dissolution measurement
The dissolution rates of rasagiline mesylate oral film formulations of examples 1 to 10 were determined as follows:
test medium: 900ml of a pH1.0 hydrochloric acid solution (37 ℃.+ -. 0.5 ℃ C.).
The dissolution method comprises the following steps: the second method (paddle method) for measuring the dissolution rate and release rate of 0931 version 2020 of Chinese pharmacopoeia has a rotation speed of 50rpm.
Sampling time: 30min.
The rasagiline mesylate oral film preparation obtained in each example was taken in 6 pieces, 1 piece at a time, and the dissolution was measured as described above, and the results are shown in table 3.
TABLE 3 Table 3
3. Mechanical Strength test
The rasagiline mesylate oral membrane formulations of examples 1 to 10 were tested for mechanical strength using a texture analyzer (model: rapid TA +, manufacturer: shanghai Techno instruments Co., ltd.) and the results are shown in Table 4.
TABLE 4 Table 4
4. Oral membrane related substance testing
The rasagiline mesylate oromembrane formulations of examples 1 to 10 were left for 30 days at an elevated temperature of 50 ℃ and the levels of the relevant substances of the formulations were examined.
The related substance detection method is measured by high performance liquid chromatography.
Solvent perchloric acid buffer solution
Taking 2 pieces of rasagiline oromembrane 2 pieces at high temperature for 10 days, cutting into proper size, precisely weighing a proper amount (equivalent to 1.3mg of rasagiline), and placing into a 10ml measuring flask; adding a proper amount of mobile phase into the sample, and carrying out ultrasonic treatment for 5 minutes to dissolve the mobile phase; diluting with mobile phase to scale, shaking; taking a proper amount of solution, centrifuging for 5 minutes at 10000 revolutions, and taking supernatant.
Chromatographic conditions used Wondasil C, 250x4.6mm,5 μm column); perchloric acid buffer (pH to 2.5) -acetonitrile (8:2) as mobile phase; the detection wavelength is 210nm; the flow rate is 1.0mL per minute; the column temperature is 30 ℃; the sample volume was 30. Mu.L and the run time was 40 minutes.
The system applicability requires that the separation degree between a main peak and an adjacent chromatographic peak in a chromatogram of a sample solution meets the requirement.
Impurity correction factor and limit
Impurity name Correction factor * Limit of
IM-A / 0.3％
IM-B 0.80 0.6％
IM-C 0.30 0.5％
IM-D 0.40 0.5％
Other single impurities / 0.3％
Total amount of impurities / 1.0％
The results of the detection of the relevant substances are shown in Table 5.
TABLE 5
The results show that the rasagiline mesylate oral films of examples 1-10 of the invention have good stability.
From the experimental data, the rasagiline mesylate oral solution composition provided by the invention has the advantages of thin thickness, rapid disintegration, stable property, good mechanical property, immediate dissolution in the oral cavity without drinking water and rapid oral absorption.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. An rasagiline mesylate oromembrane composition, comprising: active drug, film-forming material and taste masking agent; the active medicine is one or more of N-propargyl-1 (R) -aminoindene mesylate shown in a formula I and solvate thereof;
2. rasagiline mesylate oromembrane composition according to claim 1, characterized in that:
the mass percentage of the active medicine is 1.0% -40.0%, and the mass percentage refers to the mass percentage of the active medicine in the total mass of the rasagiline mesylate oral solution film composition;
And/or the number of the groups of groups,
The particle size of the active medicine is D 90 less than 200 mu m.
3. Rasagiline mesylate oromembrane composition according to claim 1 or 2, characterized in that:
The film forming material is one or more of xanthan gum, guar gum, pectin, gelatin, shellac, acacia, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, polylactic acid and silicone rubber;
preferably, the film forming material is one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, dextrin and polyethylene glycol;
Preferably, the film forming material is selected from a mixture of a first film forming material and a second film forming material, wherein the first film forming material is selected from one or more of polyvinyl alcohol, hypromellose and hypromellose, and the second film forming material is selected from one or more of dextrin and polyethylene glycol;
And/or the number of the groups of groups,
The taste masking agent is one or more of sodium polystyrene sulfonate, potassium polycleritin and polacrilin resin.
4. A rasagiline mesylate oromembrane composition according to any one of claims 1 to 3, wherein:
The mass percentage of the film forming material is 30.0% -80.0%, and the mass percentage refers to the percentage of the film forming material in the total mass of the rasagiline mesylate oral solution film composition;
And/or the number of the groups of groups,
The weight percentage of the taste masking agent is 10.0-50.0%, and the weight percentage refers to the weight percentage of the taste masking agent in the total weight of the rasagiline mesylate oral solution film composition.
5. Rasagiline mesylate oromembrane composition according to any one of claims 1 to 4, characterized in that: the rasagiline mesylate oral film composition further comprises one or more of a disintegrant, a plasticizer, a flavoring agent, a filler and a colorant.
6. An rasagiline mesylate oromembrane composition according to claim 5, wherein:
the disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium and sodium carboxymethyl starch;
And/or the number of the groups of groups,
The plasticizer is one or more of glycerol, propylene glycol, silicone oil, polypropylene glycol and hexanediol;
And/or the number of the groups of groups,
The flavoring agent is one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, spice, menthol, sodium chloride, saccharin and saccharin sodium;
And/or the number of the groups of groups,
The filler is one or more of mannitol, starch, microcrystalline cellulose, pregelatinized starch, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose;
And/or the number of the groups of groups,
The colorant is one or more of titanium dioxide, pigment and lake.
7. Rasagiline mesylate oromembrane composition according to claim 5 or 6, characterized in that:
The mass percentage of the disintegrating agent is 0-5.0%, and the mass percentage of the disintegrating agent accounts for the total mass of the rasagiline mesylate oral film composition;
And/or the number of the groups of groups,
The mass percentage of the plasticizer is 0-20.0%, and the mass percentage refers to the mass percentage of the plasticizer accounting for the total mass of the rasagiline mesylate oral film composition;
And/or the number of the groups of groups,
The weight percentage of the flavoring agent is 0-5.0%, and the weight percentage refers to the weight percentage of the flavoring agent in the total weight of the rasagiline mesylate oral solution film composition;
And/or the number of the groups of groups,
The mass percentage of the filler is 0-30.0%, and the mass percentage refers to the percentage of the filler in the total mass of the rasagiline mesylate oral solution composition;
And/or the number of the groups of groups,
The mass percentage of the colorant is 0-1.0%, and the mass percentage of the colorant accounts for the total mass of the rasagiline mesylate oral solution composition.
8. Rasagiline mesylate oromembrane composition according to any one of claims 1 to 7, characterized in that:
The rasagiline mesylate oral film composition is prepared according to any one of the following prescriptions:
Prescription 1:31.2% of rasagiline mesylate, 50.0% of polyvinyl alcohol, 6.0% of glycerin, 10.0% of potassium polycosalicylic and 2.8% of sucralose, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral dissolving film composition;
prescription 2:15.6% rasagiline mesylate, 50.0% hypromellose, 10.0% glycerol, 10.0% sodium polystyrene sulfonate, 2.4% steviol glycoside, 2.0% sodium carboxymethyl starch and 10.0% pregelatinized starch, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral film composition;
prescription 3:15.6% of rasagiline mesylate, 44.4% of polyvinyl alcohol, 10.0% of glycerol and 30.0% of potassium polycosalicyline, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution composition;
Prescription 4:3.9% of rasagiline mesylate, 58.0% of hypromellose, 20.0% of glycerol, 15.0% of potassium polycleirine, 2.5% of stevioside, 0.3% of menthol, 0.2% of essence and 0.1% of lake, wherein the mass percentages of the components account for the total mass of the rasagiline mesylate oral solution composition;
Prescription 5:3.9% of rasagiline mesylate, 40.5% of hypromellose, 13.0% of polyethylene glycol 6000, 15.0% of glycerol, 25.0% of potassium polycosaponate, 2.5% of sucralose and 0.1% of essence, wherein the mass percentages of the components account for the total mass of the rasagiline mesylate oromembrane composition;
Prescription 6: rasagiline mesylate 1.6%, polyvinyl alcohol 38.2%, glycerol 7.0%, sodium polystyrene sulfonate 20.0%, sucralose 2.0%, menthol 1.0%, essence 1.0%, lake 0.1%, titanium dioxide 0.1%, sodium carboxymethyl starch 3.0%, pregelatinized starch 16.0% and microcrystalline cellulose 10.0%, wherein the mass percentages of the components are the total mass of the rasagiline mesylate oral film composition;
Prescription 7:6.5% of rasagiline mesylate, 50.0% of polyvinyl alcohol, 1.8% of polyethylene glycol 6000 and 41.7% of potassium polycosamide, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution composition;
Prescription 8:4.0% of rasagiline mesylate, 51.9% of hypromellose, 7.8% of maltodextrin, 10.4% of glycerol and 25.9% of sodium polystyrene sulfonate, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution film composition;
Prescription 9:3.4% of rasagiline mesylate, 65.9% of hydroxypropyl cellulose, 6.6% of maltodextrin, 2.2% of titanium dioxide and 21.9% of sodium polystyrene sulfonate, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution composition;
Prescription 10:3.4% of rasagiline mesylate, 64.4% of hydroxypropyl cellulose, 10.7% of maltodextrin and 21.5% of sodium polystyrene sulfonate, wherein the mass percentage of each component accounts for the total mass of the rasagiline mesylate oral solution film composition.
9. A process for the preparation of an oral film composition of rasagiline mesylate according to any one of claims 1 to 8, comprising the steps of:
1) Preparing an active drug aqueous solution;
2) Adding a taste masking agent into the active medicine aqueous solution obtained in the step 1), and stirring to obtain a sample;
3) Centrifuging the sample obtained in the step 2), removing part of supernatant fluid, and enabling the mass of the rest lower layer material to be 10-15 times that of the active medicine to obtain medicine carrying resin;
4) Dissolving a film-forming material in water, mixing with one or more of a flavoring agent, a plasticizer, a colorant and a filler, and uniformly stirring to obtain a glue solution;
5) Transferring the drug-loaded resin obtained in the step 3) into the glue solution obtained in the step 4), fully stirring to obtain uniform glue solution, and after stirring, removing bubbles from the glue solution in vacuum, coating, drying and cutting to obtain the rasagiline mesylate oral solution preparation;
6) And 5) uniformly coating the medicine-containing glue solution obtained in the step 5) on a release film by using a coating machine, heating, drying and cutting to obtain the rasagiline mesylate oral solution film composition.
10. Use of a rasagiline mesylate oromembrane composition according to any one of claims 1 to 8 for the manufacture of a medicament for the monotherapy treatment and/or prophylaxis of primary parkinson's disease and for the combination therapy of patients with end-of-dose fluctuations.
CN202311604333.0A 2023-01-19 2023-11-28 Rasagiline mesylate oral membrane composition, preparation method and application thereof Pending CN118356414A (en)

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CN102048717B (en) * 2009-10-29 2014-02-19 重庆医药工业研究院有限责任公司 Stable rasagiline composition
CN103239427A (en) * 2012-02-13 2013-08-14 刘毅佳 Film agent for dispersing and dissolving in oral cavity
IN2013MU01782A (en) * 2013-05-20 2015-06-26 Cadila Healthcare Ltd
CN103301467A (en) * 2013-06-20 2013-09-18 北京阜康仁生物制药科技有限公司 Stable taste-masking ambroxol hydrochloride compound and preparation method thereof
CN105193748A (en) * 2015-10-28 2015-12-30 陈跃坚 Freeze-drying preparation of PD (Parkinson's disease) treatment drug and preparation method of freeze-drying preparation
CN113730363A (en) * 2020-05-28 2021-12-03 北京万全德众医药生物技术有限公司 Rasagiline mesylate orally disintegrating tablet and preparation method thereof

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